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Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity

From the Division of Psychology, Department of Psychiatry, and Divisions of Hematology and Oncology, Department of Medicine, Children's Hospital; Departments of Psychiatry and Pediatrics, Harvard Medical School; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Department of Biostatistics, Harvard School of Public Health; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, NY; Interamerican University, San Juan, Puerto Rico; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario; and Departments of Pediatric Hematology/Oncology, Division of Hematology/Oncology, Hopital Sainte Justine, Montreal, Quebec, Canada

Address reprint requests to Deborah P. Waber, PhD, Department of Psychiatry, Children's Hospital, 300 Longwood Ave, Boston, MA 02115; e-mail: deborah.waber{at}childrens.harvard.edu

PURPOSE: We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT.

PATIENTS AND METHODS: Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol.

RESULTS: Eight-year event-free survival (± SE) was 80% ± 3% for children randomly assigned to CFX and 72% ± 3% for HFX (P = .06). Overall survival was 85% ± 3% for CFX and 78% ± 3% for HFX (P = .06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P = .99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P < .05).

CONCLUSION: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.

Supported by grant Nos. CA 68484 and CA06516 from the National Cancer Institute, the Michael J. Garil Fund for Leukemia Research, and in part by Mental Retardation Center grant P30-HD18655.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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