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1
Head amp Neck Cancer When to Irradiatehellip
ESO-ESMO Latin-America 2018Talented studentshellip colleagues
2
OC OP
H
L
NC
NP
gt 15 different diseases for RT strategieshellip
HPV ndash Prognostic Marker gt2010
Trial Cases Marker Survival First author
RTOG 323 HPV 82 vs 57
(3-year)Ang 2010
TROG 185 p16INK4A 91 vs 74
(2-year)
Rischin 2010
DAHANCA 794 p16INK4A 66 vs 28
(5-year)
Lassen 2011
TAX 324 111 HPV 82 vs 35
(5-year)
Posner 2011
No data yethellip
TAFRT vs CFRT no diferences in outcome
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
2
OC OP
H
L
NC
NP
gt 15 different diseases for RT strategieshellip
HPV ndash Prognostic Marker gt2010
Trial Cases Marker Survival First author
RTOG 323 HPV 82 vs 57
(3-year)Ang 2010
TROG 185 p16INK4A 91 vs 74
(2-year)
Rischin 2010
DAHANCA 794 p16INK4A 66 vs 28
(5-year)
Lassen 2011
TAX 324 111 HPV 82 vs 35
(5-year)
Posner 2011
No data yethellip
TAFRT vs CFRT no diferences in outcome
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
HPV ndash Prognostic Marker gt2010
Trial Cases Marker Survival First author
RTOG 323 HPV 82 vs 57
(3-year)Ang 2010
TROG 185 p16INK4A 91 vs 74
(2-year)
Rischin 2010
DAHANCA 794 p16INK4A 66 vs 28
(5-year)
Lassen 2011
TAX 324 111 HPV 82 vs 35
(5-year)
Posner 2011
No data yethellip
TAFRT vs CFRT no diferences in outcome
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
No data yethellip
TAFRT vs CFRT no diferences in outcome
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
TAFRT vs CFRT no diferences in outcome
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Never smokersHPV p16 + vs -
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
7
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationOligo-recurrenceNew concepts new trials How and what (to expect)hellip
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Radiation type LC benefit 5y OS benefit 5yRT 10 all pts 24 all ptsCRT 06 all pts 03 all ptsHead amp Neck CRT 32 16Cervix CRT 33 18
48 all cancer pts indication of RT73 chemoradiation level I-II34 curative14 palliative
2012-2016Highest level of clinical evidenceAustralian National Health and Medical Research Council
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Principles of RT techniquetarget delineationbull Simulation
bullHead extendedbullSupinebullArms downbull IV contrastbull5-pt maskbullThin cut (2-3 mm)
bull Technique IMRT (except for early stage glottic cancer)
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
bull Target delineation (elective nodes)bull Primary echelon
bull Locationdrainage of primarybullLateralized (ipsilateral) vs midlineraquo (bilateral)
bull Secondary echelonbull At risk if primary echelon contains bulky orhigh-volume diseaseDose-Volume Histograms DVH
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
PARSPORT
Nutting Lancet Oncol 201112127-36
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
HampN IMRT
Practice
Heterogeneity
T2 N1 M0 Tonsil
Cancer
P Harari Radiotherapy amp Oncology 2012 Courtesy of Dr Harari
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Isodoses or Heterodoses 3D
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
IMRT decisionsboost amp fractionation sequential vs SIB
Gross Disease 70 Gy in 33-35 daily fractionsHigh-Risk 59-63 Gy in 30-35 daily fractionsRisk 50-56 Gy in 25-35 daily fractions
Macrohellip microhellip nanohellip level of risk
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
3DCRT
IMRT
IMRT
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
16
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
20
Selected topics for talentedhellip
Locally advanced stages randomized trialsRT FRACTIONATION altered vs standard
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Standard fractionation
RTOG 90-03
7000 cGy35 fx
7 weeks
Hyperfractionation8160 cGy68 fx
7 weeks (12 Gy Bid)
Accelerated fractionation split course
6720 cGy42 fx
6 weeks (16 Gy Bid)
Accelerated fractionation concomitant boost
7200 cGy42 fx
6 weeks
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Overall survival
Any Hiperfractionation
Moderately accelerated Very acceleratedFractionation RT OS 5y OS 10 yHiperfractionation 81 39Very accelerated 13 04
33 trials and 11423 patients
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Progression-free survival
Any Hiperfractionation
Moderately accelerated Very accelerated
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
24
Selected topics for talentedhellip
FRACTIONATION +- CRT
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Clin Oncol (R Coll Radiol) 2016 2850-61Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell CarcinomaGupta T1 Kannan S2 Ghosh-Laskar S3 Agarwal JP3
No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
updated meta-analysis Jan 1 2009 and July 15 2015conventional fractionation RT vs altered fractionation radiotherapy
conventional fractionation CRT vs altered fractionation radiotherapy alone Eligible trials had to start randomisation on or after Jan 1 1970 and completed accrual before Dec 31 2010
Chemoradiotherapy
33 trials and 11423 patients
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
New England Journal of Medicine 2006354567-78
LR failuresOS
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
LRC
OSOS HPV +
HPV -
The addition of an anti-EGFR agent to RT or CRT do not improve outcomes compared with CRT in LA-HNSCC Except for patients with coexisting medical conditions or decreased performance status concurrent CRT should remain the standard of care for patients with LA-HNSCC
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Why to Still Consider Induction Chemotherapybull Pros
bull Salvage subclinical M1 disease and OS benefitbull Assessment of responsebull Reduce dosevolume of RT
bull Consbull Prolongs treatment timecostbull Increases toxicitybull No clinical benefit
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
N2 N3
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Respondershellip
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
HPV Oroph
Non-Oroph N2
N3
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
bull Study terminated early due to poor accrual (145enrolled)bull Median fu 49 mosbull 3-yr OS (73 ICT vs 78 CRT NS)bull Febrile neutropenia (23 ICT vs 1 CRT)
Haddad Lancet Oncol 2013 14 257
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM) a randomised phase 3 trialLancet Oncol 2013 Mar14(3)257-64
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
OS
DFS
LRC
Induction CT Surgery +- RT
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
5 randomized trials
1022 patientsTPF induction CT
Pt Tx CRT
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
LRRDistant faliure
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
ECOG 1308Phase II trial of ICfollowed by cetuximab + 54 Gy vs 69 Gy IMRTin HPV-associated resectable oropharyngeal SCCA
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Loco-regional Advanced
when how and what to expect
- Unresectable radical chemoradiation
- Consolidation post-induction CT
- Oligo-recurrent radical rescue
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
bio-guided IMRT for oligo-recurrences
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
1105 patients
published 1976 and 2014
22 articles
The 5-year OS improved over time
18 pre-2000 35 mixed pre-2000 and post-200051 in the post-2000
(p lt 001)
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
16 publications919 patients
522 patients POreRT
bull Re-RT after salvage surgery
bull to highly selected patients with high-risk features (R+)bull Re-irradiation with highly conformal techniques and only
when a dose gt 50 Gy can be delivered
bull LC from 21 to 100bull 2-years-OS of 48 (range 24ndash81)
bull mucositis andor dyspha-giapharyngitis (11ndash52)
bull late fibrosis (range 2ndash44)
bull pharynx dysfunction (range 2ndash70)
bull death up to 68
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
45
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Soft PalateNasal choanae
Clivus
Nasopharynx Anatomy
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Treatment Approachbull Stage I
bull RT alone (10 yr LC and DSS gt 90)bull Stage II-IVb
bull Concurrent chemoradiation + adjuvant chemotherapybull Stage IVc (M1 disease)
bull Chemotherapybull RT for symptom palliation
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
RT Treatment planningbull IMRT
bull LC gt 90bull Gross disease (primary + nodes) ~70 Gybull High-risk CTV (bilateral RP II-V subclinical nasopharynx) 59-63 Gybull Low-risk CTV 56-59 Gy
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
NPC Imaging
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Induction Adjuvant
Concomitant CRT + adjuvant
Experimental armhellip all combinations
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
EBV Prognostic Marker
1 wkpost-RTLin N Engl J Med 2004 350 2461
Pre-RT
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Rmyistwr
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Nasopharynx Summarybull RT is the curative modality
bull RT alone stage Ibull CRT stage II-IVbbull IMRT standard of care
bull High rates of local control (gt 90)bull Failures predominantly systemic
bull Approaches to address to systemic relapse warrantedbull Role of adjuvant chemotherapy
bull Risk stratification via EBV
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
54
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTNew concepts new trials How and what (to expect)hellip
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Poor Imposible Volume Definition
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Ipsilateral Level 3 Failure
Damast et al Head Neck 201234900-906
T2N1 oral tongue cancer postoperative radiation
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Damast et al Head Neck 201234900-906
Submental Failure
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Postoperative IMRT for Laryngeal Cancer
Stoma gt 60 Gy
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
bull Multiple lymph nodes involvedbull Extracapsular extension (ECE)bull Positiveclose surgical marginsbull Perineural invasionbull Lymphovascular invasionbull Deep (gt5mm) invasion
Postop RT Indications
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
bull May deliver RT as soon as the wound is healedbull Ideally initiate within 6 weeks after surgerybull Intermediate Risk 60 Gy 30 fractionsbull High Risk (Positive margin ECE) 66 Gy 33 fxbull Concurrent systemic therapy in high risk patients
Postop RT Treatment Decisions
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Combined RTOGEORTC Analysis
Bernier Cooper Head Neck 200527843
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Long Term Follow Up of RTOG 9501
Patients with Positive Margin andor ECE
Cooper et al IJROBP 2012
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Loco-regional
Disease free
Survival
CRT vs RT alone postoperative
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
68
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationNew concepts new trials How and what (to expect)hellip
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
AnatomybullSupraglottis
ndashEpiglottisndashArytenoidsndashAE foldsndashFalse cordsndashVentricles
bullGlottisndashTrue vocal cords
bullSubglottisndash5mm below glottis to bottom of cricoid
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Treatment Approachbull Glottic early stage single modality
bull RT limited fieldbull Surgery partial laryngectomy cordectomy laser
bull Supraglottic early stage single modalitybull RT include regional nodes (bilateral levels II-IV)bull Surgery partial laryngectomy + neck dissection
bull Advanced stage combined modalitybull Organ preservation (concurrent chemoradiation) VA larynx RTOG 91-11bull Surgery + adjuvant RT (+- chemo)
bull Selection need to consider disease and patient characteristics
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Dose and fractionation T1 glottis(Yamazaki et al IJROBP 2006)bull Prospective Randomized Trial 1993-2001
bull 180 pts with T1N0 Glottic Cancers
bull Randomized to
A)200 Gyfraction
1)60 Gy in 30 fractions (lt23 VC)
2)66 Gy in 33 fractions (gt23 VC)
B)225 Gyfraction
1)5625 Gy in 25 fractions (lt23 VC)
2)63 Gy in 28 fractions (gt23 VC)
bullNo significant increase in acute or chronic toxicity
Conclusion Use 225 cGy per fraction to 63 Gy for T1 Glottic Ca
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
RTOG 91-11 LARYNX TRIAL
Forastiere et al NEJM 2003 3492091-2098
84
72
67
Median FU 38 years
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Long Term Update of RTOG 91-11
Forastiere et al JCO 2013
LARYNGEAL
PRESERVATION
OVERALL
SURVIVAL
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Surgery RT
RTComplete
Responders
Induction
Chemotherapy
(3 Cycles)
PRNR Surgery XRT
R
A
N
D
O
M
I
Z
E
Induction Chemotherapy Cisplatin and 5 FU
JL Lefebvre et al JNCI 88890-899 1996
EORTC 24891 Laryngeal Preservation Trial
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
EORTC 24891 Laryngeal Preservation Trial
JL Lefebvre et al JNCI 88890-899 1996 Annals Oncology 2012
Median FU 105yrs S + RT CT+ RT+ S
No of patients 94 100
10-yr PFS 85 105
10-yr Survival 138 131
Distant Mets 36 25
10 yr Alive wLarynx 87
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
T4a Laryngeal Cancer
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Patient selectionPatterns of careT4a(Grover et al IJROBP 2015)bull NCDB
bull 969 pts RT for T4a larynx cancerfrom 2003-2006bull Patterns of caresurvival
bull Resultsbull 23 treated with OP 13 withinitial TL
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
79
Selected topics for talentedhellip When RTLocally advanced stages NasopharynxPostoperative RTLaryngeal preservationRe-irradiationNew concepts new trials How and what (to expect)hellip
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
Time recruitment 2000OS 5yOS 3y
Surgery
RT
22 retrospective studiesgt550 pts
14 - 54 OS 5y51 post-2000
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
FDG-PETCT in detecting nodal disease within 6 months after treatment Systematic review + meta-analysis 20 studies (1293 patients)Sensitivity 83 specificity 91HPV positive tumors were associated with lowersensitivity(75vs89p=001)specificity (87 vs 95 p lt0005) FDG-PETCT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residualrecurrent nodal disease (less reliable in HPV positive tumors) optimal surveillance strategy remains to be determined
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
82
Ongoing RT practice oriented researchhellip 7ECOG 1308 HPV + Induction CT + Cetuximab +IMRTCetuximabRTOG 1016 HPV + IMRTCDDP vs IMRTCetuximabRTOG 1216 gt 60 Gy + CDDP vs Docetaxel vs DocetaxelCetuximabECOG 3311 HPV + risk adapted IMRT 50 vs 60 vs 66 GyCDDPRTOG 1221 HPV + IMRT 70 Gy vs surgery (PORT)RTOG 1305 IMRT 70 GyCDDP plasma EBV +- Chemoadjuvant
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
83
MOLECULAR IMAGE GUIDED RT (M-IGRT)
GTVhellip s allerNodeshellip oreMis- atch GTVhellip 20-40
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
5 cm5 cm
5 cm 18F-FDGPET
TAC
Macroscoacutepic
Daisne et al 2004
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
85T3 N2c oropharynx target adapted to M-IGRT
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
86
A GTV HipoxiaB STANDARD PLANC Dose-escalation based on HIPOXIA gradients D Dose-escalation based on HIPOXIA presence
DOSE-ESCALATION BASED ON HIPOXIA M-IGRT
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
87
TIME-IMAGE GUIDED RT (T-IGRT)
4D = time = movement = changes = adaptation = ART
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
88
Potential Target Deformations during Tx T-IGRT implications
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
89Hansen et al Int J Radiation Oncology Biol Phys 200664355ndash362
Potential Dosimetric Changes
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
90
42 mm
INCREASED MEAN DOSE TO PAROTID 5 Gy
Nishi et al Radiother and Oncol 106 (2013) 85ndash89
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
93
Selected topics for talentedhellip when how and what
HPV a d RT hellip De-escalatio Not ethellip buthellipLocall ad a ced stageshellip CRT + dose-escalation + AFXinduction CTNasophar hellip CRT tailored volumeLarynx preservation CRT supra-tailored strategyPostoperati e RThellip risk adapted CRTOligo-recurrent 50 OS radical rescue ( 40 2y OS re-RT)Ne co ceptshellip M-IGRT T-IGRT Ne trials hellip Induction CT viral status tailoring
![[C2] Preoperative radiotherapy and chemoradiotherapy for](https://img.dokumen.tips/doc/110x75/6159a52ce5e78c2242485b77/c2-preoperative-radiotherapy-and-chemoradiotherapy-for-.jpg)
