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Childhood Leukemia Treatment: Is Cranial Irradiation Necessary?

With intensified intrathecal and systemic chemotherapy, omission of prophylactic irradiation did not compromise survival.

Because treatment for childhood acute lymphoblastic leukemia (ALL) has attained 5-year event-free survival (EFS) rates of approximately 80%, research is now aimed at attenuating treatment-related late effects in patients who are expected to achieve good outcomes. One such approach, now part of most treatment regimens, has been to reduce prophylactic doses of cranial irradiation for the 20% to 25% of patients at high risk for central nervous system (CNS) recurrence. However, even lower doses of cranial irradiation have been associated with late complications, including secondary cancers, excess mortality, and adverse neuropsychological outcomes.

To assess whether prophylactic cranial irradiation can be completely eliminated without compromising survival in children with ALL, investigators conducted a clinical trial involving 498 patients (median age, 5 years; range, 1–18 years) with newly diagnosed ALL. Patients were treated according to a complex protocol based on risk stratification as determined by cytogenics, white blood cell count at presentation, and measurements of residual disease. CNS-directed therapy consisted of intrathecal cytarabine at time of diagnostic lumbar puncture and triple intrathecal chemotherapy for all subsequent treatments. The number of intrathecal treatments ranged from 13 to 25, based on patient risk status. High-risk patients were considered for allogeneic stem-cell transplantation.

Overall, patients achieved an estimated 5-year EFS rate of 85.6%, 5-year overall survival rate of 93.5%, and CNS relapse rate of 3.9% (isolated CNS relapse rate, 2.7%). All 11 patients who experienced isolated CNS relapse were alive and in second remission at the time of study publication. Risk factors independently associated with CNS relapse included T-cell disease, presence of t(1;19), and CNS involvement at presentation.

Comment: This trial is impressive for its risk-stratification and dosage schemes, its use of optimal intrathecal chemotherapy to control CNS leukemia, and its overall survival rate of >90%. Although only 15% of the study population would have been considered at high risk for CNS relapse, the very high salvage rate in patients with CNS relapse argues against prophylactic cranial irradiation even among high-risk subgroups. These results suggest that we can expect very good outcomes (and fewer long-term adverse events) in pediatric ALL patients who are treated without prophylactic cranial radiation.

— Michael G. Douvas, MD

Dr. Douvas is Assistant Professor of Medicine, Hematology/Oncology Division, at the University of Virginia Health System, Charlottesville, VA.

Published in Journal Watch Oncology and Hematology June 24, 2009

Citation(s):

Pui C-H et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009 Jun 25; 360:2730.

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