Seminars in oncology
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Phase I studies of CPT-11 (irinotecan) have been conducted in Europe, the United States, and Japan to determine the maximum tolerated dose (MTD) and the most appropriate intravenous administration schedule for further evaluation in phase II investigations. Diarrhea and/or neutropenia were the major dose-limiting toxicities in all the phase I studies. In Japanese and US investigations, the CPT-11 MTD was defined as 240 to 250 mg/m2 using a once every 3 weeks schedule and 100 and 150 mg/m2 using a weekly schedule. ⋯ European experience with a single infusion every 3 weeks showed diarrhea to be dose limiting at 350 mg/m2, but concomitant administration of high-dose loperamide allowed administration of CPT-11 at doses of up to 600 mg/m2. This latter schedule was better tolerated, achieved the highest dose intensity, and was considered to confer greater convenience in an outpatient setting when compared with the other European regimens. European phase II studies were therefore commenced using a CPT-11 schedule comprising a single intravenous infusion every 3 weeks at a dose of 350 mg/m2.
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Seminars in oncology · Feb 1996
ReviewRole of chemotherapy for advanced colorectal cancer: new opportunities.
Since the late 1950s, 5-fluorouracil (5-FU) has remained the most effective chemotherapeutic agent in the treatment of advanced colorectal cancer, although response rates to 5-FU monotherapy are typically no more than 15%. However, efforts at improving the response to this agent have involved its administration with biochemical-modulating agents and in protracted infusion schedules. The combination of 5-FU with folinic acid has evinced the most promising results, with an approximate twofold increase in response rate compared with monotherapy (23% versus 11%). ⋯ Prior disease progression on 5-FU does not affect the response to CPT-11, indicating no cross-resistance between the two agents. This suggests that CPT-11 is a promising new second-line agent for this difficult-to-treat disease. Additional studies will address the benefit of CPT-11 alone in second-line treatment and determine the role of CPT-11 in combination with thymidylate synthase inhibitors in first-line treatment.
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Seminars in oncology · Feb 1996
ReviewTransfer of drug resistance genes into hematopoietic progenitors to improve chemotherapy tolerance.
A number of drug resistance genes have been identified that may be useful in gene therapy approaches to ameliorate chemotherapy toxicity. Hematopoietic tissue is the most suitable target for drug resistance gene therapy because myelosuppression is the dose-limiting toxicity of the many chemotherapeutic agents. Recent studies have shown that murine and human hematopoietic progenitors can be transduced ex vivo using retroviral vectors to overexpress P-glycoprotein, dihydrofolate reductase, and O6-alkylguanine DNA alkyltransferase. ⋯ When compared with other somatic gene therapy approaches, drug resistance gene therapy has the aim of protecting normal cells and preventing toxicity. In addition many of these genes could be used to select for cells carrying the drug resistance gene as well as cotransduced therapeutic gene. Thus, gene transfer of drug resistance genes will have broad applications in the field of gene therapy as well as in protecting hematopoietic cells from chemotherapy toxicity.
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Seminars in oncology · Feb 1996
Multicenter Study Clinical TrialA Phase I/II study of paclitaxel and doxorubicin in the treatment of advanced breast cancer.
We designed a clinical study in which fixed doses of doxorubicin were infused by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, princeton, NJ) for the treatment of patients with advanced breast cancer, an interval selected to allow systemic clearance of doxorubicin before administration of paclitaxel in an outpatient setting. Courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 mg/m2 to 250 mg/m2 via dose escalation of 30 mg/m2) were repeated every 21 days, to a maximum of eight cycles. Maximum tolerated dose was reached if two or more of six patients at a given dose level were affected by the following events: absolute neutrophil count less than 500/microliter for > or = 7 days, absolute neutrophil count less than 100/microliter for > or = 3 days, insufficient hematopoietic recovery with absolute neutrophil count less than 1,500/microliter on day 21, febrile neutropenia, grade 4 thrombocytopenia, any World Health Organization grade 3 nonhematologic toxicity for more than 7 days. ⋯ Complete alopecia was always present. Maximum tolerated dose was not reached at paclitaxel 250 mg/m2. Ultimately, the introduction of this combination in the adjuvant setting is warranted.
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Seminars in oncology · Feb 1996
Clinical TrialPreclinical and clinical study results of the combination of paclitaxel and 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer.
Results of phase II studies have demonstrated high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) when given to intensively pretreated patients with metastatic breast cancer. In a phase I/II study of outpatients, we have added paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in an attempt to improve the results. Patients were treated weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36) with high-dose 5-FU 2.0 g/m2 by 24-hour infusion with FA 500 mg/m2 given as a 2-hour infusion prior to 5-FU. ⋯ Median time to progression was 10 months (range, 3 to 17 months). In conclusion, the combination of paclitaxel with weekly high-dose 5-FU/FA is well tolerated as second-line treatment of metastatic breast cancer, with high activity, even in patients with anthracycline-resistant disease. The regimen can be administered safely on an outpatient basis.