High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials

Abstract

Purpose: Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets.

Methods: We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.

Results: Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients.

Conclusion: Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.

Fig 1.

Study selection process. (*) Thirty patients were excluded because they received neoadjuvant therapy rather than adjuvant therapy. (†) Five patients were excluded because of a lack of cooperation after random assignment. (‡) This trial was excluded from The Cochrane Collaboration review, because the study evaluated two experimental therapies and did not include a control group receiving conventional-dose chemotherapy; also noted, patients with bony micrometastases were not excluded from the study. (§) The 2007 Journal of Clinical Oncology publication for this trial included only 536 patients. This tiral was excluded from The Cochrane Collaboration review, because it was ongoing and the data were immature. ACCOG, Anglo-Celtic Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; ECOG, Eastern Cooperative Oncology Group; GABG, German Adjuvant Breast Cancer Study Group; IBCSG, International Breast Cancer Study Group; ICCG, International Collaborative Cancer Group; JCOG, Japan Clinical Oncology Group; MCG, Michelangelo Cooperative Group; MDACC, MD Anderson Cancer Center; NKI, the Netherlands Cancer Institute; PEGASE01, Programme d'évaluation des greffes autologues dans le cancer du sein; SBG, Scandinavian Breast Group; SWOG, Southwest Oncology Group; WSG, West German Study Group.

Fig 2.

Comparison of hazard ratios (HRs) of high-dose chemotherapy (HDC) versus control (Ctrl) therapy and HRs plotted against the dose-intensity for each individual trial. For (A) overall survival (OS) and (B) relapse-free survival (RFS), the HR (solid squares) and 95% CIs (shown by whiskers on both sides of the solid squares) were derived by univariable Cox regression models (on the basis of the likelihood ratio). Adjusted HRs of death among patients on HDC versus control therapy plotted against (C) the differences in summation dose-intensity product (SDIP) between HDC and control treatment arms and (D) the differences in summation dose-intensity product (SDIP) between HDC and control treatment arms. ACCOG, Anglo-Celtic Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; ECOG, Eastern Cooperative Oncology Group; GABG, German Adjuvant Breast Cancer Study Group; IBCSG, International Breast Cancer Study Group; ICCG, International Collaborative Cancer Group; JCOG, Japan Clinical Oncology Group; MCG, Michelangelo Cooperative Group; MDACC, M.D. Anderson Cancer Center; NKI, the Netherlands Cancer Institute; PEGASE01, Programme d'évaluation des greffes autologues dans le cancer du sein; SBG, Scandinavian Breast Group; SWOG, Southwest Oncology Group; WSG, West German Study Group.

Fig 3.

Kaplan-Meier estimates of survival outcomes. Hazard ratios (HRs) are presented with 95% CIs. P values are from the log-rank test. (A) Overall survival; (B) relapse-free survival; (C) probability of survival after relapse (overall survival − relapse-free survival). Ctrl, control; HDC, high-dose chemotherapy; OS, overall survival; RFS, relapse-free survival.

Fig 4.

Kaplan-Meier estimates of overall survival (OS) comparison of high-dose chemotherapy (HDC) and control (Ctrl) therapy in prespecified subset analyses. Subsets of (A) patient age in years; (B) number of positive lymph nodes; (C) tumor size; (D) tumor histology; (E) tumor hormone receptor status (HmR); and (F) human epidermal growth factor receptor 2 status (HER2). IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma.

Fig 5.

Kaplan-Meier estimates of overall survival comparison of high-dose chemotherapy (HDC) and control (Ctrl) therapy in subsets of patients defined by hormone receptor (HmR) status and human epidermal growth factor receptor 2 (HER2) status. (A) HmR negative, HER2 negative; (B) HmR negative, HER2 positive, (C) HmR negative, HER2 either positive or negative (known); (D) HmR positive, HER2 negative; (E) HmR positive, HER2 positive; (F) HmR negative, HER2 unknown.