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Everett E. Vokes, MD Director, Section of Hematology/Oncology

Challenging Cases in Cancer: Integration of Findings from ASCO 2007 into Clinical Practice Head & Neck Cancer. Everett E. Vokes, MD Director, Section of Hematology/Oncology Vice-Chairman for Clinical Research, Department of Medicine Deputy Director, Cancer Research Center

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Everett E. Vokes, MD Director, Section of Hematology/Oncology

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  1. Challenging Cases in Cancer: Integration of Findings from ASCO 2007 into Clinical PracticeHead & Neck Cancer Everett E. Vokes, MD Director, Section of Hematology/Oncology Vice-Chairman for Clinical Research, Department of Medicine Deputy Director, Cancer Research Center John E. Ultmann Professor of Medicine, Radiation, and Cellular Oncology University of Chicago Medical Center Chicago, IL

  2. Head & Neck Cancer • 40,000 cases per year in USA • Risk factors (tobacco, alcohol, viral) • Squamous cell histology • Locoregional failure • Infrequent distant disease at presentation • Combined modality therapy goals: - Cure - Organ preservation

  3. Head & Neck Cancer • Three common clinical presentations: • Stage I/II • Stage III/IV (M0) • Resectable • Unresectable • Organ preservation goal • Stage IV (M1), recurrent

  4. Case 1Locoregionally Advanced H&N Cancer • 48-year-old male with 3-month history of throat discomfort • One month ago noted left neck mass • He has remote smoking history • Exam/bx/CTs reveal T2 N2bM0 SCCA of left tonsillar fossa • No significant co-morbidities

  5. Case 1Locoregionally Advanced H&N Cancer Which of the following treatments would you choose for this patient? • Surgical resection/ND followed by chemotherapy/XRT • Concomitant chemotherapy/XRT • Induction chemotherapy • XRT/cetuximab

  6. Case 1Locoregionally Advanced H&N Cancer Which of the following treatments would you choose for this patient? • Surgical resection/ND followed by chemotherapy/XRT • Concomitant chemotherapy/XRT • Induction chemotherapy • XRT/cetuximab Recommended Approach: • Concomitant chemotherapy/XRT

  7. Intermediate Stage H&N CancerPost-operative Therapy • Traditional therapy is surgery and/or XRT • Recent trials demonstrate efficacy of post-op CRT • Organ preservation • Novel agents

  8. Primary Surgery RANDOMIZE Post-op XRT 66 Gy / 33 f / 6.5 wks Cisplatin 100 mg/m2 d1,22,43 Post-op XRT 66 Gy / 33 f / 6.5 wks • Primary endpoint: Disease-free survival • Secondary endpoints: Acute tolerance, local control, • overall survival, late complications Post-operative ChemoXRT vs. XRT Treatment Schema

  9. XRT CT/XRT 3-year estimate 47% 61% 5-year estimate 40% 53% Hazard ratio 1 0.67 Post-operative ChemoXRT vs. XRT Overall Survival P = 0.010

  10. Patients at risk RT RT + CT 209 206 168 159 106 126 58 73 31 37 9 13 RTOG 95-01 Overall Survival RT RT + CT

  11. RANDOMIZE XRT A CDDP B XRT C CDDP 5-FU XRT Surgery INT-026: A Phase III Trial of Chemoradiotherapy in Unresectable Patients Adelstein et al: JCO, 2003; 21:92-98.

  12. CDDP/RT vs. RT P = 0.014 B C A INT-026: A Phase III Trial of Chemoradiotherapy in Unresectable Patients • Median f/u: 41 mos. • 3-year OS and median survival • RT: 23%, 12.6 mos. • CDDP/RT: 37%, 19.1 mos. Adelstein et al: JCO, 2003; 21:92-98.

  13. RTOG 9703Overall Survival Garden et al. J Clin Oncol; 22:2856-2864 2004.

  14. HPV-Associated HNSCC • HPV-16 • Oropharynx • Palatine and lingual tonsils • Poorly differentiated (basaloid) • Non-smokers, non-drinkers • Younger age • Sexual behaviors Gillison et al., J Natl Canc Inst 2000. D’souza et al., NEJM 2007.

  15. Induction Chemotherapy Concurrent Chemoradiation (CRT) R E S P O N S E R E G I S T E R R E S P O N S E 70 Gy / 35 fx / 7 weeks + Paclitaxel 30 mg/m2/wk Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV Repeat every 21 days for 2-cycles ECOG 2399 Study Design Fakhry et al. ASCO 2007. Abstract 6000.

  16. HPV Detection Results Fakhry et al. ASCO 2007. Abstract 6000.

  17. Prognostic Variables by HPV Fakhry et al. ASCO 2007. Abstract 6000.

  18. Tumor Characteristics by HPV Fakhry et al. ASCO 2007. Abstract 6000.

  19. Response Rate by Tumor HPV Status Fakhry et al. ASCO 2007. Abstract 6000.

  20. Two-year Overall Survival 95% 1.0 0.8 62% 0.6 Probability Log-rank test, P = 0.005 0.4 HPV-negative 0.2 HPV-positive 0.0 0 10 20 30 40 50 Time in Months Tumor HPV Status and Survival Fakhry et al. ASCO 2007. Abstract 6000.

  21. Two-year Progression-Free Survival 1.0 86% 0.8 53% 0.6 Probability Log-rank test, P = 0.02 0.4 HPV-negative 0.2 HPV-positive 0.0 0 10 20 30 40 50 Time in Months Tumor HPV Status and Survival Fakhry et al. ASCO 2007. Abstract 6000.

  22. Two-year Overall Survival 94% 1.0 0.8 58% 0.6 Probability 0.4 Log-rank test, P = 0.004 HPV-negative 0.2 HPV-positive 0.0 0 10 20 30 40 50 60 Time in Months Tumor HPV Status and SurvivalOropharynx Cancers Only Fakhry et al. ASCO 2007. Abstract 6000.

  23. Survival Outcomes by Tumor HPV Status Fakhry et al. ASCO 2007. Abstract 6000.

  24. HPV Conclusions • ~60% of OP-HNSCC in U.S. are HPV-positive • HPV status is associated with prognostic factors • HPV status is of prognostic significance • Explained by increased sensitivity to chemotherapy and chemo-radiation Fakhry et al. ASCO 2007. Abstract 6000.

  25. Induction Chemotherapy and Organ Preservation

  26. RANDOMIZE • Site: • Hypopharynx • AE fold Surgery/Radiotherapy PF x 3 and XRT No surgery for patients with cCR after 3-cycles EORTC Organ Preservation Study Lefebvre et al JNCI 88, 890, 1996.

  27. EORTC Organ Preservation StudySurvival Lefebvre et al JNCI 88, 890, 1996.

  28. EORTC Organ Preservation StudySurvival with Functional Larynx Lefebvre et al JNCI 88, 890, 1996.

  29. EORTC Trial Design Eligible pts were randomized between: Sequential arm (SEQ) 2 cycles CF* if PD, NC → TL ± PORT if PR, CR → 2 cycles CF* → RT 70 Gy Alternating arm (ALT) 1 cycle CF** – RT 20 Gy – 1 cycle CF** – RT 20 Gy → 1 cycle CF** – RT 20 Gy – 1 cycle CF** (RT 60 Gy) * C: 100 mg/m2 D1 + 5-FU: 1,000 mg/m2 D1-5 ** C: 20 mg/m2 D1-5 + 5-FU: 200 mg/m2 D1-5 Lefebvre et al. ASCO 2007. Abstract LBA6016.

  30. EORTC TrialRadiotherapy Lefebvre et al. ASCO 2007. Abstract LBA6016.

  31. 100 90 80 70 60 Overall Logrank test: P = 0.155 HR = 0.85 CI (0.68, 1.06) 50 40 30 20 10 0 Years 0 2 4 6 8 10 O N Number of patients at risk : Arm 160 224 105 64 28 12 Sequential 154 226 117 73 39 18 Alternating EORTC TrialSurvival with Functional Larynx Lefebvre et al. ASCO 2007. Abstract LBA6016.

  32. 100 90 80 Overall Logrank test: P = 0.446 HR = 0.91 CI (0.71, 1.16) 70 60 50 40 30 20 10 0 Years 0 2 4 6 8 10 O N Number of patients at risk : 125 224 157 97 52 20 Sequential 122 226 160 105 57 29 Alternating EORTC TrialOverall Survival Lefebvre et al. ASCO 2007. Abstract LBA6016.

  33. Conclusions • Despite a 6.7% difference in larynx function preservation rate at 3-years favoring the alternating arm • This did not translate into significant difference in survival with a functional larynx • Overall and disease free survivals were identical in both arms, around 50% and 40%,respectively, at 5-years • Alternating chemotherapy and radiotherapy, as a form of chemoradiation, did not lead to an increased incidence and severity of mucositis • There was no relevant long-term sequelae in either arm Lefebvre et al. ASCO 2007. Abstract LBA6016.

  34. XRT (70 Gy) Dx, Staging XRT (70 Gy)/Cisplatin (excluding T4) PF x 3 → XRT (70 Gy) (VA Larynx) Note: Primary Organ Preservation with surgical salvage accepted for all 3 study arms. Neck dissection included N2 and N3 disease. Larynx Intergroup Study(RTOG 91-11) Forastiere, NEJM, 2003 Forastiere et al. ASCO 2006. Abstract 5517

  35. 100 Failed / Total RT + Induction 54 / 173 RT + Concomitant 30 / 171 RT Alone 60 / 171 75 % Preserved 50 25 0 0 1 2 3 4 5 6 7 8 9 10 Years from Randomization Larynx Preservation(RTOG 91-11) Forastiere et al. ASCO 2006. Abstract 5517

  36. 100 Failed / Total RT + Induction 120 / 173 RT + Concomitant 120 / 171 RT Alone 136 / 171 / 75 / / / / / / % Alive without Disease / 50 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 25 / / / / / / / / / / / / / / / / / / / / / / / / / / 0 0 1 2 3 4 5 6 7 8 9 10 Years from Randomization Disease-Free Survival(RTOG 91-11) Forastiere et al. ASCO 2006. Abstract 5517

  37. Dead / Total RT + Induction 89 / 173 RT + Concomitant 106 / 171 RT Alone 96 / 171 100 / / / / / / / / 75 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / % Alive / 50 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 25 / / 0 0 1 2 3 4 5 6 7 8 9 10 Years from Randomization Overall Survival(RTOG 91-11) Forastiere et al. ASCO 2006. Abstract 5517

  38. Cause of Death(RTOG 91-11) Forastiere et al. ASCO 2006. Abstract 5517

  39. Larynx Preservation • Concurrent chemoradiotherapy remains the standard treatment • No role for an “alternating” approach • Induction chemotherapy is a possible alternative • Studies investigating the addition of induction to concomitant CT/X are in progress

  40. T RANDOMIZE P F EUA Surgery Daily Radiotherapy P F TAX 323: TPF vs. PF Followed by Radiotherapy A Phase III Study in Unresectable SCCHN TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 4 Remenar et al, ASCO 2006.

  41. 100 90 PF TPF Median OS 14.2 mos. 18.6 mos. 80 P = 0.0052 HR = 0.71 70 60 Survival Probability (%) 50 40 30 20 TPF (N = 177) 10 PF (N = 181) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Survival Time (months) 1 TPF: 177 163 127 91 74 64 60 43 26 16 7 Patients at Risk PF: 181 150 98 77 57 47 39 33 25 15 8 4 TAX 323: Survival Update Remenar et al, ASCO 2006.

  42. T RANDOMIZE Carboplatin - AUC 1.5 Weekly P F EUA Surgery Daily Radiotherapy P F TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3 Sequential Combined-Modality Therapy A Phase III Study: TAX 324TPF vs. PF Followed by Chemoradiotherapy Posner et al, ASCO 2006.

  43. 100 Log-rank P = 0.0058 Hazard Ratio = 0.70 90 80 70 60 50 TPF 67% PF 54% TPF 62% PF 48% 40 Survival Probability (%) 30 20 TPF (N = 255) 10 PF (N = 246) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Number of patients at risk TPF: 255 234 196 176 163 136 105 72 52 45 37 20 11 Survival Time (months) PF: 246 223 169 146 130 107 85 57 36 32 28 10 7 1 TAX 324: Survival Posner et al, ASCO 2006.

  44. Is There a Role for Induction Chemotherapy Prior to Chemoradiotherapy?

  45. Eligibility: • - Locoregionally advanced HNC • - Treatment naïve DFHX Chemoradiotherapy – 10 weeks (week on/ week off - for 5 cycles) TPF INDUCTION– 6 weeks (repeated every 21 days for 2 cycles) Off week – no treatment R A N D O M I Z E DFHX Chemoradiotherapy – 10 weeks (week on/ week off - for 5 cycles ) NO INDUCTION Off week – no treatment • Enrollment: 400 patients (200 each arm) • Primary Objective: Overall Survival DeCIDE - Phase III Induction Trial

  46. Randomized Phase II Trial Role of Induction CT in H&N CancerPaccagnella, et al. TPF → PF/X vs. PF/X • Endpoint: CR at 6-8 weeks after Rx • Enrollment goal: 96 pts. • CR rate: 19.2 vs. 46.8 (15% difference) • Endpoint met: proceed with phase III

  47. ACB T* T NR RANDOMIZE 3 Cycles of Chemotherapy P Surgery C F PR,CR Daily Radiotherapy P Q 3 Weeks Surgery XRT ACB Radiotherapy *T + ACB for Non-Responders The Paradigm StudySequential Therapy vs. ChemoradiotherapyA Phase III Study of TPF/C-XRT vs. P-ACBXRT

  48. Integration of Molecular Therapies into First-Line Regimens

  49. R A N D O I M I Z E Stratify by • Karnofsky score: • 90-100 vs. 60-80 • Regional Nodes: • Negative vs. Positive • Tumor stage: • AJCC T1-3 vs. T4 • RT fractionation: • Concomitant boost • vs. Once daily • vs. Twice daily Arm 1 Radiation therapy Arm 2 Radiation therapy + Cetuximab, weekly Wk 1: 400 mg/m2 IV no RT Wk 2-8: 250 mg/m2 followed by RT Cetuximab + RadiotherapyPhase III Study Design Bonner J, et al. NEJM, 2006.

  50. 1.0 0.9 RT + Cetuximab (54 months) RT (28 months) 0.8 0.7 0.6 Probability 0.5 P = 0.02 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Cetuximab + RadiotherapyOverall Survival Data RT=radiotherapy Bonner J, et al. NEJM, 2006.

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