Calculated versus measured creatinine clearance for dosing methotrexate in the treatment of primary central nervous system lymphoma

Background: High-dose methotrexate (HDMTX) (≥3 g/m²), the cornerstone of therapy for primary CNS lymphoma (PCNSL), is commonly dosed using a measured 24 h creatinine clearance (CrCl) every 2-4 weeks. Because these collections are cumbersome and at times unreliable, the use of a calculated CrCl was evaluated as a potential alternative. Methods: A retrospective analysis was performed on data from all 287 treatment cycles from the 25 patients with PCNSL who participated in a multi-center phase II clinical trial of HDMTX conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Results: The 25 patients had a median age of 61 years (range 32-75). Seventeen (68%) were men. The patients received a median of 14 (range 2-21) HDMTX treatments. For 256 of 287 treatments (89%), data were available to compare the measured and calculated (using the Cockcroft-Gault equation) CrCl. The average measured CrCl was 93 ml/min (95% CI, 89-96 ml/min), and the average calculated CrCl was 107 ml/min (95% CI, 102-112 ml/min). The Pearson correlation coefficient (r) was 0.49 (P < 0.0001) between the measured and calculated CrCl. The average MTX dose determined using measured CrCl was 14.1 g (95% CI, 13.6-14.5 g), and the average MTX dose determined using calculated CrCl was 14.7 g (95% CI, 14.2-15.1 g). MTX doses based on measured and calculated CrCl were significantly correlated (r = 0.72, P < 0.0001). Of the 256 HDMTX treatments evaluated, 158 (62%) had reliable 48 h serum MTX levels documented. Forty-seven levels (30%) were within target range (0.3-1 μmol/l), 99 levels (62%) were below target range (<0.3 μmol/l), 12 levels (8%) were in the range associated with mild toxicity range (>1-3 μmol/l), and no levels were in the range associated with severe toxicity (>3 μmol/l). Of these 158 treatments, the use of a calculated rather than measured CrCl would have yielded an identical MTX dose for 48 treatments (30%), a higher MTX dose for 62 treatments (40%), and a lower MTX dose for 48 treatments (30%). This distribution was not significantly different among the subsets of below target, within target range, and above target MTX levels (P = 0.87). Conclusions: In this cohort of patients with PCNSL, there is significant correlation between the calculated and measured CrCl. MTX doses determined using calculated and measured CrCl are not significantly different. For these patients, there is no clear association between the method of determining CrCl and serum MTX levels. As a result, calculated CrCl is a reasonable alternative to measured CrCl in this patient population and would avoid the inconvenience and potential inaccuracies associated with measured CrCl.