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Marshall R. Posner, MD Dana-Farber Cancer Institute

New Paradigms in Head & Neck Cancer Sequential Therapy: Redefining the Role of Induction Chemotherapy. Marshall R. Posner, MD Dana-Farber Cancer Institute. Polling Question.

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Marshall R. Posner, MD Dana-Farber Cancer Institute

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  1. New Paradigms in Head & Neck CancerSequential Therapy: Redefining the Role of Induction Chemotherapy Marshall R. Posner, MDDana-Farber Cancer Institute

  2. Polling Question • In patients for whom induction chemotherapy is a viable treatment option, I treat the following proportion of patients with induction chemotherapy: • 0% (don’t use induction chemotherapy) • 1%-10% • 11%-25% • 26%-50% • 51%-75% • >75%

  3. Polling Question • The main issue(s) which limits the use of induction chemotherapy is: • Toxicity • Lack of proven benefit for locoregional tumor control and/or overall patient survival • Patient/physician preference • 1 + 2 • 1 + 3 • 2 + 3 • All of the above (1 + 2 + 3) • None (use induction chemotherapy when indicated)

  4. Polling Question • In patients for whom induction chemotherapy is a viable treatment option, my preferred induction chemotherapy regimen is: • PF (cisplatin + 5-FU) • PT (platinum + taxane) • TPF (docetaxel + cisplatin + 5-FU) • Other

  5. Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities • Patient is a 50-year old male • Presents with a painless right neck mass • 5 pack-year smoking history, quit 30 years ago • Wine on weekends • Exam shows tumor of the right base of tongue, 5 cm right, cystic level 2 mass of lymph nodes • T3N2b - stage IVa • The tumor abuts the midline of the tongue base, does not impair speech or swallowing, and is not adjacent to the larynx • It is resectable with a total glossectomy and might be resectable with a partial glossectomy

  6. Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities • This patient has resectable stage IVa oropharyngeal cancer, good PS, and minimal comorbidities • Marginally resectable for cure • Risk of swallowing and speech problems with surgery and with organ preservation • Survival 30-50% at 5 years • Intermediate risk of metastases

  7. Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities • Which treatment option would you recommend? • Surgery – total or partial glossectomy • Organ preservation – chemoradiotherapy (cisplatin + XRT) • Organ preservation – induction chemotherapy (TPF) followed by radiotherapy • Organ preservation – sequential therapy: induction chemotherapy (TPF) followed by chemoradiotherapy and then surgery as indicated

  8. Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities • Patient is a 65-year old male • Presents with hoarseness, left ear pain and a left neck mass • 65 pack-year smoking history, quit 3 months ago • Wine on weekends • Hypertension, mild COPD • Exam shows tumor of the left pyriform sinus with extension into the parapharyngeal wall, 7.5 cm left, 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. CT Image of Neck Mass

  10. Intra-Operative View of Hypopharynx Pyriform Sinus Tumor

  11. Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities • This patient has unresectable stage IVb hypopharyngeal cancer, good PS, and minimal co-morbidities • Surgery is not an option • Estimated 5-year survival is 20%-30% with chemoradiotherapy and there is a high rate of distant metastases

  12. Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities • Which treatment option would you recommend? • Chemoradiotherapy – cisplatin/carboplatin + paclitaxel, THFX • Induction chemotherapy (TPF) followed by radiotherapy • Sequential therapy – induction chemotherapy (TPF) followed by chemoradiotherapy and then surgery as indicated

  13. Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities • What is the natural history of hypopharynx cancer? • Hypopharynx cancer is more aggressive then larynx cancer or oropharyngeal cancer • Surgery entails laryngectomy in resectable disease • Estimated 5-year survival is 20%-30% with stage III/IV cancer and there is a high rate of distant metastases

  14. CT Image of Neck Mass After 3 Cycles of TPF

  15. Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities • The patient has a CR at the primary site and a PR in the neck • Which treatment option would you recommend? • Surgery – perform a total laryngectomy and neck dissection • Surgery – only perform a neck dissection • Radiation therapy • Chemoradiotherapy – bolus cisplatin • Chemoradiotherapy – weekly carboplatin • Chemoradiotherapy – weekly carboplatin and paclitaxel

  16. New Paradigms in Head & Neck CancerSequential Therapy: Redefining the Role of Induction Chemotherapy Marshall R. Posner, MDDana-Farber Cancer Institute

  17. Hear No Induction – See No InductionSpeak No Induction

  18. Effects of Chemotherapy on Survival at 5-YearsFrom the Meta-Analysis Trial CategoryNo. of TrialsNo. PatientsDifference (%)P value All trials 65 10,850 +4<0.0001 Adjuvant 8 1,854 +10.74 Induction 31 5,269 +20.10 PF 15 2,487 +50.01 Other Chemo 16 2,782 00.91 Concomitant 26 3,727 +8<0.0001 • Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002

  19. Radiotherapy No Chemotherapy RANDOMIZE STRATIFY Surgery No Surgery (-) Biopsy Nodal Surgery Surgery Radiotherapy P (-) Biopsy Nodal Surgery No Surgery F Radiotherapy 4 Cycles of Chemotherapy Chemotherapy Studio Induction Chemotherapy Trial:Phase III Study of PF Induction Chemotherapy Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272

  20. 1 28 A group B group 27 19 14 Overall survival 0.5 6 9 19 15 10 6 0 0 12 24 36 48 60 Months from randomization Studio Induction Chemotherapy Trial:Overall Survival for Operable Patients • Conclusion: post-CT surgery did not improve survival in operable patients • Surgery may risk of local-regional recurrence • Surgical Margins Inadequate • Tumor repopulation and resistance enhanced by delay to XRT • Lack of primary site preservation A group: initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118). B group: locoregional treatment alone (n=119). Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272

  21. 100 XRT 80 PF 60 Survival (%) 40 20 0 0 20 40 60 80 100 120 Months Studio Induction Chemotherapy Trial: Overall Survival for Inoperable Patients10-Year Data • Conclusion • PF induction chemotherapy improves survival in patients with unresectable disease • Improved LRC, reduced DM PF group: initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118). XRT group: locoregional treatment alone (n=119). Zorat, P. L. et al. J Natl Cancer Inst 2004

  22. Treatment A Survival Treatment B Survival 1012 Death Chemotherapy A B 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

  23. Induction Chemotherapy and Sequential Therapy – Biological Considerations • The sequence of chemotherapy CRT should be brisk and uninterrupted • Surgery delays regional therapy • Neck surgery permits growth at primary site and partial resistance • Surgery leaves an enhanced growth environment • Accelerated tumor repopulation/potential doubling times • Expanded populations with partial resistance • The choice of chemoradiotherapy regimen can be risk-based • Response • Toxicity • A weekly regimen would provide more regional sensitization • Weekly treatment may be more biologically effective and less systemically toxic then high dose pulsed therapy

  24. Biological Assumptions of Chemoradiotherapy SCCHN is a local-regional disease • Local-regional failure became the dominant concern • Local-regional control: persistent disease • Local-regional control: recurrent disease • Local-regional control: new disease • Distant disease

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

  26. 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.

  27. A Concomitant Boost XRT 70 cGy RANDOMIZE Carboplatin 70 mg/m2/day x 5 days 5-FU 600 mg/m2/day x 5 days C F B Concomitant Boost XRT 70 cGy A Phase III Trial of Chemoradiotherapy and Concomitant Boost Radiotherapy in Locally Advanced SCCHN of the Oropharynx and Hypopharynx Staar, IJROBP, 2001; 50: 1161-1171

  28. Phase III Trial of Chemoradiotherapy and Concomitant Boost Radiotherapy Boost -XRTCF-XRT Patients127 113 T4102 (80%)91 (82%) N2 + N3109 (85%)93 (82%) 5-Year Survival Oropharynx13% 26%P < .008 Hypopharynx22% 22% Distant Metastases19% 21% Mucositis > Grade 352% 68%P < .01 Esophageal Stenosis25% 50% (Survivors at 2 years) Staar , IJROBP, 2001; 50: 1161-1171. Semrau, IJROBP, 2006.

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

  30. INT-026 – Survival Outcomes AB C XRTP-XRTPF-SC-XRT Evaluable Patients 958789 Dis. Spec. Survival (3-yr)34% 56%*42% Overall Survival (3-yr)23%37%* 27% Median Survival 12.6 Mo 19.1 Mo 13.8 Mo Rate of DM 18% (30%) 22% (51%) 19% (29%) “Feeding Tube”40%52%51% * Significant Difference A vs. B Adelstein, et al: JCO, 2003; 21:92-98

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

  32. Failed / Total RT + Induction 109 / 173 RT + Concomitant 115 / 171 RT Alone 127 / 171 100 / / / 75 / / / / / / / / / / / / % Alive Without Laryngectomy / / / 50 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 25 / / / / / / / / / / / / / / / / / / / / / / 0 0 1 2 3 4 5 6 7 8 9 10 Years From Randomization RTOG 91-11 Laryngectomy-Free Survival Forastiere AA, et al. ASCO 2006. Abstract 5517

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

  34. PFCRTXRT LFS44.6%46.6%33.9% P < .011 LRC54.9%*68.8%*51% P < .0018 DM14.3%13.2%22.3% DFS38.6%*39%27.3%* P < .0016 Survival59.2%54.6%53.5% RTOG 91-11ASCO 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

  35. 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 GORTEC: 2000-01: A Phase III Trial of TPF vs. PF Followed by Radiotherapy for Organ Preservation in Resectable Larynx and Hypopharynx Cancer Calais G, et al. ASCO 2006. Abstract 5506

  36. Overall Survival 100 P (Log-rank test) = 0.096 80 60 Percent (%) 40 20 Induction TPF (n=108) Induction PF (n=112) 0 0 6 12 18 24 30 36 42 Months 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

  37. 100 Larynx Preservation P (Log-rank test) = 0.036 80 60 Percent (%) 40 Induction TPF (n=108) 20 Induction PF (n=112) 0 0 6 12 18 24 30 36 42 Months GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx Cancer Calais et al. ASCO, 2006. Oral Presentation.

  38. 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, ASCO, 2006

  39. 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

  40. 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

  41. 100 1.0 Log-Rank = 4.04; P = .04 TPF 50 0.5 20 PF 13 PF 11 9 RT 6 4 0 (ans) 0 12 24 36 48 60 72 84 96 108 120 0 1 2 3 4 5 0.0 Can TPF Improve Overall Survival? Zorat JNCI 2004

  42. 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

  43. Trials:INT EORTC RTOG GORTEC LRF22% 18% 16% 57% DM23% 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

  44. Induction Chemotherapy and Chemoradiotherapy in Locally Advanced SCCHN • PF induction chemotherapy results in a significant 5% (P <.01) improvement in 5-year survival (Monnerat, Annals of Oncology, 2002) • PF was the onlyinduction regimen that was effective • TPF is better than PF • 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)

  45. Sequential Therapy for Head & Neck Cancer • Induction chemotherapy • High response rates, organ preservation, improved survival, systemic treatment • Reduced tumor volume, 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

  46. 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

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

  48. 100 90 80 70 60 50 Survival Probability (%) 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%

  49. TAX 324: Toxicity During Chemotherapy

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

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