Mahajan, Anita

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).

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 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.

Abstract Background: Endocrine deficiencies are common following craniospinal irradiation (CSI) in children with brain tumors, but empirical data comparing outcomes following proton (PRT) and photon radiation therapy (XRT) are limited. Methods: This retrospective chart review compared the incidence of hypothyroidism, growth hormone deficiency (GHD), and adrenal insufficiency (AI) in patients with medulloblastoma treated with XRT and PRT between 1997 and 2016. All patients received CSI and had routine endocrine screening labs to evaluate for thyroid dysfunction, GHD, and AI. We used proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) comparing the development of hypothyroidism, AI, and GHD between radiation modalities, adjusting for age at diagnosis, sex, race/ethnicity, and CSI dose.Results: We identified 118 patients with medulloblastoma who were followed for a median of 5.6 years from the end of radiotherapy. Thirty-five (31%) patients developed hypothyroidism, 71 (66%) GHD, and 20 (18%) AI. Compared to PRT, XRT was associated with a higher incidence of primary (28% vs. 6%; HR=4.61, 95% CI 1.2-17.7, p=0.03) and central hypothyroidism (33% vs. 9%; HR 2.35 (0.8-6.8, p=0.12). GHD and AI incidence rates were similar between the groups. Conclusions: Primary and central hypothyroidism occur less often after PRT CSI, compared to XRT CSI. This suggests that the thyroid and pituitary glands receive less radiation after spine and posterior fossa boost RT, respectively, using PRT.

Abstract Background Patterns of recurrence and survival with different surgical and radiotherapy (RT) techniques were evaluated to guide RT target volumes for patients with temporal lobe glioma. Methods and Materials This retrospective cohort study included patients with World Health Organization grades II to IV temporal lobe glioma treated with either partial (PTL) or complete temporal lobectomy (CTL) followed by RT covering both the parenchymal and dural resection bed (whole-cavity radiotherapy [WCRT]) or the parenchymal resection bed only (partial-cavity radiotherapy [PCRT]). Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were evaluated. Results Fifty-one patients were included and 84.3% of patients had high-grade glioma (HGG). CTL and PTL were performed for 11 (21.6%) and 40 (78.4%) patients, respectively. Median RT dose was 60 Gy (range, 40-76 Gy). There were 82.4% and 17.6% of patients who received WCRT and PCRT, respectively. Median follow-up time was 18.4 months (range, 4-161 months). Forty-six patients (90.2%) experienced disease recurrence, most commonly at the parenchymal resection bed (76.5%). No patients experienced an isolated dural recurrence. The median PFS and OS for the PCRT and WCRT cohorts were 8.6 vs 10.8 months (P = .979) and 19.9 vs 18.6 months (P = .859), respectively. PCRT was associated with a lower RT dose to the brainstem, optic, and ocular structures, hippocampus, and pituitary. Conclusion We identified no isolated dural recurrence and similar PFS and OS regardless of postoperative RT volume, whereas PCRT was associated with dose reduction to critical structures. Omission of dural RT may be considered a reasonable alternative approach. Further validation with larger comparative studies is warranted.

Abstract Pancreatic cancer is the fourth most common cause of cancer-related morality worldwide, and the prognosis remains poor despite aggressive therapy. Carbon ion radiotherapy has favorable radiobiological and physical characteristics in the treatment, including a higher linear energy transfer and higher relative biological effectiveness, which increase the cell kill while potentially reducing toxicities to nearby normal tissues. Although small, early clinical studies have shown promise in both the resectable and unresectable settings to improve local control and overall survival while minimizing toxicities. Currently, there are several trials, including 2 sponsored by institutions in the United States, investigating the role of carbon ion radiotherapy for the treatment of locally advanced pancreatic cancer.

PURPOSE Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose ( P < .001) and boost margin ( P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed ( P = .003). CONCLUSION To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.