Adult Medulloblastoma Patients Research Articles

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol

PurposeMedulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients.MethodsAdult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed.ResultsForty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn’t statistically significant.ConclusionCombined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

DISP-08. DISPARITY OF RADIATION TREATMENT AND CLINICAL OUTCOME AMONG ADULT MEDULLOBLASTOMA PATIENTS

Abstract OBJECTIVES Medulloblastoma is the most common malignant pediatric brain neoplasm, but its pattern of care among adult patients has not been standardized. Disparity in socioeconomic factors influence treatment decision and prognosis in many cancers. This study aims to analyze the impact of insurance and socioeconomic status on the clinical outcome of adult patients with medulloblastoma in the United States. METHODS Adult patients (age 18 or older) with medulloblastoma in the brain diagnosed from 2004 to 2016 were identified from the National Cancer Database (NCDB). OS was evaluated with the Kaplan-Meier and Cox proportional hazards methods. Logistic regression was performed to assess the effect on dichotomized dependent variable. RESULTS A total of 1,282 adult patients with medulloblastoma were identified. The mean age was 29 years (range 18-85). 30.9% of patients were uninsured or had Medicaid, 83.2% were white, 81.9% received radiation therapy, and 59.9% received chemotherapy. Using univariate analysis, insurance status, radiation, and chemotherapy were statistically associated with OS. Uninsured/Medicaid patients were associated with poorer OS (HR 1.36, 95% CI 1.08-1.71, p &amp;lt; 0.01) compared to those with private insurance. Treatment with radiation therapy (HR 0.43, 95% CI 0.34-0.55, p &amp;lt; 0.01) or chemotherapy (HR 0.51, 95% CI 0.41-0.62, p &amp;lt; 0.01) portended improved OS. After adjusting for age, sex, race, and Charlson-Deyo comorbidity score, statistically significant differences in OS were seen for patients with no insurance/Medicaid. Using multivariate logistic regression, patients with either no insurance or Medicaid were less likely to receive radiation therapy (OR 0.69, 95% CI 0.51-0.95, p = 0.02) compared to patients with private insurance. CONCLUSION Using a large national cohort of adult medulloblastoma patients, this study demonstrated the statistically significant disparity of patient outcomes with insurance status. An effort to address healthcare disparity and increase access to cancer care may improve the clinical outcome for adult patients with medulloblastoma.

Review of 20 years of Adult Medulloblastoma Treatment at a High-Volume Center – Chemotherapy Prescription Trends and Survival

<h3>Purpose/Objective(s)</h3> Medulloblastomas are WHO grade 4 tumors and represent less than 1% of adult brain malignancies. Standard of care is maximal safe resection follow by craniospinal and primary site radiation – the role for chemotherapy has been unclear. The objective of this study was to review 20-year chemotherapy prescribing trends in adult medulloblastoma patients at a high-volume center, with secondary objectives assessing overall and progression free-survival. We hypothesized that primary chemotherapy (concurrent or adjuvant) would be associated with prolonged survival and that patients treated in the most recent decade would have received chemotherapy more often. <h3>Materials/Methods</h3> A retrospective review was performed of adult medulloblastoma patients at a high-volume center from 1999-01-01–2020-12-31. Eligible patients were 18 years and older with a pathologic diagnosis of medulloblastoma – those with supratentorial primitive neuroectodermal tumors were excluded. Descriptive statistics were used to present population data and Kaplan–Meier estimators for survival analysis. <h3>Results</h3> Forty-nine patients were eligible; median age was 30 and male: female ratio was 2:1. Desmoplastic and classical histologies were the most common. Molecular subgroup was available for 6 patients, with SHH predominating. Of all patients, 47% (23/49 were classified as high risk – most commonly due to large cell/anaplastic histology or large residual. Only 10 (20%) received primary chemotherapy, 70% of which had high risk disease. Of the patients who received primary chemotherapy, 30% went on to receive chemotherapy for recurrence or metastases; of the entire population, this was only 39%. Primary regimens were mainly cisplatin/lomustine/vincristine, while recurrence regimens were often cisplatin/etoposide. The majority who received primary chemotherapy were treated from 2010–2020. Median overall survival was 7.8 years (95% CI 5.7–∞), with 1-, 5-, and 10-year survival 95.8%, 67.5% and 42.2% respectively. Overall survival was marginally better for those who did not receive primary chemotherapy (8.5 years) vs those who did (7.4 years) <i>but this was non-significant</i>. The main chemotherapy toxicity was hematologic and neuropathy - 90% of primary chemotherapy patients experienced toxicity <h3>Conclusion</h3> This study reviewed 20 years of treatment trends for a group of adult medulloblastoma patients at a high-volume center. We found only a small proportion of patients received chemotherapy as their primary treatment with surgery and radiation. Patients who received primary chemotherapy had marginally worse overall survival, but this was non-significant – perhaps due to baseline worse clinical status not captured by the definition of high vs. intermediate risk disease. Despite calls for adjuvant chemotherapy for all adult medulloblastoma patients, there is clinical equipoise and future randomized trials are needed.

Clinical Outcomes of Medulloblastoma Patients Treated with Proton Radiotherapy: A Systematic Review

<h3>Purpose/Objective(s)</h3> The aim of this study was to comprehensively review all studies examining clinical outcomes of proton therapy for craniospinal irradiation of medulloblastoma, to determine whether theoretical dosimetric advantages of proton therapy have translated into superior clinical outcomes, including survival and toxicities. <h3>Materials/Methods</h3> We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the PubMed (Medline), EMBASE, and Cochrane Library databases (inception to December 2021). The study was registered with PROSPERO, CRD42022302455. Articles in the English language reporting on clinical outcomes of pediatric and/or adult medulloblastoma patients treated with proton therapy were included. Two independent authors screened all titles/abstracts, reviewed full texts and extracted relevant data, with discrepancies resolved by consensus. Individual study quality was scored using Newcastle Ottawa Scale and overall evidence base by GRADE scale. <h3>Results</h3> Thirty-five studies were included, representing 629 unique patients. Publication dates ranged from 2011 to 2021, with the majority (n=32) from the United States. None of the studies were randomized, 12 were comparative, 9 were prospective, 3 mixed and 22 retrospective. Average mean/median follow up was 5.0 years (range = 4 weeks to 12.6 years). The majority of studies (n=19) reported on treatment with passive scatter proton beams exclusively. Average study quality score was 6.08 out of 9 (SD 0.688, median 5). Seven studies scored ≥8/9 on the Newcastle Ottawa Scale; an overall "moderate" GRADE score was assigned. Well-designed comparative cohort studies with adequate follow-up demonstrate superior neurocognitive outcomes, lower incidence of hypothyroidism (23% vs 69%) and reduced acute toxicities (including myelosuppression, esophagitis, diarrhea, weight loss and nausea/vomiting) in patients treated with protons compared to photons. The 10-year cumulative incidence of secondary malignancy is also lower for proton cohorts (2.1-4.9% vs 8%), but did not reach statistical significance in any individual study. Overall survival (10-yr) (85.3-86.9% for standard-risk disease), progression-free survival (10-yr), patterns of failure, and other endocrine outcomes such as incidence of GH deficiency, adrenal insufficiency and precocious puberty were similar to those reported for photon therapy. Quality of life, ototoxicity and incidence of CNS injury were also found to be comparable between proton and photon cohorts, albeit with lower quality of evidence. Overall, quality of evidence was most robust in the domains of intellectual outcomes, endocrinopathies and acute toxicity. <h3>Conclusion</h3> Moderate grade evidence supports proton beam therapy as a preferred treatment for craniospinal irradiation of medulloblastoma based on equivalent disease outcomes and comparable-to-improved toxicity versus photon beam radiotherapy.

Post-radiation cisplatin and etoposide as systemic treatment in newly diagnosed adult medulloblastomas: A retrospective, single institution, longitudinal evaluation of clinical outcomes and toxicity.

e14046 Background: Medulloblastomas are malignancies of the posterior fossa with metastatic potential to the central nervous system. While a common pediatric malignancy, they are rare in adults. Extrapolating treatment regimens from pediatrics to adults is fraught as adults can developmentally tolerate higher radiation doses, but have less bone marrow reserve and therefore risk higher myelosuppressive toxicities with adjuvant systemic therapy. A standard systemic regimen for adults has not been delineated, though craniospinal radiation alone is likely insufficient in most cases. In the absence of well-established guidelines, our institution has historically used a combination of cisplatin (60 mg/m2 on Day 1) and etoposide (60-120 mg/m2 on Days 1-3 or 1-5) repeated in three-week cycles for three to a maximum of six cycles, but the literature to support this regimen is scant. Methods: In this retrospective chart evaluation, we reviewed the medical information of patients who were seen for newly diagnosed adult medulloblastoma between 1995 and 2020 at Johns Hopkins Hospitals. Those who met our pre-specified criteria (adjuvant treatment with etoposide/cisplatin within six months of craniospinal irradiation, sufficient data on toxicity before and after radiation, during chemotherapy, and one month after completion of the regimen, as well as sufficient clinical follow-up) were included in the analysis. Hematological toxicities were graded by NCI CTCAE guidelines. Follow-up for progression and survival were calculated from the end of the last chemotherapy administration and plotted on swimmers plots. Results: Ten out of 74 total adult medulloblastoma patients had adequate data about the tolerability of the regimen and clinical follow-up. Median time to follow-up was 46 months (range 4.5-164 months). Eight patients experienced Grade 3 and 4 hematological toxicities. Seven patients completed their planned treatment course, while two patients discontinued treatment prematurely because of hematological toxicities and one due to ototoxicity and fatigue. Three out of the ten patients progressed post-chemotherapy at 1 month, 24.5 months, and 44 months. Both early-progression patients died (7 and 29.5 months respectively), while the remaining eight are alive without evidence of progression. Conclusions: The data suggest a combination regimen of cisplatin and etoposide after craniospinal radiation in newly diagnosed adult medulloblastoma patients has acceptable toxicity and survival outcomes in this small patient cohort and compare favorably to other limited datasets in the literature. Further study is warranted to validate this as a recommended regimen.

Supratentorial and spine metastatic medulloblastoma in adults

Medulloblastoma is an infratentorial primitive neuroectodermal tumor that is predominantly found in children. The incidence of medulloblastoma fluctuates between 20-35% in kids and is extraordinarily uncommon to be found in adults. A twenty-four-year-old man presented with a chief complaint of weakness of the lower extremity. Physical examination revealed myelopathy sign at the 12th thoracic level. Past medical history revealed that he had undergone total resection of a medulloblastoma of the cerebellum three years prior to the weakness. A thoracolumbar MRI with gadolinium contrast injection was performed which revealed a solid mass at thoracic vertebra 12 – lumbar 1. Four months after the total resection of the spinal mass, the patient presented again with a chief complaint of vomiting and a severe headache. A head CT scan was done followed by a head MRI with gadolinium contrast injection. A mass was found at the right temporoparietal region and craniotomy for tumor removal was immediately done to resolve the intracranial pressure problem. Pathological anatomy revealed the spinal and intracranial mass as medulloblastoma. This case report presents an adult with primary medulloblastoma of the cerebellum who presented with metastases of the spine and supratentorial regions. However, the incidence of medulloblastoma is very rare in adults and the 5-year survival rate is between 60% - 80% for all adult medulloblastoma patients. Surgeons must be careful in choosing the first management for better prognosis such as surgical management only, surgical management followed by adjuvant therapy, or just a chemotherapeutic-only approach.

RADT-25. PROTON THERAPY FOR YOUNG ADULT MEDULLOBLASTOMA: ACUTE TOXICITY AND DISEASE CONTROL OUTCOMES

Abstract BACKGROUND Report disease control, survival outcomes, and acute radiotherapy related toxicity among young adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. We reports the completion rates of planned adjuvant chemotherapy. METHODS All adult medulloblastoma patients (≥ 22 years old) who received postoperative proton CSI +/- chemotherapy at our institution between 2008 and 2020 were included. Patient, disease, and treatment details along with prospectively obtained patient-reported acute CSI toxicities were collected (CTCAE v3 or v4). Acute hematologic data were analyzed. RESULTS Twenty young adult medulloblastoma patients were included. The median age at diagnosis was 27 years (range, 22–30). 45% had high-risk disease. 75% received chemotherapy, most of whom (65%) received post-CSI chemotherapy. Eight patients (40%) received concurrent vincristine with CSI. The median CSI dose was 36 GyE (range, 23.4-36) with a median tumor bed boost of 54 GyE (54-55.8). The median duration of radiotherapy was 44 days (range, 40-49). There were no acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI (during or within 4 weeks after completion of RT). Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively. Acute grade 2 hematologic toxicity affected 36% of patients. Among patients planned to receive adjuvant chemotherapy (n=13), 100% completed at least 4 cycles and 85% completed all planned chemo cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, DFS, and OS were 90% (95% CI 53-99), 90% (95% CI 53-99), and 95% (95% CI 72-99), respectively. Two patients had disease recurrence, both with local failures in the high dose boost volume in the tumor bed. CONCLUSIONS Proton radiotherapy for CSI in young adult medulloblastoma patients is well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Decade-long disease, secondary malignancy, and brainstem injury outcomes in pediatric and young adult medulloblastoma patients treated with proton radiotherapy.

Survivors of pediatric medulloblastoma experience long-term morbidity associated with the toxic effects of postoperative radiotherapy (RT). Proton RT limits radiation dose to normal tissues thereby reducing side effects of treatment while maintaining high cure rates. However, long-term data on disease outcomes and long-term effects of proton RT remain limited. One hundred seventy-eight pediatric medulloblastoma patients treated with proton RT between 2002 and 2016 at the Massachusetts General Hospital comprise the cohort of patients who were treated with surgery, radiation therapy, and chemotherapy. We evaluated event-free survival (EFS), overall survival (OS), and local control using the Kaplan-Meier method. The cumulative incidence of brainstem injury and secondary malignancies was assessed. Median follow-up was 9.3 years. One hundred fifty-nine patients (89.3%) underwent a gross total resection (GTR). The 10-year OS for the entire cohort, standard-risk (SR), and intermediate/high-risk (IR/HR) patients was 79.3%, 86.9%, and 68.9%, respectively. The 10-year EFS for the entire cohort, SR, and IR/HR cohorts was 73.8%, 79.5%, and 66.2%. The 10-year EFS and OS for patients with GTR/NTR were 75.3% and 81.0% vs 57.7% and 61.0% for subtotal resection (STR). On univariate analysis, IR/HR status was associated with inferior EFS, while both anaplastic histology and IR/HR status were associated with worse OS. The 10-year cumulative incidence of secondary tumors and brainstem injury was 5.6% and 2.1%, respectively. In this cohort study of pediatric medulloblastoma, proton RT was effective, and disease outcomes were comparable to historically treated photon cohorts. The incidence of secondary malignancies and brainstem injury was low in this cohort with mature follow-up.

RADT-26. PROTON VERSUS PHOTON CRANIOSPINAL IRRADIATION FOR ADULT MEDULLOBLASTOMA: A DOSIMETRIC AND TOXICITY ANALYSIS

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&amp;lt; 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.

Impact of Insurance Status on Radiation Treatment and Clinical Outcome in Adult Medulloblastoma

<h3>Purpose/Objective(s)</h3> Medulloblastoma is the most common malignant pediatric brain neoplasm, but its pattern of care among adult patients has not been standardized. Recent studies demonstrated that disparity in socioeconomic factors could influence treatment decision and prognosis in many cancers. This study aims to analyze the impact of insurance and socioeconomic status on the clinical outcome of adult patients with medulloblastoma in the United States. <h3>Materials/Methods</h3> Adult patients (age 18 or older) with medulloblastoma in the brain diagnosed from 2004 to 2016 were identified from the National Cancer Database (NCDB). Patients with unknown status for race, insurance, income quartile, treatment status of radiation or chemotherapy, or overall survival (OS) were excluded. OS was evaluated with the Kaplan-Meier and Cox proportional hazards methods. Logistic regression was performed to assess the effect on dichotomized dependent variable. <h3>Results</h3> A total of 1,282 adult patients with medulloblastoma were identified. The median follow-up time was 6.9 years. The mean age was 29 years (range 18-85). 30.9% of patients were uninsured or had Medicaid, 83.2% were white, 81.9% received radiation therapy, and 59.9% received chemotherapy. Using univariate analysis, insurance status, radiation, and chemotherapy were statistically associated with OS. Uninsured/Medicaid patients were associated with poorer OS (hazards ratio [HR] 1.36, 95% CI 1.08-1.71, <i>P</i> < 0.01) compared to those with private insurance. Treatment with radiation therapy (HR 0.43, 95% CI 0.34-0.55, <i>P</i> < 0.01) or chemotherapy (HR 0.51, 95% CI 0.41-0.62, <i>P</i> < 0.01) portended improved OS. After adjusting for age, sex, race, and Charlson-Deyo comorbidity score, statistically significant differences in OS were seen for patients with no insurance/Medicaid (HR 1.48, 95% CI 1.17-1.86, <i>P</i> < 0.01). Using multivariate logistic regression, patients with either no insurance or Medicaid were less likely to receive radiation therapy (odds ratio [OR] 0.69, 95% CI 0.51-0.95, <i>P</i> = 0.02) compared to patients with private insurance, suggesting the mechanistic link between insurance status and pattern of care. <h3>Conclusion</h3> Using a large national cohort of adult medulloblastoma patients, this study demonstrated the statistically significant disparity of patient outcomes with insurance status. An effort to address healthcare disparity and increase access to cancer care may improve the clinical outcome for adult patients with medulloblastoma.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Proton therapy for adult medulloblastoma: Acute toxicity and disease control outcomes.

We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. We reviewed 20 adults with medulloblastoma (≥ 22years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed. Median age at diagnosis was 27years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively. Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator.

Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive. We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance. We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset "aSHH-MBI" (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, "neuronal" transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable "aSHH-MBII" subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome. (1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.

Medulloblastoma in adults - reviewing the literature from a surgeon's point of view.

Medulloblastoma is a common primary brain tumor in children but it is a rare cancer in adult patients. We reviewed the literature, searching PubMed for articles on this rare tumor entity, with a focus on tumor biology, advanced neurosurgical opportunities for safe tumor resection, and multimodal treatment options. Adult medulloblastoma occurs at a rate of 0.6 per one million people per year. There is a slight disparity between male and female patients, and patients with a fair skin tone are more likely to have a medulloblastoma. Patients present with cerebellar signs and signs of elevated intracranial pressure. Diagnostic efforts should consist of cerebral MRI and MRI of the spinal axis. Cerebrospinal fluid should be investigated to look for tumor dissemination. Medulloblastoma tumors can be classified as classic, desmoplastic, anaplastic, and large cell, according to the WHO tumor classification. Molecular subgroups include WNT, SHH, group 3, and group 4 tumors. Further molecular analyses suggest that there are several subgroups within the four existing subgroups, with significant differences in patient age, frequency of metastatic spread, and patient survival. As molecular markers have started to play an increasing role in determining treatment strategies and prognosis, their importance has increased rapidly. Treatment options include microsurgical tumor resection and radiotherapy and, in addition, chemotherapy that respects the tumor biology of individual patients offers targeted therapeutic approaches. For neurosurgeons, intraoperative imaging and tumor fluorescence may improve resection rates. Disseminated disease, residual tumor after surgery, lower radiation dose, and low Karnofsky performance status are all suggestive of a poor outcome. Extraneural spread occurs only in very few cases. The reported 5-year-survival rates range between 60% and 80% for all adult medulloblastoma patients.

Patterns Of Care And Outcomes Analysis For Adult Patients With Newly Diagnosed Medulloblastoma: A 30-Year Single Institution Experience

Medulloblastoma in the adult population is a rare disease with limited data regarding patient prognosis and appropriate course of treatment. A recent NCDB analysis correlated adjuvant chemoradiation to improved overall survival (OS). We performed a study of adult (age ≥18 years old) medulloblastoma patients to better understand outcomes and prognostic factors. An IRB approved chart review of adult medulloblastoma patients treated at our institution with 6-month minimum follow-up was conducted. We collected patient, disease, and treatment characteristics and outcomes including OS, progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FDM). Uni- and multivariable survival analyses were performed using Cox regression model. OS was estimated using Kaplan-Meier (KM) test methods. Statistical analysis was performed with JMP version 15.0 software with statistical significance established for p-values < 0.05. Thirty-two patients were treated (1992-2018) with postoperative radiotherapy (RT) including tumor bed/posterior fossa (median dose: 3600 cGy/20 fractions) and craniospinal irradiation (median dose: 2340 cGy/13 fractions) either alone (n = 10; 31%) or with adjuvant chemotherapy (aCTH: n = 22; 69%); of whom only 40% were known to complete the full aCTH course. Male patients demonstrated worse OS, PFS, FDM, and LC compared to their female counterparts. Univariable analysis showed sex, tumor location (lateral vs central), and completion of aCTH course to be significantly associated with OS; p<0.05. On multivariable analysis, however, only aCTH completion demonstrated a trend for better OS; HR = 0.15 (95% CI: 0.02-1.27, p = 0.08). KM survival analysis revealed superior 5-year OS and PFS in patients who completed aCTH compared to those who received RT alone or did not complete aCTH: 88.9% vs 68.6% vs 40%, p = 0.03 and 83.3% vs 59.3% vs 42%, p = 0.04, respectively. Our series demonstrates that completion of aCTH provides a significant OS and PFS advantage for adult medulloblastoma patients. Prospective studies are needed to develop optimal treatment approaches for these patients who have the potential for long term survival.Abstract 3734; TableVariableN (%)Age (median, interquartile range (IQR))29 (22-33)SexFemale: 13 (41) Male: 19 (59)Histologic subtypeClassic: 6 (19) Desmoplastic/nodular: 6 (19) Large cell/Anaplastic: 4 (12) Not available (NA):16 (50)Risk groupAverage: 19 (59) High: 6 (19) NA: 7 (22)LateralityLateral: 16 (50) Central: 16 (50)Extent of resectionGross total resection (GTR): 24 (75) Non-GTR: 8 (25)Craniospinal irradiation dose (Gray (Gy))23.4 Gy: 10 (31) 36 Gy: 17 (53) NA: 5 (16)Adjuvant chemotherapy (aCTH)None: 10 (31) A9961 CCNU: 12 (38) A9961 cyclophosphamide: 1 (3) ACNS0331: 5 (16) Other/NA: 4 (12)Treatment outcomes (months(mo), median, IQR)Local control duration: 39 (13-141) Freedom from distant metastasis duration: 47 (19-141) Overall survival duration: 54 (26-141) Open table in a new tab

Patterns Of Failure And Prognostic Factors Of Adult Medulloblastoma Treated With Radiation Therapy

Medulloblastoma (MB) is a rare adult malignancy of the central nervous system (CNS). Treatment guidelines are not well-established, as most practice is extrapolated from experience in the pediatric population. We reviewed our single institutional experience in managing adult MB to define clinical outcomes and identify potential prognostic factors. We identified and reviewed records of all adult MB patients aged ≥18 years who received upfront postoperative radiotherapy (RT) from 1997-2017 at a single institution. A total of 50 consecutive patients (29 male) were identified with histologically proven MB, reviewed at our institution but without consistent molecular classification available, and disease confined to the craniospinal axis at presentation. A total of 33 patients were classified as standard-risk, and 17 patients were classified as high-risk; 7 patients had M+ disease by Chang staging. Gross total resection was achieved in 37 patients with subtotal resection (STR) in the remaining 13 patients. Median craniospinal irradiation (CSI) dose was 36Gy (RBE) with a median tumor bed or posterior fossa dose boosted to 54Gy (RBE). Thirty-nine patients were treated with proton beam RT, 9 with photon-based RT, and 2 with mixed proton/photon RT. Eleven patients did not receive any adjuvant chemotherapy (CHT), 25 patients received concurrent and adjuvant CHT, 8 received only adjuvant CHT (after RT), and 6 received a combination of neoadjuvant CHT with concurrent and adjuvant CHT. With a median follow up of 5.3 years, 7 patients had disease recurrence: 5 within the craniospinal axis and 2 patients with extraneural recurrence. Two patients died, both from disease progression. Overall survival (OS) at 5 years was 96.3%, and event-free survival (EFS) at 5 years was 80.7%. Twenty-nine percent (2/7) of recurrences occurred after 5 years. In the seven patients with disease recurrence, all were classified as standard risk and M0 on presentation; 86% (6/7) were treated with 36Gy to CSI and 54Gy to boost volume; 4 had anaplastic histology and 3 had desmoplastic histology. Two patients deferred adjuvant CHT, four were treated with concurrent and adjuvant CHT, and one with adjuvant CHT only. Both patients with extraneural recurrence received concurrent and adjuvant CHT. On univariate analysis, time to start of RT >35 days from diagnosis was associated with worse EFS (HR 8.46, 95% CI 1.01-70.70, p = 0.049). There was no statistically significant trend for worse EFS or OS with histology, STR, high-risk, M+ disease, RT duration, or use of adjuvant CHT. Adults with MB have survival rates similar to their pediatric counterparts, but late and distant relapses are not uncommon. RT is a major component of the treatment of adult MB, however better prognostic factors, possibly from molecular subtyping, may help to define better personalized treatments for adult MB with high risk of recurrence.

Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: a long term study

BackgroundMedulloblastoma is extremely rare in adults. The role of chemotherapy for average-risk adult patients remains controversial. Surgery and radiotherapy provide a significant disease control and a good prognosis, but about 25% of average-risk patients have a relapse and die because of disease progression. No data in average-risk adult patients are available to compareradiotherapy alone and radiotherapyfollowed byadjuvant chemotherapy.MethodsWe analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016.ResultsMedian age was 29 years (range 16–61). Based on histological subtypes, 15 patients (31.3%) had classic, 15 patients (31.3%) had desmoplastic, 5 patients (10.4%) had extensive nodularity and 2 patients (4.2%) had large cells/anaplastic medulloblastoma. Twenty-four patients (50%) received adjuvant radiotherapy alone and 24 (50%) received radiotherapy and chemotherapy. After a median follow-up of 12.5 years, we found that chemotherapyincreases progression-free survival (PFS-15 82.3 ± 8.0% in patients treated with radiotherapy and chemotherapyvs. 38.5% ± 13.0% in patients treated with radiotherapy alone p = 0.05) and overall survival (OS-15 89.3% ± 7.2% vs. 52.0% ± 13.1%, p = 0.02). Among patients receiving chemotherapy, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia (6 cases of G3 neutropenia [25%] and 3 cases of G4 neutropenia [13%]), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%).ConclusionsOur study with a long follow up period suggests that adding adjuvant chemotherapy to radiotherapy might improve PFS and OS in average-risk adult medulloblastoma patients.

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study

BackgroundCombined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL).MethodsNeurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL.Results28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below − 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range.ConclusionsThis long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Trends in the Incidence and Survival of Adult-Onset Medulloblastoma

Background: Medulloblastoma (MB) is a central nervous system malignancy that rarely affects adult. Epidemiological trends of adult MB are limited. This study aimed to explore population-level trends in the incidence of adult MB and to examine potential predictors for overall survival (OS). Methods: Data for patients from 1973 to 2015 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Age-adjusted incidence rates (AAIR) were calculated for groups divided on the basis of age, gender, and ethnicity. Propensity-score matching was used to compensate for potential selection biases. Cox proportional hazard models were used to examine potential predictors for OS. Results: AAIR was stable among MB patients ≥20 yr of age. The AAIR was slightly higher in males than that in females (0.065 vs. 0.049 per 100,000). Compared to whites, the incidence was nearly doubled in individuals of black ethnicity (0.063 vs. 0.033 per 100,000). Incidence was also lower among patients ≥40 yr of age, compared to those 20-39 yr of age (0.025 vs. 0.107 per 100,000). Multivariate Cox analysis indicated that age (p <0.001) and surgical resection (p =0.002) were independent prognostic factors for OS in adult MB. PSM revealed that age (p<0.001), surgical resection (p=0.012), histology (p=0.031), insurance status (p=0.014), and marital status (p=0.040) had significant effects on OS. Conclusions: This study demonstrated that adult MB patients could benefit from GTR and young age. In addition, race-, gender- and age-disparities were linked with the trends in MB incidence and survival. Funding: This study was supported by Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2017Y9074) and the Key Clinical Specialty Discipline Construction Program of Fujian, People’s Republic of China. Conflict of Interest: The authors report no potential conflicts of interest. Ethical Approval: The data analysed and used in this study was obtained from Surveillance, Epidemiology, and End Results (SEER) database in accordance with the SEER data use agreement. Therefore, this study did not require approval of ethical board.