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C 9741

C 9741. Marc L. Citron, MD Clinical Professor of Medicine Albert Einstein College of Medicine CALGB Breast Committee. C 9741.

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C 9741

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  1. C 9741 Marc L. Citron, MDClinical Professor of MedicineAlbert Einstein College of MedicineCALGB Breast Committee

  2. C 9741 CALGB: John Carpenter, Donald Berry, Constance Cirrincione, Clifford Hudis, Eric Winer, David Hurd, James Holland, Barbara Smith, Carolyn Sartor, Eleanor Leung, Richard Schilsky, Hyman Muss, Larry Norton. ECOG: William Gradishar, Nancy Davidson. NCCTG: Edith Perez, James Ingle. SWOG: Silvana Martino, Robert Livingston. NCI: Jeffrey Abrams

  3. C 9741-CALGB 9741A Randomized Trial of Dose Dense vs. Conventionally Scheduled and Sequential vs. Concurrent Combination Chemotherapy as Post-Operative Adjuvant Treatment of Node-PositivePrimary Breast Cancer

  4. C 9741 • Dose Density: Administration of drugs with a shortened inter-treatment interval. • Sequential Therapy: Application of treatments one at a time rather than concurrently

  5. C 9741 Trial Design: Sequential ATC C 9741: • Doxorubicin reduced to 60mg/m2 • Paclitaxel reduced to 175mg/m2 • Cyclophosphamide reduced to 600mg/m2 • Based on Hudis et al.(JCO,1999. 17: 1118) Cyclophosphamide 3.0 gm/m2 Doxorubicin 90 mg/m2 Paclitaxel 250 mg/m2 9 cycles, 14 day intervals, G-CSF supported

  6. CALGB 9344 Adjuvant Study RANDOMIZE N=3,170 Node+ Statification: Premenopausal &Postmenopausal P  4 A60 C  4 A75 C  4 A90 C  4 No P A = Doxorubicin (doses shown)C = Cyclophosphamide (600 mg/m2)P = Paclitaxel (175 mg/m2 – 3 hour infusion) ER+ or PR+ patients received Tamoxifen  5 y

  7. C 9741: Trial Design (I) Sequential: A q 3 wk  T q 3 wk C q 3 wk (II) Sequential: +filgrastim A q 2 wk T q 2 wk C q 2 wk (III) Concurrent: AC q 3 wk T q 3 wk (IV) Concurrent:+ filgrastim AC q 2 wk T q 2 wk

  8. INTERGROUP C9741 q 3 wk 2X2 Factorial Design q 2 wk +Filgrastim SEQUENTIAL 24 weeksSEQ Q2 36 weeksSEQ Q3 CONCURRENT 24 weeksCON Q3 16 weeksCON Q2 doxorubicin 60 mg/m2 cyclophosphamide 600 mg/m2 paclitaxel 175 mg/m2 over 3 hours

  9. C 9741: Eligibility Criteria • Stage: T0-3, N1-2, M0 • Primary Surgery: Lumpectomy + axillary dissection or MRM with clear margins • Labs: ANC > 1000/µl platelets > 100,000/µl bilirubin = normal • Other: Normal CXR & EKG

  10. C 9741: Endpoints • Primary: Disease-free survival (DFS) Defined as date of study to Local or distant recurrence Or death without relapse • Secondary: Overall survival (OS) Toxicity

  11. C 9741: Statistics • 2 X 2 factorial design: - Dose density: 2 weeks vs. 3 weeks - Treatment: concurrent vs. sequential • Target accrual = 1584 pts in 22 mos. • First planned analysis at 3 years after complete accrual • Provided 90% power to detect a 33%reduction in hazard for either main effect

  12. C 9741: Methods • Radiation: • After completion of chemotherapy • Per institutional guidelines

  13. C 9741: Tamoxifen • Recommended 20mg per day starting within 12 weeks of completion of chemotherapy • Premenopausal patients with ER+ cancers and all postmenopausal patients irrespective of receptor status

  14. C 9741: Results • 2005 pts accrued 9/97 & 3/99 • Increased number to compensate for faster than expected accrual • 32 pts did not receive therapy • 1973 pts evaluable & analyzed

  15. First Protocol-Specified Analysis

  16. Patient Characteristics

  17. Patient Characteristics

  18. Disease-Free Survival by Density q 2 q 3

  19. Overall Survival by Density q 2 q 3

  20. Multivariate Cox Proportional Hazards Model: DFS (N=1892)

  21. Multivariate Cox Proportional Hazards Model: OS (N=1892)

  22. Estimated Annual Hazards: Q 3wk and Q 2wk

  23. Hazard Ratio: Q3wk to Q2wk

  24. Major Toxicities

  25. Secondary AML/MDS: % by year Year 9741 9344 1 0.051% 0.13% 2 0.11% 0.15% 3 0.18% 0.17% In 9741, incidence of AML/MDS does not appear to be influenced by filgrastim (slightly higher in q 3-week regimens)

  26. Dose Reductions

  27. Summary (I)36 Months Median Follow-Up • Primary Endpoint: Dose-dense treatment associated with a 26% proportional reduction in relapse (p=0.010) • 4- year DFS was 82% for dose-dense and 75% for the every three-week regimens

  28. Summary (II)36 Months Median Follow-Up • Secondary Endpoint: Dose dense treatment associated with a 31% proportional reduction in mortality (p=0.013) • 3-Year OS was 92% in the dose-dense and 90% in every 3-week regimens

  29. Summary (III) • No impact for sequentially or concurrent treatment • Grade 4 granulocytopenia (<500/µl) was more frequent on the q 3-week regimens • Toxicities were acceptable

  30. Conclusions (I) • Improved DFS and OS warrant this communication • Advantages of dose density were not accompanied by increase in toxicity • Baseline granulocyte count of 1000/µl is safe for administering chemotherapy

  31. Conclusions (II) Caveats: • Additional follow-up needed to confirm survival benefit • Maximum follow-up only 5 years & treatment-related patterns of recurrence and toxicity may emerge • Filgrastim adds cost

  32. Conclusions (III) • Results consistent with mathematical models of tumor kinetics • Mathematical concepts may be applied to other drugs and diseases

  33. Acknowledgements CALGB: John Carpenter, Donald Berry, Constance Cirrincione, Clifford Hudis, Eric Winer, David Hurd, James Holland, Barbara Smith, Carolyn Sartor, Eleanor Leung, Richard Schilsky, Hyman Muss, Larry Norton. ECOG: William Gradishar, Nancy Davidson. NCCTG: Edith Perez, James Ingle. SWOG: Silvana Martino, Robert Livingston. NCI: Jeffrey Abrams

  34. C 9741 Marc L. Citron, MDClinical Professor of MedicineAlbert Einstein College of Medicine CALGB Breast Committee

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