Nick Mulcahy

June 03, 2013

CHICAGO, Illinois — In a result that should change clinical practice, a low-dose weekly schedule of the breast cancer chemotherapy stalwart paclitaxel appears to be less toxic than the standard "dose-dense" biweekly administration of the drug, according to a large American trial.

The 2 commonly used schedules were equally effective in women with high-risk stage I to III breast cancer, report lead study author G. Thomas Budd, MD, from the Cleveland Clinic in Ohio, and colleagues.

Dr. Budd spoke at a press conference today here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

In the Southwest Oncology Group (SWOG) S0221 trial, estimated 5-year progression-free survival rates were equivalent for paclitaxel administered weekly (82%) and paclitaxel administered every 2 weeks (81%).

However, the low-dose weekly schedule was significantly less toxic than the dose-dense biweekly schedule for neurologic events (17% vs 10%; P < .001) and musculoskeletal pain (11% vs 3%; P < .001).

Neuropathy was the adverse event of most concern in the trial, which involved more than 2700 patients. "It takes 6 months to a year [to resolve] and, in some patients, does not resolve on its own," said Dr. Budd.

For patients whose livelihoods depend on their fine motor skills, the issue of reduced neuropathy with the weekly schedule will be especially compelling, said Andrew Seidman, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press conference.

"This is actually going to change my practice," said Dr. Seidman, who has "generally" used the dose-dense biweekly schedule in the past. This commitment to change is perhaps all the more impressive because the dose-dense paclitaxel approach was pioneered at Memorial Sloan-Kettering.

"These data suggest I can get the same benefit with less toxicity and possibly less cost," he added.

Cost Reductions

The weekly schedule offers a number of cost reductions, including those stemming from the general lack of need for growth factors, which is "not a trivial cost" associated with the dose-dense regimen, said Dr. Seidman.

In the SWOG S0221 trial, the growth factor pegfilgrastim was given prophylactically to boost white blood cell production in all patients in the dose-dense biweekly group.

The total cost of a typical weekly paclitaxel regimen is about $13,000, whereas the biweekly regimen is $23,000 to $40,000, Dr. Budd told Medscape Medical News.

Dr. Budd was not as emphatic as Dr. Seidman about his paclitaxel preference. "The findings provide assurance that women can choose the lower-dose therapy without sacrificing their chances of survival," he said in a press statement. However, he noted that the dose-dense biweekly option might be well suited to some women because it reduces clinic visits.

Adjuvant paclitaxel is commonly prescribed to women with high-risk early-stage breast cancer as part of an ACT regimen (anthracycline, cyclophosphamide, and a taxane), said an expert not involved with the study.

About 50% of all non-HER2-positive early breast cancer requires adjuvant chemotherapy, said ASCO spokesperson Sylvia Adams, MD, from the New York University School of Medicine in New York City, who was asked for comment by Medscape Medical News.

"In the United States, maybe 70% to 80% of these women will receive ACT for their disease," she said.

The current study is based on the multigroup ACT SWOG S0221 study. In the trial, women with node-positive or high-risk node-negative operable breast cancer first received treatment with 1 of 3 different regimens of doxorubicin plus cyclophosphamide; they were then randomized to 1 of the 2 paclitaxel regimens (weekly or biweekly) for 12 weeks. The results of the doxorubicin plus cyclophosphamide treatment were reported at ASCO in 2011.

Both paclitaxel approaches are widely used in oncology practice but have not been compared in a clinical trial, according to meeting press materials.

Biweekly Schedule Is Usually for 4 Cycles

From December 2003 to November 2010, the 2716 patients were randomized to paclitaxel 80 mg/m² weekly for 12 weeks or to paclitaxel 175 mg/m² every 2 weeks for 12 weeks (6 times total).

Adverse effects differed in the 2 groups, beyond the aforementioned neurologic events and musculoskeletal pain.

The biweekly regimen was associated with more allergic reactions than the weekly regimen (1.4% vs 0.6%).

The frequency of neurologic toxicity, which was more common with the biweekly regimen, might have been smaller had the patients received only 4 cycles (as is current practice), rather than 6. However, as Dr. Budd explained, the 6 cycles in the biweekly regimen was chosen so that patients in both groups would be on treatment for 12 weeks.

The weekly regimen was significantly associated with low blood counts, compared with the biweekly regimen. But Dr. Budd said that the differences might be related to the fact that the weekly patients had more frequent blood testing and none received blood growth factors.

A longer follow-up of patients enrolled in this study is planned. Future studies will explore genetic factors that predict the likelihood of toxic adverse effects in individual patients treated with paclitaxel, the researchers report.

The study was supported by the National Cancer Institute and Amgen. Dr. Budd reports serving as a consultant or in an advisory role for Amgen. Some of his coauthors also report relationships with the company.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA1008. Presented June 3, 2013.

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