In Reply:
Authors: Wilson C. Mertens, Donald J. Higby, David Brown, Regina Parisi, Janice Fitzgerald, Evan M. Benjamin, Peter K. Lindenauer
Journal: Journal of Clinical Oncology (2003)

To the Editor: Like the other antifoles, the renal excretion of pemetrexed poses a requirement for administration and a risk for patients.Though the phase III and extended access use of this drug have been limited to patients with a creatinine clearance of more than 40 mL/min, an early fatality conceivably related to drug toxicity was recorded in a patient with creatinine clearance estimated at 19 mL/min (Alimta, Clinical Investigator's Brochure; Eli Lilly and Co, Indianapolis, IN).On the other hand, thymidine and folinic acid have been used in the preclinical evaluation of the drug to rescue animals from lifethreatening toxicity.Therefore, the following experience is reported pertaining to a patient with acute renal failure who received pemetrexed inadvertently.A 60-year-old man with unresectable pleural mesothelioma was treated under a single patient Investigational New Drug License with pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) for three cycles.Though a partial remission ensued, cisplatin was discontinued because of severe malaise without measurable change in renal function at that juncture.The patient continued pemetrexed as a single agent without evidence of disease progression, and tolerated the treatmentrelated side effects of grade 2 mucositis and myelosuppression uneventfully.By the sixth cycle of pemetrexed administration, laboratory values suggestive of acute renal insufficiency (creatinine 3.1, potassium 6.1) were discovered after approximately 250 mg/m 2 of pemetrexed had been administered.The patient was not oliguric.The infusion was terminated and the patient was admitted to the hospital.Though there is doubt about whether hemodialysis would be effective for pemetrexed removal, hemodialysis was administered on the evening of admission.A precipitating cause for renal failure was not discovered.The urine was alkalinized and folinic acid was administered.Thymidine was provided under a special exception mechanism by the National Cancer Institute (Bethesda, MD) and initiated within 36 hours of pemetrexed infusion; 8 g/m 2 /d as a 24-hour infusion was administered for five times the estimated half-life of pemetrexed using a worst case scenario, calculated at 120 hours from the administration of pemetrexed.The patient showed no signs of drug-related toxicity and was discharged from the hospital after 5 days.In fact, no toxicity whatsoever was observed during the follow-up period.The routine coadministration of folate with pemetrexed does not abrogate mucous membrane or myeloid toxicity altogether.Therefore, this patient's clinical record suggests that thymidine may be an effective antidote for pemetrexed-related toxicity.Though the use of hemodialysis complicates the interpretation of the favorable outcome here, thymidine may well have saved this patient's life.Commercial access to this basic metabolite could remove the essential urgency, if not absolute requirement, for knowing the creatinine of each patient on the day of pemetrexed administration.Beyond this practical value, thymidine rescue might also allow for exploring dose escalation strategies of pemetrexed, analogous to methotrexate.But even if the development of thymidine never comes to fruition as part of an antitumor strategy, its value for patient safety already appears compelling.