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Marshall R. Posner, MD Dana-Farber Cancer Institute

New Paradigms to Improve Outcomes in Head and Neck Cancer The Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy. Marshall R. Posner, MD Dana-Farber Cancer Institute. Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities. Patient is a 56 year old male

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Marshall R. Posner, MD Dana-Farber Cancer Institute

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  1. New Paradigms to Improve Outcomes in Head and Neck CancerThe Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy Marshall R. Posner, MDDana-Farber Cancer Institute

  2. Case 1: T3N1 Supraglottic TumorNo Significant Co-Morbidities • Patient is a 56 year old male • Presents with hoarseness, left ear pain, 3 months duration, treated with antibiotics for 1 month • 40 pack-year smoking history, quit 3 years ago • Wine on weekends • Bank mortgage officer • MI with stent 3 years ago • Mild hypertension well controlled • Exam shows tumor of the left supraglottic larynx, paralyzed left vocal cord, 2.5 cm left level 2 lymph node T3N1, stage III

  3. Case 1: T3N1 Supraglottic TumorNo Significant Co-Morbidities • This patient has resectable stage III larynx cancer, good performance status, and minimal co-morbidities • Which treatment option would you recommend? • Total laryngectomy • Organ preservation – chemoradiotherapy • Organ preservation – induction chemotherapy followed by radiotherapy • Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 50%-60%

  4. Case 1 BAlternative Patients with the Same Tumor • The patient has the same presentation, but now has a heavy, active alcohol and smoking history with cirrhosis and minimal ascites • In this circumstance laryngectomy would be favored because of the underlying risk of severe toxicity from chemotherapy • The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics

  5. Case 1 BAlternative Patients with the Same Tumor • The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics • Which treatment option would you recommend? • Cetuximab plus radiotherapy • Concurrent carboplatin • Carboplatin plus cetuximab • Carboplatin plus paclitaxel plus cetuximab • Other

  6. Case 2: T3N2b Tumor of the OropharynxNo Significant Co-Morbidities • Patient is a 52 year old male • Presents with a painless right neck mass of 4 months duration • 5 pack-year smoking history, quit 30 years ago • Wine on weekends • A malpractice litigation lawyer • Exam shows tumor of the right base of tongue and a 5 cm right, cystic level 2 mass of lymph nodes • T3 n2b - stage IVA • The tumor abuts the midline of the tongue base and is not adjacent to the larynx • It is resectable with a total glossectomy and might be resectable with a partial glossectomy

  7. Case 2: T3N2b Tumor of the OropharynxNo Significant Co-Morbidities • This patient has marginally resectable stage IV oropharynx cancer, good performance status, and minimal co-morbidities • Which treatment option would you recommend? • Total or partial glossectomy (indeterminate until surgery is performed) • Organ preservation – chemoradiotherapy • Organ preservation – induction chemotherapy followed by radiotherapy • Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy

  8. Case 3: T3N3 Tumor of the HypopharynxNo Significant Co-Morbidities • Patient is a 63 year old male • Presents with hoarseness, left ear pain and a left neck mass for 2 months • 65 pack-year smoking history, quit 3 months ago • Wine on weekends • Retired malpractice attorney • Hypertension, mild COPD • Exam shows tumor of the left pyriform sinus with extension into the larynx, a paralyzed left vocal chord, and a 7.5 cm right, cystic level 2 mass of lymph nodes fixed to the neck • T3N3, stage IVB • On CT imaging the tumor surrounds the internal carotid • It is unresectable

  9. Case 3: T3N3 Tumor of the HypopharynxNo Significant Co-Morbidities • This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities • Surgery is not an option • Estimated 5 year survival is 20%-30% with radiotherapy and there is a high rate of distant metastases

  10. Case 3: T3N3 Tumor of the HypopharynxNo Significant Co-Morbidities • This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities • Which treatment option would you recommend? • Chemoradiotherapy • Induction chemotherapy, followed by radiotherapy • Sequential therapy: induction chemotherapy followed by chemoradiotherapy

  11. New Paradigms to Improve Outcomes in Head and Neck CancerThe Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy Marshall R. Posner, MDDana-Farber Cancer Institute

  12. Effects of Chemotherapy on Survival at 5 YearsFrom the Meta-Analysis Trial Category No. of Trials No. Patients Difference (%) P value All trials 65 10,850 +4 <0.0001 Adjuvant 8 1854 +1 0.74 Induction 31 5269 +2 0.10 PF 15 2487 +5 0.01 Other Chemo 16 2782 0 0.91 Concomitant 26 3727 +8 <0.0001 • Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002

  13. PF Induction Chemotherapy is Effective for Improving Survival and Organ Preservation for Locally Advanced SCCHN • Meta – Analysis • 2000, 2004, 2005 • Phase III Trials – Survival • Studio Trial 1994, 2004 • GETTEC Oropharynx Trial 2000 • Phase III Trials – Organ Preservation • VA Larynx Trial 1991 • EORTC Hypopharynx Trial 1994, 2004 • Intergroup 91-11 Trial 2003, 2006

  14. 100 80 60 Percent 40 20 0 0 1 2 3 4 5 6 7 8 Patients at risk Years No chemotherapy Chemotherapy 161 157 137 138 101 105 65 86 48 59 28 33 16 19 7 7 Overall SurvivalGETTEC Domenge C, et al. Br J Cancer. 2000;83:1594-1598.

  15. Carboplatin 70 mg/m2 /day x 4 days 5-FU 600 mg/m2/days x 4 days QD Radiotherapy 200 cGy/ Fx 1 2 3 4 5 6 7 0 Weeks Calais Chemoradiotherapy Regimen J Natl Cancer Inst. 1999;91:2081-2086.

  16. 100 CRT 80 XRT 60 Survival (%) 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Calais Chemoradiotherapy Study5-Year Survival • Conclusions: • Borderline statistically significant (P = .05) better overall survival with CRT (22% vs 16%) • Absolute 6% improvement • Better LRC (48% vs 25%), No change in DM (20%) • CRT is better then XRT alone for oropharynx cancer Denis, F et al. JCO. 2004.

  17. A XRT ± Surgery RANDOMIZE P 547 pts Stage III/IV glottic, supraglottic intermed. stage ± Surgery XRT B P C F XRT Surgery RTOG 91-11Phase III Trial of Larynx Preservation Forastiere, NEJM, 2003 Forastiere AA, et al. ASCO 2006. Abstract 5517

  18. PF CRT XRT LFS 44.6% 46.6% 33.9% P < .011 LRC 54.9%* 68.8%* 51% P < .0018 DM 14.3% 13.2% 22.3% DFS 38.6%* 39% 27.3%* P < .0016 Survival 59.2% 54.6% 53.5% RTOG 91-11:Phase III Trial of Larynx Preservation: 5-Year Update • PF was equivalent to CRT for LFS • CRT had better LRC than PF • DFS was identical but overall survival favored PF • Did patients fare better with PF because they had subtle improvements in function Forastiere AA, et al. ASCO 2006. Abstract 5517

  19. Pros High dose treatment, systemic exposure, transient toxicity Improved nutrition and PS Reduced tumor volume Better preparation for definitive radiotherapy and IMRT planning Improved function Established efficacy in resectable disease and organ preservation Improved survival Intermediate assessment of response/prognosis Adjusted intensity of post-induction therapy Cons Systemic toxicity increased Survival improvement may be site and stage related Increased duration of therapy, change in tumor biology No improvement in local/regional dose intensity Cisplatin-based PF was the only effective chemotherapy regimen Induction Chemotherapy

  20. Pros Improved local regional intensity Shortened treatment time Efficacy in unresectable disease Efficacy in organ preservation Effective post-operative therapy Cons Local toxicity increased Long-term toxicity not defined Esophageal stenosis, swallowing impaired Mortality from unrecognized toxicity Increased systemic toxicity Induction of systemic chemotherapy resistance No acceptable standard Assessment of response/prognosis compromised No effect on distant metastases in advanced disease IMRT planning difficult Chemoradiotherapy

  21. TPF Induction Chemotherapy has Proven Superior to PF in Multiple Phase III Trials • Organ Preservation • GORTEC Hypopharynx and Larynx Trial , 2006 • Locally Advanced Resectable and Unresectable • TAX 324 (2006) • Unresectable Disease • TAX 323 (2004, 2006)

  22. 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 750CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3 Calais G, et al. ASCO 2006. Abstract 5506

  23. Increase in Larynx Preservation with TPF vs PF Larynx preservation observed in 80% and 58% of patients following TPF and PF treatment, respectively (NR) Overall survival trend favors TPF over PF (P = .096) GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx Cancer Calais G, et al. ASCO 2006. Abstract 5506

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

  25. 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 Vermoken, ASCO, 2004

  26. 100 90 80 Log-Rank P = 0.0052 Hazard Ratio = 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) 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, ASCO, 2006

  27. Toxicity PF (n=179) TPF (n=174) > 3% of pts N (%) N (%) Alopecia 0 20 (11.5) Stomatitis / oral 20 (11.2) 8 (4.6) Infection 13 (7.3) 15 (8.6) Nausea 13 (7.3) 1 (0.6) Vomiting 9 (5.0) 1 (0.6) Diarrhea 8 (4.5) 5 (2.9) Dyspnea 8 (4.5) 6 (3.4) Dysphagia 5 (2.8) 6 (3.4) Pain 7 (3.9) 11 (6.3) Death 12 (6.6) 6 (3.4) TAX 323: Severe Adverse EventsChemotherapy Vermoken, ASCO, 2004

  28. Trials: TPF, TPFL5, TPFL4, op-TPFL Entered: 84* Local/Regional Failure: 26 (31%) Local/Regional and DM 5 (6%) DM only 0 An Analysis of Failure in Phase II TPF Induction Trials* Three Cycles of Induction Therapy Followed by BID Radiotherapy *Excludes 17 Patients with NPC Haddad, Cancer, 2003

  29. Trials: INT EORTC RTOG GORTEC LRF 22% 18% 16% 57% DM 23% 21% 20% 18% DM % of Failure 51% 54% 65% 32% The Rate of DM Was Not Reduced by CRT An Analysis of Failure in Phase III Chemoradiotherapy Trials* *Excludes Larynx Trial 91-11 Adelstein, JCO, 2003 Bernier, NEJM, 2005 Cooper, NEJM, 2005 Denis, JCO, 2005

  30. Induction Chemotherapy and Chemoradiotherapy in Locally Advanced SCCHN • PF induction chemotherapy results in a significant 5% (P <.01) improvement in 5-year survival in meta-analysis (Monnerat, annals of oncology, 2002) • PF was the only induction regimen that was effective, TPF is better • After induction chemotherapy and radiotherapy, failure is frequently local/regional (Haddad, cancer, 2003) • CRT results in a significant 8% (P <.0001) improvement in 5 year survival in meta-analysis (Monnerat, Annals of Oncology, 2002) • There is less local/regional failure, but relatively more distant metastases (Adelstein, JCO, 2003; Bernier, NEJM, 2005; Cooper, NEJM, 2005; Denis, JCO, 2005)

  31. Induction Chemotherapy Chemoradiotherapy Surgery Sequential Therapy for Head and Neck Cancer

  32. Sequential Therapy for Head and Neck Cancer • Induction chemotherapy • High response rates, organ preservation, improved survival, systemic treatment • Reduced tumor volume, better IMRT planning, improved functional outcome • An intermediate assessment of response • Chemoradiotherapy • Increased local/regional dose intensity • Adjustment based on response to induction therapy, potential toxicity, prognostic factors, and/or planned surgery • Surgery • Remove areas of initial bulk disease • Preserve primary site

  33. Treatment A Survival Treatment B Survival Death Chemotherapy A B 1012 1011 1010 Tumor Cell Number 109 108 107 106 Critical Time Frame Time A Cell Kinetic Model for Response and Survival:The Argument for Timing in Combined Modality Therapy Takimoto & Rowinsky, JCO, 2003

  34. Sequential Combined Modality Therapy A Phase III Study: TAX 324TPF vs PF Followed by Chemoradiotherapy 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

  35. TAX 324: Analysis Populations * ITT excludes 37 patients erroneously randomized and 1 patient with GCP compliance issue

  36. TAX 324: Patients Characteristics (ITT)

  37. TAX 324: SurvivalIntent to Treat Population *Cut-off: December 3, 2005; The median follow-up is 42 months

  38. 100 90 80 70 60 Survival Probability (%) 50 40 30 20 TPF (n=255) 10 PF (n=246) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Survival Time (months) Number of patients at risk TPF: 255 234 196 176 163 136 105 72 52 45 37 20 11 PF: 246 223 169 146 130 107 85 57 36 32 28 10 7 1 TAX 324: Survival Log-Rank P = 0.0058 Hazard Ratio = 0.70 TPF 67% PF 54% TPF 62% PF 48%

  39. 100 90 80 70 60 Progression Free Survival Probability (%) 50 40 30 20 TPF (n=255) 10 PF (n=246) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Progression-Free Survival Time (months) Number of patients at risk TPF: 255 198 150 135 121 100 73 50 39 35 26 16 5 PF: 246 183 125 104 92 72 57 38 30 25 14 8 2 TAX 324 : Progression-Free Survival Log-Rank P = 0.004 Hazard Ratio = 0.71 TPF 53% PF 42% TPF 49% PF 37%

  40. TAX 324: Toxicity During Chemotherapy

  41. TAX 324: Specific Safety During Chemotherapy Primary Prophylactic Antibiotics Were Given Per Protocol for TPF

  42. TAX 324: Delays During Induction Chemotherapy ** Logistic, Personal, Vacation

  43. TAX 324: Exposure to Induction Chemotherapy *6 Patients in each Arm received carboplatin to replace cisplatin

  44. TAX 324: Toxicity During Chemoradiotherapy

  45. TAX 324: Exposure to Study Treatment Chemoradiotherapy (CRT) Chemoradiotherapy toxicity was not enhanced by prior doxetaxel in TPF

  46. TAX 324: Analysis of Failure *Hazard Ratio 0.73 (0.54-0.99), P = .03 **Hazard Ratio 0.60 (0.30-1.18), P = .18

  47. TAX 324: Conclusions • TPF significantly improves survival compared to PF • There is a 14% absolute improvement in 3-year survival and a 30% reduction in mortality (P = 0.0058) for TPF • 62% of TPF patients are alive at 3-years • TPF significantly reduced local regional failure compared to PF • Local regional failure was reduced by 27% (P= .03) • Distant metastases were reduced 30% compared to PF (P = .18) • TPF was less toxic than PF • There were fewer treatment delays with TPF (30% vs 65%) • More of planned TPF was delivered than PF

  48. TAX 324: Conclusions • Sequential therapy with TPF is tolerable and safe • The toxicity of TPF is less than that of PF • The toxicity of chemoradiotherapy after induction chemotherapy was acceptable and within expected range • The toxicity of chemoradiotherapy was the same with TPF or PF • Sequential therapy with TPF followed by carboplatin-based chemoradiotherapy represents a new, acceptable standard of care for locally advanced SCCHN • Sequential therapy makes biological sense and is effective • Ongoing Phase III trials will determine how TPF-based sequential therapy compares to chemoradiotherapy

  49. Docetaxel plus PF (TPF) and SCCHN • TPF is the most effective combination regimen for induction chemotherapy* • TPF regimens engender less toxicity and improved survival in locally advanced SCCHN compared to PF • TPF is now the standard of care for induction chemotherapy • TPF is an appropriate platform for curative therapy to which new molecularly targeted therapies should be added *Remenar, 2006, Posner, 2006, Calais, 2006

  50. Sequential Therapy for Head & Neck Cancer • Induction chemotherapy • High response rates, organ preservation, improved survival, systemic treatment • Reduced tumor volume, better function • An intermediate assessment of response • Chemoradiotherapy • Increased local/regional dose intensity • Adjustment based on response to induction therapy/ potential toxicity/prognostic factors/planned surgery • Can chemoradiotherapy rescue non-responders to induction chemotherapy? • Surgery • Remove areas of initial bulk disease • Preserve primary site

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