Reducing Adjuvant Chemotherapy Dose Too Early May Impact Breast Cancer Survival

Early dose reductions in the adjuvant chemotherapy combination of 5-fluorouracil, epirubicin, cyclophosphamide, and docetaxel (FEC-D) negatively impacted survival rates for patients with intermediate- or high-risk breast cancer, according to a study published this month in JNCCN—Journal of the National Comprehensive Cancer Network. Dose reduction can be related to toxicities, such as febrile neutropenia, and may be related to dose delays with the secondary use of granulocyte colony-stimulating factor therapies like filgrastim and pegfilgrastim.

In the study, effects were seen most often when dose reductions happened early in treatment, but they appeared to not affect survival if reductions came later in treatment.

The study used data from 1302 women with stage 1 to stage 3 HER2-negative breast cancer in the Alberta Cancer Registry (ACR) in Alberta, Canada. Patients were treated with adjuvant FEC-D chemotherapy between 2007 and 2014, receiving at least 4 cycles of FEC-D, but no more than 6. The total dose was averaged across the treatments, with a value of 0% assigned for any missed cycles.

Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis, and cohorts were evaluated for uniformity.

The researchers found that 16% (n = 202) of the patients received less than 85% of the total recommended dose (TCD) relative to 85% or greater (n = 1100, 84%). That group of patients had inferior 5-year disease-free survival (79.2% vs 85.9%) and inferior overall survival (80.7% vs 88.8%) compared with those who received higher cumulative doses.

Patients who received TCD at 85% or greater relative to less than 85% had superior 5-year DFS (P = .025) and OS (P <.001).

The group who received the lower dose were then split into 2 groups so that researchers could examine the effects of dose reduction during cycles 1 to 3 versus cycles 4 to 6; the later cycles are the only ones to include docetaxel. Outcomes were not affected when dose reduction occurred only during the later cycles.

In the late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P = .002 and P <.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P = .073, and HR, 1.77; P = .011, respectively).

Dose delays of fewer than 14 or 14 days or more and granulocyte colony-stimulating factor use did not affect outcomes.

The authors said the study shows that physicians should attempt to maintain full doses of chemotherapy, especially early in treatment, saying the results show that even with the addition of taxanes, keeping total chemotherapy dose 85% or greater is important for maintaining clinical benefit.

“What surprised us the most was how dramatically early reductions in chemotherapy affect survival compared to later modifications,” said Zachary Veitch, MSc, MD, FRCPC, Department of Oncology, University of Calgary, Tom Baker Cancer Centre, in a statement. “This became even more apparent when patients were further separated based on chemotherapy dose cut-offs. Early dose reductions can be related to age, weight, or the number of other medical issues a patient has, such as kidney disease or diabetes, among other factors. 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 said the amount of docetaxel prescribed in the last 3 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.

In addition, he added that reducing the dose late may not have as much of an impact because the majority of cancer cells that are sensitive to chemotherapy may be killed in the first few treatments, rather than in the later treatments.

Reference

Veitch Z, Khan OF, Tilley D, et al. Impact of cumulative chemotherapy dose on survival with adjuvant FEC-D chemotherapy for breast cancer. J Natl Compr Canc Netw. 2019;17(8):957-967. doi: 10.6004/jnccn.2019.7286.