High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials

Abstract

Purpose: High doses of effective chemotherapy are compelling if they can be delivered safely. Substantial interest in supporting high-dose chemotherapy with bone marrow or autologous hematopoietic stem-cell transplantation in the 1980s and 1990s led to the initiation of randomized trials to evaluate its effect in the treatment of metastatic breast cancer.

Methods: We identified six randomized trials in metastatic breast cancer that evaluated high doses of chemotherapy with transplant support versus a control regimen without stem-cell support. We assembled a single database containing individual patient information from these trials. The primary analysis of overall survival was a log-rank test comparing high dose versus control. We also used Cox proportional hazards regression, adjusting for known covariates. We addressed potential treatment differences within subsets of patients.

Results: The effect of high-dose chemotherapy on overall survival was not statistically different (median, 2.16 v 2.02 years; P = .08). A statistically significant advantage in progression-free survival (median, 0.91 v 0.69 years) did not translate into survival benefit. Subset analyses found little evidence that there are groups of patients who might benefit from high-dose chemotherapy with hematopoietic support.

Conclusion: Overall survival of patients with metastatic breast cancer in the six randomized trials was not significantly improved by high-dose chemotherapy; any benefit from high doses was small. No identifiable subset of patients seems to benefit from high-dose chemotherapy.

Fig 1.

Study selection process. BBCRG, Berlin Breast Cancer Research Group; ECOG, Eastern Cooperative Oncology Group; HDC, high-dose chemotherapy; IBDIS, International Randomized Breast Cancer Dose Intensity Study; NCIC, National Cancer Institute of Canada; PEGASE, Programme d'évaluation des greffes autologues dans le cancer du sein.

Fig 2.

Survival by trial. (A) Kaplan-Meier estimates of overall survival (OS) by trial. Hazard ratios (HRs) are presented with 95% CIs. P values are from the log-rank test. (B) Adjusted HRs of OS and progression-free survival (PFS) for high-dose chemotherapy (HDC) and control therapy (Ctrl) versus differences in maximum dose-intensity (MDI). BBCRG, Berlin Breast Cancer Research Group; ECOG, Eastern Cooperative Oncology Group; IBDIS, International Randomized Breast Cancer Dose Intensity Study; NCIC, National Cancer Institute of Canada; PEGASE, Programme d'évaluation des greffes autologues dans le cancer du sein.

Fig 2.

Survival by trial. (A) Kaplan-Meier estimates of overall survival (OS) by trial. Hazard ratios (HRs) are presented with 95% CIs. P values are from the log-rank test. (B) Adjusted HRs of OS and progression-free survival (PFS) for high-dose chemotherapy (HDC) and control therapy (Ctrl) versus differences in maximum dose-intensity (MDI). BBCRG, Berlin Breast Cancer Research Group; ECOG, Eastern Cooperative Oncology Group; IBDIS, International Randomized Breast Cancer Dose Intensity Study; NCIC, National Cancer Institute of Canada; PEGASE, Programme d'évaluation des greffes autologues dans le cancer du sein.

Fig 3.

Kaplan-Meier estimates of survival outcomes based on data from all six trials. (A) Overall survival (OS); (B) progression-free survival (PFS); (C) survival postprogression (SPP). Hazard ratios (HRs) are presented with 95% CIs. P values are from the log-rank test. Ctrl, control therapy; HDC, high-dose chemotherapy.

Fig 4.

Kaplan-Meier estimates of the overall survival (OS) comparison of patients with metastatic breast cancer who received high-dose chemotherapy (HDC) versus control therapy (Ctrl) in subset analyses. (A) Age younger than 50 years; (B) age 50 years or older; (C) premenopausal; (D) postmenopausal; (E) soft tissue metastasis; (F) no soft tissue metastasis; (G) hormone positive; (H) hormone negative; (I) one metastatic site; (J) two or more metastatic sites; (K) bone-only metastasis; (L) lung-only metastasis.