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J.B. Vermorken - Head and neck - State of the art
1. State of the Art in Head and Neck Cancer Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium 3rd EASO Masterclass in Clinical Oncology Amman, 2011
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3. HN Surgeon Radiation Oncologist Medical Oncologist Anesthesiologist Internist GP Radiologist Social worker Psychologist Patient Guidelines Clinical trials Biologist Pathologist Dietician Speech Therapist
4. Evolving Systemic Therapies Alone or with Radiation Head and Neck squamous cell cancer 1960s Methotrexate (IC, CRT) 1970s Bleomycin, 5-fluorouracil, cisplatin Combination chemotherapy regimens 1980s Carboplatin Organ preservation trials start 1990s Paclitaxel, docetaxel CRT>RT 2000s Targeted therapies (MoAb) Evolving role for ICT Sequential therapy (ICT CRT)?
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9. MACH-NC Analysis: Survival Benefit of Concomitant Chemotherapy to Local Treatment a 50 concomitant trials; CRT, chemoradiation; CT, chemotherapy; RT, radiotherapy Pignon JP et al. Radiother Oncol 2009;92:4–14 Absolute survival benefit at 5 years: 6.5% (CRT) p=0.41 CRT regimen a Hazard ratio Postoperative RT 0.79 Conventional RT 0.83 Altered fractionated RT 0.73 Mono - CT 0.84 MonoPlatin 0.74 Poly - CT 0.78 5-FU + platinum 0.75 5-FU/platinum 0.83 Other CT 0.73 Pooled 0.81 (p<0.0001)
10. Acute adverse effects: Grade ≥ 3 p<0.05 ns Patients (%) p<0.01 Wendt TG, et al. J Clin Oncol 1998;16:1318–1324 0 10 20 30 40 50 60 Xerostomia Nausea/emesis Leukopenia Dermatitis Mucositis RT alone (n=140) CRT (n=130) ns, not significant CRT = CDDP + 5-FU + RT Late Toxicity Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14) 10% 12% 27% 13% 43% 0 10 20 30 40 50 Patients (%) Any severe late toxicity Feeding-tube dependence >2 yrs post-RT Pharyngeal dysfunction Laryngeal dysfunction Death Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589
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12. Enhancement of Radiation Effects Selective Targeting of Hypoxic Cells Induction of Pro-Apoptotic Mechanisms Anti- Angiogenesis Strategies Inhibition of Cox-2 Replacement of Mutated Tumor Suppressor Genes Inhibition of EGFR Several biological mechanisms that have potential to alter sensitization strategies (Choy and MacRae, 2003)
16. 5-Years Survival Update and QoL Assessment 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Time (months) Probability of overall survival Bonner JA, et al. Presented at ASTRO 2008 ERBITUX + RT RT ERBITUX + RT RT 5-year survival rate 46% 36% p=0.018, HR=0.73 (0.56-0.95) 29.3 49.0 ERBITUX + RT does not adversely affect QoL, while significantly improving overall survival Curran D, et al. J Clin Oncol 2007; 25: 2191 –2197 a Post-baseline scores for the EORTC QLQ-C30 Global health status/QoL score a 100 80 60 40 20 0 RT RT + ERBITUX Baseline Week 4 Month 4 Month 8 Month 12
17. Chemoradiation and Bioradiation No direct comparison * Pignon et al, Radioth Oncol 2009: 92; 4-14 (level I evidence); ** Bonner et al. N Engl J Med 2006; 354: 567-578 (l evel II evidence); + with mono Platin therapy 50 trials, 9615 pts (MA)* 1 trial, 424 patients HR of death 0.74 (0.67-0.82) + HR of death 0.74 (0.57-0.97)** Main effect on local failure Modest effect on DM Only effect on local failure No effect on DM Efficacy irrespective of site and of fractionation schedule Effect may be site and RT schedule specific Significant acute toxicity which may inflict on late toxicity, in particular swallowing dysfunction Grade 3-4 mucositis and radiation dermatitis not signifactly increased. Late toxicity does not seem increased. High compliance.
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20. Randomized Trials of ICT in LA-HNC Revisited Trial Arms Outcome CA 139-322 (2005) PF vs PPF CCR (TTP , OS*) Resectable/nonresectable CRT (CDP) Improved with PPF EORTC 24971/TAX 323 PF vs TPF PFS (RR, OS)° Nonresectable (2007) RT Improved with TPF TAX 324 (2007) PF vs TPF OS (PFS , RR)° Resectable/nonresectable CRT (Cb) Improved with TPF GORTEC 2000-01 PF vs TPF LP (OS, DFS) + Resectable (2009) T(P)L vs RT Improved with TPF *significant only in unresectable disease (JCO); °NEJM; + JNCI
21. SCCHN: Docetaxel in Locally-Advanced Disease Overall Survival TAX 324 30% reduction in risk of death TAX 323 27% reduction in risk of death TPF PF 50 Survival Time (months) Survival Probability (%) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 0 10 20 30 40 60 70 80 90 100 TPF PF Survival Time (months) Survival Time (months) 0 6 12 18 24 30 36 42 48 54 60 66 72 Posner et al, NEJM 2007 Resectable/unresectable disease Vermorken et al, NEJM 2007 Unresectable disease
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23. EORTC 24971/TAX 323 Toxicity NCIC-CTC Grade 3-4 PF (n=179) TPF (n=173) Toxicity % % 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 5 Hearing loss 3 0 Toxic deaths 5.5 2.3 Primary prophylactic antibiotics were given per protocol for TPF Vermorken et al, N Engl J Med 2007; 357: 1695-1704
24. EORTC 24971/TAX 323 Quality of Life Analysis: QLQ-C30 Global Health Van Herpen et al, 2010, Sept 14 [Epub ahead of print] PF TPF (N=142) (N=143) Cycle 2 Least Square Mean QLQ-C30 Score [99% CI] 100 90 80 70 60 50 40 30 20 10 0 Cycle 4 6 mos. Post RT 9 mos. Post RT Least Square Mean TPF vs PF: p=0.01 CI=Confidence Interval; RT=Radiotherapy
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26. RTOG 0522: Study Objective & Design Test hypothesis that adding cetuximab to the radiation-cisplatin platform for frontline therapy of stage III-IV HNSCC improves progression-free survival (PFS) Stage III & IV* SCC of: • Oropharynx • Larynx • Hypopharynx Stratify : • Lx vs Non-Lx • N0 vs N1-2b vs N2c-3 • Zubrod PS • 3-D vs IMRT • PET (yes vs no ) Excluded T1N+, T2N1 Ang KK et al, ASCO 2011 (abstract #5500) R A N D O M I Z E 1. AFX-CB: 72 Gy/42 F/6 W + Cisplatin: 100 mg/m 2 , q3W x 2 2. AFX-CB: 72 Gy/42 F/6 W + Cisplatin: 100 mg/m 2 , q3w x 2 Cetuximab : 400 mg/m 2 x1, then 250 mg/m 2 /w
27. RTOG 0522 Progression-Free Survival & Overall Survival # Patients at Risk Hazard Ratio (95% CI) 0.87 (0.66, 1.15) P = 0.17 (log-rank, 1-sided) Primary Endpoint Ang KK et al, ASCO 2011 (abstract #5500) Progression-Free Survival (%) 0 25 50 75 100 Years after Randomization 0 1 2 3 # Patients at Risk 448 316 217 78 447 302 197 80 Hazard Ratio (95% CI) 1.05 (0.84, 1.29) P = 0.66 (log-rank, 1-sided) 2-Year Rate (95% CI) 64.3% (59.7, 68.8) Cisplatin 63.4% (58.7, 68.0) Cisplatin+Cet Overall Survival (%) 0 25 50 75 100 Years after Randomization 0 1 2 3 448 385 266 96 447 378 251 94 2-Year Rate (95% CI) 79.7% (75.9, 83.6) Cisplatin 82.6% (78.9, 86.3) Cisplatin+Cet
28. RTOG 0522 Local-Regional Relapse & Distant Metastasis Hazard Ratio (95% CI) 0.74 (0.49, 1.11) P = 0.07 (log-rank, 1-sided) Hazard Ratio (95% CI) 1.21 (0.92, 1.60) P = 0.92 (log-rank, 1-sided) Ang KK et al, ASCO 2011 (abstract #5500) Local-Regional Progression (%) 0 25 50 75 100 Years after Randomization 0 1 2 3 # Patients at Risk 448 316 217 78 447 302 197 80 Distant Metastasis (%) 0 25 50 75 100 Years after Randomization 0 1 2 3 # Patients at Risk 2-Year Rate (95% CI) 12.0% (8.9, 15.0) Cisplatin 7.6% (5.0, 10.1) Cisplatin+Cet 2-Year Rate (95% CI) 19.8% (16.1, 23.6) Cisplatin 24.5% (20.4, 28.6) Cisplatin+Cet 448 316 217 78 447 302 197 80
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30. Randomized Trials of Sequential Therapy versus Concurrent Chemoradiation Only Group Regimen TPF (or PF) x 3 CRT (cisplatin) TTCC (Sp) CRT (cisplatin) TPF x 3 CRT (carboplatin) Boston (US) CRT (cisplatin) TPF x 2 THFX Chicago (US) THFX XRT (cetuximab) TPF x 3 XRT (PF) GCTCC (It) XRT (cetuximab) XRT (PF)
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36. Differences between HPV+ and HPV- SCCHN HPV-pos HPV-neg Anatomical Tonsil, base of tongue All sites Histology Non-keratinized Keratinized Age Younger cohorts Olders cohorts Sex ratio 3:1 men 3:1 men Stage Tx, T1-2 Variable Risk factors Sexual behaviour Alcohol, tobacco Incidence Increasing Decreasing Survival Improved Unchanging Marur et al, 2010
37. Prognostic Significance of HPV RTOG 0129, PI: K. Ang Stage III & IV SCC of : • Oral cavity • Oropharynx • Larynx • Hypopharynx Stratify : • Lx vs Non-Lx • No vs N+ • KPS 60-80 VS 90-100 R A N D O M I Z E Accrued 743 patients (by 6/’05) Collected 596 tumor specimens Excluded T1-2N1 Oropharyngeal Cancer Enrolled: 433 - Specimens: 317 Ang K et al. N Engl J Med 2010;361:24-35 2. AFX-CB: 72 Gy/42 F/6 W + CDDP: 100 mg/m 2 (d 1, 22) 1. SFX: 70 Gy/35 F/7 W + CDDP: 100 mg/m 2 (d 1, 22, 43)
39. The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group. Ang K et al. N Engl J Med 2010;361:24-35
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41. Development of Chemotherapy in R/M SCCHN 1977: cisplatin shows efficacy in 1 st -line SCCHN CABO, cisplatin, methotrexate, bleomycin, vincristine *significant Clavel et al. Ann Oncol 1994; Forastiere et al. JCO 1992; Gibson et al. JCO 2005; Grose et al. Cancer Treat Rep 1985; Vermorken et al. NEJM 2008; Wittes et al. Cancer Treat Rep 1977 N Regimen ORR (%) Median OS (months) Significant OS benefit Grose et al 1985 100 Methotrexate Cisplatin 16 8 5.0 4.5 No Forastiere et al 1992 277 Cisplatin + 5-FU Carboplatin + 5-FU Methotrexate 32* 21 10 6.6 5.0 5.6 No Clavel et al 1994 382 CABO Cisplatin + 5-FU Cisplatin 34* 31* 15 7.3 7.3 7.3 No Gibson et al 2005 218 Cisplatin + 5-FU Cisplatin + paclitaxel 27 26 8.7 8.1 No Vermorken et al 2008 442 Platinum + 5-FU Platinum + 5-FU + Cetuximab 20 36* 7.4 10.1* Yes
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43. Completed Randomized Trials in First-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS (mo) OS (mo) ECOG 5397/ Burtness et al 2005 117 Cisplatin + cetuximab Cisplatin + placebo 26 a 10 4.2 2.7 9.2 8.0 EXTREME/ Vermorken et al 2008 442 PF 1 + cetuximab PF 1 36 a 20 5.6 b 3.3 10.1 c 7.4 SPECTRUM/ Vermorken et al 2010 657 PF 2 + panitumumab PF 2 36 a 25 5.8 b 4.6 11.1 9.0 PF 1 = cisplatin or carboplatin plus 5-FU; PF 2 = cisplatin plus 5-FU a, b, c : significant differences
44. Completed Randomized Trials in 2nd-Line Recurrent/Metastatic SCCHN Study/Reference N Regimen RR (%) PFS OS (mo) IMEX Stewart et al, 2009 486 Gefitinib (250 mg) Gefitinib (500 mg) Methotrexate 2.7 7.6 3.9 ND ND ND 5.6 6.0 6.7 ECOG 1302 Argiris et al, 2009 270 D + Gefitinib D + placebo 12 6 3.3 2.2 6.8 6.2 Zalute Machiels et al, 2010 286 Z + BSC (-MTX) BSC (optional MTX) 6 1 2.3* 1.9* 6.7° 5.2° BSC = best supportive care; Z = zalutumumab; MTX = methotrexate; ND = no data *HR (95% CI): 0.62 (0.47-0.83), p=0,0010; °HR (95% CI): 0.77 (0.57-1.05), p=0.0648
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Notes de l'éditeur
M225, a murine monoclonal antibody, competitively binds to the EGFR and inhibits EGFR pathways. Clinical trials using murine monoclonal antibodies have been complicated by the development of the human antimouse antibody (HAMA) immune response. The HAMA response not only carries the risk of serious allergic reactions but also increases the clearance of the murine proteins. Thus, the clinical utility of murine monoclonal antibodies has been limited. Cetuximab is a human:murine chimeric anti-EGFR IgG monoclonal antibody that binds exclusively to the EGFR. Chimeric antibodies are composed of the variable regions of murine antibody (the regions responsible for antigen binding) and the constant region of the human Fc fragment.[1] Chimeric monoclonal antibodies have demonstrated specificity and a diminished incidence of immunologic reactions.[2,3] Cetuximab binds to the EGFR with a binding affinity that is approximately one log higher than natural ligands.[4] Cetuximab prevents binding of endogenous ligands and induces receptor internalization, which ultimately blocks the activities of the EGFR pathway. Owens RJ, Young RJ. The genetic engineering of monoclonal antibodies. J Immunol Methods 1994; 168:149–165. Shitara K, Kuwana Y, Nakamura K, et al. A mouse/human chimeric anti-(ganglioside GD3) antibody with enhanced tumor activities. Cancer Immunol Immunother . 1993; 36:373–380. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A . 1989; 86:4220–4224. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res . 1995; 1:1311–1318.
Clavel M, et al. Ann Oncol 1994;5:521–526; Forastiere A, et al. J Clin Oncol 1992;10:1245–1251; Gibson MK, et al. J Clin Oncol 2005;23:3562–3567;Grose WE, et al. Cancer Treat Rep 1985;69:577–581; Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; Wittes RE, et al. Cancer Treat Rep 1977;61359–61366.
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