As reported in the Journal of Clinical Oncology by Jeff M. Michalski, MBA, MD, and colleagues, the Children’s Oncology Group noninferiority phase III ACNS0331 trial has shown no decrease in event-free survival with reduced radiation boost volume in patients with newly diagnosed, average-risk medulloblastoma receiving radiotherapy with chemotherapy. A reduced craniospinal irradiation dose in younger children was associated with inferior event-free survival, but better neurocognitive outcomes.

Jeff M. Michalski, MBA, MD

Study Details

The trial enrolled patients aged 3 to 21 years between April 2004 and January 2014. A total of 424 evaluable patients were randomly assigned to receive involved-field radiation therapy (IFRT; smaller volume boost, n = 227) or posterior fossa radiation therapy (PFRT; standard volume boost, n = 237) to a cumulative dose of 54 Gy with concurrent and maintenance chemotherapy. Among these, 226 patients aged 3 to 7 years were also randomly assigned to receive low-dose craniospinal irradiation (18 Gy, n = 116) or standard-dose craniospinal irradiation (23.4 Gy, n = 110).  The primary endpoint was event-free survival.

Key Findings

Event-free survival at 5 years was 82.5% (95% confidence interval [CI] = 77.2%–87.8%) with IFRT vs 80.5% (95% CI = 75.2%–85.8%) with PFRT, with IFRT found to be noninferior to PFRT (hazard ratio [HR] = 0.97, 94% upper CI = 1.32, with upper CI noninferiority boundary of 1.6).

Among younger children receiving craniospinal irradiation, 5-year event-free survival was 71.4% (95% CI = 62.8%–80.0%) with low-dose craniospinal irradiation vs 82.9% (95% CI = 75.6%–90.2%) with standard-dose craniospinal irradiation, with low-dose craniospinal irradiation found to be inferior to standard-dose craniospinal irradiation (HR = 1.67, 80% upper CI = 2.10, with upper CI noninferiority boundary of 1.6).

Analysis of 362 patients with molecular subgroup data showed that 5-year event-free survival among 66 SHH subgroup patients was improved with IFRT vs PFRT (90.7% vs 74.9%, P = .018). No significant between-group differences were observed for WNT, group 3, or group 4 subtypes. Among 73 younger patients receiving craniospinal irradiation in the group 4 subgroup, 5-year event-free survival was lower with low-dose vs standard-dose craniospinal irradiation (77.2% vs 97.1%, P = .047). No between-group differences in the craniospinal irradiation comparisons were observed for WNT, SHH, or group 3 subgroups.

Children receiving standard-dose vs low-dose craniospinal irradiation had a significant 7.34-point greater decline in IQ (P = .02) between first assessment (T1 = 4­­–15 months postdiagnosis) and second assessment (T2 = 27–48 months). A 5.65-point greater decline between T1 and T3 (final assessment at 49–72 months) did not achieve significance (P = .12), potentially due to due small sample size at T3.

The investigators concluded, “Reducing the radiation boost volume in average-risk medulloblastoma is safe and does not compromise survival. Reducing craniospinal irradiation dose in young children with average-risk medulloblastoma results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with medulloblastoma to be considered for late-effect sparing approaches.”

Dr. Michalski, of the Department of Radiation Oncology, Washington University School of Medicine in St. Louis, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute and others. For full disclosures of the study authors, visit ascopubs.org.