Citations

Abstract Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p< 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Background: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. Procedure: Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1 year post-radiotherapy. Group differences in cognitive and social functioning were assessed using ANCOVA. Regression analyses examined predictors of peer relations and social skills. Results: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>0.05). However, XRT participants were younger at diagnosis (XRT M=5.0 years, PRT M=7.6 years) and further out from radiotherapy (XRT M=8.7 years, PRT M=4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p=0.01) and verbal memory (p<0.01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation (2(1)=38.67, p<0.001; 2(1)=5.63, p<0.05), and verbal memory approached significance as a unique predictor of peer relations (t=-2.01, p=0.05). Total tumor RT dose significantly predicted social skills (t=-2.23, p<0.05). Conclusions: Regardless of radiation modality, survivors are at risk for social challenges, with one-quarter being socially excluded or undervalued. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship.

Abstract PurposeTo clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM).MethodsA retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months.ResultsEighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals (DSSs) were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n=7). Prior EBRT was associated with reduced PFS (HR = 5.92, P <0.01), reduced DSS (HR = 5.84, P <0.01), and an increased risk of ARE (HR = 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR = 3.17, P = 0.01) or late salvage treatment (HR = 4.39, P <0.01). ConclusionPFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

BACKGROUNDBoth intensity‐modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity‐modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II).METHODSFrom 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard‐risk disease (63.5%). The median follow‐up was 12.8 years for group I and 8.7 years for group II.RESULTSThe 5‐year and 10‐year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard‐risk patients and 63.1% and 57.3%, respectively, for high‐risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5‐year and 10‐year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia.CONCLUSIONSThis analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT.LAY SUMMARY One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity‐modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52). The majority of children had standard‐risk disease (63.5%). The 5‐year and 10‐year overall survival rates were 88.8% and 85.1% for standard‐risk patients, respectively, and 63.1% and 57.3% for high‐risk patients, respectively, with no difference in overall survival by RT group (P = .81). The 5‐year and 10‐year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).

AbstractBackgroundAdult medulloblastoma (MB) is rare, and management guidelines are largely based on pediatric clinical trials and retrospective series. Limited data exist with respect to clinical characteristics, prognostic factors, and outcomes based on first-line treatments.MethodsTwo hundred adults with MB seen at a single institution from January 1978 to April 2017 were identified and followed for a median of 8.4 y (7.1, 10.3).ResultsPatient’s median age at diagnosis was 29 y (18, 63). One hundred eleven (55.5%) were standard-risk, 59 (29.5%) were high-risk, and 30 (15.0%) were indeterminate. Most received post-operative radiation (RT) (184 [92.0%]), and 105 (52.5%) received first-line chemotherapy. Median overall survival (OS) was 8.8 y (7.2, 12.2) and median progression-free survival (PFS) was 6.6 y (4.9, 11.2). High-risk patients had inferior OS (Hazard ratio [HR] = 2.5 [1.5, 4.2], P = .0006) and PFS (HR = 2.3 [1.3, 3.9], P = .002) compared to standard-risk patients. Age, sex, and metastatic disease were not associated with survival. After adjusting for risk status, those who received RT plus adjuvant chemotherapy had superior PFS compared to RT plus neoadjuvant chemotherapy [HR = 0.46 (0.22, 0.95), P = .0357]. Within a subgroup for whom detailed clinical data were available, those who received RT plus adjuvant chemotherapy had improved PFS compared to RT only [HR = 0.24 (0.074–0.76), P = .016]. The substitution of cisplatin for carboplatin and the elimination of vincristine did not negatively affect outcomes.ConclusionThis is the largest single-institution retrospective study of adult MB to our knowledge and identifies standard-risk status, first-line RT and adjuvant chemotherapy as factors associated with improved outcomes.

Abstract Background Proton radiotherapy (PRT) may be associated with less neurocognitive risk than photon RT (XRT) for pediatric brain tumor survivors. We compared neurocognitive and academic outcomes in long‐term survivors treated with XRT versus PRT. Methods Survivors underwent neurocognitive evaluation >1 year after craniospinal (CSI) or focal PRT or XRT. Groups were compared using separate one‐way analyses of covariance for the CSI and focal groups. Results PRT ( n = 58) and XRT ( n = 30) subgroups were similar on gender (66% male), age at RT (median = 6.5 years), age at follow‐up (median = 14.6 years), and government assistance status (32%). PRT and XRT focal groups differed on follow‐up interval, shunt history, and total RT dose (all p < .05), whereas PRT and XRT CSI groups differed on follow‐up interval, baseline neurocognitive performance score, boost volume, and CSI dose (all p < .05). The PRT focal group outperformed the XRT focal group on inhibition/switching ( p = .04). The PRT CSI group outperformed the XRT CSI group on inattention/impulsivity (both p < .05). Several clinical variables (i.e., RT dose, boost field, baseline performance) predicted neurocognitive outcomes (all p < .05). The PRT focal group performed comparably to population means on most neurocognitive measures, while both CSI groups performed below expectation on multiple measures. The XRT CSI group was most impaired. All groups fell below expectation on processing speed, fine motor, and academic fluency (most p < .01). Conclusions Findings suggest generally favorable neurocognitive and academic long‐term outcomes following focal PRT. Impairment was greatest following CSI regardless of modality. Dosimetry and baseline characteristics are important determinants of outcome alone or in combination with modality.

Abstract Purpose Intensive multi-modal regimens have improved survival for patients with atypical teratoid rhabdoid tumor, however relapse rates remain high. A better understanding of clinical and pathologic features associated with tumor relapse is critical to risk-stratifying patients. Patients and Methods ACNS0333 treatment consisted of multi-agent chemotherapy, high-dose chemotherapy, and radiation therapy, lasting approximately 6 months. Variables including patient age, sex, tumor location, M-stage, degree of resection, order of therapy, germline status, and molecular subgroup were analyzed. Cumulative incidence (CI) of event free survival due to relapse was evaluated for each variable. Results Thirty-three of 65 evaluable patients had tumor relapse. For the entire cohort, the CI of relapse was 21.8% at 6 months, 40.6% at one year and 50.3% at 4 years. For patients with infratentorial tumors, CI of relapse was 26.3%, 34.2% and 37.2%, at 6 months, 1 and 4 years respectfully compared to 15.3%, 49.9%, and 69.7% for those with supratentorial tumors (p 0.051). Patients with SHH subtype had no relapses in the first 6 months and CI of relapse of 37.5% at 4 years, while those with TYR and MYC subgroups had CI of relapse of 33.3% and 26.7% at 6 months and 46.3% and 73.3% at 4 years respectfully (p 0.088). Patients with germline mutations had a cumulative incidence of relapse of 20% at 6 months and 60% at 12 months compared to 22.6% and 37.7% respectfully for those without. No obvious trends were noted based on other analyzed variables. Conclusions ACNS0333 was not powered to determine prognostic indicators of relapse, however, this data suggest interesting trends based on tumor location, subtype and germline status. Infratentorial location and SHH subtype maybe associated with lower risk of relapse. Larger data sets must be compiled to further investigate these variables, perform multivariate analyses and inform risk-stratification on future trials.

Abstract Background This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO). Methods Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. “Clinical progression” was based on a clinical radiology report of progression and/or change in treatment for progression. Results Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4–14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. Conclusions Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

AbstractThe clinical outcomes for infants with malignant tumors are often worse than older children due to a combination of more biologically aggressive disease in some cases, and increased toxicity—or deintensification of therapies due to concern for toxicity—in others. Especially in infants and very young children, finding the appropriate balance between maximizing treatment efficacy while minimizing toxicity—in particular late side effects—is crucial. We review here the management of malignant tumors in infants and very young children, focusing on central nervous system (CNS) malignancies and rhabdomyosarcoma.

ABSTRACTRadiation therapy (RT) is an integral part of the management of many pediatric tumors; however, it is associated with both acute and permanent adverse events that can significantly impact a child's quality of life, lead to treatment delays, and potentially affect outcomes of cancer therapy. Prevention, early detection, and optimal management of these adverse effects will help reduce their impact on the patients’ quality of life and overall well‐being. Unfortunately, there has not been a coordinated effort to study the etiology, evaluate risk factors, and explore novel treatments for these conditions. Studies of supportive care for children undergoing RT are often small and uncontrolled. This review will focus on the impact of irradiation on the different organ systems and their current management. Further studies are required to improve our understanding of the contributing factors and explore novel treatment options for these adverse effects and to enable children and their families to better cope with some of the unavoidable toxicities following multimodality therapy.