August 22, 2019
Survival is significantly better for breast cancer patients who receive the full dose of adjuvant chemotherapy, particularly in the first three cycles, compared with women whose doses are reduced, report Canadian researchers.
The results were published in the August issue of the Journal of the National Comprehensive Cancer Network.
"What surprised us the most was how dramatically early reductions in chemotherapy affect survival compared to later modifications," lead author Zachary Veitch, MD, Department of Oncology, University of Calgary, Tom Baker Cancer Center, Alberta, Canada, commented in a statement.
"This became even more apparent when patients were further separated based on chemotherapy dose cutoffs," he added.
"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," Veitch commented.
An expert not involved in the study agreed. John Ward, MD, from the Huntsman Cancer Institute at the University of Utah, Salt Lake City, who is a member of the expert panel that drew up the National Comprehensive Cancer Network's clinical practice guidelines for breast cancer, commented in a statement: "Adjuvant therapy in early-stage breast cancer leads to improved survival. When chemotherapy is part of the adjuvant treatment, it is important to give the prescribed doses. This study adds further support for the need to do so."
In many cases, the dose is reduced to minimize side effects or because of comorbidities, such as kidney disease or diabetes. "Balancing side effects with efficacy is always a challenge," Ward commented.
"When a treatment is palliative, quality of life factors into dosing choices," he continued. However, "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," he said.
Chemotherapy Dose Reductions
For their study, Veitch and colleagues analyzed data from the Alberta Cancer Registry. They identified 1302 women with stage I–III HER2-negative breast cancer who were treated with an adjuvant chemotherapy regimen comprising 5-fluorouracil, epirubicin, cyclophosphamide, and docetaxel (FEC-D) during the period from 2007–2014.
Patients received at least four cycles of FEC-D, but no more than six. The total chemotherapy dose (TCD) was averaged across the treatments. A value of zero percent was assigned for any missed cycles.
The majority of the women (84%) received ≥85% of the TCD across all six cycles; 16% received reduced doses (<85% of TCD).
Women who received ≥85% of the TCD were younger than those who did not, at 54 years vs 57 years (P < .01), and were more likely to be premenopausal, at 44.5% vs 28.2% (P < .001).
They were also more likely to have a lower score on the updated Charlson comorbidity index: 84.5% had a score of 0, vs 72.8% of women who received <85% of the TCD (P < .001).
There were no significant differences between the two groups in terms of pathologic features, although there was a significant difference in tumor grade (P < .014). It is likely that the difference was driven by the fact that the women who received ≥85% of the TCD were more likely to have grade I disease, at 9.7% vs 3.5%.
As expected, women who received a larger proportion of the TCD were substantially more likely to have received six cycles of FEC-D, at 100%, vs 62.9% of those who received <85% of the TCD.
Difference in Survival
With respect to outcomes, the investigators found that the amount of chemotherapy that was received had a significant impact on survival.
The median follow-up was 59.9 months.
The analysis showed that TCD ≥85% was associated with >5-year disease-free survival (DFS), at 85.9% vs 79.2% for a lower TCD (P = .025), and better 5-year overall survival, at 88.8% vs 80.7% (P < .001).
Multivariate analysis indicated that a TCD <85% vs ≥85% was associated with significantly lower DFS, at a hazard ratio for progression of 1.45 (P = .040), and overall survival, at a hazard ratio for death of 1.50 (P = .043).
The team divided the cohort into those patients who had an early cumulative dose reduction, defined as receiving <100% of the first three FEC-D cycles, and those who received a late cumulative dose reduction, which included women who had received all of the first three cycles.
They found that outcomes were not compromised when dose reduction occurred only during the later cycles (which were the only cycles to include docetaxel). This suggests that late reductions in chemotherapy may not have as much of an impact on DFS and OS compared with early reductions, the authors comment. They note that "this finding is not completely unexpected."
Impact of Late vs Early Dose Reductions
Veitch commented that there may be several reasons for the difference in the impact of early vs late dose reductions on survival outcomes.
"First, the amount of docetaxel that was prescribed in the last three cycles may be higher than needed for the FEC-D regimen.
"Lower doses have been shown to be as effective in other standard-of-care chemotherapy regimens, and lower doses have been used in other countries with good outcomes," he said.
"Second, the majority of cancer cells that are sensitive to chemotherapy may be killed in the first few treatments, rather than in the later treatments." Hence, "reducing the dose late may not have as much of an impact," he added.
Funding for the study has not been disclosed. Coauthor Douglas A. Stewart, MD, has acted as a consultant for Apobiologix, Sandoz, and Amgen. The other authors have disclosed no relevant financial relationships.