Faculty Bibliography

Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths. The combination of ifosfamide and carboplatin had little activity as the second-line treatment in our population of patients with heavily pretreated metastatic breast cancer. Oral mesna was effective for urothelial protection, permitting outpatient administration of ifosfamide.

OBJECTIVE: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens. PATIENTS AND METHODS: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression. RESULTS: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 patients with elevated baseline CA-125s. Twenty-seven patients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia and its complications occurred primarily during the first two cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a higher incidence than in prior series. CONCLUSIONS: Taxol as a single agent has modest activity in heavily pretreated ovarian cancer patients but appears to be useful and is subjectively well tolerated by many. The high incidence of infection in comparison with other series of patients with ovarian cancer treated with chemotherapy suggests this pretreated patient population has enhanced susceptibility to develop complications from neutropenia. Safer treatment in this advanced setting should include more aggressive use of cytokines and/or less myelosuppressive regimens (e.g. shorter Taxol infusions).

Clinical trials with several toxicity protectors (cytoprotective or chemoprotective agents) have been performed during the past decade. These trials are quite complex since they must include sufficient dose-limiting events for study, and assessment of both toxicity (and therefore the efficacy of protection) and antitumor effects must be carried out. However, it is inevitable that with greater understanding of drug actions, one seeks to manipulate these for greater antitumor activity (biochemical modulation) or for lesser dose-limiting toxicity (cytoprotection) or for both. Examples of cytoprotective agents include dexrazoxane (ICRF-187), protecting against doxorubicin cardiotoxicity, and amifostine protecting against the myelosuppression of platinum and alkylating agents. In spite of the challenges encountered in the clinical development of these drugs, studies of cytoprotectors have led to a considerable understanding of important therapeutic issues and tangible clinical benefit in specific clinical situations.

It has become clear that multiple mechanisms of cellular resistance to platinum compounds exist; however, the knowledge that platinum resistance can not only be explained by processes such as reduced drug accumulation, and increased detoxification, has shifted the attention of researchers to more molecular mechanisms. The introduction of new techniques, such as the PCR technique for example, has opened the possibility to monitor genes involved in antitumor responses and may provide molecular information on the emergency of resistance.

Drug therapy for cervical cancer is slowly undergoing evaluation in early disease stages, in which it is more likely to make an impact. Cisplatin has been the principal drug used in systemic therapy for all stages, with the possible exception of the radiosensitizer hydroxyurea. Nevertheless, current studies use cisplatin in this role as well. To a limited extent, substitution of carboplatin for cisplatin also has been explored. Conflicting interpretations of carboplatin trials nonetheless support continued study of this drug; its activity is reproducible and it can be combined with radiation therapy in practical dose schedules. The major question in the systemic nonendocrine treatment of endometrial cancer revolves around whether cisplatin adds to results achievable with doxorubicin. Carboplatin, documented as active against this neoplasm, represents a potentially advantageous cisplatin substitute for elderly patients. Moreover, if combination chemotherapy should prove disappointing, single-agent carboplatin may provide the best strategy for palliative therapy.