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Failure to achieve a threshold cumulative dose of adjuvant chemotherapy for early breast cancer correlated with worse survival, particularly when dose reductions occurred early in treatment, a retrospective review of 1,300 patients showed.

Patients who received less than 85% of the planned total cumulative dose (TCD) had significantly worse 5-year disease-free survival (DFS, P=0.025) and overall survival (OS, P<0.001), as compared with patients who received 85% or more of the planned TCD. Both differences persisted in univariate and multivariate analyses, reported Zachary Veitch, MD, of the University of Toronto, and colleagues.

The hazard for both DFS and OS increased by about 50% for patients who did not attain the 85% TCD threshold, they stated in the .

Focusing on use of contemporary chemotherapy regimens, the results affirmed earlier studies evaluating the relationship between TCD and outcome with older regimens.

"What surprised us the most was how dramatically early reductions in chemotherapy affect survival compared to later modifications," Veitch said in a statement. "This became even more apparent when patients were further separated based on chemotherapy dose cutoffs. Often the first cycle of chemotherapy can be difficult for patients, and oncologists must convey the need for maintaining initial dose intensity, while using other medications to control side effects and manage comorbidities."

The study adds to an existing body of literature supporting the importance of administering prescribed doses of chemotherapy, said John Ward, MD, of the University of Utah Huntsman Cancer Institute in Salt Lake City, in the statement.

"Balancing side effects with efficacy is always a challenge," said Ward, a member of the NCCN guideline panel for breast cancer. "When a treatment is palliative, quality of life factors into dosing choices. When cure is the goal, as it is with adjuvant therapy, it is important to strive to give the therapy as planned. The juice is worth the squeeze."

Adjuvant chemotherapy has been a key component of treatment for early breast cancer for decades, and by a European collaborative research group showed a 20%-25% reduction in the relative risk of breast cancer mortality in patients treated with first-generation chemotherapy regimens. Reduced TCD for first- and second-generation chemotherapy regimens led to worse survival in prospective and retrospective studies, the current authors noted.

A published almost 25 years ago established 85% as the optimal TCD for first- and second-generation chemotherapy regimens. The results required updating to reflect advances in chemotherapy regimens, the authors continued. To date, retrospective analyses yielded mixed results because of use of heterogeneous regimens, lack of adjustment for confounding factors, and inadequate follow-up.

Seeking to address limitations of prior studies, Veitch and colleagues performed a retrospective analysis of chemotherapy TCD and outcomes in early breast cancer (stage I-III), using the historical cutoff of 85%. The study included 1,302 women with hormone receptor positive/negative, HER2-negative breast cancer treated with the same chemotherapy regimen during 2007 through 2014.

Investigators limited the analysis to patients who received three cycles of adjuvant 5-FU/epirubicin/cyclophosphamide (FEC) followed by three cycles of FEC plus docetaxel (FEC-D). They examined the effects of early (FEC±D) versus late (D only) dose reductions.

The data showed that most patients received a TCD of at least 85% -- 1,100 versus 202 who received less than 85% TCD. Patients who received ≥85% were younger and more likely to be premenopausal and have fewer comorbidities.

Patients who received at least 85% TCD had a 5-year DFS of 85.9% versus 79.2% for the <85% group. By multivariate analysis, the survival difference translated into a hazard ratio of 1.45 in favor of receiving the higher TCD (P=0.040). The 5-year OS was 88.8% in patients who received at least 85% TCD versus 80.7% for whose who received less. Multivariate analysis yielded an HR of 1.50 in favor of the higher TCD (P=0.043).

Univariate analysis suggested early versus late dose reductions were associated with worse DFS, but statistical significance disappeared in a multivariate analysis. In the OS analyses, early dose reductions were associated with worse outcomes in both univariate and multivariate analyses.

The multivariate analysis of OS yielded a hazard ratio of 1.77 (P=0.011). Factors associated with hazard ratios greater than 1.5 included comorbidity score, tumor size, hormone receptor-negative status, grade 3 histology, and lymphovascular invasion.

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