High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support for Breast Cancer in North America By Karen H. Antman, Philip A. Rowlings, William P. Vaughan, Corey J. Pelz, Joseph W. Fay, Karen K. Fields, Cesar O. Freytes, Robert Peter Gale, Bruce E. Hillner, H. Kent Holland, M. John Kennedy, John P. Klein, Hillard M. Lazarus, Philip L. McCarthy, Jr, Ruben Saez, Gory Spitzer, Edward A. Stadtmauer, Stephanie F. Williams, Steven Wolff, Kathleen A. Sobocinski, James O. Armitage, and Mary M. Horowitz Purpose: To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). Patients and Methods: Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. Results: Between 1989 and 1995, autotransplants for reast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrowderived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year

PFS probabilities were 65% (95% confidence intervals [CIs], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. Conclusion: Autotransplants increasingly are used to treat reast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

From the Breast Cancer Working Committee of the Autologous Blood and Marrow Transplant Registry of North America, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; Division of Medical Oncology, Columbia University, New York, NY; Department of Vledicine, University of Alabama, Birmingham, AL; Departmentof Medicine, Baylor University Medical Center, Dallas, TX; Department of Medicine, University of South Florida, Tampa, FL; Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, TX; Division of Bone Marrow and Stem Cell Transplantation,Salick Health Care, Inc, Los Angeles, CA; Department of Medicine, Virginia Commonwealth University, Richmond, VA; Department of Medicine, Emory Clinic, Atlanta, GA; Division of Medical Oncology, Johns Hopkins Oncology Center, Baltimore, MD; Department of Biostatistics, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; Departmentof Medicine, Ireland Cancer Center, Cleveland, OH; Department of Medicine, Baylor College of Medicine, Methodist Hospital, Houston, TX; Department of Medicine, University of Oklahoma, Oklahoma City, OK; Department of Medicine, LDS Hospital, Salt Lake City, UT; Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, PA; Department of Medicine, University of Chicago Health Sciences Center, Chicago, IL; Department of Medicine, Vanderbilt University, Nashville, TN; and Department of Medicine, University of Nebraska, Omaha, NE. Submitted September 23, 1996; accepted January 31, 1997. Supported by Public Health Service grant no. POI-CA-40053 from the National Cancer Institute, the NationalInstitute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the US Department of Health and Human Services, Bethesda, MD; grant no. DAMD1 7-95-1-5002 from the Department

of the US Army Medical Research and Development Command; and grantsfrom Alpha Therapeutic Corporation;Amgen, Inc, Thousand Oaks, CA; Astra Pharmaceutical;Baxter Healthcare Corporation; Bayer Corporation; Biogen; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Company; Frank G. Brotz Family Foundation;Cancer Center, Medical College of Wisconsin; Caremark, Inc; Centeon; Centerfor Advanced Studies in Leukemia; Chiron Therapeutics, Inc; COBE BCT, Inc; Charles E. Culpeper Foundation;Eleanor Naylor Dana Charitable Trust; Eppley Foundationfor Research; Genentech, Inc; Glaxo Wellcome Company; Hoechst Marion Roussel, Inc; Immunex Corporation; Janssen Pharmaceutica;Kettering Family Foundation;Kirin Brewery Company; Robert J. Kleberg, Jr, and Helen C. Kleberg Foundation; Herbert H. Kohl Charities; Lederle Laboratories; Eli Lilly Company Foundation;Nada and Herbert P. Mahler Charities; MGI Pharma,Inc; Milstein Family Foundation;Milwaukee Foundation/Elsa Schoeneich Research Fund; Samuel Roberts Noble Foundation; Ortho Biotech Corporation;John Oster Family Foundation; Elsa U. Pardee Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; Pharmaciaand Upjohn; RGK Foundation; Sandoz Oncology; Schering-Plough International; Walter Schroeder Foundation; Searle; Stackner Family Foundation; Starr Foundation;Joan and Jack Stein Charities; and Wyeth-Ayerst Laboratories. Address reprintrequests to Karen Antman, MD, Division of Medical Oncology, MHB 6N 435, 177 Ft. Washington Ave, New York, NY 10032; Email [email protected]. © 1997 by American Society of Clinical Oncology. 0732-183X/97/1505-0028$3.00/0

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J Clin Oncol 15:1870-1879. © 1997 by American Society of Clinical Oncology.

Journalof Clinical Oncology, Vol 15, No 5 (May), 1997: pp 1870-1879

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1871

AUTOTRANSPLANTS FOR BREAST CANCER IN NORTH AMERICA

REAST CANCER is the most common cancer and the second most common cause of cancer deaths in American women.' Survival of women with breast cancer correlates with extent of disease. Ten-year survival is 65% to 80% for women with disease confined to the breast. 2 4- Ten-year survival is 35% to 65% for those with one to three involved axillary lymph nodes, 30% to 40% for those with four to nine involved axillary nodes, and 15% to 30% in those with more than nine involved axillary nodes. 57 Recurrent disease tends to develop earlier in patients with multiple involved nodes and relapse risk persists for at least 20 years after mastectomy. Women with metastatic breast cancer have a median survival rate of approximately 2 years and a 2% to 5% probability of 5-year disease-free survival.8- " Intensive therapy (high-dose chemotherapy with or without radiation therapy) with autologous hematopoietic stem-cell support (autotransplant) is increasingly used to treat breast cancer in women at high risk of persistent or recurrent disease. However, most reports of autotransplants include relatively few subjects and there are likely to be substantial reporting biases. One small randomized study of women with metastatic breast cancer shows a statistically significant advantage in both survival and disease-free survival for high-dose chemotherapy with bone marrow transplant versus conventional-dose chemotherapy.2 Here we report results of autotransplants in more

than 5,800 consecutive women receiving autotransplants at over 130 centers between 1989 and 1995. METHODS Patients The Autologous Blood and Marrow Transplant Registry of North America (ABMTR) is a voluntary organization of more than 170 transplant institutions in the United States, Canada, and Central and South America that report data on consecutive autotransplants to a Statistical Center at the Medical College of Wisconsin. An autotransplant is defined as treatment with a sufficiently high dose of chemotherapy to require autologous bone marrow or blood-derived hematopoietic stem-cell support. The Statistical Center also collects data for allogeneic blood and bone marrow transplants (allotransplants) from centers that participate in the International Bone Marrow Transplant Registry, a similar but independent organization of allotransplant centers worldwide. The ABMTR began data collection in 1992. Data were collected retrospectively for patients who received autotransplants between 1989 and 1992 and prospectively thereafter. Participating centers register basic information on consecutive autotransplants for all disease indications. Based on data collected in the Centers for Disease Control Hospital Surveys,'3 "4 approximately half of North American autotransplants for all diseases were registered with the ABMTR during the study period. A list of participating centers is shown in the Appendix. Registration data from consecutive women with breast cancer who received an autotransplant at ABMTR centers between January 1, 1989 and June 30, 1995 were the subject of this analysis. Data regarding disease type, age, sex, and posttransplant survival

were requested for all patients. Questions regarding pretransplant disease stage and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow and/or blood-derived stem cells), high-dose conditioning regimen, and posttransplant disease progression were added to registration forms more recently. Although an attempt was made to collect this information for previously registered patients, these data are not available for all patients. Patients with primary (stages 2, 3, and inflammatory) and metastatic breast cancer were considered separately in the analysis. The ABMTR requests data on progression or death in registered patients at 6-month intervals.

Statistical Methods Comparisons of patient and treatment characteristics over time 2 used x test for categorical and Kruskal-Wallis test for continuous variables.' 5 Probabilities of 100-day mortality (death in the first 100 days as a result of toxicity, disease progression, or both), progression-free survival (PFS), and overall survival were calculated using 6 the Kaplan-Meier product limit estimate. The log-rank test was used for comparisons of 100-day mortality, PFS, and survival between groups."

RESULTS

Between January 1, 1989 and June 30, 1995, 19,291 patients receiving high-dose therapy with autologous hematopoietic stem-cell support were registered with the ABMTR. Of these, 5,886 (31%) had breast cancer. Between 1989 and 1995, autotransplants for breast cancer increased from 16% to 40% (P < .00001) of all autotransplants registered (Fig 1, Table 1). Numbers of autotransplants for breast cancer exceeded those for Hodgkin disease and non-Hodgkin lymphoma after 1992. By 1993 to 1994, breast cancer was the most common indication for stem-cell transplants of all types (Fig 1). Numbers of patients reported per year, age at transplant, pretransplant disease stage, source of stem cells, and 100-day mortality are listed in Table 1. The distribution of disease stage at transplantation changed from 7% local and 93% metastatic disease in 1989 to approxi-

II

I

E O>

89-90

91-92

93-94

*Averge numberof transplntsdon yarly innnh 2y...r perid

Fig 1. Numbers of allotransplants (hematopoietic stem cells collected from a donor) and autotransplants by year by disease for most common indications.

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ANTMAN ET AL

1872 Table 1. Autotransplants for Breast Cancer Registered With the ABMTR

No. of patients Percent of all autotransplants registered Autotransplants for breast cancer No. of centers reporting Median transplants per center Range Stage immediately before high-dose chemotherapy and autotransplant No. assessable' Local disease (%) Metastatic (%) Other (%) Age, years No. assessable Median Range Interval diagnosis to transplant (years) No. assessable < 1 (%) 1-2 (%) > 2 (%) Graft type No. assessable

BM (%) BM + PBSC (%)

PBSC (%) Conditioning regimen No. assessable CBP (%)

CT (%) CTCb (%) CTM (%)

ICE (%) CTHu (%) CEP (%) Other (%) 100-day mortality No. assessable

%

1989

1990

1991

1992

1993

1994

January to June 1995

272 16

342 16

683 25

1,069 33

1,189 33

1,513 39

818 40

34 3 1-58

45 5 1-44

66 6 1-44

85 7 1-71

99 6 1-59

105 8 1-86

101 5 1-63

213 7 93 10 positive axillary lymph nodes prior to adjuvant therapy for breast cancer. Anti Cancer Drugs 6:71, 1995 (abstr) 19. Bortin MM, Rimm AA: Increasing utilization of bone marrow transplantation. II. Results of 1985-1987 survey. Transplantation 48:453-458, 1989 20. Bortin MM, Horowitz MM, Rimm AA: Increasing utilization of allogeneic bone marrow transplantation. III. Results of the 19881990 survey. Ann Intern Med 116:505-512, 1992 21. Silberman G, Crosse MG, Peterson EA, et al: Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries. N Engl J Med 331:10631067, 1994

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