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50 Years Ago in THE JOURNAL OF PEDIATRICS

Central Nervous System Complications of Children with Acute Leukemia: An
Evaluation of Treatment Methods
Evans AE, D’Angio GJ, Mitus A. J Pediatr 1964;64:94-6

ifty years ago in The Journal, Evans et al reported an historical cohort study of 53 children symptomatic from intra-
F 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 the
methotrexate-treated patients were symptom-free 3.7 months (P = .07). Only 48% of the children undergoing simple
lumbar puncture became asymptomatic and even then for only about 2 weeks. Whether this study’s small sample size
would 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 lymphoblastic
leukemia (ALL). Indeed, the authors mention in their last paragraph the “prophylactic” use of monthly intrathecal
methotrexate in 12 patients whose central nervous system leukemia had already been eradicated and their
symptom-free survival of 7 or more months. That success was unheralded! But, by the end of the 1960s, the “Total
Therapy” studies at St. Jude Children’s Research Hospital using prophylactic craniospinal irradiation and intrathecal
methotrexate 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 many
childhood cancers have 5-year survival rates in excess of 80%, clinical trials will be cumbersome, as much larger sizes
will be necessary to demonstrate increasingly smaller increments of success. Accumulating the larger samples sizes
required will be difficult because of cost as well as the increasing division of childhood cancers into smaller and smaller
diseases based upon molecular subtypes. Surely we will conceive new clinical trial designs to tackle these logistical
issues. However, we should never give short shrift to initial observations such as that of Evans et al, even when sample
size is small, if the findings are compelling and the impact potentially immense.

Paul Graham Fisher, MD

Departments of Neurology, Pediatrics, and Human Biology
Lucile Packard Children’s Hospital
Stanford University
Palo 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.

Evaluation of Early Childhood Social-Communication Difficulties in Children Born Preterm Using the Quantitative 33
Checklist for Autism in Toddlers