Seminars in oncology
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Seminars in oncology · Feb 1996
ReviewCPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile.
CPT-11 (irinotecan) is a promising anticancer agent with a novel mechanism of action dependent on the inhibition of the DNA eukaryotic enzyme, topoisomerase I. The clinical utility of CPT-11 in advanced colorectal cancer has been documented in more than 400 patients recruited in phase II clinical trials in Europe, Japan, and United States. Among 178 eligible patients in a multicenter European study, the overall response rate to CPT-11 on a once-every-3-weeks regimen was 18%, and the median duration of response was 9.1 months. ⋯ CPT-11 appears to have activity similar to that of 5-FU in first-line treatment and, moreover, remains active after failure of 5-FU therapy. The specific gastrointestinal toxicity is manageable, and a better control of this type of toxicity is expected in the future. CPT-11 would therefore appear a welcome addition to the oncology armamentarium for this difficult-to-treat malignancy.
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Seminars in oncology · Feb 1996
ReviewPaclitaxel couplets with cyclophosphamide or cisplatin in metastatic breast cancer.
Determining active combinations containing paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to treat metastatic breast cancer has been the focus of recent clinical development. Paclitaxel combined with either cyclophosphamide or cisplatin has several potential advantages: cisplatin and cyclophosphamide are active single agents against previously untreated metastatic breast cancer, colony-stimulating factors can modulate overlapping toxicities like myelosuppression, and no mechanisms of cross-resistance between paclitaxel and these agents are yet known. Major questions include the optimal schedule of administration and the sequence dependence of toxicities with these combinations. ⋯ As expected, dose-limiting toxicity in all studies has been hematologic. However, granulocyte colony-stimulating factor has ameliorated myelosuppression and allowed considerable dose escalation of cyclophosphamide. This combination has demonstrated activity in previously treated patients with metastatic breast cancer, including the anthracycline-refractory subpopulation that will be reviewed.
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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.