Docetaxel

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Abstract
Docetaxel is a member of the taxoid class of antineoplastic agents. Its mechanism of action is primarily related to its ability to enhance microtubule assembly and to stabilise microtubules by preventing their depolymerisation, thus disrupting normal cell division. Docetaxel has significant cytotoxic activity against human breast cancer cell lines and freshly explanted human breast cancer cells in vitro. It has also shown activity in mice against mammary tumours and human mammary tumour xenografts. Docetaxel has been investigated in the treatment of patients with advanced and/or metastatic breast cancer in European and North American phase II trials using an initial dose of 100 mg/m infused over 1 hour every 3 weeks. As first-line treatment, monotherapy with docetaxel was associated with complete and partial response rates of 5 to 16% and 49 to 53%, respectively, with an overall (complete plus partial) response rate of 54 to 68%. The median overall survival time of patients in one study was ≥71 weeks. Docetaxel monotherapy has shown impressive activity as second-line therapy in patients with metastatic breast cancer who had relapsed while receiving adjuvant therapy or who had progressive disease following previous treatment, with overall response rates of 53 and 58% reported in 2 studies. A number of issues need to be addressed before the ultimate place of docetaxel in the management of metastatic breast cancer is fully established. The efficacy of docetaxel compared with standard agents and in combination regimens and its effect on quality-of-life aspects require further evaluation. Nevertheless, docetaxel is a promising new agent which has produced impressive clinical results and should be considered an alternative second-line treatment of patients with metastatic breast cancer. The cytotoxic activity of docetaxel is believed to primarily result from its ability to enhance microtubule assembly and to stabilise microtubules, preventing their depolymerisation and thus preventing normal cell division. This mechanism is supported by in vitro studies which demonstrate that docetaxel reduces the lag time for the initiation of polymerisation, decreases the minimum concentration of tubulin required for microtubule assembly and induces polymerisation in the near absence of the microtubule assembly cofactor guanosine 5-triphosphate. In vitro studies in human breast cancer cell lines or in freshly explanted human breast cancer cells show docetaxel has significant cytotoxic activity, which in most instances is greater than that reported for paclitaxel in fresh cell isolates. Docetaxel had in vivo activity against 3 of 4 murine mammary tumours studied and, at the highest tolerated dose, produced complete regression in 100% (30/30) of nude mice with human mammary tumour xenografts. Docetaxel dernonstrated schedule-dependent in vitro synergism against human breast cancer cell lines when combined with edatrexate. Synergism has also been observed in mice with mammary adenocarcinoma receiving docetaxel plus cyclophosphamide. Acquired resistance to docetaxel occurs via two identified mechanisms; one is associated with the expression of the multidrug resistance phenotype, whereas the other is associated with alterations in tubulin. Cross-resistance between docetaxel and other antitumour agents has been reported in many, but not all, cell lines which express the multidrug resistance phenotype, which suggests that cross-resistance does not automatically occur in cells expressing this gene. At doses ≥70 mg/m2, the pharmacokinetic profile of docetaxel fitted a 3-compartment model. The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were proportional to dose. In 2 studies, Cmax values were 2.41 and 3.67 mg/L and AUC values were 5.93 and 4.59 mg/L · h after doses of 100 mg/m2 administered over 1 hour. The drug is 93 to 94% protein bound. Docetaxel is primarily metabolised by cytochrome P450 (CYP) enzymes, and 4 largely inactive major metabolites have been identified. The predominant route of elimination is metabolism then faecal excretion via the biliary tract. A population pharmacokinetics study in 547 patients who received docetaxel in phase II trials estimated total body clearance and elimination half-life to be, respectively, 21 L/h · m2 and 11.2 hours. Clearance appears to be reduced in patients with moderate hepatic dysfunction. The in vitro metabolism of docetaxel is reduced by drugs which are substrates of the CYP3A4 isozyme (erythromycin, ketoconazole, nifedipine, troleandomycin, testosterone, orphenadrine and midazolam). Some in vitro inhibition of docetaxel metabolism was also produced by vinorelbine, vinblastine and doxorubicin; however, other drugs including cisplatin, fluorouracil, cyclophosphamide and etoposide had little effect on the in vitro metabolism of docetaxel. When docetaxel was administered prior to cisplatin as part of sequential therapy, the white blood cell DNA-adduct levels of cisplatin were significantly lower than when cisplatin was administered first. In dose-finding studies in patients with various solid tumours, the maximum tolerated dose of docetaxel was 80 to 115 mg/m2 per course of therapy. Based on these results, a dose of 100 mg/m2 infused once every 3 weeks was considered to be optimal for phase II trials in Europe and North America. In Japan, a lower dosage (60 mg/m2/3 weeks) was used. Four trials have evaluated docetaxel 100 mg/m2 every 3 weeks as first-line therapy in 137 evaluable patients with advanced and/or metastatic breast cancer. Complete response was reported in 5 to 16% of patients and partial response in 49 to 53%. The overall response rate (complete plus partial response) ranged from 54 to 68%. One study reported no difference in response rates between patients who had received prior adjuvant chemotherapy and those who had not. In this study, the median duration of response was ≥44 weeks and the median overall survival time was ≥71, weeks. In 2 studies which used a dosage of 75 mg/m2 every 3 weeks, the overall response rates were 40 and 52%. Docetaxel 100 mg/m2 /3 weeks has also been evaluated as second-line therapy in patients with histologically and/or cytologically verified advanced and/or metastatic breast cancer who had relapsed while receiving adjuvant therapy or who had progressive disease following previous treatment. In 2 studies which evaluated a total of 69 patients with anthracycline- or anthracenedione-resistant breast cancer, 3 patients experienced a complete response, and the partial response rates were 49 and 53%. In Japanese trials evaluating docetaxel 60 mg/m every 3 to 4 weeks, complete and partial response rates ranged, respectively, from 4 to 7% and 37 to 50% in 186 patients, most of whom had received prior chemotherapy. Neutropenia is the primary dose-limiting adverse effect of docetaxel after short term infusion, occurring in >90% of patients receiving docetaxel 100 mg/m2. However, neutropenia is generally rapidly reversible, with only 14.8% of patients requiring hospitalisation and/or treatment with antibiotics. Fluid retention, usually characterised by peripheral oedema, is related to the cumulative dose of docetaxel. However, premedication with corticosteroids delays the onset of this adverse event. Hypersensitivity reactions occur in 31.3% of patients, are usually observed within minutes of administration of docetaxel, and are reversible upon discontinuing the infusion. Premedication decreases the severity of hypersensitivity reactions and discontinuation of therapy is required only rarely. Various types of cutaneous events including mucositis, desquamation and nail changes have been reported in a large proportion of patients (up to 70%). Other reported adverse events include peripheral neuropathy, alopecia, asthenia, nausea and diarrhoea. The recommended initial intravenous dose of docetaxel is 100 mg/m2 infused over 1 hour every 3 weeks. Pretreatment with corticosteroids is recommended to reduce the incidence of docetaxel-related fluid retention and the severity of hypersensitivity reactions. Dosage reductions are recommended in patients with severe drug-related toxicity and in those with hepatic dysfunction.