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The Correlation Between Dose of Folinic Acid and Neurotoxicity in Children and Adolescents Treated for Osteosarcoma With High-dose Methotrexate (HDMTX): A Neuropsychological and Psychosocial Study

Bonda-Shkedi, Esther MSc*,†; Arush, Myriam Weyl Ben MD; Kaplinsky, Chaim MD§,∥; Ash, Shifra MD*,∥; Goshen, Yaakov MD*,∥; Yaniv, Isaac MD*,∥; Cohen, Ian J. MB, ChB*,∥

Journal of Pediatric Hematology/Oncology: May 2013 - Volume 35 - Issue 4 - p 271–275
doi: 10.1097/MPH.0b013e31828c2da1
Original Articles

Background: This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m2 or 120 to 250 mg/m2 FA in their protocols.

Methods: Eighteen tests or subtests of neuropsychological assessment were tested.

Results: Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance.

Conclusions: A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m2, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.

*Department of Hematology Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva

Department of Psychology, Hebrew University of Jerusalem, Jerusalem

Meyer Children’s Hospital, Rambam Medical Center, Haifa

§The Edmond and Lily Safra Childrens Hospital, Chaim Sheba Medical Center, Ramat Gan

Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

This study was performed by Esther Bonda-Shkedi as a part of her MSc degree requirements at the Department of Psychology at the Hebrew University of Jerusalem.

The authors declare no conflict of interest.

Reprints: Prof Ian J. Cohen, Department of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan St, Petah Tikva, 49202 Israel (e-mail:

Received March 18, 2012

Accepted October 17, 2012

© 2013 Lippincott Williams & Wilkins, Inc.