Outcomes Following Radiation Therapy (RT) for Very Young Age CNS Embryonal Tumors on COG ACNS0334 According to Molecular-Confirmed Diagnosis

Abstract

The outcomes of upfront or relapse radiation therapy (RT) for the Children's Oncology Group ACNS0334 protocol based on molecular diagnosis were assessed. Therapy included maximal safe surgery, high-dose chemotherapy with stem cell rescue, randomization for inclusion of high dose methotrexate (MTX) and optional RT. There were 24 patients that received RT on COG ACNS0334 of 77 evaluable patients with a diagnosis of either high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (SPNET). RT was a recommendation (M0: Focal, M+: CSI 18 Gy) given young patient age <36 months at enrollment. Seven RT patients were excluded for ineligible pathology (1 ATRT, 1 HGG) or insufficient tissue. The aim of this report is to review outcomes of 17 patients on ACNS0334 receiving RT (8 Upfront, 9 at relapse) with a molecular diagnosis that included MB, Pineoblastoma (PB), or Embryonal tumor with multilayered rosettes (ETMR). In the MB group, there were 9 patients irradiated with MB (Group 3 = 8, SHH = 1). 5-year OS for MB Group 3 receiving RT (median primary dose 54 Gy) was 62.5% with no difference observed comparing 6 patients treated with upfront RT versus 2 treated at relapse (p = 0.27). All upfront RT for MB Group 3 had initial partial response (PR) to 0334 chemotherapy. RT delivery for upfront RT MB Group 3 included craniospinal radiation (CSI) in 5 patients and 1 patient who received focal RT to the primary (50 Gy) and metastatic site (44 Gy). Eighty percent of CSI for upfront RT in Group 3 was 18 Gy or 23.4 Gy. Relapse RT for MB Group 3 (2 patients) utilized full dose CSI (36 Gy, 39.6 Gy) and both patients are survivors with 5+ years follow-up. CSI dose for Group 3 MB was higher for relapse RT (mean 37.8 Gy) as compared to upfront RT (mean 19.8 Gy, p = 0.013). Use of MTX was 50% in both upfront RT and relapse RT Group 3 MB cohorts. One patient with MB SHH (classic histology) underwent upfront focal RT (54 Gy) after initial PR to systemic therapy (without MTX) and is surviving 5+ years. PB: Of 4 PB patients (median primary dose 48.8 Gy) 1 had RT upfront (CSI 18 Gy) and 3 had RT at relapse (1 patient received CSI, 21 Gy). All patients with PB expired within 2 years. MTX was given in 75% (including 1 upfront RT PB). Two of 3 patients treated at relapse had prior complete response (CR). ETMR: All 4 patients (median primary dose 54 Gy) with ETMR were treated at relapse, with CSI given in 1 patient (23.4 Gy). All patients with ETMR expired within 2 years, and 2 (50%) had received MTX. Two patients (50%) had initial CR. The RT cohort for Group 3 MB on ACNS0334 exhibited long-term survival both for both upfront and relapse RT, however relapsed Group 3 MB received higher dose CSI. RT upfront for MB, including one surviving MB SHH patient receiving focal RT, was solely given for incomplete initial chemotherapy response. There were no survivors for either PB or ETMR when the majority (88%) were treated at relapse.