Dose-Intense Chemotherapy Considerations in Early Breast Cancer

Adjuvant chemotherapy with an anthracycline and a taxane became a standard of care in early breast cancer based on reduced risk of breast cancer mortality by a third, when compared to no chemotherapy. Several trials have since examined strategies to further improve outcomes with more dose-intense chemotherapy regimens, either by giving chemotherapy more frequently or by giving the two chemotherapies sequentially rather than concurrently. A recently published meta-analysis of Early Breast Cancer Trialists’ Group (EBCTCG) evaluated outcomes from 37,298 patients included in 26 clinical trials (from 1985 to 2011) that compared either 2-weekly chemotherapy (dose dense) to standard 3-weekly chemotherapy or sequential versus concurrent chemotherapy administration.

Among all patients across the 26 trials with a median follow-up of 7.4 years, those receiving an intensified chemotherapy dose had significantly better outcomes compared to those receiving standard dose. Dose-intense chemotherapy was associated with a 3.4% absolute reduction in the 10-year risk of breast cancer recurrence (28.0% vs 31.4%; RR 0.86, P<.0001), a 2.4% absolute reduction in the 10-year risk of breast cancer mortality (18.9% vs 21.3%; RR 0.87, P<.0001), and 2.7% reduction of all-cause mortality (.1% vs 24.8%; RR 0.87, P<.0001). The risk reductions were similar in trials that compared 2-weekly dose-dense chemotherapy to standard 3-weekly chemotherapy, in trials of sequential vs concurrent anthracyclines and taxane regimens, and in trials exploring both shorter intervals and sequential administration.  Improved outcomes with dose-intense chemotherapy regimens were similar in patients, regardless of estrogen receptor (ER) expression status and other patient characteristics. Of note, most patients included in the study were younger than 70 years and had node-positive disease, and only about 50% had determined human epidermal growth factor receptor 2 (HER2) status.

The investigators concluded that dose-intense chemotherapy regimens are more effective than standard chemotherapy regimens at reducing the risk of breast cancer recurrence without increasing other causes of death, and that a dose-intense chemotherapy regimen should be considered in patients with early breast cancer who are candidates for adjuvant chemotherapy. In an accompanying editorial, Sara Hurvitz, MD (University of California, Los Angeles, California, United States), commented that, while these results are meaningful for high-risk patients for whom anthracyclines are warranted, the limitations of this analysis should be taken into consideration in treatment decision making for patients with node-negative disease, HER2-positive disease, and the elderly. She highlighted advances in molecular subtyping and use of gene expression profiling for risk assessment in patients with ER-positive, node-negative breast cancer to identify women that could be spared chemotherapy. She also noted that the benefits of intensified chemotherapy were evaluated prior to the era of HER2-targeted adjuvant therapy, which is now standard of care in patients with HER2-positive breast cancer and may include HER2-targeted agents beyond trastuzumab. Finally, she questioned the benefit of dose intense chemotherapy in patients over the age of 70, where more toxic regimens could be potentially harmful. She concluded her commentary by saying, “as chemotherapy continues to evolve and new targeted therapies enter the curative scene, prospective studies will be warranted to validate the dose-dense approach in these settings.”

Lancet. 2019 Feb 7 [Epub ahead of print].

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