Methotrexate Induced Nephrotoxicity Clinical Trial
Official title:
Nephrotoxicity Induced by High-Dose Methotrexate Infusions to Children With Malignant Diseases
Infusions with high-dose methotrexate 5 g/m2 or 8 g/m2 are used to treat children with acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, medulloblastoma and ependymoma. Methotrexate is primarily excreted unchanged by the kidney where it can course acute kidney damage resulting in prolonged time of excretion of the drug. Our main hypothesis is that 12 hours of intravenous hydration before the methotrexate infusion is more efficacious in preventing methotrexate induced kidney damage compared to four hours of hydration.
Infusions with high-dose methotrexate 5 g/m2 or 8 g/m2 are according to the protocol of the
Nordic Association for Pediatric Hematology and Oncology 2000 (NOPHO-2000) used to treat
children with acute lymphoblastic leukemia (ALL). Treatment with methotrexate 5 g/m2 is also
used to treat children with non-Hodgkin lymphoma, medulloblastoma and ependymoma.
Methotrexate is primarily excreted unchanged by the kidney where it can course acute
nephrotoxicity resulting in prolonged elimination time of the drug. Data from a 10 years
retrospective investigation at our pediatric unit show, that in spite of urine
alkalinization and intensive hydration the elimination of methotrexate is prolonged in
20-50% of the infusions. The long exposure of a high serum methotrexate concentration is
associated with an increased frequency of mucositis and bone marrow suppression. Further
more the need of rescue with folic acid is problematic, because it is possibly that it can
result in a higher risk of relapse of ALL (Leukemia 2006; Skarby TV). Most ALL protocols
prescribe prehydration of 2-6 hours before initiation of the methotrexate infusion and it
has never been investigated in a randomized controlled trail if a longer time of
prehydration can prevent nephrotoxicity and reduce the risk of prolonged elimination. In our
pediatric unit the prehydration is given with a rate of 150 ml/m2/hour with a solution of 5%
glucose with 40 mmol sodium bicarbonate/L and 20 mmol potassium chloride/L.
Our main hypothesis is that 12 hours of prehydration is more efficacious in preventing
methotrexate induced nephrotoxicity compared to four hours of prehydration. A child enrolled
in the study will before half of the methotrexate infusions receive 12 hours of prehydration
and before the other half it will receive four hours of prehydration.
;
Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention