Folate status and the safety profile of antifolates.
Throughout the history of cancer chemotherapy, the control of drug-related toxicity has been a major concern. Antifolates such as methotrexate also have a reputation for sporadic and unpredictable toxicity. Pretreatment levels of plasma or red cell folate have not been found to be useful in predicting which patients will develop toxicity. During the phase II development of pemetrexed, the plasma levels of homocysteine and methylmalonic acid were studied as sensitive surrogate markers for folate and vitamin B(12) status, respectively. These were found to be strongly correlated with the subsequent development of serious drug-related toxicities (myelosuppression, diarrhea, mucosal toxicity, and infection), suggesting that toxicity was related to relative folate deficiency in some cancer patients. A policy of nutritional supplementation was introduced and led to a marked reduction in toxicity and the abolition of treatment-related deaths with apparent preservation of anticancer activity.