- 429 Downloads
Docetaxel (Taxotere®), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.
Docetaxel is an antimicrotubule agent that principally exerts its cytotoxic activity by promoting and stabilising microtubule assembly while simultaneously preventing microtubule depolymerisation. This results in inhibition of normal cell division. In vitro and in vivo, docetaxel has antineoplastic activity against a wide range of cancer cells, demonstrates synergistic activity with several antineoplastic agents and often has greater cytotoxic activity against human breast cancer cell lines than paclitaxel.
The pharmacokinetics of docetaxel are linear at clinically relevant doses and are consistent with a three-compartment model. Docetaxel is highly bound to plasma proteins, but has a large volume of distribution at steady state. It is primarily metabolised by the cytochrome P450 3A4 isoenzyme and is excreted primarily faecally via the biliary tract. Clearance of the drug is a strong independent predictor of severe haematological toxicity in cancer patients.
In women with metastatic breast cancer previously exposed to anthracyclines or alkylating agents, docetaxel monotherapy was associated with median values for overall survival of 10.4–16.0 months, objective response rate (ORR) of 30.0–47.8% and time to tumour progression (TTP) of 4.4–6.5 months. In head-to-head comparative trials, docetaxel monotherapy was at least as effective (in terms of overall survival time, ORR and TTP) as doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and was more effective than methotrexate plus fluorouracil or mitomycin plus vinblastine. Median values for survival time (15.4 vs 12.7 months), TTP (5.7 vs 3.6 months) and response duration (7.5 vs 4.6 months) were significantly (p ≤ 0.03) longer with docetaxel than with paclitaxel. Differences between docetaxel and comparators in health-related quality-of-life outcomes were generally not significant.
In phase III combination therapy studies, docetaxel combined with doxorubicin or epirubicin resulted in similar overall survival to clinically relevant comparator combinations. Outcomes were similar with docetaxel plus either capecitabine or gemcitabine and the former combination was more effective than docetaxel monotherapy.
While severe adverse events were common, the tolerability of docetaxel in comparative clinical trials was generally acceptable. Severe neutropenia affects most docetaxel recipients, with febrile neutropenia occurring in approximately one-eighth of patients. Dose-cumulative severe fluid retention was reported in 6.5% of docetaxel recipients, despite premedication with prophylactic corticosteroids. Other grade 3 or 4 adverse events include asthenia, stomatitis, infections, neurosensory, cutaneous or gastrointestinal events, nail changes, severe fever in the absence of infection, myalgia and hypersensitivity reactions.
In comparative monotherapy trials, neutropenia generally occurred more often with docetaxel than with comparators, excepting doxorubicin, where the incidence was similar. Other severe haematological, cardiac and gastrointestinal adverse events were less frequent with docetaxel than with doxorubicin. Docetaxel was associated with significantly higher incidences of grade 3 or 4 neutropenia and febrile neutropenia and several non-haematological adverse events than paclitaxel; however, patients in the docetaxel arm received more cycles of therapy than those in the paclitaxel arm (six vs four cycles). Docetaxel tolerability in combination therapy regimens was generally similar to that of comparator drugs, apart from a higher incidence of haematological adverse events.
KeywordsPaclitaxel Doxorubicin Docetaxel Trastuzumab Metastatic Breast Cancer
At the request of the journal, Aventis Pharmaceuticals Inc. provided a non-binding review of this article.
- 1.American Cancer Society. Cancer facts and figures 2005. Atlanta (GA): American Cancer Society, 2005Google Scholar
- 2.National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology — v.2.2005: breast cancer [online]. Available from URL: http://nccn.org [Accessed 2005 Aug 8]
- 3.National Cancer Institute. Breast cancer (PDQ): treatment [online]. Available from URL: http://www.cancer.gov [Accessed 2005 Aug 8]
- 11.Kollin CA, Evans SS, Su Y-Z, et al. A direct comparison of paclitaxel and docetaxel activities in human tumors [abstract no. 655]. Proc Am Soc Clin Oncol 2003; 22: 163Google Scholar
- 17.Desmedt C, Tanner M, Angelo DL, et al. p-53 gene mutations as a predictive marker in advanced breast cancer patients randomly treated either with doxorubicin or with docetaxel [abstract no. 1034]. Breast Cancer Res Treat 2004; 88 Suppl. 1: S52Google Scholar
- 18.Aventis Pharma. Taxotere (docetaxel) injection concentrate: US prescribing information. Bridgewater (NJ): Avenus Pharmaceuticals Inc., 2005 FebGoogle Scholar
- 23.Alexandre J, Rey E, Dieras V, et al. Prospective study of predictive factors of docetaxel (DCX)-induced febrile neutropenia (FN): relevance of in vivo cytochrome 3A (CYP3A) phenotyping [abstract no. 2046]. J Clin Oncol 2005; 23 (16 Suppl. Pt 1): 146SGoogle Scholar
- 24.Yamamoto N, Tamura T, Murakami H, et al. Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol. J Clin Oncol 2005 Feb 20; 23(6): 1061–9PubMedCrossRefGoogle Scholar
- 25.European Medicines Agency. Taxotere: summary of product characteristics [online]. Available from URL: http://www.emea.eu.int [Accessed 2005 Aug 8]
- 26.Esposito M, Venturini M, Vannozzi MO, et al. Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 1999; 17(4): 1132–40Google Scholar
- 30.Sjöström J, Blomqvist C, Mouridsen H, et al. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer 1999; 35: 1194–201PubMedCrossRefGoogle Scholar
- 33.Pieńkowski T, Jagiello-Gruszfeld A, Glinka-Malasnicka E, et al. Docetaxel as a second line treatment in patients with metastatic breast cancer after previous chemotherapy regimen including anthracyclines: a non-randomised multicenter study. Nowotwory 2000; 50 Suppl. 2: 15–22Google Scholar
- 37.Hakamies-Blomqvist L, Luoma ML, Sjöström J, et al. Quality of life in patients with metastatic breast cancer receiving either docetaxel or sequential methotrexate and 5-fluorouracil: a multicentre randomised phase III trial by the Scandinavian Breast Group. Eur J Cancer 2000 Jul; 36: 1411–7PubMedCrossRefGoogle Scholar
- 39.Alba E, Martin M, Ramos M, et al. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEI-CAM-9903) phase III study. J Clin Oncol 2004 Jul 1; 22(13): 2587–93PubMedCrossRefGoogle Scholar
- 40.Blohmer JU, Hauschild M, Hilfrich J, et al. Safety and efficacy of first-line epirubicin-docetaxel versus epirubicin-cyclophosphamide: a multicenter randomized phase III trial in metastatic breast cancer [abstract no. 627]. Proc Am Soc Clin Oncol 2004 Jun 5; 23: 33Google Scholar
- 41.Mackey JR, Paterson A, Dirix LY, et al. Final results of the phase III randomized trial comparing docetaxel, doxorubicin and cyclophosphamide to FAC as first line chemotherapy for patients with metastatic breast cancer [abstract no. 137]. Proc Am Soc Clin Oncol 2002 May; 21 (Pt 1): 35aGoogle Scholar
- 43.Chan S, Romieu G, Huober J, et al. Gemcitabine plus docetaxel versus capecitabine plus docetaxel for anthracycline-pretreated metastatic breast cancer patients: results of a European phase III study [abstract no. 581]. J Clin Oncol 2005 Jan 1; 23 (16 Suppl. Pt 1): 24SGoogle Scholar
- 45.Reyes S, Torrecillas L, Acosta A, et al. Capecitabine and taxanes: combination versus sequential therapy in anthracycline-pretreated metastatic breast cancer (MBC): findings from the Mexican Oncology Study Group (MOSG) phase III trial [abstract no. 447]. EJC Suppl Sep 2003; 1(5): S136Google Scholar
- 61.Marty M, Cognetti F, Maraninchi D, et al. Randomised phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005 Jul 1; 23(19): 4265–4274PubMedCrossRefGoogle Scholar
- 68.Ghersi D, Wilcken N, Simes J, et al. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2005 Apr 18; (2): CD003366Google Scholar
- 71.Bristol-Myers Squibb Company. Taxol (paclitaxel) injection: prescribing information. Princeton (NJ): Bristol-Myers Squibb Company, 2003 MarGoogle Scholar
- 73.Smith RE, Brown AM, Mamounas EP, et al. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-2. J Clin Oncol 1999 Nov; 17(11): 3403–11PubMedGoogle Scholar