|
Weekly paclitaxel increased the response rate in metastatic breast cancer but failed to improve significantly time to progression when compared with treatment every 3 weeks in a phase III trial conducted by the Anglo-Celtic Cooperative Oncology Group.
Although 43% of patients responded to weekly paclitaxel, 27% responded to paclitaxel given every 3 weeks. Weekly treatments delayed progression by 24 weeks vs. 22 weeks for patients on the slower schedule. The difference, however, was not statistically significant.
The trial had been expected to address any uncertainties left by the Cancer and Leukemia Group B (CALGB) 9840 trial, which found statistically significant improvements in objective response rate and progression-free survival with weekly dosing. Instead, the British results raise new questions about the impact of treatment duration.
"This was clearly slightly disappointing and in the context of the American study an unexpected result," Dr. Mark Verrill said in the first presentation of the Anglo-Celtic outcomes.
"Our trial is completely consistent with the findings from the United States trial, but the lack of advantage in time to progression in the U.K. trial may be explained by a mismatch in total time on treatment," said Dr. Verrill of the Northern Institute for Cancer Research Newcastle upon Tyne.
The trial enrolled 569 patients with locally advanced or metastatic disease. They had a median age of 56 years and included four men, who were randomized two to each arm of the study. One group of 278 patients received 90 mg/m² of paclitaxel weekly for 12 weeks. Another group of 291 patients was given 175 mg/m² of paclitaxel every 3 weeks for six cycles in a regimen that lasted 18 weeks.
"Basically, they received the same therapy, but the duration was different," Dr. Luca Gianni of the Istituto Nazionale dei Tumori di Milano in Italy observed in a discussion of the trial. "We know that duration matters."
Serious adverse events occurred in 167 patients and there were no major differences between the study groups. Neutropenia appeared earlier on the weekly schedule, and those patients also had slightly more neuropathy.
"Neutropenia follows a somewhat different pattern from what we expected... this is likely to be an ascertainment bias because we checked blood counts weekly in the weekly-treated patients," Dr. Verrill said. "In the patients treated weekly neurotoxicity is cumulative."
Genetic analysis of blood samples from 327 participants showed single nucleotide polymorphisms had no impact on response or survival.
Dr. Verrill thanked the U.K.'s National Cancer Research Network and Bristol-Myers-Squibb U.K. for support of the trial.
Verrill M.W. et al. Anglo-Celtic IV: First results of a UK National Cancer Research Network randomized phase 3 pharmacogenetic trial of weekly versus 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC). Abstract LBA1005.
Commentary |
This trial raises important issues regarding trial design. Specifically, to compare the clinical efficacy of these two schedules, it is critically important to ensure equal duration and dose density of the two treatment arms. That was not the case in this trial, and likely explains the difference in outcome between it and CALGB 9840. Dose and schedule do matter! — William J. Gradishar, M.D.
|