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While these developments in genetics are taking place with their promise of future advances, one immediate question for oncologists is how should advanced metastatic prostate cancer be treated? Hormone therapy is currently the standard approach, but resistance to this therapy develops, and alternative effective chemotherapy is badly needed. Suramin, a drug originally developed in the 1920s to treat trypanosome infections, is now undergoing intensive study for treating hormone-resistant prostate cancer. This drug presents problems. For activity against prostate cancer cells, blood plasma levels should ideally be over 100 but not exceeding 300 micrograms per milliliter, otherwise toxicity becomes severe. The nervous system especially is affected, but there is also a range of metabolic changes in body minerals, adrenal and kidney damage, problems in blood clotting, and rashes. To complicate matters, the half life of suramin is about 55 days, which makes it difficult to adjust dose and schedule to keep suramin blood levels within an effective, but not too toxic range.
Suramin is the subject of no fewer than six articles and an editorial in the September, 1995 issue of the authoritative Journal of Clinical Oncology. Researchers including Drs. Eisenberger, Reyno, and Egorin at the University of Maryland used what they termed adaptive control with feedback - ACF- based on the ADAPT II computer program for pharmacokinetics to calculate dosing schedules to maintain peak to trough blood suramin levels. They established that initial 5- to 7-day loading treatment, followed by intermittent infusions as needed, providing a range of 100-250 micrograms per milliliter for no longer than 3 months, gave the best results. Sixty percent of patients had 50% reduction in PSA, 37% had a 75% reduction, 40% had measurable responses in their disease, and 49% had major pain improvement. They utilized this information to design a fixed regimen to give this plasma range, removing patients whose levels exceeded 300 micrograms per milliliter. In contrast clinical scientists, including Drs. Kobayashi and Ratain at the University of Chicago Pritzker School of Medicine, used no ACF, but rather only clinical endpoints to guide them. Their dosing strategy was, however, based on the Maryland team's work, and they monitored suramin plasma levels. The study did show that the principles of pharmacokinetics-based dosing could be applied in a situation where elaborate computerized control was not available, since their results, including a PSA fall of over 50% in 75% of patients, and over 75% in 33% at a dose of 1,730 milligrams per square meter were similar to the Maryland findings. A study at the National Cancer Institute suggested the total suramin dose should be restricted to no more than 157 milligrams per kilogram body weight over 8 weeks or more, and plasma levels over 200 micrograms per milliliter to 25 days or less.