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Stephen E Jones
US Oncology Research
Professor of Medical Oncology
Hôpital St Louis
In the ten years since their initial licensing in Europe, the taxoids docetaxel (Taxotere(®)) and paclitaxel (Taxol(®)) have emerged as one of the most powerful classes of cytotoxic agents. Docetaxel and paclitaxel have had relatively parallel development and both have been approved for use in patients with metastatic breast cancer. However, until recently, there had been no direct comparison of these agents and it had not been possible to differentiate between them in the clinical setting. Paclitaxel was isolated in 1971 and, after an extensive search for taxoid derivatives with features that might improve on the potential of paclitaxel, docetaxel was identified in 1986 (see Figure 1).(1) Despite being related, early investigation revealed considerable preclinical differences between these agents. Compared with paclitaxel, docetaxel had a wider cell cycle activity and demonstrated a greater affinity for the β-tubulin-binding site(2) and a different microtubule polymerisation pattern.(3,4) These effects were accompanied by more potent induction of bcl-2 and apoptosis by docetaxel than paclitaxel, and more potent antitumour activity in in vitro and in vivo models.(5–7) Greater antitumour effects with docetaxel may have been related to the greater uptake and slower efflux of docetaxel from tumour cells, resulting in longer intracellular retention time and higher intracellular concentrations than are achieved with paclitaxel.(8) In early clinical studies, docetaxel exhibited linear pharmacokinetics(9) and less schedule dependence(10) than paclitaxel.
Differences in the drug interaction profiles of docetaxel and paclitaxel are of particular concern when these agents are used in combination with anthracyclines. While pharmacokinetic interaction between paclitaxel and anthracyclines results in increased levels of the potentially cardiotoxic metabolite doxorubicinol,(11,12) the absence of any such interaction between conventional doses of docetaxel and anthracyclines means that there is no increased risk for cardiotoxicity with this combination. With regards to toxicity profiles, neutropenia is the dose-limiting toxicity for both drugs, but differences in nonhaematological toxicities are evident. Paclitaxel is more commonly associated with anaphylaxis and severe hypersensitivity reactions, whereas fluid retention and fatigue are seen with docetaxel administration.(13,14)
Preclinical differences between the taxoids appeared to be translated to the clinical setting, with docetaxel consistently producing better outcomes than older regimens in a number of clinical trials, either as monotherapy,(15–19) or in combination with anthracyclines.(20–23) In contrast, data for paclitaxel/anthracyclines are less consistent.(16,24–26)
However, these trials did not directly compare the taxoids and, as such, it was not possible to draw any concrete conclusions from these analyses. TAX 311 is the only head-to-head randomised phase III study to compare directly the efficacy and safety of second-line docetaxel and paclitaxel as monotherapy for patients with advanced breast cancer.(27) In this rigorously designed clinical trial, each drug was given at the European Agency for the Evaluation of Medicinal Products (EMEA) and Food and Drug Administration (FDA) approved dosage and schedule, as detailed in Table 1.
Docetaxel showed a superior efficacy profile, increasing overall survival to 15.4 months compared with 12.7 months for paclitaxel – a significant improvement of 2.7 months (see Figure 2). Annual survival rates were also significantly increased for docetaxel compared with paclitaxel. The clinical relevance of this is clear, with one in three women alive at two years with docetaxel compared with one in five women treated with paclitaxel. Median time to progression, duration of response and response rates among the evaluable population were also all significantly greater with docetaxel than paclitaxel. Response rates in the intent to treat population were also higher in the docetaxel group, although this increase was not statistically significant.(27)
In the TAX 311 trial, the incidence of neutropenia was significantly greater in patients who received docetaxel compared with paclitaxel. However, this was likely to be a consequence of the longer response achieved with docetaxel, which resulted in patients receiving an increased duration of docetaxel therapy – a median total of six cycles versus only four cycles of paclitaxel. Although the incidence of adverse events due to docetaxel was higher than for paclitaxel, this did not adversely affect patients’ quality of life as measured by the Functional Assessment of Cancer Therapy (FACT-B) measurement system. With regards to the increased incidence of febrile neutropenia (FN) observed with docetaxel compared with paclitaxel (15% versus 2%, respectively), it is of extreme relevance to note that it was in fact a prerequisite of this trial that patients had not received prophylactic granulocyte-colony stimulating factor (G-CSF) or antibiotics. It is well documented that the prophylactic use of G-CSF reduces the incidence of FN occurring from docetaxel administration.(28)
A recently published study reported a significant decrease in incidence of both FN (from 17% to 1%) and related hospitalisation (from 14% to 1%) in patients who received prophylactic G-CSF compared with those who received placebo.(29) A study by the Spanish Breast Cancer Research Group (GEICAM) comparing 5-fluoropyrimidine/anthracycline/ cyclophosphamide (FAC) combination therapy with the docetaxel/anthracycline/ cyclophosphamide (TAC) regimen reported a 25% incidence of FN in the TAC group.
A protocol amendment allowing prophylaxis with G-CSF starting with the first cycle of TAC resulted in a significant reduction in the incidence of FN to 5.8%.(30) Consequently, the trial investigators recommended that G-CSF be given as primary prophylaxis for patients receiving TAC and other regimens, stating that this recommendation is in accordance with the 2005 National Comprehensive Cancer Network guidelines, which suggest prophylactic G-CSF support for regimens associated with a FN rate of more than 20%.(31)
Differences in the taxoids have been known to exist since early preclinical investigations. In the metastatic setting, docetaxel is the only drug to have shown superiority over single-agent anthracycline therapy as well as combination regimens. At the present time, the choice of taxoid-based regimen should be based on consideration of pharmacokinetics, clinical activity and dosing schedule. Whereas both taxoids are fundamental components of therapy for metastatic breast cancer, the indirect comparison of trials, now backed by the results of the TAX 311 head-to-head study, demonstrates that docetaxel is the more clinically effective taxoid. In addition, the differences in the pharmacokinetic profiles of docetaxel and paclitaxel may explain the more simple treatment schedule and favourable results for docetaxel.
Trials that demonstrate significant differences in survival in the metastatic setting are rare, and the outcomes provide strong support for use of superior agents in the adjuvant setting. Therefore, the superior efficacy of docetaxel compared with paclitaxel that was observed in the TAX 311 study, which was achieved without impacting on patients’ quality of life, supports the use of full-dose docetaxel in the adjuvant setting.