Malignant pleural mesothelioma

    Malignant pleural mesothelioma is associated with a history of asbestos exposure in about 70 to 80 percent of all cases and there is no approved or very effective chemotherapy for the disease. Researchers hypothesized that pemetrexed might prove effective in treating this disease because it targets key enzymes thought to play a role in allowing the rapid growth of this tumor.

    Early Phase I trial results in 11 patients tested with pemetrexed and cisplatin were promising and a definitive randomized Phase III trial was developed. Since there are no established therapies for this condition, a standard chemotherapy agent called cisplatin that has shown efficacy in treating other diseases, was used as the control arm. The Phase III study initially planned to enroll 456 patients from April 1999 to March 2001. However, after enrolling 150 patients, a high rate of severe toxicity and death was associated with the pemetrexed and cisplatin arm of the trial. Elevated levels of homocysteine, a chemical byproduct that results when proteins are broken down in the blood, were found, which provided a basis for redesign of the trial to reduce the dangerous drug side effects.

    Two hundred and eighty patients were enrolled to the revised protocol. Using a strategy to reduce drug side effects that has been successful in the past, this new protocol added folic acid to the regimen because pemetrexed as an antifolate agent reduces levels of this important vitamin. Folic acid was given prior to and during the trial, and vitamin B12 was given only during the trial. Both vitamins should boost folic acid levels, reduce homocysteine formation, and hence reduce toxicity to pemetrexed. "We now have a significantly less toxic regimen than the one we started with," said Vogelzang.

    Because of the presumed importance of the vitamins to the study, the researchers examined not only the combination therapy versus the single drug therapy, but also looked at the results of patients on the vitamin supplements versus those early enrollees who had not initially received vitamins.

    Standard treatment for malignant mesothelioma has been surgery. Surgical treatment rarely results in cure and long-term survival is unusual. Use of radiation therapy and/or chemotherapy following surgery has not improved survival for patients but radiation treatments may alleviate some pain associated with the disease.