High-dose chemotherapy in the adjuvant setting offers a long-term survival advantage for women with very-high-risk stage III breast cancer, but does not improve survival odds for women with lower-risk cancers, an analysis of 20 years of follow-up data shows.
Among 885 women younger than 56 years at the time of treatment who had 4 or more involved axilliary lymph nodes, there was no overall survival difference over 2 decades between the total population of women randomized to receive adjuvant high-dose chemotherapy (HDCT) and those assigned to receive conventional-dose chemotherapy (CDCT).
However, women with 10 or more involved axilliary nodes and those with triple-negative breast cancer had an approximately 15% absolute improvement in 20-year overall survival with high-dose chemotherapy, although the difference for triple-negative disease fell just short of statistical significance, reported Tessa G. Steenbruggen, MD, from the Netherlands Cancer Institute in Amsterdam and colleagues.
“Our analysis confirms earlier results that HDCT has no significant overall survival benefit compared with CDCT for unselected patients with stage III [breast cancer]. However, we found a 14.6%improvement in 20-year OS estimates with HDCT in the predefined subgroup of patients with 10 or more involved [axilliary lymph nodes],” they wrote in JAMA Oncology.
And although other studies of chemotherapy regimens containing high doses of alkylating agents have shown increases in risk of late second malignancies and major cardiovascular events, there were no significant increases of either adverse event with HDCT in this study, the authors noted.
They reported 20-year follow-up results for 885 women who were enrolled in a 10-center randomized clinical trial conducted in the Netherlands from August 1, 1993, through July 31, 1999.
The participants were younger than age 56 years with breast cancer involving at least 4 axillary lymph nodes. All patients underwent surgery with complete axillary clearance and were then randomized to receive either conventional chemotherapy, which consisted of five cycles of fluorouracil 500mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500mg/m2 (FEC), or high-dose chemotherapy, with the first 4 cycles identical to conventional-dose chemotherapy but the fifth cycle consisting of cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2, supported with autologous hematopoietic stem cell transplant.
In addition, all patients received radiotherapy according to the local standard and 2 years of adjuvant tamoxifen.
After a median follow-up of 20.4 years, the 20-year overall survival (OS) rates were 45.3% for patients who had received high-dose chemotherapy and 41.5% for those who had received the conventional dose. This translated into a nonsignificant hazard ratio of 0.89.
However, for patients with 10 or more involved axillary nodes, the 20-year OS rates were 44.5% with HDCT and 29.9% with CDCT, translating into an absolute OS advantage for high-dose chemotherapy of 14.6% and an HR of 0.72 (P = .02).
Respective 20-year OS rates for women with triple-negative breast cancer were 52.9% and 37.5%, an absolute difference of 15.4% and a HR of 0.67, which fell just short of statistical significance, possibly because of the small number of patients with triple-negative breast cancer (140).
“In our 20-year follow-up analysis, there was no increase in cumulative risk for a second malignant neoplasm or for incidence of major cardiovascular events after HDCT,” the investigators wrote.
They noted that women randomized to high-dose chemotherapy had more frequent dysrhythmias, hypertension, and hypercholesterolemia, adding that the latter two adverse events may be partly attributable to a higher incidence of menopause induction among women who received HDCT.
The study was sponsored by University Medical Center Groningen and the The Netherlands Cancer Institute. Dr Steenbruggen reported receiving grants from the Dutch Health Insurance Council during the conduct of the study.
SOURCE: Steenbruggen TG et al. JAMA Oncology. 2020 Jan 30. doi: 10.1001/jamaoncol.2019.6276.