Background In a phase II study, topotecan was evaluated for response and toxicity in patients with advanced pancreatic carcinoma at the schedule of 0.7 mg/m2/day q 21 days q 28 days. Methods Responses were assessed after at least 2 courses using WHO criteria, and toxicity was evaluated after each course according to the CTC-NCI standards. Between December 1995 and September 1997, 15 assessable patients (median age, 55 years; range, 36-74; median ECOG performance, 1; range, 0-3) were included in the study. All had biopsy-proven and measurable disease, a life-expectancy of at least 3 months, and normal bone marrow, liver, and renal function. None of the patients had undergone prior cytotoxic or radiation therapy, and 10 were initially treated by surgery. Twenty-five cycles were assessable for toxicity. Plasma was collected from 7 patients who had received a total of 10 cycles and was, after extraction with methanol at −20°C, analyzed for total topotecan by an HPLC method. The thus determined steady-state concentrations were assessed for their capacity to affect growth and DNA integrity in the BxPC-3 human pancreatic carcinoma cell line after 21 days of continuous exposure. For these purposes, we used a sulforhodamine B staining assay, and agarose gel electrophoresis, respectively. Results Grades 3-4 leukopenia, thrombocytopenia, granulocytopenia, and anemia occurred in 8, 6, 8 and 8 cycles, respectively. Other mild to moderate side effects (grades 1-2) included malaise, nausea and vomiting, anorexia, and alopecia. No objective tumor response was documented. HPLC analysis of patients' plasma showed the attainment of constant steady-state levels of 1.0 ± 0.1 ng/mL during the entire infusion period. At such a concentration, topotecan did not significantly affect growth or DNA integrity in the BxPC-3 cells. Fifty percent cell growth inhibition and appreciable oligonucleosomal DNA fragmentation were only evident with 21 days topotecan ≥ 50 ng/mL. Conclusions Our data suggest that the lack of clinical activity of 0.7 mg/m2 daily topotecan for 21 days q 28 days in patients with advanced pancreatic carcinoma might be partially attributed to the achievement of non-tumoricidal plasma drug concentrations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.