Management of Advanced Head Neck Squamous Cell Carcinoma

Management of Advanced Head & Neck Squamous Cell Carcinoma in The Molecular Era Mohamed Abdulla (M. D. ) Department of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Alexandria, 15/01/09

Epidemiology of SCCHN Squamous cell carcinoma of the head and neck (SCCHN): 98 000 new cases in Europe annually SCCHN: mortality in Europe is 43 000 annually Worldwide annual incidence of SCCHN: 485 000 new patients; 261 000 deaths SCCHN accounts for 6% of all malignancies GLOBOCAN 2002 (http: //www-dep. iar. fr)

Challenging Issues: Stages III & IV SCCHN Patients: n n n 2/3 of Patients at Presentation. 5 -Year OAS = 30 -35%. 20% will develop failures below the clavicles. Many Modalities of Treatment with Different Sequencing Matters. Impact of Innovations in Loco-regional Management upon Patient’s Survival.

Treatment Modalities in SCCHN Early stage RT alone Locally advanced Recurrent and/or metastatic Refractory CT RT + CT Surgery Palliation

Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years Investigator No. of Trials 28 No. of Patients 3977 Browman, 1994 10 1626 All n. Concurrent Neoadjuvant Munro, 1995 54 7443 n El-Sayed & Nelson, 1996 25 -- Bourhis & Pignon, 1999 -- 10741 Stell, 1992 Sequencing n All n. Concurrent n. All n. Concurrent Survival Advantage n 2. 8% n 7% Negative 6. 5% n 12. 1% n 4% n 8% n 2. 8 – 6. 5% n

Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years n Ø Ø Ø Cancer Care Ontario Practice Guidelines, 2000: 18 Randomized Controlled Trials. 3192 Patients. Absolute Mortality Risk Reduction with Concurrent Cth = 11%. Absolute Mortality Risk Reduction with Monotherapy Platinum Based Cth = 12%. The Cost of Incremental Acute Toxicity.

Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years Ø Ø Ø 1. 2. 3. ASCO 2004: 87 Trials. 16000 Patients. Survival Advantage: All: 5% at 5 y. Concurrent: 11% at 5 y. Platinum Monotherapy ASCO 2007

Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years n n n Concurrent Chemotherapy Improves Survival by 8 -11%. Platinum Monotherapy is Preferred. Little Role in Pure Neoadjuvant or Adjuvant Fashions.

Molecular Biology of Head & Neck SCC.

EGF Pathway n EGFR family EGFR HER 2 HER 3 Adapted from: Ciardiello F, et al. N Engl J Med. 2008; 358: 1160 -1174. HER 4

EGF Pathway n EGFR: transmembrane protein Extracellular Domain Transmembran e Domain Intracellular Domain Tyrosine Kinase Domain Adapted from: Ciardiello F, et al. N Engl J Med. 2008; 358: 1160 -1174.

EGF Pathway n Receptor specific ligands NRGs β-cellulin HB-EGF TGFα β-cellulin HB-EGF Epiregulin Amphireguli n EGFR NRGs HER 2 HER 3 Adapted from: Ciardiello F, et al. N Engl J Med. 2008; 358: 1160 -1174. HER 4

EGF Pathway § EGFR activation mediates multiple processes Shc PI 3 K Grb 2 Ras AKT MEKK-1 m. TOR Adapted from: Ciardiello F, et al. N Engl J Med. 2008; 358: 1160 -1174. Sos-1 MKK-7 Raf MEK ERK JNK

EGF Pathway Angiogenesis Metastasis TGFα Interleukin-8 b. FGF VEGF Shc Grb 2 PI 3 K AKT Ras MEKK-1 Raf MKK-7 MEK m. TOR JNK Apoptosis Resistance Sos-1 Proliferation ERK Transcription

Prognostic & Predictive Importance of EGFR Over expression: n n > 90% of all HNSCC Patients. Poor Response to ttt with Chemo-Radiotherapy Through Repopulation of Clonogenic Cells during ttt. Compromised L. C. , DFS, OAS. Associated with Cisplatin-Resistance.

Cetuximab Experience: ERBITUX + RT in locally advanced SCCHN: Phase III study design RT (n=213) Stage III and IV non-metastatic SCCHN (n=424) Stratified by • KPS • Nodal involvement • Tumor stage • RT regimena R ERBITUX + RT (n=211) ERBITUX initial dose (400 mg/m 2) 1 week before RT ERBITUX (250 mg/m 2) + RT (weeks 2– 8) Primary endpoint: Duration of locoregional Control Secondary endpoints: OS, PFS, RR, and safety a Investigators’ choice Bonner J, et al. N Engl J Med 2006; 354: 567– 578

Cetuximab Experience: Probability of Overall Survival ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years 1. 0 0. 9 0. 8 ERBITUX + RT RT pvalue 46% 36% 0. 02 5 -year OS rate 0. 7 0. 6 ERBITUX + RT 0. 5 0. 4 0. 3 RT 0. 2 HR=0. 73 (0. 56– 0. 95) 0. 1 p = 0. 02 0. 0 0 10 Treatment Total 20 30 Death 40 Months Alive 50 60 70 Median RT 213 130 83 Erbitux + RT 211 110 101 49. 0 29. 3 Bonner J. A, et al. as presented ASTRO 2008

Bonner Trial Overview: n n n Significant Increase in Durability of Locoregional Control (HR = 0. 68, P = 0. 05). Better Median Duration for Locoregional Control (24. 4 vs 14. 9 months). Significant Reduction in Risk of Death (26%) (HR 0. 74, P = 0. 03). Independent Clinical Benefit. No Significant Increase in Grade 3 Co-morbid Events Apart From Acniform Rash & Fusion Reactions. No Significant Adverse Affection of Quality of Life. Incorporation of Molecularly Targeted Agents in The Primary Treatment of Squamous Cell Carcinoma of The Head & Neck. Jacques Bernier. Hematol Oncol Clin N Am. 22(2008)1193 -1208.

Forest Plot of the Hazard Ratios by Pre. Treatment Characteristics – 5 -year Update Subgroup Primary tumor site Oropharynx Larynx Hypopharynx Tumor stage T 1–T 3 T 4 RT regimen Once daily Twice daily Concomitant boost Overall stage Stage I-III Stage IV Nodal stage N 0 N 1–N 3 KPS 50– 80 90– 100 Gender Male Female EGFR status ≤ 50% positive >50% positive Unknown Age <65 years ≥ 65 years 0. 0 0. 6 Benefit under CTX + ERBITUX 1. 2 1. 8 Benefit under CTX alone Bonner J. A, et al. as presented ASTRO 2008

ERBITUX + RT: Overall Survival by Severity of Acne/Rash Probability of survival (%) 1. 00 ERBITUX + RT Grade 2 -4 Acne/Rash 0. 75 0. 50 0. 25 0. 00 grade 0– 1 grade 2 -4 n 81 127 Median 25. 6 68. 8+ p=0. 002 HR (CI)= 0. 49 (0. 34 – 0. 72) 0 10 20 30 ERBITUX + RT Grade 0 -1 Acne/Rash 40 50 60 70 Time (Month) Bonner J. A, et al. as presented ASTRO 2008

ERBITUX + RT: Relevant grade 3– 5 adverse events Adverse event a RT (n=212) ERBITUX + RT (n=208) pvaluea Mucositis/stomatitis 52% 56% 0. 44 Dysphagia 30% 26% 0. 45 Radiation dermatitis 18% 23% 0. 27 Xerostomia 3% 5% 0. 32 Fatigue/malaise 5% 4% 0. 64 Acne-like rash 1% 17% <0. 001 Infusion-related reactionsb 0% 3% 0. 01 Fisher’s exact test Listed for its relationship to ERBITUX b Bonner J, et al. N Engl J Med 2006; 354: 567– 578

Cetuximab + Rth CRT • No Phase III Direct Head to Head Comparison. • Between-Study Comparison of Phase III Studies 20 & 18 months Survival Advantages. • Discretion of The Treating Physician.

Cetuximab + Rth vs CRT? ? • Retrospective Analysis at ONE Center. • 29 Patients (Cetuximab + Rth) vs 103 Patients (CRT). Caudell JJ, Sawrie SM, Spencer SA, et al. Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment. Int J Radiat Oncol Biol Phys 2008 [E-pub]. Item Cetuximab + Rth CRT P-Value 3 -Y L. C. 71% 75% NS Distant Metastases FS 92% 87% NS Disease Specific Survival 79% 77% NS 3 -Y OAS 76% 61% 0. 02

• Considerable Number of Non-Protocol Patients in CRT Arm. • Inclusion of Higher Number of T-4 Patients in CRT Arm.

Comparison of overall survival advantage of different combinations (MACH-NC meta-analyses, Bonner study) Hazard ratio (95% CI) At 2 yearsa At 5 yearsa Adjuvant CT+RT 1 0. 98 (0. 85– 1. 19) 0. 74 1% 1% Neoadjuvant CT +RT 1 0. 95 (0. 88– 1. 01) 0. 10 2% 2% Concomitant CT + RT 1 0. 81 (0. 76– 0. 88) <0. 0001 7% 8% 0. 73 (0. 56– 0. 95) 0. 02 7% 10% ERBITUX + RT 2 a Absolute benefit CT or Erbitux effect (p-value) Assuming survival rates of 50% at 2 years and 32% at 5 years in control groups Pignon JP, et al. Lancet 2000; 355: 949– 955 Bonner J. A, et al. as presented ASTRO 2008

Comparison of the reduction in the risk of death (MACH-NC meta-analyses, Bonner study) ERBITUX+RT provides a high reduction in the risk of death at 5 years Adjuvant Neoadjuvant Concomitant CT+RT 1 ERBITUX +RT 2 0% -5% -10% -2% -5% -15% -20% -19% -25% -30% 1) Pignon JP, et al. Lancet 2000; 355: 949– 955 -27% 2) Bonner J. A, et al. ASTRO 2008

Cetuximab + CRT in Phase III Trials in Advanced HNSCC: n n Radiation Therapy Oncology Group: Cisplatin-Based CRT +/- Cetuximab. Groupe Oncologie Radiotherapie Tet et Cou: Rth + Cetuximab vs Cetuximab + Carboplatin/5 -Fu-Based CRT. Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase III study of a new combined-modality paradigm. J Clin Oncol 2006; 24(7): 1072– 8

Other Epidermal Growth Factor Receptor. Targeted Monoclonal Antibodies Phase I/II: n n n Panitumumab (Vectibix). Zalutumumab (Humax-EGFr). Nimotuzumab (Theraloc). Epidermal Growth Factor Tyrosin Kinase Inhibitors Phase I/II Trials: n n Gefitinib (Iressa) + Cisplatin + Accelerated Rth: CR in 52% (46 Patients). Erlotinib (Tarceva) + Cisplatin-Based CRT: CR in 84% (25 Patients).

VEGF Inhibitor, Bevacizumab (Avastin): n n Phase I/II trials. Significant Morbidity included; Fistula Formation (11%) & Ulceration/Tissue Necrosis (9%). Agents Directed at Multiple Molecular Targets: n n Lapatinib (Tycerb): Phase II Trial; Cisplatin-Based CRT +/- Lapatinib. Vandetanib (Zactema): Phase II Vandetanib and Docetaxel in Locally Advanced HNSCC not amenable to Surgery or Rth.