Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Dose-dense chemotherapy has become a mainstay regimen in the adjuvant setting for women with high-risk breast cancer. We performed a systematic review and meta-analysis of the existing data from randomized controlled trials regarding the efficacy and toxicity of the dose-dense chemotherapy approach in nonmetastatic breast cancer.

Methods: Randomized controlled trials that compared a dose-dense chemotherapy protocol with a standard chemotherapy schedule in the neoadjuvant or adjuvant setting in adult women older than 18 years with breast cancer were identified by searching The Cochrane Cancer Network register of trials, The Cochrane Library, and LILACS and MEDLINE databases (from January 1966 to January 2010). Hazard ratios (HRs) of death and recurrence and relative risks of adverse events were estimated and pooled. All statistical tests were two-sided.

Results: Ten trials met the inclusion criteria and were classified into two categories based on trial methodology. Three trials enrolling 3337 patients compared dose-dense chemotherapy with a conventional chemotherapy schedule (similar agents). Patients who received dose-dense chemotherapy had better overall survival (HR of death = 0.84, 95% confidence interval [CI] = 0.72 to 0.98, P = .03) and better disease-free survival (HR of recurrence or death = 0.83, 95% CI = 0.73 to 0.94, P = .005) than those on the conventional schedule. No benefit was observed in patients with hormone receptor-positive tumors. Seven trials enrolling 8652 patients compared dose-dense chemotherapy with regimens that use standard intervals but with different agents and/or dosages in the treatment arms. Similar results were obtained for these trials with respect to overall survival (HR of death = 0.85, 95% CI = 0.75 to 0.96, P = .01) and disease-free survival (HR of recurrence or death = 0.81, 95% CI = 0.73 to 0.88, P < .001). The rate of nonhematological adverse events was higher in the dose-dense chemotherapy arms than in the conventional chemotherapy arms.

Conclusion: Dose-dense chemotherapy results in better overall and disease-free survival, particularly in women with hormone receptor-negative breast cancer. However, additional data from randomized controlled trials are needed before dose-dense chemotherapy can be considered as the standard of care.

Figure 1

Randomized controlled trials search and selection. pCR = pathological complete response; RFS = relapse-free survival.

Figure 2

Forest plot of hazard ratios (HRs) comparing overall survival for patients who received dose-dense chemotherapy vs those who received conventional chemotherapy in the conserved dose-dense chemotherapy trials, in the modified dose-dense chemotherapy trials, and for all trials combined. Hazard ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis fixed effect of all trials.

Figure 3

Forest plot of hazard ratios (HRs) comparing disease-free survival for patients who received dose-dense chemotherapy vs those who received conventional chemotherapy in the conserved dose-dense chemotherapy trials, in the modified dose-dense chemotherapy trials, and for all trials combined. Hazard ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represents the estimated overall effect based on the meta-analysis fixed effect of all trials. ‡EC then T (dose-dense arm) vs AC then T. §EC then T (dose-dense arm) vs CEF.

Figure 4

Forest plot of hazard ratios (HRs) comparing disease-free survival for estrogen receptor–positive and estrogen receptor–negative patients who received dose-dense chemotherapy vs those who received conventional chemotherapy in the conserved dose-dense chemotherapy trials. A) Estrogen receptor–positive patients. B) Estrogen receptor–negative patients. Hazard ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represents the estimated overall effect based on the meta-analysis fixed effect of all trials.

Figure 5

Funnel plot of overall survival in all dose-dense chemotherapy trials for the visual detection of systematic publication bias and small study effect. Each circle represents treatment effect expressed as the logarithm of the hazard ratio of overall survival in each trial plotted against standard error as a measure of study size. The diamond and the vertical line represent the pooled estimate from the meta-analysis.

Figure 6

Forest plots of relative risks (RRs) of adverse events for patients who received dose-dense chemotherapy vs those who received conventional chemotherapy in the conserved dose-dense chemotherapy trials. A) All grade 3–4 adverse events. B) Grade 3–4 adverse events except leukopenia. Relative risks for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represents the estimated overall effect based on the meta-analysis fixed effect of all trials.