Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer.
Paclitaxel is a new anticancer agent with a novel mechanism of action. It promotes polymerisation of tubulin dimers to form microtubules and stabilises microtubules by preventing depolymerisation. In noncomparative trials, continuous infusion of paclitaxel 110 to 300 mg/m2 over 3 to 96 hours every 3 to 4 weeks produced a complete or partial response in 16 to 48% of patients with ovarian cancer and 25 to 61.5% of patients with metastatic breast cancer, many of whom were refractory to treatment with cisplatin or doxorubicin, respectively. 23 to 100% of patients with ovarian cancer achieved complete or partial responses with paclitaxel in combination with cisplatin, carboplatin, cyclophosphamide, altretamine and/or doxorubicin. Similarly, response rates of 30 to 100% were observed with paclitaxel plus doxorubicin, cisplatin, mitoxantrone and/or cyclophosphamide in patients with metastatic breast cancer. Comparative trials in patients with advanced ovarian cancer showed paclitaxel therapy to produce greater response rates than treatment with parenteral hydroxyurea (71 vs 0%) or cyclophosphamide (when both agents were combined with cisplatin) [79 vs 63%]. Paclitaxel was also more effective than mitomycin in 50 patients with previously untreated breast cancer (partial response in 20 vs 4% of patients). Paclitaxel therapy also produced promising results in patients with advanced squamous cell carcinoma of the head and neck, malignant melanoma, advanced non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), germ cell cancer, urothelial cancer, oesophageal cancer, non-Hodgkin's lymphoma or multiple myeloma, and was successfully combined with cisplatin, carboplatin and/or etoposide in patients with NSCLC, SCLC or advanced squamous cell carcinoma of the head and neck. Hypersensitivity reactions were initially a concern with administration of paclitaxel, although current dosage regimens have reduced the incidence of these events to less than 5%. The major dose-limiting adverse effects of paclitaxel are leucopenia (neutropenia) and peripheral neuropathy. Other haematological toxicity was generally mild. Cardiac toxicity was reported in small numbers of patients and most patients developed total alopecia. Several aspects of paclitaxel use remain to be clarified, including the optimal treatment schedule and infusion time, confirmation of the tolerability profile and efficacy of combination regimens in an expanded range of malignancies. Long term follow-up of paclitaxel recipients will also allow the effects of the drug on patient survival to be determined. Nevertheless, paclitaxel is a promising addition to the current therapies available, with significant activity reported in patients with advanced ovarian or breast cancer or other types of tumors.(ABSTRACT TRUNCATED AT 400 WORDS)
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Adis International Limited, Auckland, New Zealand.
Faulds
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D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D017239:Paclitaxel