Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 micrograms/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide.

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.