This systematic review and meta-analysis shows that dose-dense chemotherapy for the treatment of women with high-risk breast cancer improves both disease-free and overall survival compared with conventional chemotherapy. The dose-dense chemotherapy approach resulted in better overall survival and better disease-free survival in trials that evaluated similar doses of agents in both treatment arms but with a condensed schedule in one arm as well as in trials that compared a condensed schedule with standard one but used different agents or doses in the two arms. The results for all trials combined were statistically significant, with no statistical heterogeneity among the trials.
The other important finding of this systematic review is the paucity of randomized controlled trials with an adequate study design, that is, trials that evaluate the same agents and doses in the conventional arm as in the investigational arm. Most of the trials included in the meta-analysis did not preserve this last characteristic, which is why we classified the trials according to their design.
Two recent trials have addressed the dose-dense chemotherapy approach. The recently published Canadian MA21 trial (23
), which included three treatment arms that were anthracycline based, may provide key answers about the efficacy of the dose-dense approach with and without the use of taxane therapy. The PREPARE trial (24
), which evaluated the effect of preoperative dose-dense and dose-intensified chemotherapy with anthracycline and taxane with or without darbepoetin alfa in breast cancer patients, was not included in the meta-analysis due to lack of outcome data.
Our meta-analysis of the efficacy of dose-dense chemotherapy according to hormone receptor status revealed that hormone receptor–positive patients did not benefit from dose-dense chemotherapy. This result was based on data from the conserved dose-dense chemotherapy trials; data from the modified dose-dense chemotherapy trials were not available. Nevertheless, data from the MA21 trial further support this finding. In the MA21 trial, relapse-free survival did not differ between the treatment arms in estrogen receptor–positive patients. Restricting the use of dose-dense chemotherapy to hormone receptor–negative patients may be justified, both in terms of the costs and the potential adverse events (25
We also found that there was no increase in overall treatment-related adverse events associated with the dose-dense approach. Because a dose-dense chemotherapy schedule requires granulocyte colony-stimulating factor support, we performed an analysis of adverse events that excluded bone marrow–related events. In the conserved dose-dense chemotherapy trials, the number of nonhematological adverse events for the dose-dense chemotherapy arms was higher compared with that in the conventional chemotherapy arm. However, because of high heterogeneity among the modified dose-dense chemotherapy trials, the increase in adverse events for dose-dense vs conventional chemotherapy was not statistically significant.
The dose-dense chemotherapy approach uses prophylactic growth factor support to facilitate the safe delivery of dose-dense chemotherapy (26
). The economic burden of this issue, as well as possible unrecognized growth factor–related toxicities, such as pulmonary toxicity, should be considered (28
Several limitations of this analysis must be acknowledged. First, only three randomized controlled trials used the same agents and doses in the conventional chemotherapy arm as in the investigational (ie, dose-dense chemotherapy) arm. The fact that most of the included trials did not evaluate the same agents and dose in both arms resulted in major statistical heterogeneity among the trials. Second, the slight asymmetry of the funnel plot of the primary outcome suggests small study effects. Although results of the Egger and Begg–Mazumdar tests did not support the possibility of publication bias, the small number of included trials makes it difficult to distinguish a chance finding from true asymmetry. Also, the small number of included trials makes the outcomes more likely to have been influenced by a potential publication bias. We attempted to avoid such bias by searching for and including in our meta-analysis conference proceedings, databases of ongoing trials, and unpublished data.
Studies are needed to better define the patient population that will benefit the most from dose-dense chemotherapy. The concept of metronomic chemotherapy as evaluated, for example, by the Southwest Oncology Group (29
) is a variation of the dose-dense strategy whereby chemotherapy is administered as relatively low and minimally toxic doses at frequent and regular intervals (30
). Assessing the efficacy and feasibility of this milder chemotherapeutic approach might identify ways to integrate biological performance with the best treatment. This analysis indicates that dose-dense chemotherapy has a clear benefit for patients with hormone receptor–negative breast cancer. The lack of obvious benefit in patients with hormone receptor–positive breast cancer shown by this analysis indicates the need for further prospective randomized trials of the classical conserved design in this patient population.