A phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer

Purpose: In a phase II study with combination paclitaxel and cisplatin inmetastatic breast cancer using circadian timing, we attempted to maximiseresponse and minimise toxicity.Materials and methods: Forty-one patients with histologically-provenmetastatic breast cancer with or without previous chemotherapy were treatedwith Paclitaxel 135 mg/m² administered as a three-hourinfusion at 06.00 hours followed by cisplatin 75 mg/m² as aone-hour infusion at 18.00 hours utilising circadian timing. Six cycles wereplanned once every 21 days. Response assessment was performed every twocycles, and toxicity was measured using WHO criteria.Results: All patients were evaluable for response and toxicity. There werenine (22%) complete responses (CR), and 24 (59%) partialresponses (PR), for an overall response rate of 80% (95%confidence interval (CI) 69–92). Responses were seen in patientspreviously treated with anthracyclines (75%) (95% CI57–92), and in patients who had had no prior chemotherapy (90%)(95% CI 71–100). Responses were seen in all metastatic sites:liver 80%, lung 76%, bone 69%, and soft tissues71%. The overall median response duration was seven months (range3–26, 95% CI 5.0–9.8), and 14 of the responses(42%), (95% CI 28–62) were durable. A total of 212 cyclesof chemotherapy were given. There were 15 episodes (7%) of grade3–4neutropenia, seven (3.2%) of grade 3–4 neurologic toxicity, andthree(1.4%) of grade 3–4 nephrotoxicity. There were no toxic deaths.Conclusion: The combination of paclitaxel and cisplatin is very effectivein metastatic breast cancer, and with application of circadian timing,toxicity has been acceptable. This combination is being tested as primarytherapy in locally-advanced breast cancer at our institution.