"These data clearly demonstrate the advantage of weekly paclitaxel over every-third-week dosing, whether with trastuzumab(Drug information on trastuzumab) [Herceptin] for patients with HER-2-positive breast cancer or without it for HER-2-negative breast cancer," said Dr. Seidman, associate attending physician, Breast Cancer Medicine, Memorial Sloan-Kettering Cancer Center. He maintained that the weekly paclitaxel schedule should be adopted as a new standard of practice when taxanes are used in the metastatic setting.
CALGB 9840 involved 738 patients, including 580 treated on this study and an additional 158 patients treated with every-3-week paclitaxel at 176 mg/m2 in the prior CALGB 9342 trial (Winer et al: J Clin Oncol 22:2061-2068, 2004). Patients could have received one prior chemotherapy regimen for metastatic or locally advanced disease or as adjuvant or neoadjuvant therapy. Prior taxane was allowed only if more than 12 months had passed since the last administration, and no prior trastuzumab was allowed.
The 580 new patients were randomized 40:60 to receive paclitaxel 175 mg/m2 every 3 weeks or weekly paclitaxel 80 mg/m2. Patients were assessed for HER-2 status, and those with overexpression received trastuzumab, while those with normal HER-2 status (HER-2 negative) were randomized to trastuzumab or no trastuzumab.
Weekly paclitaxel produced a significantly greater tumor response, with or without trastuzumab, compared with the every-3-week regimen: 40% vs 28% (P = .017). Time to disease progression was also significantly improved with the weekly therapy: 9 months vs 5 months (P = .0008). There was a trend toward longer survival among patients on weekly paclitaxel: 24 vs 16 months (P = .17).
When the results were analyzed for only those patients recruited to CALGB 9840 (eliminating those borrowed from the previous CALGB study), the results were still significant. Dr. Seidman explained that the populations were combined in order to reach the target number of patients and have statistical power while "conserving resources."
The side effect profiles differed slightly, with less grade 3-4 granulocytopenia on the weekly arm (5% vs 15%; P = .013), but more grade 3-4 sensory neuropathy (23% vs 12%, P = .001) and motor neuropathy (8% vs 4%, P = .04).
"CALGB 9840 should be a practice-changing study for those physicians who have not been using weekly paclitaxel," Dr. Seidman commented. "The improvement in terms of time to progression, in particularwhere we saw an almost doubling with weekly paclitaxelis very meaningful, and provides important benefits to patients."
The study also aimed to determine to what degree women with normal HER-2 status might benefit from trastuzumab therapy. CALGB 9840 found no significant improvement with the addition of trastuzumab in the HER-2-normal group, Dr. Seidman said. Response rates were 35% in the trastuzumab arm vs 29% without trastuzumab; time to progression was 7 months vs 6 month; and overall survival was 22 months vs 20 months. The investigators concluded that trastuzumab does not contribute to the efficacy of paclitaxel in the absence of HER-2 overexpression.
The study also provided some contribution to the ongoing question of dose intensity vs dose density (frequency). Dr. Seidman noted, "When considered together with the results of CALGB 9342, where an increase in paclitaxel dose did not improve outcome, the present results are consistent with the concept that the frequency of drug administration, or density, may account for the improved efficacy that was observed."