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CHICAGO -- Breast cancer patients obtained the same disease control with less toxicity when they received weekly low-dose chemotherapy instead of a higher dose given every 2 weeks, results of a randomized trial showed.

The estimated 5-year survival was 82% among patients who received weekly paclitaxel and 81% among those who received dose-dense paclitaxel, G. Thomas Budd, MD, of the Cleveland Clinic, reported here at the American Society of Clinical Oncology (ASCO) meeting.

Analysis of overall survival also showed no difference between the two paclitaxel schedules.

The two regimens had similar rates of grade 3/4 toxicity (35% to 36%), but their toxicity profiles differed. The weekly regimen was associated with more hematologic toxicity, whereas the dose-dense regimen led to more allergy-related reactions, musculoskeletal pain, and neuropathy.

"Either regimen can be selected on the basis of efficacy," Budd said. "So in practice, treatment can be selected based on other considerations, such as toxicity.

The results could have a practice-changing impact on breast cancer management, Andrew Seidman, MD, of Memorial Sloan-Kettering Cancer Center in New York City, said during an ASCO press briefing. A supporter of the dose-dense approach developed at Sloan-Kettering, Seidman said he plans to start treating patients with the weekly regimen.

The lower cost and more favorable toxicity profile will likely persuade other breast oncologists to make the switch, he added.

The results complete a trial that began with the objective of comparing two different schedules of one of the most widely used chemotherapy regimens in the U.S.: doxorubicin-cyclophosphamide followed by paclitaxel (often abbreviated AC-T).

Both the AC and paclitaxel components of the regimen have been given on a weekly, low-dose schedule or a bi-weekly dose-dense schedule. Investigators in the Southwest Oncology Group trial S0221 designed a study to determine whether one schedule leads to better results than the other.

"Anthracyclines, primarily doxorubicin, and taxanes are components of most modern chemotherapy regimens," Budd said. "The addition of new chemotherapy drugs has not improved outcomes. Thus, we need to give the active drugs in the best way."

As originally planned, investigators were to randomize 3,250 patients with stages I-III breast cancer to receive conventionally dosed AC plus granulocyte colony stimulating factor (G-CSF) every 2 weeks or weekly lower-dose AC-G. Each treatment group was further randomized to dose-dense paclitaxel plus G-CSF every 2 weeks for six cycles or to weekly, lower-dose paclitaxel without G-CSF.

The primary endpoint was 5-year disease-free survival, and the trial had the statistical power to detect an 18% relative difference between groups (HR ≤0.82).

An interim analysis after enrollment of 2,712 patients showed that the comparison of AC-G schedules had crossed the boundary for futility, and the trial resumed with all patients receiving the standard AC-G schedule, reduced to four cycles total.

Evaluation of the randomized paclitaxel schedules continued. Budd noted that patients randomized to dose-dense paclitaxel received six cycles of therapy (instead of the usual four) so that patients in each group continued treatment for a total of 12 weeks.

Patient accrual ended in January 2012 with 3,294 patients. At the third interim analysis (of a planned six) in September 2012, investigators learned that the futility boundary had been crossed for the paclitaxel comparison.

After a median follow-up of 4.4 years, comparison of the two paclitaxel arms produced a hazard ratio of 1.05 for weekly versus dose-dense therapy.

"Since this was not conducted as a noninferiority study, we cannot make a statistical conclusion about the lack of difference," Budd said during his presentation to ASCO attendees. "However, the Kaplan-Meier curves and computed hazard ratios suggest little difference between the two arms."

Subgroup analysis showed no significant differences between the groups with respect to hormone-receptor or HER2 status.

On balance, the toxicity favored weekly paclitaxel, which also costs substantially less than dose-dense therapy that requires immunologic support with granulocyte-colony stimulating factor (G-CSF), according to Budd.

"Low blood counts were observed more commonly with weekly paclitaxel, but these patients had blood counts checked more often [leading to ascertainment bias] and did not receive blood growth factors," Budd said at the press briefing.

"Allergic reactions, aching, and nerve pain were more common in patients treated every 2 weeks. Weekly paclitaxel is less toxic for most patients."

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