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Sequential Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck

The Evolution of Induction Chemotherapy:. Sequential Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck. Biologic Principles, Changing Paradigms, and New Therapies. Frankfurt am Main January, 2006. Head and Neck Cancer: Morbidity of Treatment.

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Sequential Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck

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  1. The Evolution of Induction Chemotherapy: Sequential Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck Biologic Principles, Changing Paradigms, and New Therapies Frankfurt am Main January, 2006

  2. Head and Neck Cancer: Morbidity of Treatment • SCCHN Differs from Many Other Tumor Sites • The Structures of the Head and Neck are Constantly Functioning • Patients Can Spend a Year or More to Reasonable Recovery • Morbidity Can be Significant and Prolonged • Chemotherapy • Mucositis, Neutropenia, Nausea/Vomiting, Neuropathy • Radiotherapy and Chemoradiotherapy • Pain, Mucositis, Esophageal Stenosis, Muscular Dysfunction, Scarring/Fibrosis, Dry Mouth • Surgery • Impaired Swallowing, Breathing and Speech, Shoulder Dysfunction

  3. Effects of Chemotherapy on Survival at 5 Years:From the Meta-Analysis Trial Category No. of Trials No. Patients Difference(%) P value All trials 65 10850 +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.

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

  5. 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.

  6. Studio Induction Chemotherapy Trial: Overall Survival for Inoperable Patients – 10 Year Data • Conclusion • PF induction chemotherapy improves survival in patients with unresectable disease 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

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

  8. TAX 323- TPF vs PF Followed by RadiotherapyA Phase III Study in Unresectable SCCHN T RANDOMIZE P F EUA Surgery Daily Radiotherapy P F TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 4 Vermoken, ASCO, 2004

  9. PF (N=181) TPF (N=177) N (%) N (%) CR 36 (19.9) 59 (33.3) PR 70 (38.7) 69 (39.0) NC 39 (21.5) 24 (13.6) PD 13 ( 7.2) 11 ( 6.2) Not evaluable 23 (12.7) 14 ( 7.9) RRate p=0.008 58.6 % 72.3 % CRRate p=0.004 19.9 % 33.3 % Best Overall Response to Chemotherapy and Radiotherapy* * Intent-to-treat analysis Vermoken, ASCO, 2004

  10. Overall Survival 100 90 80 70 Logrank test: p=0.016 Hazard ratio 0.73 95% CI (0.57 ; 0.94) 60 50 40 30 20 10 0 (years) 0 1 2 3 4 5 O N Number of patients at risk : Randomized Arm 128 181 97 50 20 4 PF 108 177 127 59 21 1 TPF Vermoken, ASCO, 2004

  11. Severe Adverse Events: Chemotherapy Toxicity in 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) Vermoken, ASCO, 2004

  12. An Analysis of Failure in DFCI-Taxotere Induction Trials Three Cycles of Induction Therapy Followed by BID Radiotherapy TPFL5 TPFL4 opTPFL TPF Total Evaluable23 30 34 14 101 Local/Regional 4 10 10 1 25 LR/Distant Mets 1 3 1 0 5 LR SubTotal 6 13 11 1 30 Distant Mets 1 3 2 0 6 Total Failures61613136 Total DM 2 6 3 0 11 Late Relapse 2 5 1 0 8

  13. TPF/TPFL Trials Combined Overall Survival 101 Patients - Minimum 5-Year Follow-up

  14. BIOLOGICAL ASSUMPTIONS OF CHEMORADIOTHERAPY SCCHN is a Local Regional Disease • Local-Regional Control -Persistent Disease • Local-Regional Control -Recurrent Disease • Local-Regional Control -New Disease • Distant Disease

  15. BIOLOGICAL ASSUMPTIONS OF CHEMORADIOTHERAPY CHEMORADIOTHERAPY INCREASES LOCAL REGIONAL CONTROL BY INCREASING LOCAL-REGIONAL DOSE INTENSITY • Which Mechanism is Active? • Direct Anti-Tumor Activity • Radiation Sensitizing Effect • Which Mechanism is Desired? • For Local/Regional Treatment • For Systemic Treatment • How is Toxicity Effected? • Local/Regional Toxicity • SHORT TERM vs LONG TERM • Systemic Toxicity

  16. Calais Chemoradiotherapy Regimen Carboplatinum 70 mg/M2 /day x 4 days 5-FU 600 mg/M2/days x 4 days QD RADIOTHERAPY 200 cGy/ Fx Weeks 0 1 2 3 4 5 6 7 J Natl Cancer Inst. 1999;91:2081-2086.

  17. Calais Chemoradiotherapy Study: 5 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.

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

  19. INT -026 - Survival Outcomes A B C XRTP-XRTPF-SC-XRT Evaluable Patients 95 87 89 Disease Specific Survival 3 yr 34% 56%* 42% Overall Survival 3 yr 23% 37%* 27% MedianSurvival12.6 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

  20. 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 Cisplatinum-Based PF was the Only Effective Chemotherapy Regimen Pros High Dose Treatment, Systemic Exposure, Transient Toxicity Improved Nutrition and PS Reduced Tumor Volume Better Preparation for Definitive Radiotherapy, Improved Function Established Efficacy in Resectable Disease and Organ Preservation Improved Survival Intermediate Assessment of Response/Prognosis Adjusted Intensity of Post-Induction Therapy INDUCTION CHEMOTHERAPY

  21. 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 CHEMORADIOTHERAPY

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

  23. Sequential Therapy for Head and 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 • Surgery • Remove Areas of Initial Bulk Disease • Preserve Primary Site

  24. Sequential TC Induction Chemotherapy/THFX Chemoradiotherapy Paclitaxel 135 mg/M2 Weekly x 6 Carboplatinum, AUC 2 Paclitaxel 100 mg/M2 5-Fluorouracil 600 mg/M2/day x 5 Hydroxyurea 500 mg bid Radiotherapy BID Weeks 0 2 4 6 8 Vokes et al, JCO, 2003; 21:320

  25. Sequential Combined Modality Therapy forLocally Advanced Oropharynx TC Plus T Chemoradiotherapy - UP NR Surgery Taxol 30 mg/M2 Weekly Nodal Surgery Taxol 200 mg/M2 Carboplatinum AUC 6.0 G-CSF G-CSF Adjuvant CT x 2 Daily Radiotherapy Carboplatinum and Paclitaxel q3 weeks x 2 cycles Machtay, JCO 2002; 19:3964

  26. Sequential Combined Modality TherapyThe Madrid Phase III Study: Taxol-PF vs PF Followed by Chemoradiotherapy T RANDOMIZE P Cisplatinum 100 mg/M2 F Salvage Surgery Neck Surgery Daily Radiotherapy P F CR Rate: TPF 33% vs PF 14% P <.001 TPF: Paclitaxel 175D1 + Cisplatin 100D2 + 5-FU 500 CI-D2-6 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Hitt et al, JCO,2005

  27. Overall Survival – All Patients P < .03 TPF PF Hitt et al, JCO,2005

  28. Overall Survival – Resectable Patients P < .51 TPF PF Hitt et al, JCO,2005

  29. Overall Survival – Unresectable Patients P < .03 TPF PF Hitt et al, JCO,2005

  30. The Madrid Study: 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 Chemoradiotherapy Regimen Can be Improved • A Weekly Regimen Would Provide More Regional Sensitization • There Is No Provision for More Intensive Therapy for Patients with Poor Responses to Induction Therapy

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

  32. 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

  33. Taxane plus PF and SCCHN TPF is The Most Effective Combination Regimen for Induction Chemotherapy TPF Regimens Engender less Toxicity and Improve Survival in Locally Advanced SCCHN Compared to PF TPF is the Appropriate Platform for Curative Therapy to which New Molecularly Targeted Therapies Should be Added

  34. Sequential Therapy for Head and 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

  35. Carboplatinum/TaxolChemoradiotherapy Regimen Carboplatinum AUC 1.5 Weekly Taxol 45 mg/M2 Weekly QD Radiotherapy 180 cGy/ Fx Weeks 0 1 2 3 4 5 6 7 Suthralingam, IJROBP, 2000, 47:49

  36. Sequential Chemoradiotherapy:Taxotere: Phase I Schema AFTER 1-3 CYCLES of INDUCTION CHEMOTHERAPY CONCOMITTANT BOOST CHEMORADIOTHERAPY TAXOTERE 20 or 25 mg/M2/wk 7 0 1 2 3 4 5 6 WEEKS

  37. RTOG 97-03 A Randomized Phase II Trial of 3 Concurrent Regimens for Advanced SCCHN P 20 mg/M2 T 30 mg/M2 RANDOMIZE P 10 mg/M2/day 5-FU 400 mg/M2/day 5-FU 800 mg/M2/day HU 1 gm BID Garden, JCO, 2004, 22:2856

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

  39. SWOG Phase III Oropharynx TrialS0427 <50% Response T RANDOMIZE Surgery P P F Q 3 Weeks >50% Response 2 Cycles Surgery P Daily Radiotherapy Q 3 Weeks XRT Surgery Daily Radiotherapy * Cisplatinum (P); Docetaxel (D); 5-Fuorouracil (F)

  40. Proposed Phase III Sequential Trial:University of Chicago: T T 2 Cycles of Chemotherapy* RANDOMIZE 6 Cycles of Every Other Week Chemoradiotherapy* H P F F X T H 6 Cycles of Every Other Week Chemoradiotherapy* F X * Cisplatinum (P); Docetaxel (T); Hydroxyurea (H); 5-Fuorouracil (F); BID Radiotherapy (X)

  41. ECOG Phase II Sequential Therapy Study- E2303 5-7 Cycles of Chemoradiotherapy* Taxol (P) Carbo (C) Biopsy C225 (C) 6 Cycles of Weekly Induction Chemotherapy* Radiotherapy - 70 Gy SFX Biopsy at 50 Gy • Carboplatinum (C) AUC 2 ; Paclitaxel (T) 90 mg/M2 ; C225 400/250 mg/M2 weekly • Carboplatinum AUC 1; Paclitaxel 30 mg/M2; C225 250 mg/M2 ; XRT 200 cGy/day

  42. Sequential Therapy is Appropriate for Treatment of SCCHN • There is Supportive Phase II Data - Phase III Data Suggests an Advantage for TPF Regimens • Sequential Therapy Remains Experimental, but Makes Sound Biological Sense and is Reasonable Treatment for Patients with Advanced Disease • Treatment Should be Brisk - Minimal Delay Between Modalities • Treatment Breaks and Delays Reduce Local/Regional Control • When Surgery is Planned Think of Organ Preservation, Tumor Repopulation, Bulk Disease • The Short and Long Term Side Effects of Treatment Require Considerable Attention • Combined Modality Treatment Requires Careful Coordination and Communication

  43. Head and Neck Cancer - 2006 • A Considerable Fraction of Patients With Advanced Disease and Without Significant Co-Morbidities Can Now be Cured • Sequential Chemotherapy, Chemoradiotherapy, Post-Operative Chemoradiotherapy • Better Assessment of Risk Factors, Extent of Disease • New Agents to Improve Survival • Therapy is Long, Difficult and Requires Considerable Physician Care • New Agents with Reduced Toxicity • Improved Interventions During Therapy to Reduce Acute Toxicity and Improve Late Function

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