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The topoisomerase I inhibitor topotecan has shown antitumour activity against a variety of tumour types in vitro and in vivo. Topotecan in combination with drugs that induce DNA damage generally results in synergistic killing of tumour cells in vitro. As the activity of topotecan is related to exposure time, the drug is administered by intravenous infusion either continuously or once daily over a 30-minute period for several consecutive days.
A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of up to ≈20% in patients with advanced ovarian cancer who had failed to respond to platinum-based regimens or relapsed after initial response to such regimens. No significant differences in efficacy were apparent between topotecan and paclitaxel in a phase III study in patients with recurrent ovarian cancer, although a trend in favour of topotecan was evident for all major efficacy parameters.
Non-cumulative myelosuppression, including neutropenia, thrombocytopenia and anaemia, is the dose-limiting toxicity associated with topotecan. Myelosuppression was significantly more common with topotecan than with paclitaxel in a single comparative study. Non-haematological adverse events in topotecan recipients are generally mild and include alopecia, nausea, vomiting, and other gastrointestinal problems.
Thus, topotecan has modest efficacy in the treatment of recurrent advanced ovarian cancer, with clinical activity similar to that of paclitaxel in a large randomised phase III study in this setting. Combinations of paclitaxel and a platinum compound are being used increasingly for first-line therapy, although relapse rates remain significant. Topotecan is therefore a suitable second-line option, providing antitumour response for some patients whose disease has relapsed after, or is refractory to, platinum-based therapy. Its wider potential when used either alone or in combination regimens should become clearer from ongoing studies.
Topotecan is a water soluble semisynthetic derivative of camptothecin which exerts an antineoplastic effect by inhibiting the nuclear enzyme topoisomerase I.
The cytotoxicity of topotecan in vitro is related to exposure time and is significantly greater with continuous exposure to low concentrations of the drug than brief exposure to higher concentrations. Topotecan exhibited some selectivity for human ovarian tumour cells in vitro.
Intraperitoneal administration of topotecan 10 mg/kg once every 4 days increased median survival time in mice with an intraperitoneal human ovarian cancer xenograft and was more effective than doxorubicin 5 mg/kg, cisplatin 4 or 6 mg/kg and carboplatin 60 mg/kg.
The degree of enhancement of cytotoxicity with combinations of topotecan and a variety of other antineoplastic drugs depended on tumour type, duration of exposure, drug concentrations, calculation methods and drug sequence. The addition of drugs that induce DNA damage, such as cisplatin, carmustine or melphalan, to topotecan generally resulted in synergistic killing of hamster V79 cells and a variety of human cancer cell lines.
Classical multidrug-resistant Chinese hamster ovary cells expressing a high level of P-glycoprotein were modestly cross-resistant to topotecan and other camptothecin derivatives. Topotecan exhibited similar activity against susceptible and multidrug-resistant murine leukaemia in vivo.
Topotecan, like other camptothecin derivatives, is present in plasma as an active closed-ring lactone and an inactive open-ring form (carboxylate). After intravenous infusion of topotecan 0.5 to 22.5 mg/m2 /day over a 30-minute period, there was a linear relationship between dose and mean peak plasma concentrations and the area under the plasma concentration-time curve for the lactone. During 24-hour infusion steady-state concentrations of the carboxylated form were 1.5 to 1.9 times those of the lactone in adults.
Protein binding of topotecan is low (6.6 to 31.3%) and apparent volume of distribution (Vd) has varied between 15 and 86.1 L/m.
Reported mean total plasma clearance (CL) rates were between 17.2 and 69.5 L/h/m2 for the lactone and between 6.5 and 30 L/h/m2 for total topotecan. 24-hour urinary recovery rates were between 20.4 and 41.6%. Mean elimination half-lives were between 1.78 and 4.7 hours.
In patients with impaired renal function (creatinine clearance <3.6 L/h) values for CL and Vd were about half those in patients with normal renal function. Pharmacokinetic parameters are not influenced by hepatic impairment.
A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks produced response rates of 13.8 to 20.5% in the 3 largest phase II/III studies in women with advanced ovarian cancer who had either failed to respond to or had relapsed after an initial response to platinum-based chemotherapy (n = 92 to 139). Continuous 21-day infusion of topotecan 0.3 to 0.5 mg/m2 has shown efficacy in 2 small phase II studies.
There were no statistically significant differences in efficacy between topotecan (1.5 mg/m /day for 5 consecutive days every 21 days) and paclitaxel (175 mg/m /day given over 3 hours every 21 days) in a randomised phase III study in women with advanced ovarian cancer that had failed to respond to or had relapsed after platinum-based therapy. However, a trend in favour of topotecan was evident for response rate (20.5 vs 14.0%) as well as for response duration, time to disease progression and survival duration.
In 3 large clinical trials, response to topotecan was higher in patients who were platinum sensitive (19.2 to 29%) than in those whose disease was platinum resistant or refractory (11.3 to 13.3%) [not statistically significant in 1 study, statistical analysis not reported in the other 2 trials].
Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of topotecan. It is reversible, dose-related and non-cumulative. In 2 large studies, topotecan produced grade 4 neutropenia in 78 and 79% of patients and in 40 and 37% of all treatment courses (febrile neutropenia occurred during 3% of 552 courses in 1 study). Grade 4 thrombocytopenia was seen in 18 and 25% of patients and in 6 and 10% of all courses, respectively. Grade 4 neutropenia was significantly more common in patients receiving topotecan than in those receiving paclitaxel (79 vs 23%), as was grade 4 thrombocytopenia (25 vs 2%), in a single randomised clinical trial.
Non-haematological adverse events during topotecan therapy were mostly mild, did not necessitate dose reduction, and included alopecia, nausea, vomiting, other gastrointestinal effects, stomatitis, dyspnoea and asthenia. Patients receiving topotecan experienced more nausea and vomiting, fatigue, constipation and fever than paclitaxel recipients in a single randomised trial (paclitaxel recipients were pretreated with dexamethasone and histamine H1 receptor antagonists for hypersensitivity reactions, which may have contributed to the lower incidence of nausea and vomiting). Paclitaxel recipients had a higher incidence of alopecia, abdominal pain, arthralgia, myalgia and neuropathy than topotecan recipients (statistical analysis of between-group differences was not provided).
Dosage and Administration
The recommended dosage regimen of topotecan for the treatment of women with advanced ovarian cancer is 1.5 mg/m2 /day by intravenous infusion over 30 minutes for 5 consecutive days starting on day 1 of a 21-day course. A minimum of 4 courses is recommended because median time to response has been 9 to 12 weeks.
Before starting treatment with topotecan, patients must have a baseline neutrophil count of >1500 cells/μl and a platelet count of >100 000/μl.
Dosage should be reduced to 0.75 mg/m2 /day in patients with moderate renal impairment [creatinine clearance <40 ml/min (2.4 L/h)].
KeywordsOvarian Cancer Paclitaxel Adis International Limited Lactone Epithelial Ovarian Cancer
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