Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma

Abstract

Purpose: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume.

Methods: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time.

Results: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021).

Conclusion: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB 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 MB to be considered for late-effect sparing approaches.

Conflict of interest statement

Jeff M. MichalskiStock and Other Ownership Interests: ViewRayConsulting or Advisory Role: Mevion Medical Systems, Boston Scientific, Merck Sharp & Dohme, Blue Earth DiagnosticsResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Boston Scientific, Merck Sharp & DohmeOpen Payments Link: https://openpaymentsdata.cms.gov/physician/221723 Kristina K. HardyEmployment: BayerHonoraria: BayerSpeakers' Bureau: BayerTravel, Accommodations, Expenses: Bayer Stephanie M. PerkinsConsulting or Advisory Role: Mevion Medical Systems Thomas E. MerchantTravel, Accommodations, Expenses: Philips Healthcare Nancy J. TarbellConsulting or Advisory Role: Mevion Medical Systems, Advanced OncoPatents, Royalties, Other Intellectual Property: Spouse is an editor for UpToDate Maryam FouladiResearch Funding: PTC Therapeutics, Bayer Schering Pharma Roger J. PackerHonoraria: NovartisConsulting or Advisory Role: Novartis, AstraZeneca Amar GajjarConsulting or Advisory Role: Roche/Genentech, QED TherapeuticsResearch Funding: Genentech, Kazia TherapeuticsNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. NOTE. All patients received weekly vincristine (six doses) during radiation phase of therapy. aBoth random assignments occurred at the time of study enrollment. bPatients age 3-7 years randomly assigned to the reduced-dose (18 Gy) craniospinal radiation were given an additional dose of 5.4 Gy to the posterior fossa (18 Gy + 5.4 Gy = total 23.4 Gy) before the final boost dose (cumulative 54 Gy). IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; PFRT, posterior fossa radiation therapy; SDCSI, standard-dose craniospinal irradiation.

FIG 2.

Molecular classification of patients in ACNS0331. (A) Pie charts summarizing the molecular classification results for eligible and evaluable patients (molecular cohort) profiled by DNA methylation array. (B) t-SNE plot summarizing molecular subgroup distribution of tumors profiled by DNA methylation array. (C) Oncoprint summarizing recurrently mutated genes and chromosomal events by molecular subgroup (NGS cohort). CSI, craniospinal irradiation; IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; MB, medulloblastoma; NGS, next-generation sequencing; PFRT, posterior fossa radiation therapy; SDCSI, standard-dose craniospinal irradiation; SHH, Sonic Hedgehog; SNV, single nucleotide variant; t-SNE, t-distributed stochastic neighbor embedding; WNT, Wingless.

FIG 3.

Outcomes by random assignment arm. (A and B) EFS and OS of all eligible and evaluable patients by RT group. (C and D) EFS and OS of all eligible and evaluable patients by CSI group. CSI, craniospinal irradiation; EFS, event-free survival; IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; OS, overall survival; PFRT, posterior fossa radiation therapy; RT, radiation therapy; SDCSI, standard-dose craniospinal irradiation.

FIG 4.

Outcomes by molecular subgroup. (A and B) EFS and OS of all molecularly classified patients by subgroup. (C and D) Distribution of patients by trial random assignment according to molecular subgroup (CSI and RT groups, respectively). CSI, craniospinal irradiation; EFS, event-free survival; IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; OS, overall survival; PFRT, posterior fossa radiation therapy; RT, radiation therapy; SDCSI, standard-dose craniospinal irradiation; SHH, Sonic Hedgehog; WNT, Wingless.

FIG 5.

Random assignment outcomes by molecular subgroup. (A-D) EFS for each molecular subgroup stratified by RT group of WNT, SHH, group 3, and group 4, respectively. (E-H) EFS for each molecular subgroup stratified by CSI group. CSI, craniospinal irradiation; EFS, event-free survival; IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; PFRT, posterior fossa radiation therapy; RT, radiation therapy; SDCSI, standard-dose craniospinal irradiation; SHH, Sonic Hedgehog; WNT, Wingless.

FIG 6.

Pattern of failure by random assignment arm. (A) Cumulative incidence of local failure (local and local plus distant) by RT group. (B) Cumulative incidence of isolated distant failure by CSI group (3-7 years). (C) Pattern of failure by molecular subgroup. CSI, craniospinal irradiation; IFRT, involved field radiation therapy; LDCSI, low-dose craniospinal irradiation; PFRT, posterior fossa radiation therapy; RT, radiation therapy; SDCSI, standard-dose craniospinal irradiation; SHH, Sonic Hedgehog; WNT, Wingless.

FIG 7.

Neurocognitive outcomes by trial random assignment. (A) Decrease of IQ from T1 to T2 is 7.34 units more (P = .02) in SDCSI group compared with LDCSI group in patients between 3 and 7 years old on the basis of the GLM, which controls sex, age at diagnosis, and insurance status. Decrease of IQ from T1 to T3 is not significantly different between LDCSI and SDCSI groups in patients between 3 and 7 years old on the basis of the GLM, which controls sex, age at diagnosis, and insurance status (T1 to T3 estimate = 5.65, P = .12). (B) Decrease of PSI from T1 to T2 is not significantly different between LDCSI and SDCSI groups in patients between 3 and 7 years old on the basis of the GLM, which controls sex, age at diagnosis, and insurance status (T1 to T2 estimate = −2.35, P = .65; T1 to T3 estimate = −5.75, P = .25). (C) At T2, IQ of reduced boost group is 6.04 units more (P = .01) than PF boost group on the basis of the GLM, which controls sex, age at diagnosis, and insurance status. CSI, craniospinal irradiation; GLM, generalized linear model; IFRT, involved field radiation therapy; IQ, intelligence quotient; LDCSI, low-dose craniospinal irradiation; PFRT, posterior fossa radiation therapy; RT, radiation therapy; SDCSI, standard-dose craniospinal irradiation.