Presentation on theme: "Mohamed Abdulla (M.D.) Department of Clinical Oncology"— Presentation transcript:
1Management of Advanced Head & Neck Squamous Cell Carcinoma in The Molecular Era Mohamed Abdulla (M.D.)Department of Clinical OncologyKasr El-Aini School of MedicineCairo UniversityAlexandria, 15/01/09
2Epidemiology of SCCHNSquamous cell carcinoma of the head and neck (SCCHN): new cases in Europe annuallySCCHN: mortality in Europe is annuallySCCHN accounts for 6% of all malignanciesWorldwide annual incidence of SCCHN: new patients; deathsGLOBOCAN 2002 (http://www-dep.iar.fr)
3Challenging 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 Patient’s Survival.
4Treatment Modalities in SCCHN Early stage Locally advancedRecurrent and/or metastaticRefractoryRT aloneCTPalliationRT + CTSurgery
5Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years InvestigatorNo. of TrialsNo. of PatientsSequencingSurvival AdvantageStell, 1992283977AllConcurrent2.8%7%Browman, 1994101626NeoadjuvantNegativeMunro, 19955474436.5%12.1%El-Sayed & Nelson, 199625--4%8%Bourhis & Pignon, 1999107412.8 – 6.5%7 – 12.1%
6Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years 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.
7Lessons Learned from Meta-Analysis of Chemotherapy Trials over Years ASCO 2004:87 Trials.16000 Patients.Survival Advantage:All: 5% at 5 y.Concurrent: 11% at 5 y.Platinum MonotherapyASCO 2007
8Lessons 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.
11EGF Pathway EGFR family EGFR HER2 HER3 HER4 Adapted from: The ErbB family of Proteins comprises 4 structurally related receptor tyrosin kinasesEGFRHER2HER3HER4Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:
16Prognostic & 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.
18Cetuximab Experience: ERBITUX + RT in locally advanced SCCHN: Phase III study designRT (n=213)Stage III and IV non-metastatic SCCHN(n=424)RERBITUX + RT (n=211)ERBITUX initial dose (400 mg/m2) 1 week before RTERBITUX (250 mg/m2) + RT (weeks 2–8)Stratified byKPSNodal involvementTumor stageRT regimenaTo date the only targeted therapy that has demonstrated significant improvement in the outcome of patients with locally advanced HNSCC patients compared with standard therapy alone in a controlled phase III is the EGFR targeting monoclonal antibody Cetuximab (Erbitox)Primary endpoint: Duration of locoregional ControlSecondary endpoints: OS, PFS, RR, and safetyaInvestigators’ choiceBonner J, et al. N Engl J Med 2006;354:567–578
19Cetuximab Experience: ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years1.00.90.80.18.104.22.168.22.214.171.124ERBITUX + RTRTp-value5-year OS rate46%36%0.02ERBITUX + RTProbability of Overall SurvivalRTHR=0.73 (0.56–0.95)p = 0.02MonthsTreatment Total Death Alive MedianErbitux + RTRTBonner J.A, et al. as presented ASTRO 2008
20Bonner 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)
21Benefit under CTX + ERBITUX Forest Plot of the Hazard Ratios by Pre-Treatment Characteristics – 5-year UpdateSubgroupPrimary tumor site Oropharynx Larynx Hypopharynx Tumor stage T1–T3 T4RT regimen Once daily Twice daily Concomitant boost Overall stage Stage I-III Stage IV Nodal stage N0 N1–N3KPS 50–80 90–100Gender Male FemaleEGFR status ≤50% positive >50% positive UnknownAge <65 years ≥65 years0.00.61.21.8Benefit under CTX + ERBITUXBenefit under CTX aloneBonner J.A, et al. as presented ASTRO 2008
22ERBITUX + RT: Overall Survival by Severity of Acne/Rash 1.000.750.500.250.00ERBITUX + RT Grade 2-4 Acne/RashProbability of survival (%)grade 0–1 grade 2-4nMedianp=0.002HR (CI)= 0.49 (0.34 – 0.72)ERBITUX + RT Grade 0-1 Acne/RashTime (Month)Bonner J.A, et al. as presented ASTRO 2008
23ERBITUX + RT: Relevant grade 3–5 adverse events RT (n=212)ERBITUX + RT (n=208)p-valueaMucositis/stomatitis52%56%0.44Dysphagia30%26%0.45Radiation dermatitis18%23%0.27Xerostomia3%5%0.32Fatigue/malaise4%0.64Acne-like rash1%17%<0.001Infusion-related reactionsb0%0.01aFisher’s exact testbListed for its relationship to ERBITUXBonner J, et al. N Engl J Med 2006;354:567–578
24No Phase III Direct Head to Head Comparison. Cetuximab + RthCRTNo Phase III Direct Head to Head Comparison.Between-Study Comparison of Phase III Studies 20 & months Survival Advantages.Discretion of The Treating Physician.
25Disease Specific Survival 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 + RthCRTP-Value3-Y L.C.71%75%NSDistant Metastases FS92%87%Disease Specific Survival79%77%3-Y OAS76%61%0.02
26Considerable Number of Non-Protocol Patients in CRT Arm. Inclusion of Higher Number of T-4 Patients in CRT Arm.
27CT or Erbitux effect (p-value) Comparison of overall survival advantage of different combinations (MACH-NC meta-analyses, Bonner study)Hazard ratio (95% CI)CT or Erbitux effect (p-value)Absolute benefitAt 2 yearsaAt 5 yearsaAdjuvant CT+RT10.98 (0.85–1.19)0.741%Neoadjuvant CT +RT10.95 (0.88–1.01)0.102%Concomitant CT + RT10.81 (0.76–0.88)<0.00017%8%ERBITUX + RT20.73 (0.56–0.95)0.0210%aAssuming survival rates of 50% at 2 years and 32% at 5 years in control groupsPignon JP, et al. Lancet 2000;355:949–955Bonner J.A, et al. as presented ASTRO 2008
28ERBITUX+RT provides a high reduction in the risk of death at 5 years 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 yearsAdjuvant CT+RT1Neoadjuvant CT+RT1Concomitant CT+RT1ERBITUX +RT20%-5%-2%-5%-10%-15%-20%-19%-25%-30%-27%1) Pignon JP, et al. Lancet 2000;355:949–9552) Bonner J.A, et al. ASTRO 2008
29Cetuximab + 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.Also there is some published data about the incorporation of Cetuximab into neoadjuvant chemotherapy protocols as Paclitaxel/Carboplatin and TPF with reported higher response rates as well as pathologic complete remissions.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
31VEGF 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.