Krasin, Matthew J.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

Background Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi‐institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma. Methods Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression‐free survival (PFS), and overall survival (OS) were calculated using the Kaplan‐Meier method. Results Fourteen patients with a median age of 17 years (range, 4‐25 years) were treated to 37 distinct metastatic lesions. With a median follow‐up of 6.8 months (30.5 months in surviving patients), the Kaplan‐Meier patient‐specific and lesion‐specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log‐rank P = .03) and OS (median not reached vs 12.7 months; log‐rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities. Conclusions SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

AbstractThis report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image‐guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in‐room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.

Abstract Abstract 664 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) who received prophylactic cranial radiation therapy (CRT) are at increased risk for deficits in neurocognitive skills, including attention, working memory and processing speed. As survivors age, global brain injury from CRT may reduce cognitive reserve, placing them at risk for early onset dementia or long-term memory deficits. The prevalence of dementia and memory abnormalities in adult survivors of childhood ALL has not previously been established. Methods: Analyses were conducted on 265 of 445 (60%) eligible survivors of childhood ALL (median age 36 years, range 26–54 years; 52% female) treated with 18Gy (n=127) or 24Gy (n=138) CRT with a median time from CRT of 30 years (range 15–46 years). Participants completed the Wechsler Memory Scale IV, including the Brief Cognitive Status Exam (BSCE), and the Wechsler Abbreviated Scale of Intelligence (WASI). Age-adjusted standard scores were calculated and the BSCE was also adjusted for education level. Prevalence of memory impairment (<1 SD below age-expected mean), stratified by RT dose exposure, is reported and logistic regression used to identify risk factors for impairment. A subset of survivors (n=85) completed brain magnetic resonance imaging (MRI), including assessment of hippocampal volume, cortical thickness, white matter volume, diffusion tensor imaging, and functional MRI (fMRI) during a cued-recall memory task. Results: Survivors who received 24 Gy CRT had increased impairment on global measures of both short-term recall (33%; p<0.001) and long-term recall (30%; p<0.001), while no increase in impairment was seen after 18Gy. Impaired short-term recall was associated with smaller right (p=0.02) and left (p<0.01) temporal lobe volumes, while impaired long-term recall was associated with thinner parietal and frontal cortices. On subtests evaluating narrative memory (i.e. story recall) and design memory, increasing RT dose (24 vs. 18Gy) was associated with an increased prevalence of long-term memory impairment (narrative: 28% vs. 12%, p=0.001; designs: 13% vs. 3.2%, p=0.003). However, no CRT dose response was identified for short term narrative and design memory. Survivors with impaired long-term memory for designs demonstrated a compensatory increase in left hippocampal fMRI activation (p=0.005), and the effect was greater in the higher dose group (p = 0.04). The mean score for long-term narrative memory among survivors who received 24Gy was equivalent to the mean score of a 70–74 year old adult population. Neither young age (0–4 years) at CRT (Odds Ratio [OR] 1.4, 95% confidence interval [CI] 0.8–2.7), time from CRT (OR 1.0, 95% CI 0.9–1.1) nor intrathecal methotrexate exposure (OR 3.9, 95% CI 0.4–36.1) were significantly associated with long-term memory deficits. Reduced cognitive status (by BSCE) was identified after 18Gy (9%, p=0.11) and 24Gy (18%, p<0.001), suggesting a CRT dose-response effect. On diffusion tensor imaging, increased radial diffusivity in the frontal, parietal and temporal regions, an inverse measure of white matter integrity, was associated with reduced BSCE. Current employment rates were equivalent (63%) in both CRT dose groups, suggesting no difference in functional status. Conclusions: Aging adult survivors of ALL who received 24Gy CRT have reduced cognitive status and significant impairment in short-term and long-term memory. There appears to be a dose response effect selective for long-term narrative and design memory, but not for short term narrative and design memory. These patterns are consistent with early onset of age-related (long-term) memory loss, and early stage dementia, yet at a median age of only 36 years. After 24Gy, survivors have the narrative memory equivalent to a 70 year-old in the general population. Survivors with memory impairment demonstrated reduced integrity on structural and functional neuroimaging in anatomical regions established as essential for memory formation and long-term recall. However, these memory impairments do not seem to affect functional status (employment rates) suggesting that, rather than frank dementia, deficits in middle adulthood are consistent with mild cognitive impairment (MCI). Longitudinal evaluation of this population is needed as MCI often progresses into early onset dementia with age. Disclosures: No relevant conflicts of interest to declare.