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Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Purpose: Our first objective was to evaluate the feasibility of administering a combination of Doxil, a pegylated liposome formulation of doxorubicin, and cisplatin and to determine the maximum tolerated dose of the combination. A secondary objective was to examine Doxil peak and 7-day postinjection plasma levels at the various dose levels tested.
Methods: Patients with advanced solid tumors were treated every 4 weeks with cisplatin on day 1 and Doxil on day 2. In the first three dose levels, the dose of Doxil was fixed at 40 mg/m2, whereas the dose of cisplatin was escalated from 40 to 50 and 60 mg/m2. At the fourth and fifth dose levels, the dose of cisplatin was fixed at 60 mg/m2, whereas the dose of Doxil was escalated to 50 and to 60 mg/m2. Plasma Doxil (doxorubicin-equivalent) levels were measured by a high-performance liquid chromatography assay with fluorescence detection at 1 h and 7 days after infusion of Doxil.
Results: Twenty-six patients entered the study. Twenty-four patients completed a minimum of 2 courses and were fully assessable for toxicity and efficacy. Eighteen patients had received prior chemotherapy, 11 of them with anthracycline-containing regimens. A total of 177 courses were administered within the study. In 12 patients, cisplatin was discontinued after 1 to 13 courses, and Doxil was continued alone for 1–22 courses. All other patients received both drugs until discontinuation of therapy. The dose-limiting toxicities were neutropenia and mucositis. Grade 4 neutropenia was seen in 3 patients (one with neutropenic fever) at dose levels 4 and 5. Grade 3 mucositis was observed in 4 patients at dose levels 3, 4, and 5. In contrast, the most severe palmar-plantar erythrodysesthesia manifestation was grade 2 seen in 1 patient only. Tumor responses included seven partial responses, of which three were in ovarian cancer patients. In four of seven responders, the time to disease progression exceeded 1 year. Doxil 1-h (Cmax equivalent) levels were assessed in 20 patients. The mean Doxil Cmax (mg/l plasma) increased gradually with dose escalation from 14.7 ± 1.9 for 40 mg/m2, to 17.3 ± 3.0 for 50 mg/m2, and 23.3 ± 5.5 for 60 mg/m2. The 60 mg/m2 Cmax was similar to data obtained in parallel clinical studies at our institution with single-agent Doxil at 60 mg/m2. However, the 7-day Doxil postinfusion levels were significantly lower in patients receiving the Doxil-cisplatin combination than in those receiving single-agent Doxil.
Conclusion: Doxil can be administered at full maximum tolerated dose (50 mg/m2 every 4 weeks) in combination with 60 mg/m2 cisplatin, with no evidence of major overlapping toxicities. Palmar-plantar erythrodysesthesia incidence and severity appears to be diminished, in comparison with data available for single-agent Doxil. Plasma concentration data point to an accelerated clearance of Doxil when administered after cisplatin.
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