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CHEMORADIOTHERAPY IN HEAD AND NECK CANCER
Dr David Boote
Consultant in Clinical Oncology
Portsmouth Oncology Centre
May 2007
MANAGEMENT OF THE PRIMARY TUMOUR
• Most T1 and T2 tumours controlled equally well by surgery or RT
• Choice of treatment influenced by:- tumour site, accessibility, histological grade, fitness and patient preference
• Surgery preferable when tumour involves bone
MANAGEMENT OF THE PRIMARY TUMOUR
• Most T3 and T4 tumours require combinations of radiotherapy, chemotherapy and surgery
• Chemoradiotherapy becoming more popular for inoperable tumours
RADIOTHERAPY
a) Primary treatment – typical dose 66Gy in 33 fractions over 6½ weeks
b) Post-operative (adjuvant) – indications include close or involved resection margins, poorly differentiated tumours, extensive lymph node involvement
c) Palliative e.g. bleeding, pain
RADIOTHERAPY CONSIDERATIONS
• Unhealthy teeth in the radiotherapy treatment volume need to be removed before starting radiotherapy
• Treat in a plastic mask (shell) to ensure accuracy and to avoid ink marks on skin
• A mouth-bite can be used when treating e.g. Ca tongue, floor of mouth, to dispace the upper jaw out of the field
CLINICAL CHALLENGES
• Excess alcohol/tobacco intake
• Poor nutrition, ? Need PEG
• Medically unfit e.g. COPD
• Poor social support
• May need dental extractions
• RT planning is complex and time-consuming
TREATMENT OPTIONS IN ADVANCED DISEASE
Surgery ± Radiotherapy ± Chemotherapy
CHEMOTHERAPY OPTIONS IN HEAD AND NECK
CANCER
Can use chemo in 4 main ways:-
1. Neoadjuvant (Induction) chemotherapy2. Concurrent (Concomitant) chemotherapy3. Adjuvant (Post-op) chemotherapy4. Palliative chemotherapy
1. INDUCTION CHEMOTHERAPY
• Given prior to radiotherapy or surgery• “gold standard” Cisplatin + 5-FU for 2-3 courses• Leads to a major response in 60 – 90% patients• Until recently, no significant effect on overall
survival• Can be used for organ sparing e.g. as alternative to
laryngectomy• ? Use dropped after Pignon meta analysis (Lancet
2000)
EFFECTS OF CHEMOTHERAPY ON SURVIVAL
AT 5 YEARS:FROM THE META-ANALYSIS
Trial No. of No. DifferenceCategory Trials Patients (%) P value
All trials 65 10850 +4<0.0001
Adjuvant 8 1854 +10.74
Induction 31 5269 +20.10
PF 15 2487 +50.01
Other Chemo 16 2782 00.91
Concomitant 26 3727 +8 <0.0001
ADVANTAGES INDUCTION CHEMOTHERAPY
survival
• organ preservationdistant mets
• Prompt symptom relief
• Use whilst waiting for RT
DISADVANTAGES INDUCTION CHEMOTHERAPY
• Toxicity e.g. neutropenia
• Toxic deaths
• Delays (C)RT
2. CONCURRENT CHEMOTHERAPY
• Most commonly single agent Cisplatin for 2–3 courses• Pignon meta-analysis showed an 8% absolute survival
benefit when chemo added to RT• Several randomised trials in unresectable disease show
significant improvement in local control and survival• Regarded by most clinicians as the best time to give
chemotherapy• Increased toxicity (especially mucositis) means only
suitable for fit patients
ADVANTAGES/DISADVANTAGES CONCURRENT CHEMOTHERAPY
Advantages survival
local control
Disadvantages • Toxicity
• RT mucositis
Induction CT + Locoregional RT
Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.
Vermorken JB, et al. ASCO 2004, abstract 5508.
EORTC 24971/TAX 323 - Study Design
Neck Dissectio
nInoperable
SCCHNStage 3-4.
Stratification:
1º tumor site
Institution
TPF arm (n=177) Docetaxel (75
mg/m²) Cisplatin (75
mg/m²) 5-FU (750
mg/m²/dx5)Q 3 weeks x 4 cycles
PF arm (n=181) Cisplatin (100
mg/m²) 5-FU (1000
mg/m²/dx5)Q 3 weeks x 4 cycles
Radiotherapy(~70 Gy over
7 weeks)Follow up
Surgery for
Residual Disease
Treatment arms were well balanced in baseline
characteristics
Primary Objective: PFS
Overall Survival
EORTC 24971/TAX 323
(months)0
0
10
20
30
40
50
60
70
80
90
100
6 12 18 24 30 36 42 48 54 60 66 72
Treatment
PFTPF
Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.
Vermorken JB, et al. ASCO 2004, abstract 5508.
PF TPF
Median OS, mo 14.2 18.6
Hazard ratio (95% CI)
0.71 (0.56, 0.90)
P-value 0.0055
Toxicity
EORTC 24971/TAX 323
NCIC-CTC Grade 3-4Toxicity
PF (n=179)patient
percentage
TPF (n=173) patient
percentage
Anemia/thrombocytopenia
13/18 9/3
Neutropenia 53 77
Nausea/vomiting 7/4 <1/<1
Diarrhea 3 3
Stomatitis 11 5
Infection 6 7
Febrile neutropenia 3 5Primary prophylactic antibiotics were givenper protocol for TPF
QOL Analysis: PSS-HN
Bernier et al. ASCO 2006; Abstract 5522.
EORTC 24971/TAX 323
PSS-HN data showed that eating disturbances and disturbances of speech were higher in patients treated with PF vs those
treated with TPF
ParameterTreatment
s
Results End of
Treatment(difference in least
square mean)
Results End of Follow-up
(difference in leastsquare mean)
P-value
Normal dietTPF vs
PF + 5.5 + 16.8 0.0064
SpeechTPF vs
PF + 3.7 + 3.9 <0.0001
Public eating
TPF vs PF + 6.6 + 17.3 0.0002
Performance Status Scale – Head & Neck
Conclusions
EORTC 24971/TAX 323
Treatment with TPF was superior to PF Median PFS (primary endpoint; p=.007) Median overall survival (p=.013)TPF has a manageable toxicity profile
Health-related QOL and clinical benefit outcomes generally favored TPF
Induction CT CRT Surgery
Posner RM, et al. ASCO 2006, abstract SPS24.
TAX 324 - Study Design
Treatment arms were well balanced in baseline demographic
and disease characteristics
Primary Objective: OS
Radiotherapy(70Gy d1-5)+ Weekly
Carboplatin(AUC 1.5 7)
Surgery is
needed
PF arm (n=246) Cisplatin (100
mg/m²/d1) 5-FU (1000 mg/m²/d
5) Q 3 weeks x 3 cycles
TPF arm (n=255) Docetaxel (75
mg/m²) Cisplatin (100
mg/m²d1) 5-FU (1000
mg/m²/d 4)Q 3 weeks x 3 cycles
N=538Stage III/IVEpidermoidcarcinoma,
no prior surgery,
no hospitalizationfor COPD 1y
Stratification:• Center• N status• Primary site
Posner RM, et al. ASCO 2006, abstract SPS24.
TAX 324 - Study Design
Primary Endpoint: Overall Survival
0 6 12 18 24 30 36 42 48 54 60 66 720
3-Year OSTPF 62%PF 48%
2-Year OSTPF 67%PF 54%
Survival Time (months)
Log-Rank p = .0058Hazard ratio = 0.70
TPF (n=255)
PF (n=246)
TPF significantly improvedoverall survival vs PF30% reduction in mortality
Su
rviv
al P
rob
ab
ilit
y (
%)
10
20
30
40
50
60
70
80
90
100
Posner et al. ASCO 2006.
TAX 324
Specific Safety During Chemotherapy
TPF(N=251)
PF(N=243)
Deaths due to toxicity 1% 2%
Neutropenia Grade 3/4 84% 56%
Febrile NeutropeniaNeutropenic Infection
12% 12%
7% 9%
Primary prophylactic antibiotics were given per protocol for TPF
Conclusions
TPF significantly improves survival in 2 phase IIItrials TAX 323: 29% reduction in mortality (p=0.0055) TAX 324: 30% reduction in mortality (p=0.0058)
Sequential therapy with TPF is tolerable and safe
Hitt R, et al. ASCO 2006, abstract 5515.
Phase III Trial PF ± Docetaxel CRT vs CRT
Study Design
Primary endpoint phase III: TTF
SCHNNStage III, IV
(locally advanced)Unresectable
PF 3 cycles q 21
days Cisplatin Infusional 5-
FU
(N=340)
TPF 3 cycles q 21
days Docetaxel Cisplatin Infusional 5-
FU CRT
CRT
Hitt R, et al. ASCO 2006, abstract 5515.
Phase III Trial PF ± Docetaxel CRT vs CRT
Patient Characteristics
TPF PF CRT
Age, years Median (range) 57 (35-78) 58 (36-85) 55 (25-79)
Gender, % Men 93 92 89
PS (ECOG), % 0 8 13 8
1 92 87 92
Anatomic site, % Oropharynx 41 43 43
Hyppharynx 19 18 19
Larynx 19 17 18
Oral cavity 21 22 20
Tumor grading, % T4 N0 19 10 17
T4 N1 18 16 21
T4 N2 43 41 32
T4 N3 0 8 6
No significant differences between treatments arms in baseline patient characteristics
Hitt R, et al. ASCO 2006, abstract 5515.
Phase III Trial PF ± Docetaxel CRT vs CRT
Efficacy ResultsTime to Treatment Failure (TTF) favored
the docetaxel-containing (TPF) arm
1.000
0.875
0.750
0.625
0.500
0.375
0.250
0.125
0.000
0.0 3.5 7.0 10.5 14.0 17.5 21.0 24.5 28.0 31.5 35.0
Time to treatment failure
Times (months)
TPF PF CRT
Median: TPF 16 months, PF 12 months, CRT 8 months.Log rank 0.031
Hitt R, et al. ASCO 2006, abstract 5515.
Phase III Trial PF ± Docetaxel CRT vs CRT
Toxicity During Chemotherapy
Patient Percentage
Grade 3/4 Toxicity TPF PF CRT
Leucocytes 9 11 11
Granulocytes 28 18 18
Platelets 7 6 6
Febrile neutropenia 6 1 2
Asthenia 11 9 5
Mucositis 53 58 35
Renal 2 4 6
Dermatitis 7 22 13
Calais G, et al. ASCO 2006, abstract 5506.
GORTEC 2000-01 - Study Design
Induction CT Larynx Preservation
Primary Objective: larynx preservation rate
Larynx orhypopharynx
tumors
Resectabletumors or
nodes requiringtotal
(pharyngo[P]laryngectomy)
No previoustreatment
TPF arm Docetaxel (75 mg/m² d1) Cisplatin (75 mg/m² d1) 5-FU (750 mg/m²/dx5)Q 3 weeks x 3 cycles
PF arm Cisplatin (100 mg/m²) 5-FU (1000 mg/m²/dx5)Q 3 weeks x 3 cycles
Non-responders:
Total (P)laryngecto
my+ post-op RT
Responders:RT alone
Responseto
induction
treatmentYe
s
No
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Patient and Disease Characteristics
TPF (n=110) PF (n=103)
Age, years Median (range)
56.6 (38-75)
56.8 (32-75)
Gender, % Men/women 101/9 97/6
PS (ECOG), % 0 51 51
1 59 52
Anatomic site, %
Hypopharynx 61 54
Larynx 49 49
Tumor grading, % T2 15 24
T3 80 63T4 15 16
p=(0.14)
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Larynx Preservation
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 6 12 18 24 30 36
TPF
PF
Time from randomization(months)
Lary
nx p
reserv
ati
on
, %
Median follow-up: 30 months
Larynx preservation rate higherin TPF group p=0.036
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Grade 3/4 Acute Toxicities
NCI/CTC Grade 3/4* TPF PF p
Mucositis 4.6 7.8 0.49
Neutropenia 55.6 37.3 0.01
Febrile neutropenia 13.9 7.8 0.24
Thrombocytopenia 1.9 7.8 0.09
Deaths 3.6 2.9 0.71
% of patients
*Among patients treated with RT alone, no differences were observed betweenthe 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with permanent feeding tube.
Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Relative to Other Studies of PFInduction Followed by RT
Study 5-Year LPR (N function)
Veteran (larynx) 39%
EORTC (hypopharynx) 35%
RTOG 91-11 (larynx) 43%*
GORTEC 2000-01 41.4% (3-year)
*Endpoint was 5-year laryngectomy-free survival(45% in the concomitant group).
Results with PF arm from GORTEC 2000-01 are consistent with those observed in other studies
Adding Targeted Therapies in SCCHN- The Next Step
Potential role in induction, adjuvant treatment, and radiation sensitization
These agents can be added to induction/sequential
therapy and to chemoradiotherapy to improve
outcomesAgents with early experiences for recurrent/advanced disease:
EGFR-inhibitors Combined EGFR/HER2 inhibitors Angiogenesis Other targets
EGFR is an important target for cancer therapy
• EGFR over-expression is associated with a poor prognosis3-7
• Erbitux® specifically targets EGFR, which is over-expressed in SCCHN8,9
References:
1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.2. Wells A. Int J Biochem Cell Biol 1999;31(6):637-643.3. Ang KK et al. Cancer Res 2002;62(24):7350-7356.4. Rubin Grandis J et al. J Nat Cancer Inst 1998;90:824-832.5. Maurizi M et al. Br J Cancer 1996;74:1253-1257.
6. Magne N et al. Eur J Cancer 2001;37(17):2169-2177.7. Hitt R et al. Eur J Cancer 2005;41(3):453-460.8. Baselga J et al. J Clin Oncol 2005;23(24):5568-5577.9. Bonner JA et al. N Engl J Med 2006;354:567-578.
Erbitux® specifically targets EGFR1
• Erbitux® is an innovative chimeric monoclonal antibody1
• By binding to EGFR, Erbitux® inhibits the signalling cascade leading to
multiple effects2,3
• Erbitux® inhibits post-radiation DNA damage repair4
References:
1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.2. Ciardiello F and Tortora G. Clin Cancer Res 2001;7(10):2958-2970.3. Arteaga CL. J Clin Oncol 2001;19(18 Suppl):32S-40S.4. Huang SM et al. Clin Cancer Res 2000;6(6):2166-2174.
A new approach: Erbitux® + radiotherapy in locally advanced SCCHN
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
Characteristics RT (n=213)
Erbitux® + RT (n=211)
Karnofksy performance status: 60–80 90–100
71141
63147
Site of primary tumour: Oropharynx Larynx Hypopharynx
1355127
1185736
Nodal involvement: NONodal involvement: N+
38175
42169
Tumor stage: T1–3Tumor stage: T4
14865
14862
Fractionation:RT was administered as: once-daily (26%), twice daily (18%) or concomitant boost (56%)
Erbitux® + radiotherapy significantly prolongs locoregional control in SCCHN1
The addition of Erbitux® to RT vs RT alone:
• significantly prolongs the duration
of locoregional control by almost
10 months (24.4 months vs 14.9 months, p=0.005)1
• resulted in a 32% reduction in the risk of locoregional progression (Hazard ratio = 0.68,
95% CI = 0.52-0.89)1
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
Erbitux® + radiotherapy significantly prolongs
survival in SCCHN1
The addition of Erbitux® to RT vs RT alone:
• significantly prolongs median overall survival by almost 20 months
(49.0 vs 29.3 months, p=0.03)1
• resulted in a 26% reduction in the risk of death (Hazard ratio = 0.74,
95% CI = 0.57-0.97)1
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
Frequently observed* adverse events (grades 3–5)1
RT (%)Erbitux® + RT (%)
p value‡
Adverse event n=212 n=208
Mucositis 52 56 0.44
Acneform rash 1 17 <0.001
Radiation dermatitis 18 23 0.27
Weight loss 7 11 0.12
Dry mouth 3 5 0.32
Dysphagia 30 26 0.45
Asthenia 5 4 0.64
Nausea 2 2 1.00
Constipation 5 5 1.00
Erbitux® does not significantly increase radiotherapy-related side effects
• Erbitux® does not significantly exacerbate typical radiotherapy-associated toxicities such as
mucositis, xerostomia and dysphagia in locally
advanced SCCHN1
• The most frequently observed
adverse events related to Erbitux® are skin reactions1
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
* Frequently observed = All grades in ≥30% of subjects‡ p values were determined with the use of a Fisher’s exact test
Erbitux® in practice
• No EGFR testing is required
• An average patient treatment cost for
Erbitux® is approximately £5,700
• Erbitux® + RT is associated with
an incremental cost per QALY of approximately £6,870 compared
to RT alone over the expected patient lifetime1
• Erbitux® + RT is estimated to cost: – £6,558 per extra life year1
– £5,688 per progression-free life year1
Reference:
1. Data on file, UKECRC05020.
INDUCTION CHEMOTHERAPY IN PORTSMOUTH
• Until 2000 – Cisplatin + 5-FU (“waiting list chemo”)• Nov 1999, JCO, Colevas et al, phase 2 study, TPF (+
leucovorin) induction chemo in H+N Ca 93% RR (63%CR) but 1 toxic death (neutropenic sepsis) and generally toxic. Also needed g-csf and prophylactic antibiotics
• Decided to use TPF but lower doses, omitting leucovorin, no g-csf or prophylactic antibiotics
DRUG DOSES (mg/m2)
T
P
F
323
75
75
3750
324
75
100
4000
Boote
40
80
2800
PORTSMOUTH RESULTS
• Approximately 80 patients treated so far
• Have audited results on first 43 patients
• Average age 58 (range 44-81)
• Male 79%, Female (21%)
• Primary:- Tonsil 28%, Base tongue 23%, unknown 13%, Hypopharynx 10%, Larynx 8%, other 18%
PORTSMOUTH RESULTS (cont’d)
• Stage:- nodes unknown primary 13%, stage II 5%, stage III 38%, stage IV 44%
• Majority (70%) received 2 cycles (range 1-3)• 39/43 underwent radical RT• 2 underwent surgery followed by RT• 1 underwent surgery alone• Overall response rate 85% (70% CR, 15%PR)• Average follow-up (first 43 pts) 18 months
PORTSMOUTH RESULTS (cont’d)
• Of the CR’s 4 patients recurred at an average of 10 months (range 6-15 months)
• 3 of the PR’s have progressed at an average of 6 months after treatment. One of these PR’s underwent surgery and remains disease free,
• All patients who progressed on treatment have died
CHEMOTHERAPY TOXICITY
• No toxic deaths
• No grade 4 toxicity
• One grade 3 toxicity (neutropenia)
• One grade 2 toxicity (vomiting)
• Most patients grade 1 toxicity only
• Most toxicity seen in PS2 patients
CHEMOTHERAPY TOXICITY (cont’d)
• 2 patients had impaired renal function after their first cycle and were changed to Carboplatin
• 1 myocardial infarction ? Treatment related
• 6 extravasations – no long term complications
• 1 episode of hypotension ? Cause
• No increase in radiotherapy toxicity
ACTUAL CASE
• Mr D.K. age 56• Presented with lump in neck December 2000• Investigations showed carcinoma of base of
tongue with bilateral neck nodes (stage T2, N2)• Given 3 courses TPF, well-tolerated (bursitis)• Complete response after chemo• Then had RT (66Gy/33/6½ weeks)• Last seen in clinic July 2006 – alive and well –
discharged