Risks and Benefits of Taxanes in Breast and Ovarian Cancer

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Abstract
The taxanes are a unique class of agents with a broad spectrum of clinical activity. They act by binding to tubulin, producing unnaturally stable microtubules and subsequent cell death. The distribution and elimination of paclitaxel depend on dose and administration rate. This nonlinearity is much less evident at lower infusion rates (24-hour infusions) and more evident at high plasma concentrations (3-hour infusions). The pharmacokinetics of docetaxel also suggest the presence of nonlinear pathways, but these appear to be clinically insignificant at the current doses utilised (60 to 100 mg/m2). Both agents undergo hepatic metabolism and biliary excretion and require dose adjustment in the setting of liver dysfunction. Drug interactions are quite common with these agents, some of which are sequence-dependent and clinically significant. The optimal dose of paclitaxel is not known at this time, and controversy over possible dose- or schedule-related differences in efficacy still remain. Docetaxel is somewhat more consistent in its dose and scheduling information, but controversy remains regarding a dose-benefit relationship as well as scheduling differences (weekly vs every 3 weeks). Toxicity profiles for these agents are somewhat different. Paclitaxel is more likely to be associated with peripheral neuropathy and myalgias/arthralgias than docetaxel. Docetaxel is more likely to be associated with a cumulative fluid retention syndrome that can be dose limiting. Paclitaxel and docetaxel are both highly active agents against breast cancer, including tumours that are resistant to anthracyclines. Docetaxel tends to have higher response rates overall, but direct comparisons at maximally tolerated doses have not been completed. Combination regimens with many different agents are attempting to improve on the responses seen with single-agent taxanes. The combination of paclitaxel and a platinum compound should be utilised as first-line therapy of advanced ovarian cancer. Controversy lies in the choice of the platinum compound and the dose and administration schedule of paclitaxel. Substitution of docetaxel for paclitaxel in these platinum-containing regimens is also being investigated. The taxanes also exhibit activity against ovarian cancer in patients previously exposed to platinum agents. These agents may also be administered intraperitoneally for local therapy of metastatic ovarian cancer. Although docetaxel and paclitaxel are often considered similar in activity and tolerability, this review emphasises the fact that these agents are indeed different. Clinicians need to be familiar with the benefits and adverse events related to each agent in order to make informed, appropriate clinical decisions.