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Journal of Clinical Oncology, Vol 25, No 6 (February 20), 2007: pp. 734-735 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5687
Comparison of Long-Term Neurocognitive Outcomes in Young Children With Acute Lymphatic Leukemia Treated With Cranial Radiation or High-Dose or Very High-Dose Intravenous MethotrexateSchneider Children's Medical Center of Israel, Petah Tikva, Israel To the Editor: Dr Spiegler et al1 have made a significant contribution to the literature with their report that it is possible to give 8 g/m2 or 33.6 g/m2 of high-dose methotrexate (MTX) without causing the neurotoxicity seen after cranial irradiation in the treatment of childhood acute lymphatic leukemia. They suggest that the use of higher doses of leucovorin (folinic acid) after the larger doses of MTX could be a possible mechanism in the prevention of neurotoxicity. This is in keeping with our analysis of the published data,2 which was able to show that for every dose of MTX there is an appropriate dose of folinic acid that can prevent neurotoxicity. They used at least 172 mg/m2 after 8 g/m2 MTX (we suggested 180 mg/m2 of folinic acid as the dose that should be used to prevent neurotoxicity with this dose of MTX) and a minimum of 272 mg/m2 folinic acid after 33.6 g/m2 MTX, both were obviously adequate. They mention studies by two groups from Holland that have found no neurotoxicity after MTX (Kingma et al3) and neurologic damage after MTX (Buizer et al4,5) and note that the investigators did not report the doses of leucovorin rescue used. In 2006, this problem is easily overcome, authors give their e-mail addresses with their mailing address and my experience2 is that they are pleased and willing to answer questions about the research they publish. The world is truly only an e-mail away. I have taken the liberty of contacting both authors by e-mail and with their permission would like to share with you the personal communications that I received from them. Dr Kingma reported that the patients who had no evidence of neurotoxicity were on national protocol 7 and had received a total of 210 mg/m2 folinic acid after the MTX dose of 5 g/m2. This is well above the dose of folinic acid that we suggested would prevent neurotoxicity (105 mg/m2).2 In contrast, Dr Buizer told me that of the children tested for neurotoxicity in her study, 17 were on protocol 8 and 13 were on protocol 9. Both groups received 45 mg/m2 folinic acid after MTX. The doses of MTX were 2 g/m2 for standard risk and 5 g/m2 and 3 g/m2 for high-risk patients, respectively, in the two studies. Paradoxically, the patients with higher than expected MTX levels were at less risk of neurotoxicity because in protocols 6, 8, and 9 folinic acid was continued if the levels were higher than anticipated. Even if some patients did receive larger doses, certainly a proportion of the children tested would be expected to develop neurotoxicity. We have found successful prevention of neurotoxicity with 45 mg/m2 folinic acid after 1 g/m2 MTX or less. An additional two children were on protocol 6 in which patients received also 25 mg/mg2, 50 mg/m2, and 75 mg/m2 folinic acid after 2 g/m2 MTX, depending on age, and were also in the risk group for inadequate rescue. Only four children were on protocol 7 and all received adequate leucovorin rescue. Readers should be aware that the current Acute Lymphatic Leukemia Berlin-Frankfurt-Münster protocol 2000 uses 45 mg/m2 folinic acid after 5 g/m2 MTX, so we can anticipate a lot of potentially avoidable neurotoxicity. Some worry has been expressed that there is an increased danger of relapse when the folinic acid dose is increased2 (even though no evidence has been published that supports this view). It is hoped that Dr Spiegler's group will be able to show that the increased dose of folinic acid used in the protocols did not reduce the cure rate. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Spiegler BJ, Kennedy K, Maze R, et al: Comparison of long term neurocognitive outcomes in young children with acute lymphatic leukemia treated with cranial radiation or high dose or very high dose intravenous methotrexate. J Clin Oncol 24:3858-3864, 2006 2. Cohen IJ: Defining the appropriate dose of folinic acid after high-dose mtx for childhood acute lymphoblast leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system. J Pediar Hematol Oncol 26:156-163, 2004 3. Kingma A, Van Dommelen RI, Mooyaart EL, et al: No major cognitive impairment in young children with acute lymphatic leukemia using chemotherapy only: A prospective longitudinal study. J Pediatr Hematol Oncol 24:106-114, 2002[CrossRef][Medline] 4. Buizer AL, De Sonneville LM, Van Den Heuvel-Eibrink MM, et al: Chemotherapy and attentional dysfunction in survivors of childhood acute lymphatic leukemia: Effect of treatment intensity. Pediatr Blood Cancer 45:281-290, 2005[CrossRef][Medline] 5. Buizer AL, De Sonneville LM, van den Heuvel-Eibrink MM, et al: Visuomotor control in survivors of childhood acute lymphatic leukemia treated with chemotherapy only. J Int Neuropsychol Soc 11:554-565,2005[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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