Eleven RCTs were included (12,722 participants, range 150 to 3114) and 10 of these were suitable for pooling: three conserved dose-dense chemotherapy (3,337 participants) and seven modified dose-dense chemotherapy (8,652 participants). Three RCTs were considered to have an adequate study design (all conserved dose-intensity).
Conserved dose-dense chemotherapy was associated with significantly better overall and disease-free survival than standard chemotherapy (HR for death 0.84, 95% CI 0.72 to 0.98, I2=0%; three RCTs and HR for relapse/death 0.83, 95% CI 0.73 to 0.94, I2=0%; three RCTs). In subgroup analysis by receptor status, improved disease-free survival in the dose-dense group applied only to receptor-negative women (HR 0.71, 0.56 to 0.89, I2=0%; two RCTs).
Modified dose-dense chemotherapy was associated with significantly better overall and disease-free survival than standard chemotherapy (HR for death 0.85, 95% CI 0.75 to 0.96, I2=15.5%; six RCTs and HR for relapse/death 0.81, 95% CI 0.73 to 0.88, I2=53.9%; seven RCTs). Findings for survival were similar when all RCTs were pooled, with no significant heterogeneity.
There was slight asymmetry in the funnel plot, but the Begg and Egger tests showed no significant evidence of publication bias.
The overall rate of adverse events did not differ significantly between the groups. When bone marrow toxicity was excluded, adverse events were significantly more common with conserved dose-dense chemotherapy than with standard therapy (RR 1.13, 95% CI 0.91 to 1.39, I2=0%) and findings in the modified dose-dense RCTs were inconclusive, with high heterogeneity (I2=95.8%).