High-Dose Chemotherapy and Breast Cancer
Authors: William J. Gradishar
Journal: JAMA (1999)

THE RAPID TRANSFER OF MEDICAL TECHNOLOGY FROM academic research institutions into the medical community at large is perhaps not better exemplified than with the widespread use of high-dose chemotherapy (HDC) and peripheral blood stem cell transplantation (PBSCT) as treatments for breast cancer during the late 1980s and the 1990s. With better supportive care measures, particularly use of hematopoietic growth factors, morbidity and mortality due to HDC administration dramatically declined, and the length of hospital stays needed for patients to recover from treatment effects decreased significantly. Peripheral blood stem cells proved to be more reliable and “patient-friendly” in ensuring engraftment, compared with autologous bone marrow. Subsequent data from pilot or feasibility trials in patients with metastatic disease showed that HDC-PBSCT improved tumor response rates compared with conventional-dose chemotherapy. Many medical oncologists, patients, and advocates were quick to assume that HDC-PBSCT was superior to other therapies used to treat metastatic breast cancer. Unfortunately, several fundamental questions regarding HDC-PBSCT as a breast cancer treatment were inadequately addressed by small pilot studies before the treatment was widely adopted in the community. One such question is: “What are the characteristics of a patient with metastatic breast cancer who is most likely to benefit from HDC-PBSCT?” In this issue of THE JOURNAL, Rowlings and colleagues, on behalf of the Autologous Blood and Marrow Transplant Registry (ABMTR), present an analysis of data from 1188 patients with advanced breast cancer; these data were voluntarily submitted from 63 institutions in the United States, Canada, South America, and Russia. Although this was not a prospective study, and several large academic programs did not contribute to the registry, the ABMTR is an important data set. One of the most frequent criticisms of HDCPBSCT clinical trials is that their small size prevents any definitive conclusions from being made. The ABMTR report is impressive because of the number of patients involved and the long-term follow-up of the patients. In the ABMTR study, benefit was assessed in terms of analyzing patient-, disease-, and treatment-related characteristics in relation to the clinical end point of time to treatment failure from the time of HDC-PBSCT. Many of the factors that predicted an increased risk of HDC-PBSCT treatment failure are similar to factors that predict a poor outcome with standard-dose, non– marrow-ablative chemotherapy: a suboptimal performance status, a hormone receptor–negative tumor, prior adjuvant therapy, significant visceral or central nervous system involvement by metastases, and multiorgan involvement. Similar surveys of conventional chemotherapy regimens among patients with metastatic disease suggest that patients with a complete clinical response have a better survival rate than those with a partial clinical response. The ABMTR report reaffirms that patients with poor clinical features and/or tumors with aggressive biological features tend to have poorer outcomes following treatment with HDCPBSCT compared with patients receiving the same treatment but who possess more favorable clinical features. Another question is whether HDC-PBSCT offers any advantage compared with standard-dose chemotherapy to patients with metastatic disease. Although data from HDC-PBSCT pilot trials have been compared with those from historical controls (eg, patients treated with standard-dose chemotherapy), few data were available from prospective, randomized clinical trials comparing the 2 treatment approaches. A randomized clinical trial reported by Bezwoda and colleagues from South Africa demonstrated a higher tumor response rate (95% vs 53%) and improved median survival (90 weeks vs 45 weeks) with 2 courses of HDCPBSCT vs standard-dose chemotherapy. However, critics have cited the trial’s relatively small size (45 patients per treatment group), lower than expected tumor response rate for those receiving standard-dose chemotherapy, and greater number of patients in the HDC group who received tamoxifen as possible reasons for the better outcome seen in those receiving HDC.