Small steps for small kids can result in big leaps. Advancing by incremental steps in the past 40 years, the curability of childhood acute lymphoblastic leukemia (ALL) stands as one of modern medicine's crowning achievements. For children with standard-risk ALL, a cure can be obtained in more than 80% of the cases. This achievement poses 2 difficult questions: (1) How can we reach 100%? (2) How can we improve on the worse prognosis for adolescents and adults? The answer is simply to perform well-designed, narrowly focused randomized clinical trials built upon previous regimens and to follow the protocols religiously.
In this issue, Bostrom and colleagues (page 3809) report a Children's Cancer Group (CCG) trial for children with standard-risk ALL. Two hypotheses were posed: substitution of dexamethasone for prednisone reduces central nervous system (CNS) relapse, and the substitution of intravenous for oral administration of 6-mercaptopurine improves event-free survival by improving drug bioavailability. While the second hypothesis was not supported, the first was. Dexamethasone was associated with a 50% reduction in the incidence of CNS relapse and an increase in the 6-year event-free survival from 77% to 85%. Overall toxicity was comparable, although myopathy and hyperglycemia were increased in the dexamethasone group. Most patients, parents, and oncologists would gladly tolerate these side effects in lieu of leukemic relapse. Results may have been biased in favor of dexamethasone because its dose was not bioequivalent to prednisone. The strengths of this study were that the study population was large (more than 1000 patients), it was built on previous CCG ALL protocols, it incorporated new strategies based on smaller studies, and it was hypothesis driven. Now, investigators can move on and ask whether another of the antileukemic drugs can be better used or whether a new agent can be added to the old.
