Taxane-Induced Neuropathy Gives No Clue to Breast Cancer Outcomes

[Hopeful]

Elsevier Global Medical News. 2011 Sept 20, S London

SAN FRANCISCO (EGMN) - The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women's cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn't appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Hopeful