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Clinical Evidence for Topotecan-Paclitaxel Non–Cross-Resistance in Ovarian Cancer

From the Royal Marsden Hospital; Department of Oncology, North Middlesex Hospital, London; CRC Department of Clinical Oncology, City Hospital, Nottingham; YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield; SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom; Netherlands Cancer Institute, Amsterdam, The Netherlands; Texas Oncology PA, Dallas, TX; Institute of Obstetrics and Gynaecology, University School of Medicine, Poznan, Poland; Centre François Baclesse, Caen; Centre Oscar Lambret, Lille, France; Obstetric and Gynaecology Clinic, University of Milan, Milan; Department of Gynaecology, Civile Hospital, Voghera, Italy; Gynaecology and Oncology Department, University Hospital, Linköping, Sweden; Department of OB/GYN, Division of GYN Oncology, Albany Medical College of Union University, Albany, NY; and SmithKline Beecham Pharmaceuticals, Collegeville, PA.

Address reprint requests to Martin Gore, MD, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK; email: Martin.Gore{at}rmh .nthames.nhs.uk.

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non–cross-resistance between these two compounds.

PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m²/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m² over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy.

RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P = .638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients).

CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non–cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

S.Z.F. and G.R. are employees of SmithKline Beecham Pharmaceuticals.

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