J.B. Vermorken - Head and neck - State of the art

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  • 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.
  • J.B. Vermorken - Head and neck - State of the art

    1. 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
    2. 2. <ul><li>5-6% of all cancers (about 650.000 new cases/year) </li></ul><ul><li>> 90% squamous cell origin (Western world) </li></ul><ul><li>Risk factors: </li></ul><ul><ul><li>tobacco smoking </li></ul></ul><ul><ul><li>alcohol use </li></ul></ul><ul><ul><li>betel chewing </li></ul></ul><ul><ul><li>HPV </li></ul></ul><ul><li>Localized disease 40%, regional mets 50% distant mets 10% </li></ul><ul><li>2/3 locally/regionally advanced </li></ul><ul><li>Major threat: local recurrence, SPT, SFT </li></ul>Head and Neck Cancer Epidemiology, risk factors and presentation
    3. 3. HN Surgeon Radiation Oncologist Medical Oncologist Anesthesiologist Internist GP Radiologist Social worker Psychologist Patient Guidelines Clinical trials Biologist Pathologist Dietician Speech Therapist
    4. 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)?
    5. 5. Treatment Modalities in SCCHN 2011 <ul><li>Surgery as single modality </li></ul><ul><li>Radiotherapy (RT) or in combination </li></ul><ul><li>Chemotherapy (CT) </li></ul><ul><ul><li>combined modality treatment (CMT): </li></ul></ul><ul><ul><li>Induction CT (ICT); concomitant CT and RT (CCRT); sequential therapy (ICT  CCRT); adjuvant CCRT postoperative </li></ul></ul><ul><ul><li>Palliative therapy </li></ul></ul><ul><li>Targeted therapy (TT) </li></ul><ul><ul><li>Alone or combined with RT, CMT or palliative CT </li></ul></ul>
    6. 6. Results of Present Therapies <ul><li>Early stages (I and II)  single modality TRT </li></ul><ul><li> 5-yr S: 60-90% </li></ul><ul><li>Advanced stages (III and IV)  combined modality </li></ul><ul><li> 5-yr S: < 35% </li></ul><ul><ul><li>Resectable: > 60% LRR, 20% DM, 10-40% SPT </li></ul></ul><ul><ul><li>Unresectable: 5-yr S < 20%, majority † < 18 months </li></ul></ul><ul><li>Recurrent/metastatic disease  chemotherapy </li></ul><ul><li>Median survival 6-12 months, 1-year survival 20-40% </li></ul>
    7. 7. New Findings in Recent Years <ul><li>HPV is a risk factor for cancer of the oropharynx </li></ul><ul><li>Therapeutic agents against molecular targets (EGFR) </li></ul><ul><li>Expanded role of chemotherapy (IC, CCRT) </li></ul><ul><li>Improved irradiation techniques (IMRT) </li></ul><ul><li>New imaging techniques (PET) </li></ul><ul><li>Survivorship issues </li></ul><ul><li>Haddad RI, Shin DM N Engl J Med 2008; 359: 1143-54 </li></ul>
    8. 8. Treatment of Locoregionally Advanced SCCHN <ul><li>Historically: Surgery ( + RT) or RT alone </li></ul><ul><li>Outcomes poor for OS and OP </li></ul><ul><li>Currently there are three multimodality treatment approaches: </li></ul><ul><li>Surgery  adjuvant concurrent CRT </li></ul><ul><li>Definitive concurrent CRT, with surgery as an optional salvage or completion treatment </li></ul><ul><li>Induction CT  definitive local therapy </li></ul><ul><li>Seiwert et al, 2007; OS = overall survival; OP = organ preservation </li></ul>
    9. 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. 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
    11. 11. How to proceed? <ul><li>Explore options to reduce toxicity </li></ul><ul><li>- in terms of RT techniques </li></ul><ul><li>- in terms of targets for response and sensitization </li></ul><ul><li>Explore concepts that have more impact on distant mets </li></ul><ul><li>Study the relevance of ICT and the further integration of targeted therapies </li></ul><ul><li>Make a better selection of patients who might need less and who might need more treatment </li></ul>
    12. 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)
    13. 13. Cetuximab: Properties and Mechanism of Action <ul><li>IgG 1 monoclonal antibody </li></ul><ul><li>Specifically binds to the EGFR with higher affinity than its natural ligands (TGFα, EGF), thus competitively inhibiting their binding </li></ul><ul><li>H igh affinity: K d = 0.39 nM </li></ul><ul><li>Induces apoptosis and ADCC1 </li></ul><ul><li>Preclinical synergistic activity in combination with chemotherapy and radiotherapy </li></ul>ADCC = antibody-dependent cellular cytotoxicity
    14. 14. Bonner et al. N Engl J Med 2006; 354: 567-578
    15. 15. The Cetuximab/Radiotherapy Phase III Trial <ul><li>Radiotherapy BioRadiotherapy P-value </li></ul><ul><li> (n=213) (n=211) </li></ul><ul><li>Toxicity * </li></ul><ul><li>Mucositis 52% 56% </li></ul><ul><li>Acneiform rash 1% 17% < .001 </li></ul><ul><li>Radiation dermatitis 18% 23% </li></ul><ul><li>Infusion reactions NA 3% </li></ul><ul><li>(Late Peg dependency 17% 19% ) </li></ul><ul><li>Efficacy </li></ul><ul><li>3-Yr Survival* 45% 55% .03 </li></ul><ul><li>2-yr PFS 37% 46% .006 </li></ul><ul><li>2-Yr LRC 41% 50% .005 </li></ul><ul><li>2- Yr DM 17% 16% </li></ul><ul><li>Bonner, NEJM 2006 (*Grade 3-5); * 5-yr survival 36% vs 46% (p=0.02) </li></ul>
    16. 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. 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.
    18. 18. How to proceed? <ul><li>Explore options to reduce toxicity </li></ul><ul><li>- in terms of RT techniques </li></ul><ul><li>- in terms of targets for response and sensitization </li></ul><ul><li>Explore concepts that have more impact on distant mets </li></ul><ul><li>Study the relevance of ICT and the further integration of targeted therapies </li></ul><ul><li>Make a better selection of patients who might need less and who might need more treatment </li></ul>
    19. 19. Rationale for Induction Chemotherapy (ICT) <ul><li>Optimal drug delivery: high response rates: transient toxicity </li></ul><ul><li>Improves nutritional status and performance status </li></ul><ul><li>Has an established efficacy in organ preservation strategies </li></ul><ul><li>No compromise of subsequent RT or surgery </li></ul><ul><li>Response to ICT predicts response to RT </li></ul><ul><li>Is an early systemic treatment of occult disease </li></ul><ul><li>Improves survival (MACH-NC): ICT with PF in 15 trials (2487 pts) leads to 5% increase in 5-yr survival (p=0.01) </li></ul>
    20. 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. 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
    22. 22. EORTC 24971/TAX 323 Chemotherapy regimens <ul><li>Standard arm (PF) </li></ul><ul><ul><li>Cisplatin 100 mg/m², day 1 </li></ul></ul><ul><ul><li>5-FU 1000 mg/m²/day, day 1 to 5 </li></ul></ul><ul><li>Experimental arm (TPF) </li></ul><ul><ul><li>Docetaxel 75 mg/m², day 1 </li></ul></ul><ul><ul><li>Cisplatin 75 mg/m², day 1 </li></ul></ul><ul><ul><li>5-FU 750 mg/m²/day, day 1 to 5 </li></ul></ul><ul><li>Premedication: dexamethasone 8 mg bid (3 days) </li></ul><ul><li>ciprofloxacin 500 mg bid (d5-15) </li></ul>Vermorken et al, N Engl J Med 2007; 357: 1695-1704
    23. 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. 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
    25. 25. Questions Raised after Bioradiation and TPF Studies (1) <ul><li>Is Bioradiation (BRT)  concurrent Chemoradiation (CRT)? </li></ul><ul><ul><li>panitumumab + AF-RT vs cisplatin + SF-RT (NCT00820248) </li></ul></ul><ul><ul><li>zalutumumab + RT vs cisplatin+RT (NCT00496652) </li></ul></ul><ul><li>Will EGFR inhibition enhance the effect of CRT? </li></ul><ul><ul><li>cetuximab + CDDP + AF-RT vs CDDP + AF-RT (RTOG 0522) </li></ul></ul><ul><ul><li>panitumumab + CRT vs CRT postop (EORTC 22071-24071) </li></ul></ul><ul><ul><li>panitumumab + CCDP + SF-RT vs CDDP + SF-RT (NCT00500760) </li></ul></ul><ul><ul><li>erlotinib + CRT vs CRT (NCT00410826) </li></ul></ul><ul><ul><li>lapatinib + CRT vs CRT (NCT00387127) </li></ul></ul>
    26. 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. 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. 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
    29. 29. Questions Raised after Bioradiation and TPF Studies (2) <ul><li>Is TPF induction followed by RT ≥ CRT? </li></ul><ul><li>Is TPF induction followed by CRT > CRT? </li></ul><ul><li>Can EGFR inhibition be used in the post-induction setting, thereby reducing toxicity in sequential design? </li></ul><ul><li>Can EGFR inhibition be combined with ICT? </li></ul><ul><li>Can we be more selective in the choice of HNC treatment? </li></ul>
    30. 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)
    31. 31. The Randomized Phase II Study: TREMPLIN <ul><li>Previously untreated SCC larynx/hypopharynx suitable for TL </li></ul><ul><li>Primary endpoint : larynx preservation 3 months after treatment </li></ul><ul><li>Secondary endpoints : larynx function preservation and survival 18 months after treatment </li></ul>Total laryngectomy + postop RT RT 70 Gy Cisplatin 100 mg/m² on days 1, 22 and 43 RT 70 Gy Cetuximab 400 mg/m² 1 wk prior to RT then 250 mg/m² weekly on wks 1 to 7 TPF 3 cycles, 1 cycle q3weeks T = 75 mg/m² on day 1 P = 75 mg/m² on day 1 5-FU = 750 mg/m² on day 1 to 5 Response evaluation by endoscopy and CT scan R <PR Lefebvre et al for GORTEC and GETTEC groups (abstract #6010) 5-fluorouracil, T=docetaxel TL=total laryngectomy, PR=partial response, RT=radiation therapy, CT=computed tomography ≥ PR
    32. 32. Compliance to treatment <ul><li>Radiotherapy Cisplatin arm (n=60) Cetuximab arm (n=56) </li></ul><ul><li>Not done 2 0 </li></ul><ul><li>Mean dose 69 (24**-74) 69.5 (56-76) </li></ul><ul><li>No of cycles: 7 - 40 (71%) </li></ul><ul><li>6 - 4 </li></ul><ul><li>5 - 4 </li></ul><ul><li>4 - 1 </li></ul><ul><li>3 26 (43%) 1 </li></ul><ul><li>2 24 2 </li></ul><ul><li>1 8 2 </li></ul><ul><li>0 2* 3*** </li></ul><ul><li>*1refusal and 1 rapid evolution, **another rapid evoluation, ***3 infusion-related reactions </li></ul><ul><li>Lefebvre et al, ASCO 2011 (abstract #5501) </li></ul>
    33. 33. Acute Toxicity <ul><li> CDDP arm (n=58*) CET arm (n=56) p-value </li></ul><ul><li>Grade 3 mucositis 25 (43%) 24(43%) NS </li></ul><ul><li>Grade 4 mucositis 2 1 </li></ul><ul><li>Grade 3 infield skin tox. 14 (24%) 29 (52%) <0.001 </li></ul><ul><li>Grade 4 infield skin tox. 1 3 </li></ul><ul><li>Other tox. Justifying dose </li></ul><ul><li>modification </li></ul><ul><li>- renal 9 (15.5%) 0 </li></ul><ul><li>- hematologic 8 (14.0) 0 </li></ul><ul><li>- poor general condition 7 (12.0%) 1 (1.7%) </li></ul><ul><li>- infusion –related react. 0 3 (5.0%) </li></ul><ul><li>- Protocol modifications** 33 (57%) 19 (29%) 0.02 </li></ul><ul><li>* 2 patients did not start; ** due to acute toxicity. Lefebvre et al, ASCO 2011 (abstract #5501) </li></ul>
    34. 34. Assesment of Failures (Intent to Treat) * Data missing for 1 patient lost to follow-up at 5 months Lefebvre et al, ASCO 2011 (abstract #5501) At 18 months after end of treatment cisplatin arm cetuximab arm p value Total of local (+/- regional) failures 5 (8.3 %) 8 (14.3 %) Log-rank: 0.30 <ul><ul><ul><li>Feasible salvage </li></ul></ul></ul><ul><ul><ul><li>total laryngectomy </li></ul></ul></ul>0/4* 7/8 0.01 <ul><ul><ul><li>Successful salvage </li></ul></ul></ul><ul><ul><ul><li>total laryngectomy </li></ul></ul></ul><ul><ul><li>Ultimate local failure rate </li></ul></ul>Regional failure alone 5 (8.3 %) 5 (8.9 %) NS Distant metastases Second primary tumor Last evaluation with a median follow-up of 36 months cisplatin arm cetuximab arm p value 7 (11.7 %) 12 (21.4 %) Log-rank: 0.14 1/6* 9/12 (1 refused) 0.04 0/1 7/8 6 (10 %)* 5 (8.9 %) NS 5 (8.3 %) 5 (8.9 %) NS 2 (3.3 %) 2 (3.6 %) NS 3 (5 %) 3 (5.3 %) NS
    35. 35. <ul><li>Incidence increasing for HPV-related </li></ul><ul><li>Incidence decreasing for HPV-unrelated </li></ul><ul><li>Equalization in 2004 </li></ul>Incidence Trends in the US Chaturvedi et al, J Clin Oncol 2008; 26: 612-619
    36. 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. 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)
    38. 38. Prognostic Significance of HPV Overall Survival Ang K et al. N Engl J Med 2010;361:24-35
    39. 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
    40. 40. Recurrent and/or metastatic SCCHN: Background <ul><li>Over 50% of newly diagnosed cases are not cured and will relapse locally or at distant sites </li></ul><ul><li>10% of newly diagnosed cases present with distant metastases </li></ul><ul><li>Treatment options: - Chemotherapy (CT) - Re-irradiation - Salvage surgery - Best supportive care (BSC) </li></ul><ul><li>Cisplatin-based CT: - Response rate: 30% - Overall survival: 6 – 9 months </li></ul>
    41. 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
    42. 42. The Role of Cetuximab in First-Line R/M - SCCHN <ul><li>Adding cetuximab to platinum/5-fluorouracil: </li></ul><ul><ul><li>significantly improves overall survival 1 </li></ul></ul><ul><ul><li>significantly increases PFS 1 </li></ul></ul><ul><ul><li>almost doubles the response rate 1 </li></ul></ul><ul><ul><li>is feasible with an acceptable side-effect profile 1 </li></ul></ul><ul><ul><li>significantly reduces pain and swallowing problems 2 </li></ul></ul><ul><ul><li>has no negative effect on quality of life 2 </li></ul></ul><ul><li>First regimen to show survival benefit in 30 years </li></ul><ul><li>Is a new standard regiment for R/M-SCCHN 3,4 </li></ul><ul><li>1 Vermorken et al, N Engl J Med 2008; 359: 1116-1127 </li></ul><ul><li>2 Mesia et al, Ann Oncol 2010 (doi 10,1093/annonc/mdq077) </li></ul><ul><li>3 Gregoire et al, Ann Oncol 2010; 21 Suppl 5: v184-6 </li></ul><ul><li>4 Petrelli et al, J Clin Oncol 2009; 27: 6052-6069 </li></ul>
    43. 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. 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
    45. 45. Other Novel Targeted Agents in SCCHN <ul><li>Anti-angiogenesis </li></ul><ul><ul><li>VEGF </li></ul></ul><ul><ul><li>VEGFR </li></ul></ul><ul><li>Integrin inhibitors </li></ul><ul><li>Histone deacetylase inhibitors </li></ul><ul><li>SRC inhibitors </li></ul><ul><li>Proteasome inhibitors </li></ul><ul><li>IGFR inhibitors </li></ul><ul><li>No phase III data! </li></ul>
    46. 46. Conclusions (1) <ul><li>Concurrent chemoradiation (CRT) has a very solid background and is still used for many advanced H&N tumors </li></ul><ul><li>CDDP 100 mg/m² 3x during RT most optimal CRT?? </li></ul><ul><li>Is bioradiation similar to CRT? </li></ul><ul><li>TPF is a more active and less toxic new standard for induction and its sequential use with CRT and BRT are presently tested </li></ul><ul><li>There is a tendency to a more personalized treatment, with selection based on risk considerations, HPV status and biomarkers </li></ul>
    47. 47. Conclusions (2) <ul><li>In R/M SCCHN the PFE regimen is a new standard. Regimens with higher efficacy (and less toxicity) are urgently needed. </li></ul><ul><li>A plethora of new targeted therapies are in various stages of preclinical and clinical development: how to integrate the active ones is an important goal. </li></ul>

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