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Statements Head and Neck Cancer 2008 Perspectives

Statements Head and Neck Cancer 2008 Perspectives. Jan B. Vermorken, MD, PhD University Hospital Antwerp Edegem, Belgium. Goals in Head & Neck SCC Management. Purpose: removal cancer load, maintenance of QoL, prevention of subsequent primaries 1 Choice based on:

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Statements Head and Neck Cancer 2008 Perspectives

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  1. Statements Head and Neck Cancer 2008Perspectives Jan B. Vermorken, MD, PhD University Hospital Antwerp Edegem, Belgium

  2. Goals in Head & Neck SCC Management Purpose: removal cancer load, maintenance of QoL, prevention of subsequent primaries1 Choice based on: • High LRC and survival rates in limited disease • Increased survival in advanced disease (LRC, DM, SP) • Increased organ-function preservation in resectable and unresectable disease • Increased therapeutic ratio (cure/toxicity ratio) Corvò, 2007 (1Shah & Lydiatt, 1995)

  3. Treatment of Head and Neck CancerMultidisciplinary HN surgeon Radiation oncologist Medical oncologist Anesthesiol. Internist Decision making Radiologist Patient Guidelines Clinical trials

  4. EBM for Treatment in Early Stage SCCHN Selection treatment modality (ERT vs BT vs S) based on: • Primary tumor site • Age • Comorbidity • Occupation, preference and compliance • Quality of life following the treatment • Availability of expertise in RT or surgery • History of a previous malignant lesion in the H&N Corvò R, 2007

  5. EBM for Treatment in Locoregionally Advanced SCCHN Strategy Trial Strength Local of Design endpoint evidence Accelerated RT RCT A 1 Hyperfractionated RT RCT A 1 Concomitant CRT (unresectable dis) RCT A 1 Concomitant CRT (resectable dis) RCT C 1 Concomitant CRT (adjuvant) RCT A 1 Induction CT  RT (CF) RCT B 2 Induction CT  CRT non-R D 3 Radiosensitizer – RT DB-RCT B 1 Targeted therapy – RT RCT A 2 A = total mortality; B = cause – specific mortality; C = carefully assessed QoL; D = indirect surrogated (Corvò R, 2007)

  6. Patients with measurable locally advanced SCCHN (stratified by KPS;node+/0;T1-3/4; RT regimen) Randomization RT once or twice daily or concomitant boost for 7 – 8 weeks RT as before + ERBITUX initial 400 mg/m2 2-h infusion then 250 mg/m21-h infusion weekly for at least 7 doses Follow-up until disease progression or up to 5 years Cetuximab + RT in locally advanced SCCHN: Study design Bonner et al. N Eng J Med 2006;354:567-578

  7. The Cetuximab/Radiotherapy Phase III Trial Radiotherapy BioRadiotherapy P-value (n=213) (n=211) Toxicity* Mucositis 52% 56% Acneiform rash 1% 17% < .001 Radiation dermatitis 18% 23% Infusion reactions NA 3% (Late Peg dependency 17% 19% ) Efficacy 3-Yr Survival 45% 55% .03 2-yr PFS 37% 46% .006 2-Yr LRC 41% 50% .005 2- Yr DM 17% 16% Bonner, NEJM 2006 (*Grade 3-5)

  8. CRT vs RT: Median Survival

  9. Probability of Severe Toxicity with Different Altered fractionation Schedules and Concomitant (Bio)Chemoradiation Severe Toxicity Acc.RT HF.RT *RS.RT CRT °Targeted.RT Epidermitis ++ + + + + Mucositis +++ ++ ++ +++ + Hematologic tox. - - - +++ + Systemic side-effects - - + +++ ++ Acneiform rash - - + - +++ Xerostomia 2-D technique ++ ++ ++ ++ ++ Xerostomia 3-D RT/IMRT + + + + + Late mucosa atrophy + + + ++ + Fibrosis + + + + + *RS = radiosensitizer (mimorazole); ° Cetuximab

  10. Impact of Age on Treatment Effect in LA-HNCBourhis et al (Abstract # 5501) Alt-RT vs Standard RT Concomitant CT + RT vs RT Age # HR p Trend # HR p Trend patients (95% CI) Test patients (95% CI) Test 50 or less 1,311 0.78 (0.65; 0.94) 0.007 2,584 0.76 (0.66; 0.86) 0.003 51-60 2,300 0.95 (0.83; 1.09) 3,306 0.78 (0.70; 0.87) 61-70 2,346 0.92 (0.81; 1.06) 2,698 0.88 (0.78; 1.00) 71+ 1,085 1.08 (0.89; 1.30) 692 0.97 (0.76; 1.23)

  11. Analysis of Failures in Phase III CRT Trials

  12. EBM for Treatment in Locally Advanced SCCHN Strategy Trial Strength Local of Design endpoint evidence Accelerated RT RCT A 1 Hyperfractionated RT RCT A 1 Concomitant CRT (unresectable dis) RCT A 1 Concomitant CRT (resectable dis) RCT C 1 Concomitant CRT (adjuvant) RCT A 1 Induction CT  RT (CF) RCT B 2 Induction CT  CRT non-R D 3 Radiosensitizer – RT DB-RCT B 1 Targeted therapy – RT RCT A 2 A = total mortality; B = cause – specific mortality; C = carefully assessed Qol; D = indirect surrogated (Corvò R, 2007)

  13. EORTC 24971/TAX 323Study design R A N D O M I Z E • N = 358 • Unresectable SCCHN • Stratification by: • Institution • Primary site (neck dissection) Surgery? TPF x 4 q 3 wks Radiation CF, AF, or HF Follow PF x 4 q 3 wks (neck dissection) Planned Sample Size: 348 pts Number of events: 260 progression events needed to show 50% increase in PFS (10 to 15 months; Hazard ratio 0.67) Vermorken et al, NEJM 2007

  14. Overall Survival Vermorken et al, NEJM 2007 (median FUP 32,5 months)

  15. Sequential Combined Modality TherapyA Phase III Study: TAX 324TPF vs PF Followed by Chemoradiotherapy T RANDOMIZE Carboplatinum - AUC 1.5 Weekly P F EUA Surgery Daily Radiotherapy P F TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

  16. Posner et al, NEJM 2007

  17. GORTEC:2000-01: A Phase III Trial of TPF vs PF Followed by Radiotherapy for Organ Preservation in Resectable Larynx and Hypopharynx Cancer T RANDOMIZE P Surgery F No Response Response P F Daily Radiotherapy: STD or ACB TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x 3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Calais, ASCO, 2006

  18. Abstract 5506: The GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx 100 80 60 Percent (%) 40 20 0 0 6 12 18 24 30 36 42 Larynx Preservation (Months) P (Log-rank test) = 0.036 Induction TPF (n=108) Induction PF (n=112) Calais et al. ASCO, 2006. Oral Presentation.

  19. 3. Signal transduction pathways Ras, raf, MAPK, MEK, ERK, AKT protein kinase C, PI3K 1. Growth factors and growth-factor receptors HER family, c-kit/SCFR 1 3 2 2. Extracellular matrix/ angiogenic pathwaysVEGFR, integrins, MMPs 4 4. Cell-survival pathways Cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2 5 5. Protein productionProteasome Targets for Next-generation Therapy Tumor cell Nucleus

  20. EXTREME:Study design Randomized Group A Either cisplatin (100 mg/m2 IV, d1) Or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m2 IV, d1-4): 3-week cycles + cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly Group B Either cisplatin (100 mg/m2 IV, d1) Or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m2 IV, d1-4): 3-week cycles 6 chemotherapy cycles maximum Cetuximab Notreatment Progressive disease or unacceptable toxicity

  21. EXTREME: Overall Survival 1.0 | | | | | CTX only CTX + CET 0.9 | | | | 0.8 HR (95%CI): 0.797 (0.644, 0.986) | | | Strat. log-rank test: 0.0362 0.7 | 0.6 10.1 months Survival probability 0.5 7.4 months | 0.4 | | | | | 0.3 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.2 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.1 0.0 0 3 6 9 12 15 18 21 24 Survival time (months) Patients at risk CTX only 220 173 127 83 65 47 19 8 1 CTX + CET 222 184 153 118 82 57 30 15 3 10.1 months 7.4 months

  22. EXTREME:Progression-Free Survival (PFS) 1.0 | | | | | | | | | | | | | | | | | | CTX only CTX + CET 0.9 | | | 0.8 HR (95%CI): 0.538 (0.431, 0.672) | | | Strat. log-rank test: <.0001 | | | | | 0.7 | 0.6 | | Progression free (%) | 0.5 | | | 0.4 | | 0.3 0.2 0.1 0.0 0 3 6 9 12 15 PFS time (months) Patients at risk CTX only 220 103 29 8 3 1 CTX + CET 222 138 72 29 12 7 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 5.6 months 3.3 months | | | | | | | | | | | | | | | | | |

  23. Global Health Status/QoL Social Functioning 100 80 60 40 20 0 -20 100 80 60 40 20 0 -20 Cet/CTX CTX Cet/CTX CTX 95% Confidence Interval for difference in treatment groups 95% Confidence Interval for difference in treatment groups Baseline (n=109) (n=94) Cycle 3 (n=80) (n=63) 6 months (n=45) (n=20) Baseline (n=111) (n=96) Cycle 3 (n=80) (n=64) 6 months (n=44) (n=21) Cet/CTX CTX Cet/CTX CTX Pain Scores Swallowing Scores 100 80 60 40 20 0 -20 100 80 60 40 20 0 -20 Cet/CTX CTX Cet/CTX CTX 95% Confidence Interval for difference in treatment groups 95% Confidence Interval for difference in treatment groups Baseline (n=112) (n=95) Cycle 3 (n=80) (n=63) 6 months (n=45) (n=21) Baseline (n=111) (n=94) Cycle 3 (n=79) (n=60) 6 months (n=44) (n=20) Cet/CTX CTX Cet/CTX CTX EXTREME: Quality of Lifea a<50% of patients completed a baseline questionnaire

  24. Conclusions • Multidisciplinary decision making is essential • A better selection of patients groups for specific therapeutic approaches need to be obtained • The optimal approach to larynx preservation has still not been decided on, despite the fact that concomitant chemoradiation is used mostly • Targeted therapies are promising both in locally advanced settings and in recurrent/metastatic SCCHN

  25. What is missing? • A direct comparison of concomitant chemoradiation vs bioradiotherapy: • Efficacy • Toxicity (late) • QoL • Combination of induction chemotherapy followed by a form of local treatment which is inducing less late toxicity • A direct comparison of surgical vs non-surgical approaches

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