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NSABP B-38: Addition of gemcitabine to AC-P failed to improve outcomes in breast cancer
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CHICAGO — The addition of gemcitabine to a dose-dense doxorubicin plus cyclophosphamide followed by paclitaxel regimen was not linked to improved 5-year DFS outcomes in a cohort of patients with breast cancer.
Sandra M. Swain, MD, medical director of the Washington Cancer Institute of the Washington Hospital Center and professor of medicine at Georgetown University, said the primary aim of the study was to determine whether dose-dense doxorubicin plus cyclophosphamide followed by paclitaxel (AC-P) plus gemcitabine demonstrated superiority to two other regimens for women with operable, node-positive breast cancer: dose-dense AC-P; and docetaxel, doxorubicin and cyclophosphamide (TAC). Survival and toxicity comprised the secondary endpoints.
These regimens, which have different toxicity profiles, “have not been compared in a single prospective trial, so this design also provided an opportunity to directly compare toxicities and efficacy,” said Swain, who is also ASCO president.
Randomization occurred between Nov. 3, 2004, and May 3, 2007. The analysis included 4,894 women, and the breakdown was as follows: 1,630 women to dose-dense AC-P plus gemcitabine; 1,634 to women to dose-dense AC-P; 1,630 women to TAC.
Investigators used erythropoiesis-stimulating agents on a discretionary basis, and primary granulocyte colony–stimulating factor support was required.
The median follow-up duration was 5.3 years.
Results indicated that 5-year DFS was 80.6% in the AC-P plus gemcitabine group vs. 82.2% (HR=1.1; P=.27) in the AC-P group and 80.1 % (HR=0.97; P=.71) in TAC group.
“Results … show no significant differences in DFS between dose-dense [AC-P plus gemcitabine] and either of the control arms,” Swain said. “There were no significant differences in hazard ratios across different categories in ER status, number of nodes, type of surgery, or extent of radiation. There was no interaction between treatment arms and stratification factors.”
Five-year OS was 90.8% in the AC-P plus gemcitabine group, 89.1% (HR=0.89; P=.25) in the AC-P group and 89.6% (HR=0.9; P=.32) in TAC group.
“There were no significant differences in overall survival between the three arms,” Swain said.
The HRs for DFS and OS of AC-P vs. TAC were 0.89 (P=.14) and 1.01 (P=.92), respectively.
Grade-3 or -4 toxicities occurred at the following rates: febrile neutropenia was 4% in the gemcitabine regimen, 4% in the AC-P regimen and 9% in the TAC regimen (P<.001); sensory neuropathy was 6% for gemcitabine, 7% for AC-P and less than 1% for TAC (P<.001); diarrhea was 2% for both AC-P regimens and 8% for TAC (P<.001).
“Overall, fewer grade-3 toxicities occurred with TAC than in the dose-dense regimens,” Swain said.
Hemoglobin was less than 10% in 33% of gemcitabine patients vs. 26% for those receiving AC-P and 12% for those receiving TAC. Erythropoiesis-stimulating agents were used in 51.6% of patients in the gemcitabine group, 47% of AC-P and 35.2% of TAC. Transfusion rates were 9.4%, 6.3% and 2.7% for AC-P plus gemcitabine, AC-P and TAC, respectively.
There were seven deaths in the gemcitabine group, five in the AC-P group and 13 in the TAC group (P=.2). Eighty-eight percent of patients in both AC-P groups completed all cycles of treatment vs. 91% in the TAC patients.
“The addition of gemcitabine to dose-dense AC-paclitaxel did not improve outcomes,” Swain concluded. “There was no difference in efficacy between dose-dense AC followed by paclitaxel and TAC.”
For more information:
Swain SM. #LBA1000. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: Dr. Swain reports a consultant or advisory role with Genentech, Nektar Therapeutics, Novartis, Roche and Sanofi; she received research funding from Bristol-Myers Squibb, Novartis, Pfizer, Roche/Genentech and Sanofi; and she received other remuneration from Sanofi
Perspective
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Kathy D. Miller, MD
This new agent, gemcitabine, could be added to sequential regimens but could not be safely added to concurrent regimens. In this study, we see these two sequential regimens compared to isolate the impact of a new agent. This also gives us the opportunity to see a sequential compared to a concurrent strategy.
The efficacy results were similar, but toxicities differed. There were more toxicities of the most potentially life-threatening and troublesome, including neutropenia and diarrhea with TAC but more neuropathy and anemia with the sequential arm. There was no benefit to the addition of gemcitabine.
Dr. Swain reported these results as the definitive analysis of the B38 trial. Based on the statistical design, that’s a proper characterization. But I’ll remind you that 80% of the patients in this study have HR-positive disease, and for those patients, more than half of the disease-free survival events have yet to occur. So while statistically it is a definitive analysis, clinically it cannot be so.
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