Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy

Abstract

Purpose: We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL).

Patients and methods: We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT.

Results: Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8).

Conclusion: CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols.

Fig 1.

Five-year (A) overall survival and (B) cumulative incidence of any event for all patients included in the protocols. Forest plots present the raw cumulative 5-year estimates for each protocol, with the 99% CIs. The meta-analysis summary estimate, model based, is presented in the form of a diamond (its width represents the 95% CI). *CIs are 99% CIs for primary study effects and 95% CIs for summary effects. AIEOP, Associazione Italiana Ematologia ed Oncologia Pediatrica; BFM, Berlin-Frankfurt-Münster; COALL, Cooperative Acute Lymphoblastic Leukemia Group; COG, Children’s Oncology Group; DCOG, Dutch Children’s Oncology Group; DFCI, Dana-Farber Cancer Institute; JACLS, Japanese Childhood Leukemia Study Group; NOPHO, Nordic Pediatric Hematology and Oncology Study Group; UK, United Kingdom and Ireland Group.

Fig 2.

Five-year outcomes in the subgroup of patients with overt CNS involvement (CNS3) at diagnosis. (A) Five-year overall cumulative incidence (any event). (B) Five-year crude cumulative incidence of isolated bone marrow (BM) relapses. (C) Five-year crude cumulative incidence of isolated CNS relapses. (D) Five-year crude cumulative incidence of any CNS relapse. All forest plots present the raw cumulative 5-year estimates for each protocol, with the 99% CIs, grouped into not administering cranial radiotherapy (CRT; open blue circles) and administering CRT (gray circles). Three meta-analysis summary estimates, model based, are also presented in the form of a diamond (its width represents the 95% CIs) for protocols not administering CRT, for protocols administering CRT, and for all protocols. *CIs are 99% CIs for primary study effects and 95% CIs for summary effects. AIEOP, Associazione Italiana Ematologia ed Oncologia Pediatrica; BFM, Berlin-Frankfurt-Münster; COALL, Cooperative Acute Lymphoblastic Leukemia Group; COG, Children’s Oncology Group; DCOG, Dutch Children’s Oncology Group; DFCI, Dana-Farber Cancer Institute; JACLS, Japanese Childhood Leukemia Study Group; NOPHO, Nordic Pediatric Hematology and Oncology Study Group; NS, not significant; UK, United Kingdom and Ireland Group.