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Multimodular treatment in
Head and Neck Squamous Cell
Carcinoma (HNSCC)
Amanda Psyrri, MD,FACPAttikon University Hospital
Athens, Greece
Learning objectives
After reading and reviewing this material, the participant should
be able to:
Evaluate the role of induction, definitive concurrent chemotherapy
and sequential therapy in locally advanced HNSCC
Describe organ preservation strategies
Discuss the common indications for postoperative chemoradiation
Define the role of bioradiotherapy with cetuximab
Understand HPV-associated oropharyngeal cancers
Outline
Introduction
Concurrent chemoradiotherapy
Induction chemotherapy
Sequential therapy
Bioradiotherapy with cetuximab
HPV-associated oropharyngeal cancers
Surgical management of the neck
Many subsites
Heterogeneous group of tumours of varying primary sites
95% are HNSCC
Oral cavity
Oropharynx/hypopharynx
Larynx
Nasopharynx
Other anatomic sites
Paranasal sinuses
Salivary glands
Lip
Image courtesy of Massachusetts General Hospital Cancer Center
Etiology
Traditionally, tobacco and alcohol use account for the majority
of HNSCC
A growing proportion of oropharyngeal squamous cell carcinomas
is caused by high-risk Human Papillomaviruses (HPV),
especially HPV16
Incidence in the USA
In 2015, 45,780 new cases of oral cavity and pharynx cancer and
8,650 deaths are expected to occur in the United States
Oral cavity and pharynx
All races
White
Black
Stage distribution by raceUnited States 2004–2010
5-year relative survival rates
by race and stageUnited States 2004–2010
20
40
60
80
100
0Localised Regional Distant
31 32
20
47 47 49
18 1627
20
40
60
80
100
0Localised Regional Distant
83 8377
61 62
4237 38
24
All stages
63 64
44
Redrawn from Siegel MPH, et al. CA Cancer J Clin 2015;65:5–29
Incidence and Mortality Worldwide
1. Ferlay J, et al. GLOBOCAN 2012 v1.0. Available from: http://globocan.iarc.fr, accessed December 2013
2. Ferlay J, et al. Eur J Cancer 2013;49:1374–1403
15th most common
cancer in Europe1
• Lip and oral cavity cancer in Europe
(2012):
• 61,400 new cases diagnosed (2% total)
• ~34,100 cases of other pharyngeal cancer
diagnosed (1% total cancer cases)1
• Highest World age-standardised incidence
rates in Hungary (both men and women);
lowest rates in Greece for men and
Cyprus for women
• Worldwide (2012):
• >142,000 cases of other pharyngeal
cancer diagnosed (1% total cancer cases)
• Lip and oral cavity cancer incidence rates
highest in Melanesia and lowest in
Western Africa, partly reflecting varying
data quality worldwide
• Incidence rates of other pharyngeal
cancer highest in Western Europe and
lowest in Western Africa1
WHO Europe region (adults)
Estimated numbers (x100)
Epidemic of HPV-associated OPC*
Incidence rates for overall oropharyngeal
cancer, HPV-positive oropharyngeal cancer,
and HPV-negative oropharyngeal cancer from
1988 to 2004 in Hawaii, Iowa, and Los Angeles
Estimated age-standardised incidence of human
papillomavirus (HPV)-positive and HPV-negative
tonsillar cancer squamous cell carcinoma cases
per 100,000 person-years, Stockholm, Sweden,
1970-2006
Chaturvedi AK, et al. J Clin Oncol 2011;29:4294–301.
Reprinted with permission. © 2011 American Society of
Clinical Oncology. All rights reserved
Error bars indicate 95% CI.
Näsman A, et al. Int J Cancer 2009;125:362–6. Reproduced with
permission from Wiley
Staging overview
T and N stages vary by anatomic site
≥N2 or T4 tumours locoregionally advanced (Stage IV)
Typically T1: ≤2 cm, T2: 2-4 cm, T3: ≥4 cm, T4: invades adj. structures
N1: single LN ≤3 cm, N2: LN ≥2 cm or several LN, N3: >6 cm
TNM: tumour nodes metastases
Stage TNM
Stage 0 TisN0M0
Stage I T1N0M0
Stage II T2N0M0
Stage III T3N0, T1-3N1, M0
Stage IVA T4a N0-2,M0, T1-3N2,M0
Stage IVB
Stage IVC
Any T, N3, M0, T4b, Any N, M0
M1, any T or N
Patel SG, et al. CA Cancer J Clin 2005;55;242-258
HNC, head and neck cancer; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; SCC, squamous cell
carcinoma; ORR, overall risk reduction; RR, relative risk.
Pignon JP, et al. Lancet 2000;355:949-955
Trials N RR P valueAbsolute benefit
(5 Yrs), %
Adjuvant 8 1854 0.98 NS 1
Induction 31 5245 0.95 NS 2
Concomitant 26 3727 0.81 < 0.0001 8
Meta-analysis of chemotherapy in HNC
(MACH-NC)
63 randomised trials (1965-1993)
n = 10,717 pts with SCC of the oropharynx, oral cavity, larynx, or
hypopharynx
Comparison of locoregional treatment with and without
chemotherapy
Median follow-up: 6 years
Overall benefit 4% at 5 years (32% vs. 36%)
MACH-NC, meta-analysis of chemotherapy in head and neck cancer; IC: induction chemotherapy
Pignon JP, et al. Radiother Oncol 2009;92:4-14
MACH-NC: An Update
24 added trials–87 studies, 16,485 patients
MACH-HN I: 8% absolute benefit concurrent-no significant effect
of IC
No significant difference (p = 0.19) was seen between
mono-chemotherapy (HR 0.84) and poly-chemotherapy (HR 0.78)
In the mono-chemotherapy group, the effect of chemotherapy was
significantly higher (p = 0.006) with platin than with other types of
mono-chemotherapies
Age matters
Younger than 50 years of age: 24% increased survival
Older than 70 years of age: 3% increased survival
Pluses and minuses of chemoradiation
Improves locoregional control
Facilitates organ preservation
Beneficial impact on survival
Doubles the rate of severe acute mucositis
Use may be excessive based on stage
Long-term functional deficits in speech, swallowing, mobility
Study Eligibility N
T + PF
CR/PR,
n/N (%)
PF
CR/PR,
n/N (%)
TPF/PF
PFS, Mos
TPF/PF OS,
Mos
P Value
(HR)
Hitt
JCO 2005Stage III-IV
38
2
33/47
(80)
14/54
(68)
20
12
43
37
2 yrs:
66%/61%
.035
(0.67)
TAX 323
NEJM 2007Unresectable
35
8(68) (54)
11
8
18.6
14.2
3 yrs:
24%/18%
.005
(0.71)
Gortec
ASCO 2006
L/HP
II-IV
20
5
43/39
(82)
30/30
(60)
LP:
63%/41%.036
TAX 324
NEJM 2007III-IV
50
1
17/55
(72)
15/49
(64)
2-yr PFS:
53%/42%
70
30
3 yrs:
62%/48%
.006
(0.7)
CR, complete response; HP, hypopharynx; HR, hazard ratio; L, larynx; LP, larynx preservation; OS, overall survival;
PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; PR, partial response; T, docetaxel;
TPF, docetaxel, cisplatin, 5-fluorouracil.
Randomised trials of induction
PF ± taxane
Trial Eligibility Target N*Control
TxExp Tx OS
DeCIDE
U ChicagoN2-3
400
285DHFX
TPF x 2
DHFXNS
Paradigm
DFCIStages III-IV
300
145
Cisplatin
CB-RT
TPF x 3
Carbo-RT or
D-CB-RT
NS
SWOG Oropharynx 400Cisplatin
RT
TPF x 1-3
surgery or
cisplatin-RT
*All powered to show survival difference of 10% to 15%.
Carbo, carboplatin; CB, concomitant boost; chemoRT, chemoradiation therapy; DFCI, Dana-Farber Cancer Institute;
RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil. DHFX, docetaxel, fluorouracil, and hydroxyurea
Randomised trials of sequential therapy*:
Definitive chemo RT ± induction
Psyrri A, Presented at ASCO 2013 Lecture: EGFR, new data and best use of inhibitors (adapted from
http://www.slideshare.net/melodyhsiao/scchn-cancer-report
1. Psyrri A, et al. Clin Can Res 2005;11:5856-62; 2. Baumann M, Krause M. Radiother Oncol 2004;72:257‒266;
3.Ang KK, et al. Cancer Res 2002;62:7350–7356
EGFR as a molecular target in HNSCC
EGFR expression linked to poorer outcome1 and reduced response
to radiotherapy2,3
*ADCC: antibody dependent cellular cytotoxicity
EGFR, epidermal growth factor receptor; mAb
Li S, et al. Cancer Cell 2005;7:301–311
Figure courtesy of Psyrri A. Presented at ASCO 2013; adapted from Vermorken JB, MCO 2011; ESO-ESMO Masterclass in
Clinical Oncology www.slideshare.net
Cetuximab
Cetuximab
IgG1 mAb
Chimeric protein
Specifically binds with high affinity
to FcγRI (EC50 = 0.13 nM) and
FcγRIIIa (EC50 = 6 nM)
Induces apoptosis and ADCC*
Preclinical synergistic activity in
combination with chemotherapy
and radiotherapy
Arm 2 (RT + C)
Radiation therapy +
cetuximab wkly
R
A
N
D
O
M
I
S
E
Arm 1 (RT)
Radiation therapy
Bonner JA, et al. N Engl J Med 2006;354:567-578
Eligibility
Patients with locoregionally
advanced squamous cell
carcinoma of either the oropharynx,
hypopharynx, or larynx
Primary endpoints:
Overall survival,
locoregional control
Phase III Study Design
Stratified by
Karnofsky score: 90-100 vs. 60-80
Regional nodes: Negative vs. positive
Tumour stage: AJCC T1-3 vs. T4
RT fractionation: Concomitant
boost vs. once daily vs. twice
daily
Toxicity, %
RT (n = 212) RT + C (n = 208)
All Grades Grades 3/4 All GradesGrades
3/4
Skin reaction 91 18 97† 34‡
Mucositis/stomatitis 93 52 91 54
Dysphagia 63 30 64 25
Xerostomia 70 3 64 4
Fatigue/malaise 50 5 52 4
Infusion reaction* -- – 14‡ 3†
*Listed for its relationship to cetuximab; †P < 0.05; ‡P < 0.001, Fisher’s exact test.
Bonner JA, et al. N Engl J Med 2006;354:567-578
Most common adverse events
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 10 20 30 40 50 60 70
Months
Pro
babili
ty o
f o
ve
rall
su
rviv
al
ERBITUX + RT
RT
ERBITUX + RT RT p-value
5-year OS rate 46% 36% 0.02
p = 0.02
ERBITUX + RT improves significantly long term survival,
with nearly half of the patients alive at 5 years
HR=0.73 (0.56–0.95)
Bonner JA, et al. Lancet Oncol 2010;1:21–28. Reprinted from The Lancet, Copyright (2010). With permission from Elsevier
Treatment Total Dead Alive Median
Erbitux + RT 211 110 101 49.0
RT 213 130 83 29.3
ERBITUX + RT: Overall survival
5 year update
Forastiere AA, et al. N Engl J Med 2003;349:2091-2098
R
A
N
D
O
M
I
S
E
Location
1. Glottic
2. SupraglotticS
T
R
A
T
I
F
Y
T Stage
1. T2
2. T3, fixed cord
3. T3, no cord fixation
4. T4, with base of tongue ≤ 1 cm
N Stage
1. N0, N1
2. N2, N3
Chemotherapy
Arm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3
Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT
Arm 1:
Arm 2:
Arm 3:
CR, PR x 3 d cycle RT
CDDP/5-FU
x 2 cycles
NR surgery RT
Radiation therapy + CDDP
Radiation therapy
RTOG 9111: Larynx Preservation Trial
Phase III larynx preservation trial: induction chemotherapy and radiation
therapy vs. concomitant chemotherapy and radiation therapy vs. radiation
therapy alone
5-FU, 5-fluorouracil; cDDP, cisplatin; DFS, disease-free survival; DMFS, distant metastasis-free survival; FS, free survival;
KPS, Karnofsky performance score; LFS, laryngectomy-free survival; OS, overall survival; RT, radiation therapy;
SGL, supraglottal larynx; SS, statistically significant.
Forastiere AA, et al. N Engl J Med 2003;349:2091-2098
Arm cDDP/5-FU RT RT/cDDP RT
Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173)
2-yr laryngectomy FS, % 59 66 53
5-yr DMFS, % 85 88 78
5-yr DFS, % 38 36 27
5-yr OS,% 55 54 56
RTOG 9111: Larynx Preservation Trial
The median follow-up among surviving patients, 3.8 years
Demographics: median age 59 years; 94% KPS 80; 50% N0; 68% SGL;
28% N2-3
Conclusions
RT/cDDP: stat signif in LFS (P = 0.01)
No SS diff in survival
Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved
P<0.001
P=0.53 P=0.0015
P=0.02
(A) Laryngeal preservation, (B) laryngectomy-free survival, (C)
overall survival, and (D) locoregional control according to
treatment group; conc., concomitant; ind., induction; RT,
radiation therapy
P=0.03
Survival, limited to (A) deaths from study cancer and (B) deaths
not caused by study cancer according to treatment group;
conc., concomitant; ind., induction; RT, radiation therapy
Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved
5-FU, 5-fluorouracil; CI, confidence interval; HR, hazard ratio; RT, radiation therapy; SCCHN, squamous cell carcinoma of the
head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil; Ctx: chemotherapy
1. Pignon JP, et al. Lancet 2000;355:949-955; 2. Bonner JA, et al. Lancet Oncol 2009;11:21-8;
3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704; 4. Posner MR, et al. N Engl J Med 2007;357:1705-1715.
Nonsurgical treatment options for locally
advanced HNSCC
Trial RT (Gy)F/U,
mosLRC, % DFS, % OS, %
RTOG 9501[1]
≥ 2 LN, ECE, +
margins
n = 459
(60-66)46
81 vs. 70
(P = 0.01)
33 vs. 25
(P = 0.04)
45 vs. 38
(P = 0.19)
EORTC 22931[2]
N2-3, ECE, +
margins
n = 350
(66)60
82 vs. 69
(P = 0.007)
47 vs. 36
(P = 0.04)
53 vs. 40
(P = 0.002)
Bachaud[3]
+ ECE
n = 83
(> 60) 60
70 vs. 55
(P = 0.05)
45 vs. 23
(P < 0.02)
36 vs. 13
(P < 0.01)
1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944; 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952;
3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246.
DDP, cisplatin; CT, chemotherapy; DFS, disease-free survival; ECE, extracapsular extension; F/U, follow-up;
LN, lymph node; LRC, locoregional control; OS, overall survival; RT, radiation therapy;
HNSSC, head and neck squamous cell carcinoma
Adjuvant Trials: HNSCC RT ± CT (DDP)
Adapted from Bernier J, et al. Head and Neck Volume 27 Issue 5 Oct 2005
EORTC versus RTOG eligibility
Stage III-IV
OP, Ocw
Level 4 or 5
pos. nodes
Perineural
Disease
Vascular
Embolisms
EORTC
2+ pos. nodes
RTOG
Margins+
ECE
Separate trials are currently designed for
intermediate-risk and high-risk groups
Cooper JS, et al. N Engl J Med 2004;350:1937-1944; Bernier J, et al. N Engl J Med 2004;350:1945-1952;
Ang KK, et al. Int J Radiat Oncol Biol Phys 2001;51:571-578
Risk stratification
Category Standard of care
Favourable None
Low 56-60 Gy
Intermediate (ECE-/margin-) 60-66 Gy
High (ECE+/margin+) 60-66 Gy + cisplatin
Refining adjuvant therapy
CRT: chemoradiotherapy; OS: overall survival
Strategies to improve outcomes in
HNSCC utilising EGFR inhibitors
Treatment intensification of locally advanced HNSCC to improve OS
Randomised trials: CRT+EGFR inhibitor versus CRT
EGFR inhibition in the post-induction setting to reduce toxicity in
sequential design
Randomised phase II studies of induction chemotherapy followed by
either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity
without compromising efficacy
Author # pts Treatment ComparatorPrimary
endpointSetting S vs. E
P
value
Giralt et al.
2012150 C+EBRT+P C+ EBRT 2 yr LRC
Locally
advanced
68%
vs.
61%
0.3
Martins et al.
2013204
C+RT+
Erlotinib
C+RTCRR
Locally
advanced
40%
vs.
52%
0.08
Ang et al.
2011895
C+RT+
cetuximabC+RT PFS
Locally
advanced
64%
vs.
63%
NS
C: cisplatin; EBRT: external beam radiation therapy; RT: radiation therapy; S: standard, E: experimental arm; P: Panitumumab;
CRR: complete response rate
Randomised trials of EGFR inhibitor plus
chemoradiation in HNSCC
Toxicity Grade ≥3
AuthorMucositis Skin reactions
Skin reactions
out of field
E S E S E S
Ang 43% 33% 25% 15% 29% 1%
Giralt 11% 5% 28% 13% 11% 0%
Martins 48% 48% 13% 2% NR NR
EGFR inhibitor + chemoradiation: Toxicity
CRT: chemoradiotherapy; OS: overall survival
Strategies to improve outcomes in
HNSCC utilising EGFR inhibitors
Treatment intensification of locally advanced HNSCC to improve OS
Randomised trials: CRT+EGFR inhibitor versus CRT
EGFR inhibition in the post-induction setting to reduce toxicity in
sequential design
Randomised phase II studies of induction chemotherapy followed by
either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity
without compromising efficacy
TPF (153 patients)
3 cycles, 1 cycle q3w
T = 75 mg/m² on day 1
P = 75 mg/m² on day 1
F = 750 mg/m² on day 1 to 5
60 patients: RT 70 Gy
Cisplatin 100 mg/m² on days 1, 22 and 43
56 patients: RT 70 Gy
ERBITUX 400 mg/m² 1 wk prior to RT
then 250 mg/m² weekly on wks 1 to 7
R
Total laryngectomy
+ post-op RT
< PR
23
≥ PR
116
P: cisplatin; F: 5-fluorouracil; T: docetaxel; TL: total laryngectomy; PR: partial response ; RT: radiotherapy;
CT: computed tomography; Tx: treatment
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
The randomised Phase II Study:
TREMPLIN
Previously untreated SCC larynx/hypopharynx suitable for TL
Primary endpoint: Larynx preservation 3 months after treatment
Secondary endpoints: Larynx function preservation and survival
18 months after treatment
Cisplatin
n = 58
ERBITUX
n = 56p-value
Grade 3 mucositis
Grade 4 mucositis
25 (43%)
2
24 (43%)
1NS
Grade 3 in field skin toxicity
Grade 4 in field skin toxicity
14 (24%)
1
29 (52%)
3
< 0.001
Other toxicities, any grade,
justifying a protocol
modification
Renal toxicity
Hematological toxicity
Poor general condition
Infusion-related reaction
9 (15.5%)
8 (14.0%)
7 (12.0%)
0
0
0
1 (1.7%)
3 (5.0%)
Protocol modification due to
acute toxicity33 (57%) 19 (29%) 0.02
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
Acute toxicity during RT
*2 patients did not start the treatment in the cisplatin arm
At 18 months after end
of treatment
Last evaluation with a median
follow-up of 36 months
Cisplatin ERBITUX p-value Cisplatin ERBITUX p-value
Total of local (+/- regional)
failures5 (8.3%) 8 (14.3%)
Log-rank:
0.307 (11.7%)
12
(21.4%)
Log-rank:
0.14
Feasible salvage
total laryngectomy0/4* 7/8 0.01 1/6*
9/12(1 refused)
0.04
Successful salvage
total laryngectomy0/1 7/8
Ultimate local failure rate 6 (10%)* 5 (8.9%) NS
Regional failure alone 5 (8.3%) 5 (8.9%) NS 5 (8.3%) 5 (8.9%) NS
Distant metastases 2 (3.3%) 2 (3.6%) NS
Second primary tumour 3 (5.0%) 3 (5.3%) NS
*Data missing for 1 patient lost to follow-up at 5 months
ITT: intention to treat
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
Carcinologic events (ITT)
Primary endpoint
(3 months after end of Tx)Cisplatin
n = 60
ERBITUXn = 56
p-value
Larynx preservation, n (%)
(larynx in place without tumour)57 (95%) 52 (93%) 0.63
Secondary endpoints
(18 months after end of Tx)Cisplatin
n = 60
ERBITUXn = 56
p-value
Larynx function preservation, n (%)
(larynx in place without
tumour/trach/feeding tube)
NB: At 18 months or at death
52 (87%) 46 (82%) 0.68
Overall survival
NB: Since randomisation92 % 89 % Log-rank: 0.44
Endpoints (ITT)
NB: 1 pt lost to FU in the Cisplatin arm is considered as failure
Lefebvre JL, et al. J Clin Oncol 2013;31:853-859
With permission of Maria Ghi, et al. ASCO 2012, abstract 5513
A phase II/III study comparing CRT to
cetuximab/RT with or without induction
TPF in locally advanced HNSCC
CT/RT
(n=215)%
RT/cetuximab
(n=133)%
p value
Skin rash any grade
Grade 3-4
5
1
55
8
<0.01
<0.01
Nausea any grade
Grade 3-4
23
0
10
0
<0.01
Vomiting any grade
Grade 3-4
11
0
7
0
0.22
Renal any grade
Grade 3-4
3
0
0
0
0.05
Neurological any grade
Grade 3-4
4
1
2
1
0.33
0.58
Neutropenia
Grade 3-4
5
3
2
1
0.08
0.19
Febrile neutropenia 4 0 0.04
Mucositis any grade
Grade 3
Grade 4
78
37
4
76
35
2
0.63
0.79
0.45
In-field skin toxicity any grade
Grade 3
Grade 4
59
13
1
69
20
1
0.05
0.07
0.58
Maria Ghi, et al. ASCO 2012, abstract 5513
HPV+,p16+
p16-
Weinberger PM, et al. J Clin Oncol 2006;24:736–47.
Reprinted with permission. © 2006 American Society
of Clinical Oncology. All rights reserved
Oropharyngeal cancer disease variants:
tobacco-related, HPV-related and mixed
Forastiere A, et al. N Engl J Med 2001;345:1890-1900;
Koontongkaew S. J Cancer 2013;4:66-83. Available from http://www.jcancer.org/v04p0066.htm. CC BY-NC-ND 3.0
HPV and survival
The relative survival for HPV positive patient is independent of
therapy as long as this therapy is within the current standard of care
Risk of death is consistently less than 60% that of HPV negative
cancers across studies
The absolute survival difference is consistently higher than 30%
Adapted from: Ang KK, et al. N Engl J Med 2010;363:24–35
Oropharynx: Classification of patients
into risk-of-death categories
>10 pack-years
(n=65)
≤10 pack-years
(n=23)
>10 pack-years
(n=90)
≤10 pack-years
(n=88)
N0-N2a
(n=26)
N2b-N3
(n=64)
T2-T3
(n=15)
T4
(n=8)
42.9% at low risk
3 year OS = 93.0%
27.4% at high risk
3 year OS = 46.2%
29.7% at intermediate risk
3 year OS = 70.8%
HPV-positive
(n=178)
HPV-negative
(n=88)
Oropharyngeal cancer
(n=266)
Huang SH, et al. J Clin Oncol 2015;33:836–45. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved
OS by UICC/AJCC TNM Stage
(7th edition)
Prognostic
Grouping
Model of
HPV(+) OPC
M1 disease considered Group IVB
Too few cases to analyse; policies too varied
Huang SH, et al. J Clin Oncol 2015;33:836–45. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.
Treatment deintensification
Aims to reduce treatment-related morbidity and improve patient
quality of life without compromising treatment effectiveness
Patients with HPV+ OPSCC are younger and expected to live long;
therefore, morbidity resulting from late toxicity is a concern in these
patients
Deintensification strategies include: administering radiotherapy
alone, reducing the dose of radiotherapy and substituting
chemotherapy with cetuximab
Stage III/IV
Oropharynx
p16+R
A
N
D
O
M
I
S
E
II: Accelerated IMRT
70 Gy/6 weeks (cetuximabx8)
I: Accelerated IMRT 70 Gy/6 weeks
(cisplatin 100 mg/m², d1, 22)
Stratification factors: cN-stage (cN0-2a vs. cN2b- cN3), cT-stage (T1-2 vs.T3-4)
Zuprod Performance Status (0 vs. 1), smoking history (<10py vs. >10py)
Radiation therapy oncology group 1016 :
Study Design
Cmelak A, et al. ASCO 2014
Cisplatin 75/m2 d1
Paclitaxel 90/m2 d1, 8, 15
Cetuximab 250/m2 d1, 8, 15
Q 21 days for 3 cycles
CLINICAL CR
Low dose IMRT 54 Gy /
27 fx* + Cetuximab qWeek
CLINICAL PR/SD
Full dose IMRT 69.3 Gy /
33 fx* + Cetuximab qWeek
Induction
chemotherapy
Concurrent
chemoradiation
IMRT margins for primary: 1.0 to 1.5 cm around gross disease
Nodal margin: 1 cm margin minimum, treat entire nodal level
Primary Objective: 2-year PFS after low-dose IMRT (stat aim: 2-year 85% or better)
Eligibility
OPSCC
resectable
HPV ISH +
and / or p16+
Stage III, IVA
IMRT: intensity modulated radiation therapy
Cmelak A, et al. ASCO 2014
ECOG 1308: Phase II Schema
R
E
S
P
O
N
S
E
E
V
A
L
U
A
T
I
O
N
Cohort (n) 2 year PFS (90% CI) 2 year OS (90% CI)
All low dose pts (62) 0.80 (0.70, 0.88) 0.93 (0.85, 0.97)
T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97)
Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98)
N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99)
Non-N2c (43) 0.82 (0.69, 0.90) 0.93 (0.82, 0.97)
Smoker >10 pk-yrs (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94)
Smoker ≤10 pk-yrs (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995)
Smoker ≤10 pk-yrs, <T4,
N2c (27)0.96 (0.82, 0.99) 0.96 (0.82, 0.99)
All high-dose pts (15)* 0.65 (0.41, 0.82) 0.87 (0.63. 0.96)
*3 high-dose pts did not go on to receive RT
Cmelak A, et al. ASCO 2014
Endpoint: 2yr PFS and OS
Neck dissection
Always: Patients who have any clinically apparent residual disease
after chemoradiotherapy
If surgical salvage is necessary for the primary tumour, a neck
dissection may be required to access the primary or for donor
vessels for free flap reconstruction
Observation is acceptable if: No lymph node or lymph node <1 cm at
CT/MRI and negative PET/CT after chemoradiotherapy
Conclusions
Cisplatin chemoradiotherapy remains the standard of care for locally
advanced (LA) HNSCC
Cetuximab is approved with radiation for LA-HNSCC but no
prospective comparison with cisplatin-RT has been performed
TPF is the preferred induction regimen
Sequential therapy is not superior to chemoradiotherapy alone
HPV-positive patients constitute a separate prognostic and
therapeutic cohort
Deintensification trials for HPV-associated oropharyngeal cancers
are ongoing
Thank you!