50 years ago in the journal of pediatrics
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January 2014 ORIGINAL ARTICLES
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50 Years Ago in THE JOURNAL OF PEDIATRICS
Central Nervous System Complications of Children with Acute Leukemia: AnEvaluation of Treatment MethodsEvans AE, D’Angio GJ, Mitus A. J Pediatr 1964;64:94-6
Fifty years ago in The Journal, Evans et al reported an historical cohort study of 53 children symptomatic from intra-cranial leukemia, treated by either lumbar puncture alone, cranial irradiation, or intrathecal methotrexate. Today
the results are not surprising; 98% of the irradiated patients became symptom-free for 2.8 months, and 88% of themethotrexate-treated patients were symptom-free 3.7 months (P = .07). Only 48% of the children undergoing simplelumbar puncture became asymptomatic and even then for only about 2 weeks. Whether this study’s small sample sizewould have survived today’s peer review process to merit publication is debatable.
Nonetheless, this paper presaged a landmark shift in the management and cure of childhood acute lymphoblasticleukemia (ALL). Indeed, the authors mention in their last paragraph the “prophylactic” use of monthly intrathecalmethotrexate in 12 patients whose central nervous system leukemia had already been eradicated and theirsymptom-free survival of 7 or more months. That success was unheralded! But, by the end of the 1960s, the “TotalTherapy” studies at St. Jude Children’s Research Hospital using prophylactic craniospinal irradiation and intrathecalmethotrexate reduced the rate of leukemia relapse into the central nervous system from more than 50% to approx-imately 10%, and afforded cures in greater than 50% of children in an era when ALL took the lives of 80% or more.1
The next 50 years of advancing cures in ALL and other childhood cancers will be more challenging. Now that manychildhood cancers have 5-year survival rates in excess of 80%, clinical trials will be cumbersome, as much larger sizeswill be necessary to demonstrate increasingly smaller increments of success. Accumulating the larger samples sizesrequired will be difficult because of cost as well as the increasing division of childhood cancers into smaller and smallerdiseases based upon molecular subtypes. Surely we will conceive new clinical trial designs to tackle these logisticalissues. However, we should never give short shrift to initial observations such as that of Evans et al, even when samplesize is small, if the findings are compelling and the impact potentially immense.
Paul Graham Fisher, MDDepartments of Neurology, Pediatrics, and Human Biology
Lucile Packard Children’s HospitalStanford UniversityPalo Alto, California
http://dx.doi.org/10.1016/j.jpeds.2013.08.003
Reference
1. Simone J, Aur RJA, Hustu HO, Pinkel D. “Total therapy” studies of acute lymphocytic leukemia in children: current results and prospects for
cure. Cancer 1972;30:1488-94.
in Children Born Preterm Using the Quantitative 33