Question: What is the role of topotecan in the treatment of patients with progressive or relapsed ovarian cancer who have previously been treated with platinum-containing first-line chemotherapy? Perspective: Evidence was collected and reviewed by two members of the Gynecology Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. This practice guideline report has been reviewed, discussed, and approved by the Gynecology DSG, which includes gynaecologic, medical, and radiation oncologists, a pathologist, an oncology nurse, a community representative, and methodologists. Methodology: Sources of Evidence. A systematic search of the MEDLINE, CANCERLIT, and Pub Med databases, the Cochrane Library, and relevant conference proceedings was undertaken. Article bibliographies and personal files were also reviewed. Patient Population. Studies enrolling women with progressive or relapsed ovarian cancer who had been previously treated with platinum-containing first-line chemotherapy were eligible. Outcomes of Interest. Survival, response rate, and duration of response were the primary outcomes of interest. Adverse effects were also considered. Results: Search Results. Ten phase II studies (including a large international phase II trial) and a multi-centre phase III trial of topotecan met the inclusion criteria for this analysis. In regard to other chemotherapeutic agents, 11 phase II trials of paclitaxel, 5 phase II trials of hexamethylmelamine, 6 phase II trials of etoposide, 2 phase II trials of ifosfamide, and 1 phase II trial of 5-fluorouracil/leucovorin were reviewed. Benefits. Ten phase II studies have demonstrated activity for topotecan as a second-line agent. In these studies, patients receiving at least one platinum-based regimen (with or without paclitaxel) experienced tumour response rates in the 7-35% range. The weighted average response rate was 15% (95% confidence interval [CI]: 12-18%). One of these studies was a large phase II trial that evaluated topotecan as second-line therapy in patients who had failed prior platinum-based chemotherapy. Platinum-resistant and platinum-sensitive patients had response rates of 11% and 27%, respectively. The median time-to-response was 10.4 weeks for both groups. The best available evidence to date on this topic came from a multi-centre, randomised, stratified phase III trial that compared topotecan with paclitaxel for the treatment of patients with advanced ovarian cancer who had failed one platinum-based regimen. This trial found that patients receiving topotecan achieved a response rate of 21%, versus 14% for patients receiving paclitaxel (p = 0.196). It also found that, compared to patients receiving paclitaxel, patients receiving topotecan had a longer time-to-progression (median of 19 weeks vs. 15 weeks, p = 0.072), a longer median duration of response (26 weeks vs. 22 weeks, p = 0.476), a longer median time-to-response (8 weeks vs. 6 weeks, p = 0.147), and a longer estimated median survival (63 weeks vs. 53 weeks, p = 0.872). These differences were not statistically significant. Harms. Myelosuppression, particularly neutropenia, appears to be the most dose-limiting adverse effect of topotecan. Thrombocytopenia may be more of a problem with infusional protocols. It is recommended that topotecan be administered only in patients with adequate bone marrow reserve and that blood counts be monitored frequently. Caution might be considered with respect to potential bone marrow reserve in patients who have previously received whole abdominal or pelvic radiotherapy.
