Beyond pancreatic cancer: irinotecan and gemcitabine in solid tumors and hematologic malignancies.

Non-platinum combinations including gemcitabine and irinotecan (Gemzar; Eli Lilly and Company, Indianapolis, IN) for the management of a variety of malignancies have started to emerge. Gemcitabine and irinotecan are well-tolerated single agents, each with a broad spectrum of antitumor activity. Preclinical data suggests synergy for the two drugs when used in combination. A phase I trial has defined a well-tolerated combination regimen using both drugs on a day-1, -8 schedule every 3 weeks. Phase II data suggest activity for the combination in pancreatic cancer, and a phase III trial of the two-drug combination versus gemcitabine alone is underway in previously untreated pancreatic cancer patients. Other phase II trials evaluating the impact of this combination on a variety of other tumors, such as non-small cell lung, small cell lung, breast, colorectal, and non-Hodgkin's lymphoma, are either forthcoming or in progress. Semin Oncol 28 (suppl 10):34-43.

Adjuvant sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide (ATC) for high-risk breast cancer is feasible in the community setting.

PURPOSE: This study evaluated the feasibility, when given in the community, of dose-dense, sequential ATC (doxorubicin, paclitaxel, cyclophosphamide) as adjuvant therapy for breast cancer with four or more metastatic axillary lymph nodes. PATIENTS AND METHODS: Patients were recruited after definitive breast cancer surgery if four or more axillary nodes were involved by metastatic cancer and if distant metastases were not present on computed tomographic scan or bone scan. Forty patients received doxorubicin, 90 mg/m2 every 14 days for three cycles; paclitaxel, 250 mg/m2 every 14 days for three cycles; and cyclophosphamide, 3 g/m2 every 14 days for three cycles with filgrastim support. Chemotherapy was administered by the referring physician. RESULTS: Mean dose intensity was 99% for doxorubicin, 96% for paclitaxel, and 99% for cyclophosphamide. Grade 3 toxicities included mucositis (13%), nausea/vomiting (10%), neuropathy (13%), and myalgia/arthralgia (10%). Thirteen patients had neutropenic fever. One patient developed acute leukemia. Three relapses have occurred. Ninety percent of patients are alive and disease-free at a median follow-up of 24 months. DISCUSSION: ATC can be administered in the community at full doses with acceptable toxicity. Preliminary efficacy data suggest that this high-dose, intensively scheduled regimen warrants comparison with standard therapy for high-risk patients.

A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days.

Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS)