Taxane Doublets for Metastatic Breast Cancer: Do We Need Another Cytotoxic Pair or Another Approach?

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In the 15 years since taxanes were approved for use in metastatic breast cancer, they have played a prominent role in clinical trials evaluating combination therapy for this disease. A number of randomizedtrialshavebeenconductedaddressingthequestionofsingleagentversuscombinationtherapyortherelatedquestionofsequential versuscombinationtherapy.Someofthesehaveshownthecombination arm to be superior in response rate (RR), progression-free survival (PFS), and even overall survival (OS). Notable examples of successful taxane doublets include the combination of gemcitabine and paclitaxel 1 and the combination of docetaxel and capecitabine, 2 both of which showed improved time to progression (TTP), RR, and OS for the doublet compared with single-agent taxane alone in firstline treatment of metastatic breast cancer. However, later analysis of the docetaxel and capecitabine study showed that in patients who received single-agent docetaxel, poststudy treatment with capecitabine improved survival more than other poststudy treatments. This finding raises the possibility that sequential single-agent therapy may confer the same benefit as combined doublet therapy. 3 Other trials have shown that combination cytotoxic therapy is no better than single-agent or single-agent sequential therapy, 4 and most studies have shown higher toxicity in the combination arms. A recent Cochrane report 5 concluded that combination chemotherapy regimens yielded statistically significant improvements in OS, TTP, and RR yet greater toxicity. However, this report included primarily nontaxane combinations and did not evaluate sequential single agents as a comparison. The National Comprehensive Cancer Network guidelines, version2.2011, 6 statethatthereislittleornocompellingevidencethat combination chemotherapy is superior to sequential single agents. Thus a common consensus opinion is that combination cytotoxic therapy should be used in patients with rapidly progressive disease or in patients with visceral disease and symptoms, where more rapid response is needed. All others should be treated with single agents in sequence. Inthiscontext,Nielsenetal 7 presentinJournalofClinicalOncology a randomized phase III trial conducted by the Danish Breast Cancer Cooperative Group to evaluate the combination of gemcitabine and docetaxel compared with docetaxel alone in the treatment of metastatic breast cancer. This study was conducted between 2001 and2005andincluded337patientswithmetastaticbreastcancerwho