Use of weekly paclitaxel had efficacy similar to an every-two-week regimen but with less toxicity, according to the results of a large cooperative group trial reported at the American Society of Clinical Oncology Annual Meeting (Abstract CRA1008).
“Either schedule can be recommended based on efficacy, so, in practice, treatment can be selected based on other considerations, such as toxicity,” said G. Thomas Budd, MD, a medical oncologist at the Cleveland Clinic, who presented the data.
Additionally, the weekly regimen may be more cost-effective. The patients treated in the weekly paclitaxel arm did not receive prophylactic growth factor support with pegfilgrastim, which was provided to women in the every two-week arm. “We haven't done a formal pharmaco-economic analysis that includes cost of toxicities, etc., but a back-of-the-envelope calculation does show that the weekly schedule involves less in drug costs,” he said during the discussion following his presentation.
Survival Curves Overlap
As originally designed, the trial, SWOG S0221, included two sequential randomizations—the first testing three different regimens of doxorubicin and cyclophosphamide and the second to compare weekly versus standard every-two-week dosing of paclitaxel. Researchers reported in 2011 that there was no difference among the doxorubicin and cyclophosphamide regimens. The current report focuses just on the second question of paclitaxel dosing.
A total of 3,294 women with Stages 1 to 3 breast cancer enrolled in the study. To be eligible, women had to have node-positive or high-risk node-negative disease, defined as any tumor 2 cm or larger, or a tumor 1 cm or larger in the case of hormone-receptor negativity or a recurrence score of 26 or higher. HER2-positive patients were allowed and received trastuzumab with the paclitaxel.
With a median follow-up of 4.4 years, disease-free survival is similar in the two arms, with a non-significant hazard ratio of 1.05. The estimated five-year survival rate is 82 percent in the weekly paclitaxel arm and 81 percent in the every-two-week arm.
“Since this was not conducted as a noninferiority study, we cannot make a statistical conclusion about the lack of difference. However, the Kaplan-Meier curves and computed hazard ratio suggest little difference in efficacy between these two arms,” Budd said, pointing at the Kaplan-Meier curves that lie on top of one another.
Similarly, there was no difference in overall survival, with a hazard ratio of 1.12, and the medians have not been reached.
Neurologic Toxicity Lower in Weekly Arm
The differences between the two arms appear in their side-effects profiles. Patients in the weekly paclitaxel arm had fewer Grade 3-4 allergic reactions compared with the every-two-week arm (1.4% vs. 0.6%), and less musculoskeletal pain (11% vs. 3%) and neurologic pain (17% vs. 10%).
Grade 3-4 hematologic toxicities were higher in the weekly arm, compared with the control arm (17% vs. 6%). Specifically, leukopenia was more common (6% vs. 1%), as was neutropenia (11% vs. 2%), but there was no difference in febrile neutropenia (0.4% vs. 0.1%).
Budd noted that these differences were likely influenced by the fact that patients in the every two-week arm received regular growth factor support with pegfilgrastim whereas those in the weekly arm did not. Additionally, there may have been ascertainment bias in favor of the standard arm because patients in the weekly-treatment group had their blood cell counts checked every week, compared with every-other week in the control arm.
During the discussion, Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs at Memorial Sloan-Kettering Cancer Center, who helped develop the idea of dose-dense regimens, noted that both of the regimens in the trial are dose dense. He also pointed out that there may be advantages with the every-two week regimen for some patients, especially those who have to travel a distance for treatment.
“This is going to change my practice,” said Andrew D. Seidman, MD, an ASCO spokesperson and attending physician for the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, speaking during a news conference that included the study.
“I've generally given every-two-week, or dose-dense paclitaxel. These data suggest to me that I can get the same benefit with less toxicity, possibly with less cost, with weekly paclitaxel.”
The results mean that patients now have options, Budd said. “What this tells me, in terms of efficacy, is that you do have a choice, that treatment can be individualized by the patient and her physician. I think there will be a move to more weekly treatment since hematologic growth factor support is not required.”