Single-agent paclitaxel cannot be recommended as a standard regimen after surgery for women with primary breast cancer and 0 to 3 positive axillary nodes.
This is the latest conclusion from Cancer and Leukemia Group B (CALGB) 40101, a phase 3 randomized clinical trial of 3871 women with early breast cancer that began in 2002.
For this analysis, the investigators compared adjuvant single-agent paclitaxel with doxorubicin plus cyclophosphamide (AC).
AC has been a standard regimen for many "better-risk" patients with primary breast cancer, report the investigators, led by Lawrence Shulman, MD, from the Dana-Farber Cancer Institute in Boston.
However, in an effort to find a less toxic regimen with similar efficacy, the team compared this standard with a hypothetically good idea: a single taxane.
The primary outcome of this noninferiority study was recurrence-free survival.
After 437 recurrence-free survival events, the hazard ratio of 1.26 favored AC, so the noninferiority of paclitaxel could not be established.
This conclusion, reached after a median follow-up of 6.1 years, "is unlikely to change with additional events and follow-up," Dr. Shulman and colleagues report.
The study was published online June 16 in the Journal of Clinical Oncology.
In addition to being noninferior, paclitaxel might actually be less effective than AC, suggest a trio of experts not involved with the study who penned an accompanying editorial. They are Pamela Goodwin, MD, from the University of Toronto; Karla Ballman, MD, from the Mayo Clinic in Rochester, Minnesota; and Mark Levine, MD, from McMaster University in Hamilton, Ontario, Canada.
In fact, the estimated absolute advantage of AC over paclitaxel at 5 years is 3% for recurrence-free survival (91% vs 88%) and 1% for overall survival (95% vs 94%).
The idea of using a single-agent taxane in early-stage disease was based on other studies in locally advanced or metastatic disease, the investigators explain. Research showed that single-agent taxanes seemed to have "relatively equivalent efficacy compared with combination chemotherapy built on the AC backbone," they write.
The editorialists believe that the noninferiority results provide "some push back" against clinicians "who want to abandon anthracyclines" in early-stage breast cancer. But the trio also has some criticisms of CALGB 40101.
Foremost, they say, the results might have "limited generalizability" to current practice because many women now receive both taxanes and anthracyclines.
With regard to toxicity, paclitaxel was preferable to AC, which is what the investigators hypothesized.
All 9 treatment-related deaths were in the AC group. Hematologic toxicity was more common in patients treated with AC, whereas neuropathy was more common in patients treated with paclitaxel.
In the trial, AC consisted of intravenous (IV) doxorubicin 60 mg/m² and IV cyclophosphamide 600 mg/m². IV paclitaxel was administered 80 mg/m² when given weekly and 175 mg/m² when given once every 2 weeks.
2 Questions
The editorialists call CALGB 40101 "an extremely complex trial" because the investigators used of a 2 × 2 factorial design to answer 2 questions.
First, are 6 cycles of adjuvant chemotherapy for breast cancer better than 4? (Both paclitaxel and AC were administered as the different regimens.)
The investigators reported at the 2010 San Antonio Breast Cancer Symposium that more cycles do not improve outcomes.
Specifically, at 4 years, recurrence-free survival was 91.6% for those randomized to 6 cycles and 91.8% for those randomized to 4 cycles (hazard ratio, 1.10; P = .42).
Now, the investigators answer the question about single-agent paclitaxel.
But the editorialists believe the findings have been weakened for a number of reasons.
Notably, the trial was plagued by slow accrual. The problem of enrolling women was associated with several protocol modifications during the study that made an already complex trial even more complex, they say.
The modifications were necessary, the investigators assert.
For example, in 2003, the superiority of dose-dense chemotherapy (every 2 weeks) over standard chemotherapy (every 3 weeks) was demonstrated in CALGB 97415. After that, CALGB 40101 was amended to allow dose-dense administration of both AC and paclitaxel. This amendment, in turn, allowed white blood cell growth-factor support.
In 2005, eligibility was expanded beyond node-negative breast cancer to include women with 1 to 3 positive axillary nodes in an attempt to expand the pool of eligible patients. Targeted therapy (trastuzumab) for HER2-positive disease was also allowed.
But these and other changes "clouded the interpretation of the results," the editorialists say.
Dr. Shulman and colleagues acknowledge that various changes in breast cancer chemotherapy occurred during the trial, such as the emergence of molecular testing.
"Chemotherapy use is increasingly based on molecular features of the tumor (such as multigene prediction assays) to determine which patients should receive chemotherapy," they write.
However, they are firm in their conclusions from CALGB 40101. "These findings support AC as an option as standard of care, whereas our previous findings support 4 cycles of therapy as a standard duration of therapy for these patients," they write.
This study was supported in part by grants from the Alliance for Clinical Trials in Oncology, the North Central Cancer Treatment Group, the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the National Cancer Institute. Many of the authors have financial ties to industry, as detailed in the publication.
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