Seminars in oncology
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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.
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Seminars in oncology · Feb 1996
Activity and safety of epirubicin plus paclitaxel in advanced breast cancer.
We performed a dose-escalation study to evaluate the maximum tolerated dose (MTD) of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus a fixed dose of epirubicin. Epirubicin was administered as a 90 mg/m2 bolus immediately followed by a 3-hour infusion of paclitaxel starting at 135 mg/m2 and escalating by 20mg/m2 for each triplet of patients as long as no dose-limiting toxicity had occurred; courses were repeated every 3 weeks. The MTD was defined as that at which any of the following toxicities occurred in at least two of six patients: absolute neutrophil count less than 500/microliter for more that 7 days or less than 100/microliter for more than 3 days; any episode of febrile neutropenia requiring intravenous antibiotics and hospitalization; grade 4 thrombocytopenia requiring platelet transfusion; failure to recover absolute neutrophil count to > or = 1,500/microliter and/or platelets to > or = 100,000/microliter by day 28; and any grade > or = 3 nonhematologic toxicity. ⋯ In conclusion, neutropenia is the most frequent toxicity of this novel combination. However, the MTD has not yet been reached. The combination of epirubicin plus paclitaxel is highly active, and no signs of cumulative myocardiopathy have been observed.