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City Hospital Birmingham
Among the novel chemotherapeutic drugs introduced in the 1990s, the taxoids have emerged as the most powerful compounds in metastatic breast cancer. Until this time, only indirect clinical comparisons of these agents had been performed, which were imprecise owing to differences in patient populations.
The recently published TAX 311 study addressed this need and is the only head-to-head randomised phase III study comparing directly the efficacy and safety of docetaxel (Taxotere(®)) and paclitaxel (Taxol(®)) as second-line treatment for patients with advanced breast cancer. In this large study, 449 patients were randomised to receive the Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products (EMEA) approved doses of docetaxel (n=225) or paclitaxel (n=224). Compared with paclitaxel, docetaxel exhibited a superior efficacy profile – manifested by a longer overall survival and time to progression – without compromising quality of life.(1)
With the introduction of targeted therapies, trastuzumab has been identified as the treatment of choice for patients with human epidermal growth factor receptor (HER)2+ disease.(2) In an attempt to maximise the potential of this agent in breast cancer, investigations were conducted to assess its performance with cytotoxic agents, in particular the taxoids. Preclinical studies used combination index (CI) values to classify the interaction between taxoids and trastuzumab. Values less than 1.0 indicated a synergistic interaction, and values equal to 1.0 indicated an additive effect. The results revealed that the combination of trastuzumab with paclitaxel had an additive effect, with CIs in the range of 0.85–0.91. However, the combination of trastuzumab with docetaxel was found to be synergistic, with CIs in the range of 0.30–0.62.(3) The advantage of the docetaxel/trastuzumab combination has now been demonstrated in the clinical setting, with the recently published M77001 trial reporting an impressive overall survival of 31.2 months for this combination – significantly greater than the corresponding 22.7-month figure for docetaxel monotherapy.(4) A similar trial investigating the trastuzumab/paclitaxel combination reported an overall survival of 22.1 months, which did not differ significantly from that achieved with paclitaxel alone.(5) Importantly, the efficacy gain for the docetaxel/trastuzumab combination was achieved without a significant increase in cardiotoxicity, the incidence of symptomatic heart failure being 2% versus 0% for the combination and monotherapy, respectively.(4) When compared with the reported 28% risk for heart failure associated with a trastuzumab/doxorubicin combination,(6) and a 9% incidence of cardiotoxicity among patients receiving a paclitaxel/trastuzumab combination,(7) the absence of an increase in cardiotoxicity observed with the trastuzumab/docetaxel combination suggests that docetaxel may at least be a more suitable partner for trastuzumab than doxorubicin.
Even with the TAX 311 results(1) in mind, the decision as to which taxoid to use may not be immediately apparent. However, a number of differences between these agents contribute to the patient management approach that is required for each therapy. For example, differences in the toxicity profiles of docetaxel and paclitaxel necessitate different premedication regimens for these agents. As such, in the TAX 311 trial, only one premedication (dexamethasone) was required for docetaxel, whereas three (dexamethasone, diphenhydramine and cimetidine or ranitidine) were required for paclitaxel.(1) Dexamethasone premedication has been further simplified by a recent development outlining that a three-day regimen is as effective as the originally recommended five-day regimen.(8)
Although neutropenia commonly occurs after administration of docetaxel, the nadir appears early, at days 5 to 7, and is of relatively short duration. The incidence of docetaxel- induced febrile neutropenia (FN) in the TAX 311 trial was 14.7%; however, it was a prerequisite that patients had not received granulocyte-colony stimulating factor (G-CSF) prophylaxis. Prevention of FN occurrence in at-risk patients can be effectively achieved through tailoring therapy by dose reduction. Investigation of the dose–response relationship for docetaxel in patients with advanced breast cancer demonstrated a reduction in FN incidence from 14% for the 100mg dose to 5% for a 60mg dose. The demonstration of maintained efficacy across this range of doses identifies the flexibility of docetaxel therapy for such patients.(9) The benefits of G-CSF prophylaxis in the adjuvant setting have been clearly demonstrated by a significant reduction in the incidence of FN from 24.6% to 5.8% in patients receiving the TAC (docetaxel/anthracycline/ cyclophosphamide) regimen,(10) and it is accepted that such practice is a viable option for these patients. The situation for patients with metastatic disease is less clear, but data supporting such practice do exist. A recently published study in a cohort comprising approximately 60% of patients with metastatic disease reported a significantly lower incidence of FN (1% versus 17%) and related hospitalisation (1% versus 14%) in patients who received G-CSF compared with those who were given placebo.(11)
Ease of scheduling is also a factor to be borne in mind. Docetaxel exhibits linear pharmacokinetics, whereas paclitaxel exhibits nonlinear pharmacokinetics.(12) Although these differences may support a simpler treatment schedule for docetaxel than paclitaxel, as seen by the recommended administration times of one hour for docetaxel versus three hours for paclitaxel, the practicalities of a busy clinic mean that the advantages of docetaxel are most apparent when it is used as combination therapy. This is particularly important in patients who are classified as being at increased risk of a cardiac event. In such situations, a long infusion time is required for paclitaxel in order to prevent interaction with doxorubicin, an effect that has been shown, in some studies,(13,14) to result in an increase in cardiotoxicity. In contrast, there is no interaction between docetaxel and doxorubicin(15,16) and, accordingly, there is no evidence of increased cardiotoxicity for this combination compared with conventional anthracycline-containing regimens.
Such interactions have implications for the adjuvant treatment of breast cancer. For example, the TAC regimen is an efficacious regimen with a less than 2% incidence of congestive heart failure.(17) The demonstrated efficacy of the docetaxel/trastuzumab combination in the metastatic setting, in spite of the exclusion of an anthracycline, and the subsequent lack of cardiotoxicity of this doublet(4) offer a real hope for its use in the adjuvant setting. Similarly, preliminary phase II(18) and pending phase III data from the Breast Cancer International Research Group (BCIRG) 007 trial suggest that triple therapy comprising trastuzumab, docetaxel and carboplatin may be a promising option for patients with metastatic HER2+ disease. The advantages of such combinations look set to extend to the adjuvant setting, and the BCIRG 006 study will shortly report on the efficacy and safety of both triple therapy with trastuzumab/docetaxel/carboplatin and of sequential docetaxel/trastuzumab therapy following a doxorubicin/cyclophosphamide doublet.
A number of factors need to be taken into account when considering the use of taxoid therapy. Docetaxel has demonstrated superior efficacy over paclitaxel in the metastatic setting, and it also has a favourable interaction profile with both anthracyclines and trastuzumab. It is clear that improvements are being made in the treatment of metastatic breast cancer, but, as is the nature of chemotherapy, inevitably toxicities exist. The availability of therapies with demonstrated efficacy advantages, such as docetaxel, and of effective G-CSF prophylaxis and dose reduction strategies for managing FN means that the oncology team is in a position to tailor chemotherapy and supportive therapy to obtain the best possible outcomes in the breast cancer clinic.