Pilot study of ambulatory infusional delivery of a multidrug regimen: cisplatin, 5-fluorouracil and leucovorin (PFL) +/- etoposide.

PURPOSE: To determine the feasibility of ambulatory infusional administration 24 hours per day, 7 days per week of a three-drug regimen of cisplatin or carboplatin, leucovorin, and 5-fluorouracil (5-FU) (PLF) utilizing an alternating weekly sequential design and to introduce infusional etoposide as PLEF to the regimen. PATIENTS AND METHODS: Forty-three patients with diverse malignancies received a sequential infusion of 5-FU 200 mg/M2/day on days 1 to 14 and 21 to 35 with leucovorin admixed for day 1 to 7 and 21 to 28. Cisplatin (20 patients) or carboplatin (23 patients) infusion was administered at a dose of 10 mg/M2/day or 30 mg/M2/day, respectively, day 7 to 14 and 35 to 42. Cycles were planned to be repeated consecutively in the absence of toxicity in patients with stable or responding disease. Sixteen patients also received etoposide 30 mg/M2/day as an admixture concomitant with administration of the platinum analogue. Therefore, the distribution of therapies was PLF 19, CLF 8, PLEF 14, and CLEF 2. RESULTS: A total of 63 courses of PLF +/- E was administered as outlined above. Hematologic toxicity was minimal with or without the addition of etoposide. Sixteen percent of patients developed an elevated creatinine with a median of 1.6 and a range of 1.6 to 3.2 mg %. Tumor responses were observed in seven of fourteen evaluable patients with squamous cell carcinoma of the lung (all of whom received concomitant etoposide). In addition, one patient with metastatic gallbladder cancer achieved a complete clinical response. CONCLUSION: Ambulatory infusional PLF with carboplatin or cisplatin using sequentially alternating delivery of the component antineoplastic agents is feasible and active with minimal toxicity. The addition of infusional etoposide to the PLF regimen does not substantially increase hematologic toxicity. Extended phase II studies in aerodigestive cancers are ongoing and a phase III trial comparing this ambulatory regimen to short-term PLF infusion (5-day) may be justified to compare the relative cost and benefits of the two schedules.

Multi-day fractionated administration schedule for paclitaxel.

PURPOSE: To establish the feasibility of fractionating paclitaxel administration by utilizing daily one-hour infusions for three, four or five days with dose escalating to determine the patterns of hematologic and non hematologic toxicities. PATTERNS AND METHODS: Forty patients received 87 courses of daily fractionated paclitaxel for three, four or five days; cycles were repeated every 21 days. Six patients received concomitant daily cisplatin. The median number of cycles delivered per patient was two with a range of one to six. RESULTS: Cumulative doses per cycle ranged from 120 mg/m2 to 250 mg/m2 with 25% of the cycles delivering 200 mg/m2 or more. Ten cycles (11.5%) were associated with dose limiting neutropenia (grade 3 [7 cycles]; grade 4 [3 cycles]). No hypersensitivity reactions were observed and no patient required cytokine support. No patient required hospitalization. CONCLUSIONS: Administering paclitaxel on a daily fractioned schedule in an ambulatory setting is logistically feasible; does not require premedication; is associated with a toxicity pattern similar to single day schedules (e.g. 24-hour or three-hour infusion); is capable of delivering a higher dose per cycle than published 96- or 120-hour infusion schedules; and could possibly be escalated to doses higher than 250 mg/m2 in carefully selected patients. The optimal dose rate for five-day multifractionated administration of paclitaxel is 40 to 50 mg/m2/d or a cumulative cycle dose of 200 to 250 mg/m2 and does not require cytokine usage. Adding cisplatin on a fractionated daily schedule may accentuate the neurotoxicity associated with both agents. A prospective comparison of four-day fractionated vs. four-day continuous infusional paclitaxel has been proposed as a randomized study to determine clinical differences in response, dose intensity and toxicity.

Pilot study of ambulatory infusional ifosfamide admixed with carboplatin.

BACKGROUND: Ifosfamide and carboplatin are agents that have completed Phase I studies using a continuous infusion schedule for as long as 14 days. The in vitro compatibility of the two drugs allows for the simultaneous administration in an admixture, and a pilot study was undertaken to determine the feasibility and tolerability of the infusion schedule for the combination. METHODS: Ifosfamide at 500 mg/M2/day and carboplatin at 15 or 20 mg/M2/day were administered for 14-day cycles repeated at 28 days in 29 patients, with a total of 60 courses administered. RESULTS: Total cumulative dose per cycle was: ifosfamide 7.0 g/M2 and carboplatin 210-280 mg/M2. Hematuria developed in five patients, four of whom had prior urologic disease, severe thrombocytopenia, or pelvic radiation. In all patients, the hematuria was transient and inconsequential despite the absence of mesna. Grade 3 or 4 leukopenia was observed in eight patients with or without thrombocytopenia and delayed subsequent treatment cycles. Thrombocytopenia was less frequent (Grade 3, 2 patients: Grade 4, 1 patient). No significant episodes of sepsis or hemorrhage were noted. Anemia requiring transfusion developed in 12 of 29 patients. Twenty-one of the 29 patients had received prior chemotherapy. Five of seven previously untreated patients with non-small cell lung cancer achieved a complete (1) or partial (4) response. CONCLUSIONS: A continuous 14-day infusion of ifosfamide admixed with carboplatin is feasible in an ambulatory setting with no need for adding mesna for urologic protection and full dosage administration for each agent. Phase 2 studies in non-small cell lung cancer would be reasonable at the optimal doses of ifosfamide 500 mg/M2/day and carboplatin 15 mg/M2/day, and the potential exists for the introduction of additional agents, such as etoposide.