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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.

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Forty-five patients received escalating dose rates of continuous infusion thio-triethylene thiophosphoramide (TEPA) for either five (26 patients) or 28 (19 patients) days. Dose rate limiting toxicity for the 5-day infusion was myelosuppression with leukocyte and platelet nadirs on days 21 and 28, respectively. The nadir was influenced by the presence and degree of liver disease. The optimal dose rate for 5-day infusion in the absence of liver disease was 12 mg/m2/d and was reduced to 8 mg/m2/d in patients with major liver disease. Dose rate limiting toxicity for the protracted 28-day infusion was leukopenia. The optimal dose rate for the 28-day infusion was 4 mg/m2/d. Pharmacologic studies included determination of plasma steady state concentrations (CSS) of thio-TEPA and TEPA. Dose rates up to 10 mg/m2/d produced thio-TEPA and TEPA CSS below the levels of detection of available analytical methodology, except in three patients infused at dose rates of 1, 2, and 4 mg/m2/d, respectively.

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Fifty-two patients received one of two doxorubicin (DOX)-based admixtures; DOX plus cyclophosphamide (CTX) or DOX plus vinblastine (VBL) administered as a continuous 24-hour infusion for protracted periods. Compatibility and stability of the two-drug admixture was established for a minimum of 7 days. Twenty patients on the DOX/CTX admixture were infused for a median of 20 days (range, 7-56 days). DOX/VLB was infused in 32 patients for a median of 18 days (range, 5-48 days). Dose limiting toxicity was leukopenia observed in 14/52 patients; 4/20 on DOX/CTX and 10/32 on DOX/VLB. Additional toxicities observed included stomatitis (15%) and subclavian vein thrombosis (23%). Tumor responses were observed in 11 patients, including 6/13 breast cancer; 2/2 hepatoma; 2/4 sarcoma and 1/1 ovarian cancer. Responses were relatively short-lived and no responses were noted in known anthracycline resistant tumors. Admixtures of chemotherapeutic agents represents a novel, but feasible, mechanism for delivery of multiple drugs with an infusion schedule and can be considered for Phase III comparative clinical trials.

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Infusion delivery systems have been evaluated for administration of many individual chemotherapeutic agents including 5-fluorouracil (5-FU) and methotrexate (MTX). This study combined the two drugs as an admixture, and in a Phase I trial design established a useful dose schedule for each of the component drugs. 5-FU at a fixed dose rate of 300 mg/M2/day was delivered with methotrexate (MTX) at four different dose rates (0.75, 1.0, 1.5, or 2.0 mg/M2/day, respectively). The drug solution was delivered via a subclavian venous access with a portable infusion pump in an ambulatory setting. Twenty-nine patients received a total of 38 courses of the two-drug infusion: 21 courses were delivered with the two agents admixed constantly throughout treatment (Schedule A) and 17 were administered the treatment with 5-FU delivered continuously and MTX added to the 5-FU for alternate 14-day cycles (Schedule B). For the former schedule, dose-rate-limiting toxicity was related to MTX and included stomatitis developing at days 8 to 14 (median, day 8) with the higher dose rates (1.5-2.0 mg/M2/day) and thrombocytopenia developing at days 11 to 56 (median, day 14) at the lowest dose rates (1.0 mg/M2/day). For Schedule B, dose-rate-limiting toxicity was similarly due to the MTX with thrombocytopenia and/or chemical hepatitis developing in six of seven courses of MTX at 1.0 mg/M2/day and in five of ten courses delivered at 0.75 mg/M2/day. On Schedule B the MTX-associated toxicities were reversed when the MTX administration was interrupted and in the face of continued 5-FU infusion. A reasonable dose rate and schedule for continuous infusion of 5-FU combined with MTX is: 5-FU 300 mg/M2/day X 28 days and MTX 0.75 mg/M2/day for days 1 to 14, with cycles administered consecutively each 28 days.

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Streptozotocin was administered at a dose of 500 mg/m2/day by continuous infusion for 120 hours to 14 patients with advanced malignant melanoma. No responses were observed in this group of patients and the median survival for the entire group was 2 months. At the dose and schedule delivered, streptozotocin is inactive against malignant melanoma.

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A three-drug regimen composed of adriamycin, 50 mg/m2 and cyclophosphamide, 500 mg/m2 administered on day 1; and VP-16-213, 50 mg/m2 days 1-5, with courses repeated at 3-week intervals, was studied in 24 consecutive patients with extensive-stage small cell lung cancer (SCLC). Twelve of 33 patients (36%) evaluable for toxicity developed life-threatening marrow suppression and 12% died of septicemia following the first course of treatment. Eleven of 24 patients (46%) with extensive disease achieved an objective response and only one was classified as a complete response. Survival was related to performance status and metastatic site but was not influenced by tumor response. The present study is distinctive from that of previous reports of the same or similar three-drug regimen in that the response rate is lower and toxicity is substantial. Nonetheless, survival as measured by median duration (7.9 months) and proportion alive at 1 year (35%) is comparable to that of previous reports.

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Twenty-six patients received vinblastine by ambulatory pump infusion via the subclavian vein for a median duration of 30 days of continuous therapy at an average dose rate of 0.5 mg/m2/day. Drug toxicity was minimal compared to the standard bolus schedule but bone marrow suppression was dose-limiting. There was no gastrointestinal or neurologic toxicity. The maximum duration of continuous therapy was 89 days (at 0.5 mg/m2/day) with the duration of therapy specifically related to the daily dose rate. Nondrug-related toxicity included subclavian vein thrombosis in two patients. Two of 11 patients with malignant melanoma had transient objective responses and 1/3 patients with soft tissue sarcoma had a partial response. Expanded phase II studies are ongoing at the dose of 0.5 mg/m2/day for a minimum duration of 30 days.

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A continuous infusion schedule for cisplatin employing a portable infusion pump was studied in a phase-I trial designed to establish an optimal daily dose rate to deliver drug for protracted periods (up to 30 days). Fifteen trials were carried out in 14 patients at daily dose rates of 5, 6.5, 7.5, and 10.0 mg/M2 X day. The median duration of therapy at the respective doses was 21, 17, 8, and 7 days. Dose-limiting toxicity was recalcitrant and protracted nausea was observed in all patients receiving greater than 5 mg/M2 X day. One patient did develop mild thrombocytopenia (98,000) at day 35. Renal failure was relatively minor considering the absence of a concomitantly delivered hydration regimen but 3 patients did develop a transient rise in serum creatinine, 2 of whom had a solitary kidney or partial urinary tract obstruction. No patient developed renal failure at 5 mg/M2 X day. At the recommended dose of 5 mg/M2 X day, the cumulative dose of cisplatin delivered by a protracted infusion schedule is comparable to the intermittent high-dose regimen with less adverse drug complications.

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