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Docetaxel

An Update of its Use in Advanced Breast Cancer

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Summary

Abstract

Docetaxel, a semisynthetic member of the taxoid class of antineoplastic agents, is effective in the treatment of patients with advanced (locally advanced or metastatic) breast cancer. Reported objective response rates for docetaxel 100 mg/m2 ranged from 54 to 69% and 53 to 82% as first-line monotherapy or combination therapy, respectively. Objective response rates of 23 to 65% and 30 to 81% have been reported for docetaxel as second-line monotherapy or combination therapy, respectively. In Japanese studies, second-line docetaxel 60 mg/m2 produced objective response rates of 42 to 55%.

At the recommended dose of 100 mg/m2 given as a 1-hour intravenous (IV) infusion every 3 weeks, docetaxel had significantly greater efficacy than doxorubicin, mitomycin plus vinblastine and methotrexate plus fluorouracil, and similar efficacy to fluorouracil plus vinorelbine in pretreated patients with advanced breast cancer.

In chemotherapy-naive patients, first-line combined therapy with docetaxel and doxorubicin had significantly greater efficacy than doxorubicin plus cyclophosphamide. Promising results have been achieved in phase I/II trials of a weekly regimen of docetaxel (generally 30 to 45 mg/m2). Preliminary data indicate a potential role for docetaxel in the neoadjuvant therapy of early breast cancer.

The major dose-limiting adverse event associated with docetaxel is neutropenia. Although other adverse events are common, the tolerability profile of docetaxel is generally acceptable in the majority of patients, particularly in comparison with other antineoplastic regimens.

Conclusions: Although no single standard regimen has been identified as optimal for the treatment of advanced breast cancer, phase III trials have shown that docetaxel has improved efficacy over doxorubicin alone (considered one of the current gold standards), methotrexate/fluorouracil and mitomycin/vinblastine in second-line therapy. In combination with doxorubicin, docetaxel has demonstrated better efficacy than doxorubicin/cyclophosphamide in first-line therapy. These results provide a basis for therapy choice in advanced breast cancer. Clinical trials comparing docetaxel monotherapy versus paclitaxel monotherapy and versus docetaxel combination therapy are warranted. The role of docetaxel in the adjuvant and neoadjuvant treatment of early breast cancer is being evaluated.

Overview of Pharmacodynamic Properties

Docetaxel, a member of the taxoid class of antineoplastic agents, is derived from a precursor obtained from the European yew. The principal mechanism by which docetaxel is thought to exert its cytotoxic activity is through enhancement and stabilisation of microtubule assembly, while simultaneously preventing microtubule depolymerisation. In turn, this prevents normal cell division. Docetaxel has also been shown to induce cell death by apoptosis and cell lysis, to phosphorylate the apoptosis-blocking oncoprotein bcl-2 and to have antiangiogenic properties.

In vitro, docetaxel has often shown greater cytotoxic activity than that of paclitaxel against a range of human tumour cells, including breast cancer cells. Docetaxel has synergistic in vitro cytotoxicity when combined with several other agents, including topotecan, tamoxifen, fulvestrant, edatrexate and trastuzumab. Combined with irinotecan, docetaxel has antitumour activity in human breast tumour-bearing animals; against human tumour xenografts in mice, docetaxel enhances the activity of capecitabine. Docetaxel has also demonstrated in vivo antitumour activity alone and synergistic in vivo activity in combination with fluorouracil, cyclophosphamide, etoposide, methotrexate or vinorelbine. The radiopotentiating activity of docetaxel has been shown in animal models.

A number of mechanisms of cellular resistance to docetaxel have been identified: alterations in the tubulin subunits, increased expression of the multidrug resistance protein (mdr-1) gene-encoded membrane glycoprotein p170mdr−1, expression of the membrane phosphoglycoprotein MRP, and expression of the transmembrane glycoprotein p185c-erbB2. There is some evidence that resistance to doxorubicin or paclitaxel may not result in complete cross-resistance to docetaxel.

Overview of Pharmacokinetic Properties

At the recommended docetaxel dose of 100 mg/m2 administered as a 1-hour infusion, the pharmacokinetic profile of docetaxel is best described as a 3-compartment model. In contrast with paclitaxel, the disposition of docetaxel is linear. Approximately 93 to 94% of docetaxel is protein bound at clinically relevant concentrations. High interindividual variability of plasma binding most likely results from variable ga1-acid glycoprotein (AAG) concentrations.

Population pharmacokinetic studies indicate that docetaxel clearance is a strong predictor of grade 4 neutropenia and febrile neutropenia, whereas cumulative dose best predicts fluid retention. Clearance appears to be reduced in patients with elevated liver enzymes.

Docetaxel is primarily metabolised by cytochrome P450 enzymes to yield 4 inactive metabolites. The predominant route of docetaxel elimination is faecal excretion via the biliary tract, with approximately 4% of a dose eliminated unchanged in the urine. There appears to be no cross-race difference in docetaxel elimination between Western and Japanese patients.

In phase I clinical trials, the pharmacokinetic profile of docetaxel was not significantly altered by coadministration with fluorouracil, vinorelbine, ifosfamide, epirubicin or methotrexate. Docetaxel did not significantly affect the pharmacokinetics of doxorubicin. When docetaxel was administered before cisplatin as part of sequential therapy, cisplatin white blood cell DNA-adduct levels were significantly lower than when docetaxel was administered after cisplatin. Oral dexamethasone premedication 8mg twice daily for 5 days did not affect the pharmacokinetics of docetaxel.

Clinical Efficacy

Dose-finding studies established the optimal dose and schedule of docetaxel as 60 to 100 mg/m2 given as a 1-hour intravenous (IV) infusion every 3 weeks. In Japanese studies, the optimal docetaxel dose was established as 60 mg/m2 by 1-hour IV infusion every 3 weeks.

Monotherapy: Objective response rates obtained with docetaxel as second-line monotherapy in phase I/II trials have ranged from 23 to 65%. A large multicentre UK study of docetaxel in 331 pretreated patients with locally advanced or metastatic breast cancer yielded an objective response rate of 46% and a median survival of 194 days. In Japanese studies, docetaxel 60 mg/m2 produced objective response rates of 42 to 55% in 186 patients.

Docetaxel as second-line monotherapy demonstrated significantly better clinical efficacy (in terms of response rate and, in some studies, time to disease progression and overall survival) than doxorubicin, mitomycin/vinblastine or methotrexate/fluorouracil. However, its efficacy appeared similar to that of fluorouracil/vinorelbine in a preliminary report.

Although limited, data from trials evaluating weekly docetaxel administration indicate that response rates of about 55% can be achieved in previously treated patients with advanced breast cancer.

Objective response rates to docetaxel monotherapy in chemotherapy-naive patients have ranged between 54 and 69% in phase II trials. A large multicentre study (n = 288) reported objective responses in 59% of patients with a median duration of 9.2 months and a median time to disease progression of 7 months. Docetaxel as first-line monotherapy has not been adequately investigated compared with other antineoplastic agents.

Combination therapy: As second-line therapy, objective response rates ranged from 30 to 81% in trials that evaluated docetaxel in combination with fluorouracil, vinorelbine, epirubicin, doxorubicin, cisplatin, gemcitabine or mitoxantrone.

As first-line therapy, the combination of docetaxel and doxorubicin has been the most widely evaluated. Objective response rates for docetaxel/doxorubicin ranged from 55 to 78%, similar to those achieved for docetaxel in combination with other antineoplastic agents (range: 53 to 82%), including cisplatin, cyclophosphamide, epirubicin, mitoxantrone and vinorelbine.

Docetaxel 75 mg/m2 plus doxorubicin 50 mg/m2 produced a significantly greater objective response rate than doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (60 vs 47%, respectively; p = 0.008) in a phase III comparative trial in 429 anthracycline-naive patients. Response rates were also higher in subgroups of patients with unfavourable prognostic factors treated with combined docetaxel/doxorubicin than in those treated with doxorubicin/cyclophosphamide.

Limited data indicate that docetaxel, particularly in combination with doxorubicin, has efficacy in the neoadjuvant treatment of early breast cancer. Large ongoing trials should clarify the role of docetaxel in the adjuvant/neoadjuvant setting.

Sequential therapy: Docetaxel administered sequentially with doxorubicin plus cyclophosphamide produced a response rate of 71%, with a median duration of 53 weeks, median time to disease progression of 46 weeks and a median overall survival duration of 25 months. Alternate administration of docetaxel with fluorouracil/epirubicin/cyclophosphamide gave objective response rates of 64 to 68% depending on the order of administration.

Overview of Pharmacoeconomic Considerations

Cost-utility analyses, compiled in the absence of direct comparative clinical data, suggest that docetaxel offers utility gains versus paclitaxel in the treatment of metastatic breast cancer. The incremental cost for these gains is within the accepted range for healthcare interventions.

Tolerability

The most common adverse events (all grades) associated with docetaxel in phase II trials were neutropenia (91.5%), alopecia (83.4%), asthenia (68.2%), dermatological effects (64.3%), neurosensory effects (47.9%), fluid retention (46.7%), nausea (44.5%), diarrhoea (43.3%), mucositis/stomatitis (42.7%), fever (35.8%) and hypersensitivity reactions (31.3%). Neutropenia is the primary dose-limiting adverse event associated with docetaxel, occurring within 5 to 12 days of docetaxel administration and lasting for a mean duration of 7 to 8 days. Docetaxel 30 to 45 mg/m2 given as a weekly infusion appears to be associated with a lower incidence of haematological adverse events than the standard 3-weekly regimen.

Grade 4 neutropenia occurred with similar frequency in docetaxel or doxorubicin-treated patients in a comparative study, although the incidence of febrile neutropenia and severe infections was statistically higher in doxorubicin-treated patients. Docetaxel was also associated with a lower incidence of toxic deaths, anaemia, need for red blood cell transfusion and thrombocytopenia than doxorubicin. Quality-of-life evolution was relatively stable and not statistically significantly different between docetaxel- and doxorubicin-treated patients.

Overall, docetaxel tolerability compared favourably with combinations of mitomycin/vinblastine, methotrexate/fluorouracil and appeared better than fluorouracil/vinorelbine as second-line therapy in patients with advanced breast cancer. However, docetaxel was generally associated with a higher incidence of haematological adverse events than each of these drug combinations.

Docetaxel is commonly associated with neurological toxicity and, in phase III studies, this adverse event and fluid retention occurred more frequently in docetaxel-treated patients than in all other comparator treatment groups. Fluid retention, associated with the cumulative docetaxel dose, is possibly related to docetaxel-induced capillary permeability and insufficient lymphatic drainage.

Corticosteroid premedication delays the onset and reduces the incidence and severity of fluid retention and reduces the severity of hypersensitivity reactions; however, it has no effect on the incidence or severity of neurological events. Cardiac toxicity is not commonly associated with docetaxel, and the incidence of doxorubicin-induced cardiomyopathy does not appear to be influenced by docetaxel.

Dosage and Administration

The recommended starting dose and schedule of docetaxel for patients with advanced breast cancer is 60 to 100 mg/m2 in the US and 100 mg/m2 in Europe, administered as a 1-hour IV infusion every 3 weeks. Docetaxel 60 mg/m2 every 3 weeks is the recommended dose in Japan. The dose of docetaxel should be decreased or discontinued in patients experiencing febrile neutropenia, myelosuppression, severe or cumulative cutaneous reactions, severe peripheral neuropathy, or elevated liver function. All patients should receive oral corticosteroid premedication for 3 days to reduce the incidence and severity of fluid retention and the severity of hypersensitivity reactions.

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Correspondence to David P. Figgitt.

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Various sections of the manuscript reviewed by: G.J. Berchem, Centre Hospitalier De Luxembourg, Luxembourg; S. Chan, Department of Clinical Oncology, City Hospital, Nottingham, England; S.J. Clarke, Department of Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; M. D’Incalci, Department of Oncology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy; D. de Valeriola, Laboratoire d’Oncopharmacologie, Unité de Chimiothérapie, Institut Jules Bordet, Brussels, Belgium; P. Fumoleau, Department of Medical Oncology, Centre René Gauducheau, CRLCC Nantes-Atlantique, Nantes-St- Herblain, France; O. Pagani, Department of Oncology, Institute of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland; E. Salminen, Department of Radiotherapy and Oncology, Turku University Hospital, Turku, Finland; J.A. Sparano, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center (Weiler Division), Department of Medical Oncology, Bronx, New York, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on Docetaxel, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Docetaxel’ and ‘breast-cancer’ or ‘Docetaxel adj pd/pk’. Medline search terms were ‘Docetaxel’ and ‘breast-neoplasms’. Searches were last updated 29 February 2000.

Selection: Studies in patients with advanced breast cancer who received docetaxel. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Docetaxel, advanced breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use, adverse events, pharmacoeconomics, dosage and administration.

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Figgitt, D.P., Wiseman, L.R. Docetaxel. Drugs 59, 621–651 (2000). https://doi.org/10.2165/00003495-200059030-00015

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