Nanoparticle Albumin–Bound Paclitaxel for Metastatic Breast Cancer (2005)

The taxanes, paclitaxel and docetaxel, are among the most important drugs in the modern treatment of metastatic breast cancer. By the mid 1990s, several phase II trials had demonstrated both agents to have considerable activity in the metastatic setting. Phase III trials were then conducted to compare these agents with the then reference agent, doxorubicin. In 1999, a large randomized trial comparing docetaxel with doxorubicin found an improved response rate in patients who received docetaxel (48% v 33%; P .008), though differences in time to progression (26 v 21 weeks) and survival (15 v 14 months) were not statistically significant. A similar study that compared paclitaxel at a dose of 200 mg/m given over 3 hours, with doxorubicin 75 mg/m, showed paclitaxel to have an inferior response rate (25% v 41%; P .003) and time to progression (3.9 v 7.5 months; P .001) but again, overall survival was not statistically different between the two arms (15.6 v 18.3 months), possibly as a result of the preplanned cross-over on progression. Both agents, however, were rapidly adopted for the treatment of metastatic breast cancer, especially for the many women who had received an anthracycline in the adjuvant setting. Trials were subsequently launched to examine taxane combinations in advanced disease, and while some have demonstrated improved efficacy compared with single agents, this benefit has to be balanced against the excess toxicities seen with some of these regimens. This encouraging activity of taxanes in advanced disease led investigators to examine their role in addition to anthracyclines in the adjuvant setting. The first to be reported was CALGB (Cancer and Leukemia Group B) 9344 and the final analysis of this trial showed improvements in 5-year disease-free and overall survival with the addition of four cycles of paclitaxel to four cycles of doxorubicin cyclophosphamide (disease-free survival [DFS] 70% v 65%, P .0023; overall survival [OS] 80% v 77%, P .0064). Other paclitaxel adjuvant studies have shown less convincing benefits. Docetaxel has also been evaluated in several adjuvant trials. In the Breast Cancer International Research Group study (BCIRG 001), six cycles of doxorubicin, docetaxel, and cyclophosphamide (TAC) were found to be associated with superior DFS and OS compared with doxorubicin, fluorouracil, and cyclophosphamide (FAC; DFS 75% v 68%; P .001; OS 87% v 81%, P .008). Taxanes are now commonly used in adjuvant regimens for women with high-risk disease. Parallel to these studies, major advances have been achieved for women with HER-2–overexpressing breast cancer by employing schedules combining taxanes plus trastuzumab in advanced disease and in the adjuvant setting. Despite their widespread use, both docetaxel and paclitaxel are associated with significant toxicities, including alopecia, fatigue, myalgia, nail changes, myelosuppression, neuropathy, and hypersensitivity reactions. Although these adverse effects are manageable for the majority of patients, it has meant there are limitations on the duration of therapy and on combining the taxanes with other agents with overlapping toxicity profiles. Paclitaxel and docetaxel are highly hydrophobic, and therefore have to be delivered in synthetic vehicles. In the case of paclitaxel the vehicle is polyoxyethylated castor oil (Cremophor EL) and ethanol, whereas the combination of polysorbate 80 and ethanol are used for docetaxel. It has become increasingly recognized that the vehicles may be responsible for some of the “taxane-associated toxicity,” particularly fluid retention and hypersensitivity. The experiences from the early phase I and II trials of these drugs found that the incidence of such reactions could be reduced to acceptable levels with the use of premedication schedules containing antihistamines together with moderate to high doses of corticosteroids. It is in large part because of the toxicities associated with the current formulations of taxanes that strategies to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 31 NOVEMBER 1 2005