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 Primary treatment – typical dose 66Gy in 33 fractions over 6½ weeks Post-operative (adjuvant) – indications include close or involved resection margins, poorly differentiated tumours, extensive lymph node involvement 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:- Neoadjuvant (Induction) chemotherapy Concurrent (Concomitant) chemotherapy Adjuvant (Post-op) chemotherapy 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. Difference Category Trials Patients (%) P value All trials 65 10850 +4 <0.0001 Adjuvant 8 1854 +1 0.74 Induction 31 5269 +2 0.10 PF 15 2487 +5 0.01 Other Chemo 16 2782 0 0.91 Concomitant 26 3727 +8 <0.0001

ADVANTAGES INDUCTION CHEMOTHERAPY survival organ preservation distant 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

EORTC 24971/TAX 323 - Study Design Induction CT + Locoregional RT Neck Dissection Surgery for Residual Disease TPF arm (n=177)  Docetaxel (75 mg/m²)  Cisplatin (75 mg/m²)  5-FU (750 mg/m²/dx5) Q 3 weeks x 4 cycles Inoperable SCCHN Stage 3-4. Radiotherapy (~70 Gy over 7 weeks) Follow up R Stratification: 1º tumor site Institution PF arm (n=181)  Cisplatin (100 mg/m²)  5-FU (1000 mg/m²/dx5) Q 3 weeks x 4 cycles Primary Objective: PFS Treatment arms were well balanced in baseline characteristics 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 Overall Survival PF TPF Treatment PF TPF 10 20 30 10 20 30 40 50 60 70 80 90 100 PF TPF Median OS, mo 14.2 18.6 Hazard ratio (95% CI) 0.71 (0.56, 0.90) P-value 0.0055 Treatment PF TPF 6 12 18 24 30 36 42 48 54 60 66 72 (months) Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522. Vermorken JB, et al. ASCO 2004, abstract 5508.

Primary prophylactic antibiotics were given EORTC 24971/TAX 323 Toxicity NCIC-CTC Grade 3-4 Toxicity 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 Stomatitis 11 5 Infection 6 7 Febrile neutropenia Primary prophylactic antibiotics were given per protocol for TPF

Performance Status Scale – Head & Neck EORTC 24971/TAX 323 QOL Analysis: PSS-HN PSS-HN data showed that eating disturbances and disturbances of speech were higher in patients treated with PF vs those treated with TPF Performance Status Scale – Head & Neck Parameter Treatments Results End of Treatment (difference in least square mean) End of Follow-up P-value Normal diet TPF vs PF + 5.5 + 16.8 0.0064 Speech + 3.7 + 3.9 <0.0001 Public eating + 6.6 + 17.3 0.0002 Bernier et al. ASCO 2006; Abstract 5522.

EORTC 24971/TAX 323 Conclusions 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 + Weekly Carboplatin (AUC 1.5 7) TAX 324 - Study Design Induction CT  CRT  Surgery N=538 Primary Objective: OS Stage III/IV Epidermoid carcinoma, no prior surgery, no hospitalization for COPD 1y PF arm (n=246)  Cisplatin (100 mg/m²/d1)  5-FU (1000 mg/m²/d 5) Q 3 weeks x 3 cycles Radiotherapy (70Gy d1-5) + Weekly Carboplatin (AUC 1.5 7) Surgery is needed R 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 Stratification: Center N status Primary site Treatment arms were well balanced in baseline demographic and disease characteristics Posner RM, et al. ASCO 2006, abstract SPS24.

Primary Endpoint: Overall Survival Survival Probability (%) TAX 324 - Study Design Primary Endpoint: Overall Survival 100 TPF significantly improved overall survival vs PF 30% reduction in mortality 90 80 70 60 TPF (n=255) Survival Probability (%) 50 PF (n=246) 40 2-Year OS TPF 67% PF 54% 3-Year OS TPF 62% PF 48% 30 Log-Rank p = .0058 Hazard ratio = 0.70 20 10 6 12 18 24 30 36 42 48 54 60 66 72 Survival Time (months) Posner RM, et al. ASCO 2006, abstract SPS24.

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 Neutropenia Neutropenic Infection 12% 7% 9% Primary prophylactic antibiotics were given per protocol for TPF Posner et al. ASCO 2006.

Conclusions TPF significantly improves survival in 2 phase III trials  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

Phase III Trial PF ± Docetaxel  CRT vs CRT Study Design Primary endpoint phase III: TTF PF  3 cycles q 21 days Cisplatin Infusional 5-FU (N=340) SCHNN Stage III, IV (locally advanced) Unresectable CRT TPF  3 cycles q 21 days Docetaxel Cisplatin Infusional 5-FU R CRT Hitt R, et al. ASCO 2006, abstract 5515.

Phase III Trial PF ± Docetaxel  CRT vs CRT Patient Characteristics No significant differences between treatments arms in baseline 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), % 8 13 1 87 Anatomic site, % Oropharynx 41 43 Hyppharynx 19 18 Larynx 17 Oral cavity 21 22 20 Tumor grading, % T4 N0 10 T4 N1 16 T4 N2 32 T4 N3 6 Hitt R, et al. ASCO 2006, abstract 5515.

Phase III Trial PF ± Docetaxel  CRT vs CRT Efficacy Results Time to Treatment Failure (TTF) favored the docetaxel-containing (TPF) arm Time to treatment failure 1.000 TPF PF CRT 0.875 0.750 0.625 0.500 0.375 0.250 Median: TPF 16 months, PF 12 months, CRT 8 months. Log rank 0.031 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 Times (months) 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 Granulocytes 28 18 Platelets 7 6 Febrile neutropenia 1 2 Asthenia 5 Mucositis 53 58 35 Renal 4 Dermatitis 22 13 Hitt R, et al. ASCO 2006, abstract 5515.

GORTEC 2000-01 - Study Design Induction CT  Larynx Preservation R Larynx or hypopharynx tumors Resectable tumors or nodes requiring total (pharyngo[P] laryngectomy) No previous treatment TPF arm  Docetaxel (75 mg/m² d1)  Cisplatin (75 mg/m² d1)  5-FU (750 mg/m²/dx5) Q 3 weeks x 3 cycles Non-responders: Total (P)laryngectomy + post-op RT No Response to induction treatment R PF arm  Cisplatin (100 mg/m²)  5-FU (1000 mg/m²/dx5) Q 3 weeks x 3 cycles Responders: RT alone Yes Primary Objective: larynx preservation rate Calais G, et al. ASCO 2006, abstract 5506.

Patient and Disease Characteristics 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), % 51 1 59 52 Anatomic site, % Hypopharynx 61 54 Larynx 49 Tumor grading, % T2 15 24 T3 80 63 T4 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 TPF PF Median follow-up: 30 months 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 TPF PF Larynx preservation, % Median follow-up: 30 months Larynx preservation rate higher in TPF group p=0.036 Time from randomization (months) 6 12 18 24 30 36 Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.

Grade 3/4 Acute Toxicities GORTEC 2000-01 Grade 3/4 Acute Toxicities % of patients 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 0.24 Thrombocytopenia 1.9 0.09 Deaths 3.6 2.9 0.71 *Among patients treated with RT alone, no differences were observed between the 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with permanent feeding tube. Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.

GORTEC 2000-01 Relative to Other Studies of PF Induction Followed by RT Results with PF arm from GORTEC 2000-01 are consistent with those observed in other studies 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). Calais G, et al. ASCO 2006, Abstract 5506.

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 outcomes Agents 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 Characteristics RT (n=213) Erbitux® + RT (n=211) Karnofksy performance status: 60–80 90–100 71 141 63 147 Site of primary tumour: Oropharynx Larynx Hypopharynx 135 51 27 118 57 36 Nodal involvement: NO Nodal involvement: N+ 38 175 42 169 Tumor stage: T1–3 Tumor stage: T4 148 65 62 Fractionation: RT was administered as: once-daily (26%), twice daily (18%) or concomitant boost (56%) Reference: 1. Bonner JA et al. N Engl J Med 2006;354:567-578.  

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 Erbitux® does not significantly increase radiotherapy-related side effects 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 4 0.64 Nausea 2 1.00 Constipation • 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 * Frequently observed = All grades in ≥30% of subjects ‡ p values were determined with the use of a Fisher’s exact test   Reference: 1. Bonner JA et al. N Engl J Med 2006;354:567-578.  

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 3750 324 100 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