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Management of Advanced Head & Neck Squamous Cell Carcinoma in The Molecular Era Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School.

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Presentation on theme: "Management of Advanced Head & Neck Squamous Cell Carcinoma in The Molecular Era Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School."— Presentation transcript:

1 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

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

3 Challenging Issues: Stages III & IV SCCHN Patients: 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 Patients Survival.

4 Treatment Modalities in SCCHN CTRT alonePalliation RT + CT Early stage Locally advanced Recurrent and/or metastatic Refractory Surgery

5 Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years Investigator No. of Trials No. of Patients Sequencing Survival Advantage Stell, All Concurrent 2.8% 7% Browman, NeoadjuvantNegative Munro, All Concurrent 6.5% 12.1% El-Sayed & Nelson, All Concurrent 4% 8% Bourhis & Pignon, All Concurrent 2.8 – 6.5% 7 – 12.1%

6 Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years Cancer Care Ontario Practice Guidelines, 2000: 18 Randomized Controlled Trials 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.

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

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

9 Molecular Biology of Head & Neck SCC.

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11 EGF Pathway EGFR family EGFR family EGFRHER2HER3HER4 Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:

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

13 EGF Pathway Receptor specific ligands Receptor specific ligands EGF TGFα β-cellulin HB-EGF Epiregulin Amphireguli n EGFRHER2HER3HER4 NRGs β-cellulin HB-EGF NRGs Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:

14 Shc PI3K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 EGFR activation mediates multiple processes EGFR activation mediates multiple processes EGF Pathway Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:

15 ProliferationApoptosis ResistanceTranscription TGFα Interleukin-8 bFGF VEGF Metastasis Angiogenesis Shc PI3K RafMEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 EGF Pathway

16 Prognostic & Predictive Importance of EGFR Over expression: > 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.

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

19 Months Probability of Overall Survival Treatment TotalDeathAliveMedian RT Erbitux + RT 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 J.A, et al. as presented ASTRO 2008 Cetuximab Experience:

20 Bonner Trial Overview: 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)

21 Primary tumor siteOropharynx Larynx Hypopharynx Tumor stageT1–T3 T4 RT regimenOnce daily Twice daily Concomitant boost Overall stageStage I-III Stage IV Nodal stageN0 N1–N3 KPS50–80 90–100 GenderMale Female EGFR status50% positive >50% positive Unknown Age<65 years65 years Forest Plot of the Hazard Ratios by Pre- Treatment Characteristics – 5-year Update Subgroup Benefit under CTX + ERBITUX Benefit under CTX alone Bonner J.A, et al. as presented ASTRO 2008

22 Time (Month) Probability of survival (%) ERBITUX + RT: Overall Survival by Severity of Acne/Rash ERBITUX + RT Grade 2-4 Acne/Rash Bonner J.A, et al. as presented ASTRO 2008 ERBITUX + RT Grade 0-1 Acne/Rash grade 0–1 grade 2-4 n81127 Median p=0.002 HR (CI)= 0.49 (0.34 – 0.72)

23 Adverse event RT (n=212) ERBITUX + RT (n=208) p- value a Mucositis/stomatitis52%56%0.44 Dysphagia30%26%0.45 Radiation dermatitis 18%23%0.27 Xerostomia3%5%0.32 Fatigue/malaise5%4%0.64 Acne-like rash 1%17%<0.001 Infusion-related reactions b 0%3%0.01 a Fishers exact test b Listed for its relationship to ERBITUX ERBITUX + RT: Relevant grade 3–5 adverse events Bonner J, et al. N Engl J Med 2006;354:567–578

24 Cetuximab + RthCRT 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.

25 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]. ItemCetuximab + Rth CRTP-Value 3-Y L.C.71%75%NS Distant Metastases FS 92%87%NS Disease Specific Survival 79%77%NS 3-Y OAS76%61%0.02

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

27 Comparison of overall survival advantage of different combinations (MACH-NC meta-analyses, Bonner study) Pignon JP, et al. Lancet 2000;355:949–955 Hazard ratio (95% CI) CT or Erbitux effect (p-value) Absolute benefit At 2 years a At 5 years a Adjuvant CT+RT (0.85–1.19) 0.741% Neoadjuvant CT +RT (0.88–1.01) 0.102% Concomitant CT + RT (0.76–0.88) < %8% ERBITUX + RT (0.56– 0.95) 0.027%10% a Assuming survival rates of 50% at 2 years and 32% at 5 years in control groups Bonner J.A, et al. as presented ASTRO 2008

28 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 0% -5% -10% -15% -20% -25% -30% Adjuvant CT+RT 1 ERBITUX +RT 2 -2% -5% -19% -27% 1) Pignon JP, et al. Lancet 2000;355:949–955 2) Bonner J.A, et al. ASTRO 2008 Neoadjuvant CT+RT 1 Concomitant CT+RT 1

29 Cetuximab + CRT in Phase III Trials in Advanced HNSCC: 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

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

31 VEGF Inhibitor, Bevacizumab (Avastin): Phase I/II trials. Significant Morbidity included; Fistula Formation (11%) & Ulceration/Tissue Necrosis (9%). Agents Directed at Multiple Molecular Targets: 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.


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