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Larry Norton, M.D. Memorial Sloan-Kettering Cancer Center New York, New York

TAXOL® ( paclitaxel ) for Adjuvant Treatment of Node Positive Breast Cancer Oncologic Drug Advisory Committee Adjuvant Chemotherapy of Breast Cancer. Larry Norton, M.D. Memorial Sloan-Kettering Cancer Center New York, New York. Adjuvant Chemotherapy of Primary Breast Cancer: What We Know.

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Larry Norton, M.D. Memorial Sloan-Kettering Cancer Center New York, New York

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  1. TAXOL® (paclitaxel) for Adjuvant Treatment of Node Positive Breast CancerOncologic Drug Advisory Committee Adjuvant Chemotherapy of Breast Cancer Larry Norton, M.D. Memorial Sloan-Kettering Cancer Center New York, New York

  2. Adjuvant Chemotherapy of Primary Breast Cancer: What We Know • Chemotherapy Improves Disease-Free and Overall Survival • Polychemotherapy > Monochemotherapy • Multiple Cycles > Single Exposure • No Major Advantage to Durations > 3 Months • Anthracycline Combinations > CMF

  3. Early Breast Cancer Trialists’ Collaborative Group Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of... Comparison (N) CMF vs. Nil (8,150) CMF+ vs. Nil (3,218) Anthracyclines+ vs. CMF (6,950) Longer vs. Shorter (6,104) Recurrence +24 ± 3 +20 ± 5 +12 ± 4 +7 ± 4 Death +14 ± 4 +15 ± 5 +11 ± 5 -1 ± 5 Lancet Vol. 352, 9/98

  4. Simulation of Impact of Chemotherapy Annual Odds of Recurrence: Nil = 15%/Yr CMF = 11.4%/Yr (Reduced by 24%) AC = 10%/Yr (Reduced by 12%) 100 80 60 % Free of Recurrence 40 AC CMF 20 Nil 0 0 2 4 6 8 10 Years

  5. Adjuvant Chemotherapy of Primary Breast Cancer: What Else We Know • Adriamycin Doses < 40mg/m2 are Inferior to 60 mg/m2 (CALGB 8541) • Cyclophosphamide Doses > 600 mg/m2 are not Superior (NSABP B-22) • Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG)

  6. Early Breast Cancer Trialists’ Collaborative Group Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of... Subgroup (N) Age < 50, ER- (1398) Age < 50, ER+ (1115) Age  50, ER- (3240) Age  50, ER+ (6793) Recurrence +40 ± 7 +33 ± 8 +30 ± 5 +18 ± 4 Death +35 ± 9 +20 ± 10 +17 ± 6 +9 ± 5 Lancet Vol. 352, 9/98

  7. Adjuvant Chemotherapy of Primary Breast Cancer: How To Improve • Dose-Escalate Anthracycline? • Integrate New Agents? • Chemotherapy? • Biological Agents? • Improve Drug Scheduling? • Dose-Density, Sequential?

  8. Recently Approved New Drugs for the Treatment of (Advanced) Breast Cancer: • Paclitaxel • Docetaxel • Capecitabine • Trastuzumab

  9. Adjuvant Chemotherapy of Primary Breast Cancer: Why Paclitaxel? • Active as First Chemotherapy for Stage IV: 52-59% Response Rates (M.D. Anderson, MSKCC et al.) • Active after Extensive Prior Chemotherapy, Including Anthracycline-Resistant Disease: 22-30% Response Rates (NCI, MSKCC et al.)

  10. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months A 1&2 “Normal” Dose Intensity & Dose Escalation

  11. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months A 1&2 “Normal” Dose Intensity & Dose Escalation

  12. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months “Normal” Dose Intensity & Increased Dose Density B1&3

  13. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months “Normal” Dose Intensity & Increased Dose Density

  14. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months C4&5 Alternating Therapy is Not Dose Dense

  15. 1012 1010 108 Cell Number 106 104 102 1 0 1 2 3 4 5 6 7 Months Sequential Therapy is Dose Dense 3&6

  16. Stage II Breast Cancer with 4 Involved Axillary Lymph Nodes Doxorubicin CMF Bonadonna et al., JAMA, 1995

  17. Stage II Breast Cancer with >4 Involved Axillary Lymph Nodes % at 10 Years p = .002 Bonadonna et al., JAMA, 1995

  18. Paclitaxel 175 mg/m2 CALGB 9141 (Pilot)Node-Positive Stage II-IIIA (N=172) Cyclophosphamide 2000 mg/m2 + G-CSF Doxorubicin 75 mg/m2 130/145 (89.7%)of Patients Starting Paclitaxel Completed Rx. On Paclitaxel: 25% Grade IV Leukopenia 4% Grade IV Thrombocytopenia Demetri et al., ASCO-1997

  19. Intergroup 0148/CALGB 9344Node-Positive Stage II-IIIA Cyclophosphamide Paclitaxel 175 mg/m2 600 mg/m2 Tamoxifen forHR(+) 60 Randomize Doxorubicin mg/m2 75 No Further Chemotherapy 90 G-CSF

  20. Relationship ofCALGB 9344 (Int 0148)toCurrent U.S.Cooperative Group Trials

  21. Cyclophosphamide Paclitaxel 225 mg/m2 600 mg/m2 Doxorubicin 60 mg/m2 NSABP B-28Node-Positive Stage II-IIIA (Survival) No Further Chemotherapy Concomitant Tamoxifen x 5 Years for HR(+) or Postmenopausal (Age  50)

  22. Intergroup/CALGB 9741 Node-Positive Stage II-IIIA 3-Week Cycles 2-Week Cycles (w/ G-CSF) Doxorubicin (A) 60 mg/m2 Paclitaxel (T) 175 mg/m2 Cyclophosphamide (C) 600 mg/m2

  23. Intergroup/SWOG 4-9 LN+ Trial C T A Randomize STAMP I or STAMP V C A

  24. Intergroup/ECOG Stage II TrialHER2 (-) Paclitaxel Tamoxifen if HR(+) Cyclophosphamide 600 mg/m2 Doxorubicin 60 mg/m2 Docetaxel

  25. Integration of Biological Agent:Trastuzumab (Herceptin)

  26. Etc. NSABP Stage II TrialHER2 (+) Paclitaxel Cyclophosphamide 600 mg/m2 Tamoxifen if HR(+) Doxorubicin 60 mg/m2 Herceptin

  27. Intergroup/NCCTG Stage II TrialHER2 (+) Paclitaxel Tamoxifen if HR(+) Cyclophosphamide 600 mg/m2 52 wks Doxorubicin 60 mg/m2 52 wks Herceptin

  28. CALGB Stage IIIB Trial(HER2+) Cyclophosphamide 600 mg/m2 Paclitaxel 90 mg/m2 Surgery & RT Tamoxifen if HR(+) Doxorubicin 60 mg/m2 Herceptin for a Year or Not Dexrazoxane or Not Herceptin or Not

  29. Summary of Advantagesof This Approach • Integrates Paclitaxel • Active as a Single Agent • Active Post-Anthracycline • Minimizes Incremental Toxicity • Allows Integration of Biological Therapy

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