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Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944)

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Abstract

Purpose To describe long-term results of a multimodality strategy for stage III breast cancer utilizing neoadjuvant doxorubicin followed by mastectomy, CMF, and radiotherapy. Patients and methods Women with biopsy-proven, clinical stage III breast cancer and adequate organ function were eligible. Neoadjuvant doxorubicin (30 mg/m2 days 1–3, every 28 days for 4 cycles) was followed by mastectomy, in stable or responding patients. Sixteen weeks of postoperative CMF followed (continuous oral cyclophosphamide (2 mg/kg/day); methotrexate (0.7 mg/kg IV) and fluorouracil (12 mg/kg IV) weekly, weeks 1–8, and than biweekly, weeks 9–16). Radiation therapy followed adjuvant chemotherapy. Results Clinical response rate was 71% (79/111, 95% CI = 62–79%), with 19% complete clinical response. Pathologic complete response was 5% (95% CI = 2–11%). Median follow-up is 15.6 years. Half of the patients progressed by 2.2 years; half died by 5.4 years (range 6 months–15 years). The hazard of dying was greatest in the first 5 years after diagnosis and declined thereafter. Time to progression and overall survival were predicted by number of pathologically involved lymph nodes (TTP: HR [10 vs. 1 node] 2.40, 95% CI = 1.63–3.53, P < 0.0001; OS: HR 2.50, 95% CI = 1.74–3.58, P < 0.0001). Conclusions After multimodality treatment for locally advanced breast cancer, long-term survival was correlated with the number of pathologically positive lymph nodes, but not to clinical response. The hazard of death was highest during the first 5 years after diagnosis and declined thereafter, indicating a possible intermediate endpoint for future trials of neoadjuvant treatment.

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Acknowledgements

This research for CALGB 8944 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, Chairman), to the CALGB Statistical Center (Stephen George, PhD, CA33601) and to the Eastern Cooperative Oncology Group (Robert L. Comis, Chairman). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: (1) CALGB Statistical Center, Duke University Medical Center, Durham, NC—Stephen George, Ph.D., supported by CA33601; (2) Dana-Farber Cancer Institute, Boston, MA—Eric P. Winer, M.D., supported by CA32291; (3) Duke University Medical Center, Durham, NC—Jeffrey Crawford, M.D., supported by CA47577; (4) Eastern Maine Medical Center, Bangor, ME, Philip L. Brooks, M.D., supported by CA35406; (5) Kaiser Permanente, San Diago, CA, Joathan A. Polikoff, M.D., supported by CA45374; (6) Massachusetts General Hospital, Boston, MA—Michael L. Grossbard, M.D., supported by CA12449; (7) North Shore - Long Island Jewish Medical Center, Manhasset, NY—Daniel R Budman, M.D., supported by CA35279; (8) Rhode Island Hospital, Providence, RI—William Sikov, M.D., supported by CA08025; (9) Roswell Park Cancer Institute, Buffalo, NY—Ellis Levine, M.D., supported by CA02599; (10) Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC—James N. Atkins, M.D., supported by CA45808; (11) Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV—John Ellerton, M.D., supported by CA35421; (12) State University of New York Upstate Medical University, Syracuse, NY—Stephen L. Graziano, M.D., supported by CA21060; (13) Syracuse Hematology-Oncology Association CCOP, Syracuse, NY, Stephen L Graziano, M.D., supported by CA21060; (14) University of Alabama Birmingham, Birmingham, AL—Robert Diasio, M.D., supported by CA47545; (15) University of Chicago, Chicago, IL—Gini Fleming, M.D., supported by CA41287; (16) University of Maryland Greenebaum Cancer Center, Baltimore, MD—Martin Edelman, M.D., supported by CA31983; (17) University of Massachusetts Medical School, Worcester, MA—William V. Walsh, M.D., supported by CA37135; (18) University of Minnesota, Minneapolis, MN—Bruce A Peterson, M.D., supported by CA16450; (19) University of Missouri/Ellis Fischel Cancer Center, Columbia, MO—Michael C Perry, M.D., supported by CA12046; (20) University of California at San Diego, San Diego, CA—Joanne Mortimer, M.D., supported by CA11789; (21) University of Tennessee Memphis, Memphis, TN—Harvey B. Niell, M.D., supported by CA47555; (22) Wake Forest University School of Medicine, Winston-Salem, NC—David D Hurd, M.D., supported by CA03927; (23) Walter Reed Army Medical Center, Washington, DC—Thomas Reid, M.D., supported by CA26806; (24) Washington University School of Medicine, St. Louis, MO—Nancy Bartlett, M.D., supported by CA77440; and (25) Weill Medical College of Cornell University, New York, NY—Scott Wadler, M.D., supported by CA07968.

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Authors and Affiliations

  1. Duke University Medical Center, Trent Drive, Suite 3800, Duke South, P.O. Box 3204, Durham, NC, 27710, USA

    G. G. Kimmick

  2. CALGB Statistical Center, Duke University Medical Center, Durham, NC, USA

    C. Cirrincione

  3. SUNY Upstate Medical University, Syracuse, NY, USA

    D. B. Duggan & S. Lemke

  4. H. Lee Moffitt Cancer Center, Tampa, USA

    K. Bhalla

  5. Inova Fairfax Hospital Institute of Research, Falls Church, VA, USA

    N. Robert

  6. Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA

    D. Berry

  7. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    L. Norton & C. Hudis

  8. University of California San Francisco, San Francisco, CA, USA

    I. C. Henderson

  9. Dana Farber Cancer Institute, Boston, MA, USA

    E. Winer

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  1. G. G. Kimmick
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  2. C. Cirrincione
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  9. I. C. Henderson
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On Behalf of the Cancer and Leukemia Group B

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Correspondence to G. G. Kimmick.

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Memorial Sloan Kettering Cancer Center, New York, NY—L. Norton, supported by CA77651.

University of California San Francisco, San Francisco, CA—I. C. Henderson, supported by CA60138.

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Kimmick, G.G., Cirrincione, C., Duggan, D.B. et al. Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944). Breast Cancer Res Treat 113, 479–490 (2009). https://doi.org/10.1007/s10549-008-9943-2

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