SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has shown a 20-25% relative risk reduction in breast cancer mortality with first-generation adjuvant chemotherapy regimens such as CMF (Cyclophosphamide/Methotrexate/Fluorouracil) and additional survival benefit with the Anthracyclines and Taxane based regimens.
Chemotherapy dose reductions are often considered for patients with obesity, BSA of more than 2.0 m2, age over 65 years, comorbidities such as kidney disease or diabetes, and febrile neutropenia. ASCO guidelines recommend full weight-based chemotherapy doses in the treatment of obese patients. Dose reductions to less than 85% of the optimal (total cumulative) chemotherapy dose (mg/m2) and cycle delay have shown inferior survival outcomes in both prospective and some retrospective studies. However, it is unclear if dose reductions made for third-generation Anthracycline/Taxane-based regimens as well as sequential regimens such as Taxanes following Anthracycline based regimens, has an impact on survival.
The authors therefore performed a retrospective analysis to evaluate the effect of Total Cumulative Dose (TCD) of adjuvant chemotherapy, on breast cancer outcomes, in women diagnosed with Stage I-III, Hormone Receptor positive or negative, HER2-negative breast cancer, treated with adjuvant FEC (5-FU 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) for 3 cycles followed by Docetaxel 100 mg/m2 for 3 cycles (FEC-D chemotherapy regimen) from 2007 through 2014. Using the historical cutoff of 85% as the optimal Total Cumulative Dose (TCD), this study focused on data from the Alberta Cancer Registry on 1,302 women with Stage I to III breast cancer.
The TCD for cycles 1-6 of less than 85% or 85% and more was calculated. The majority of patients (84%) received 85% or more of the TCD across all six cycles. Sixteen percent (16%) received reduced doses (less than 85% of TCD). Those receiving a TCD of 85% or more were more likely to be younger (median age of 54 yrs) and premenopausal, with a lower number of comorbidities, compared with those with a TCD of less than 85%. The average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy, to explore the effects of early (FEC) versus late (Docetaxel only) dose reduction. The median follow up was 60 months.
It was noted that the amount of chemotherapy delivered had a significant impact on survival. Patients receiving a TCD of 85% or more had a 5-year Disease Free Survival (DFS) of 85.9% versus 79.2% for those receiving a lower TCD (P=0.025). The 5-year Overall Survival (OS) was also superior at 88.8% versus 80.7% (P<0.001), respectively. When the researchers split the lower TCD group into two cohorts based on dose reduction during cycles 1-3 versus cycles 4-6, they found that outcomes were not compromised when dose reduction occurred only during the later cycles (which were the only cycles to include Docetaxel), suggesting that late dose reductions in chemotherapy may not have as much of an impact on DFS and OS, compared with early dose reductions. The authors hypothesized that majority of cancer cells that are sensitive to chemotherapy are eradicated during the first few treatments, rather than in the later treatments. Further, the amount of Docetaxel that was prescribed in the last three cycles may be higher than needed for the FEC-D regimen. Menopausal status, use of G-CSF and dose delay of 14 days or more, were not shown to affect OS.
It was concluded that early dose reductions in adjuvant FEC-D chemotherapy results in inferior outcomes, with adverse affect on DFS and OS. Conversely, late reductions in chemotherapy dose (Docetaxel only) appear to have minimal impact on survival. Based on this data, the authors recommended that Medical Oncologists should strive to deliver full-dose FEC when prescribing adjuvant FEC-D chemotherapy for breast cancer. Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer. Veitch Z, Khan OF, Tilley D, et al. J Natl Compr Canc Netw. 2019;17:957-967.