Adult Medulloblastoma Research Articles

309P Patients with relapsed adult medulloblastoma (MB) treated by the GEINO (Spanish cooperative group for research in neuro-oncology) group oncologists: Natural history and patterns of care

Most pediatric patients with MB that experience recurrence present with distant dissemination within the neuroaxis and rarely benefit from local rescue strategies such as surgery and radiotherapy. However, adult MB has important biological differences that impact clinical behavior and patient outcomes.

149: Review of 20 Years of Adult Medulloblastoma Treatment at a High-Volume Centre - Chemotherapy Prescription Trends and Survival

149: Review of 20 Years of Adult Medulloblastoma Treatment at a High-Volume Centre - Chemotherapy Prescription Trends and Survival

Adult medulloblastoma: a case report

BackgroundMedulloblastoma is a malignant brain tumor that is common in children but very uncommon in adults, especially those older than 40 years, accounting for less than 1% of all primary brain tumors in adults. Although surgery and radiotherapy play an important role treatment of adult medulloblastoma, the use of chemotherapy is controversial. This is the first instance of adult medulloblastoma at the Ocean Road Cancer Institute in Tanzania.Case descriptionWe report the case of a 51-year-old female of African ethnicity who was diagnosed with high-risk hemispheric posterior cranial fossa medulloblastoma of classic type with World Health Organization central nervous system grade 4 and Chang stage M0. Immunohistochemistry, reticulin stain, and molecular subtyping could not be done because they were not available. She was treated by subtotal posterior cranial fossa tumor resection followed by adjuvant concurrent chemo-craniospinal radiation and adjuvant chemotherapy.ConclusionEven in adults over 50 years old, medulloblastoma should be included in the differential diagnosis of posterior fossa tumor. Adult medulloblastoma is a very rare and very heterogeneous tumor, but it has a good prognosis. Immunohistochemistry and molecular subclustering are difficult to implement in low-income countries such as Tanzania owing to cost. Treatment of adult medulloblastoma is highly heterogeneous among (and even within) facilities. There is no evidence that the extent of resection enhances survival. While craniospinal radiation therapy improves survival, there is controversy about the role of chemotherapy in managing adult MB.

Adult Medulloblastoma: Updates on Current Management and Future Perspectives.

Simple SummaryAdult medulloblastoma is an extremely rare tumor of the central nervous system. Standard multimodal treatment, comprising maximal safe surgical resection followed by craniospinal radiotherapy and multi-agent chemotherapy, can improve the prognosis of this disease, producing, however, important acute and long-term toxicities. Herein, we review the state of the art for adult medulloblastoma diagnosis and treatment, presenting novel molecular advances and their therapeutic implications and discussing the central role of hub centers to guarantee the highest quality of care and a better overall outcome for this rare tumor.Medulloblastoma (MB) is a malignant embryonal tumor of the posterior fossa belonging to the family of primitive neuro-ectodermic tumors (PNET). MB generally occurs in pediatric age, but in 14–30% of cases, it affects the adults, mostly below the age of 40, with an incidence of 0.6 per million per year, representing about 0.4–1% of tumors of the nervous system in adults. Unlike pediatric MB, robust prospective trials are scarce for the post-puberal population, due to the low incidence of MB in adolescent and young adults. Thus, current MB treatments for older patients are largely extrapolated from the pediatric experience, but the transferability and applicability of these paradigms to adults remain an open question. Adult MB is distinct from MB in children from a molecular and clinical perspective. Here, we review the management of adult MB, reporting the recent published literature focusing on the effectiveness of upfront chemotherapy, the development of targeted therapies, and the potential role of a reduced dose of radiotherapy in treating this disease.

Adult medulloblastoma in an Australian population

Medulloblastoma in adult patients is a rare condition with limited contemporary demographic and treatment outcome data available in an Australian population. We conducted a retrospective review of patterns of care and outcomes of adult patients diagnosed with medulloblastoma treated at major neuro-oncology centres across Australia between January 2010 and December 2019. A total of 80 patients were identified and the median follow-up after diagnosis was 59.2 (range 0.5–204) months. A variety of chemotherapy regimens were used in the adjuvant and recurrent settings. The median overall survival (mOS) was 78 months (IQR 17.5–94.8). Patients who had no residual disease post-resection or with SHH-subtype tumours had a numerically longer 5-year survival rate than those with residual disease post resection or non-SHH subtypes respectively. The median time to recurrence from diagnosis was 18.4 months. The median OS from 1st relapse was 22.1 months (95% CI 11.7–31.4) and mOS from second relapse was 10.2 months (95% CI 6.6 - NR). This is the largest dataset examining patterns of care of adult patients with medulloblastoma in an Australian population. Substantial variation existed in the chemotherapy agents used in the adjuvant and recurrent setting. As has been demonstrated in a paediatric population, trials such as the upcoming EORTC 1634-BTG/NOA-23 trial (PersoMed-1 study) which are tailoring treatments to molecular profiles are likely to improve outcome in adult medulloblastoma.

Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience.

Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

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.

OC-0589 Successful pregnancies after helical Tomotherapy craniospinal irradiation for adult medulloblastoma

OC-0589 Successful pregnancies after helical Tomotherapy craniospinal irradiation for adult medulloblastoma

The Role of Chemotherapy in the Treatment of Adult Medulloblastoma

The role of chemotherapy (CT) in the treatment of adult patients with medulloblastoma (MB) is unclear. The aim of this study is to compare the survival difference between adult patients with MB treated with and without chemotherapy. Data were derived from the SEER (Surveillance Epidemiology and End Results) database from 2010 to 2018. The Kaplan-Meier method with log-rank tests, univariate and multivariate Cox proportional hazard analyses, and propensity score matching (PSM) were used to investigate the association between chemotherapy and survival. We further conducted an exploratory subgroup analysis. The outcomes of interest were cancer-specific survival (CSS) and overall survival (OS). We included 333 patients in this study, with 227 patients in the CT cohort and 106 in the nonchemotherapy cohort. The median follow-up time and the median age of the study population were 61 months and 30 years, respectively. The 5-year CSS of the CT cohort was superior to the nonchemotherapy cohort, whereas the 5-year OS was not. Kaplan-Meier curves after PSM supported the survival benefit of CT on CSS but not on OS. In the multivariate analysis after PSM, CT was the only prognostic factor for CSS, whereas there were no independent prognostic factors for OS. The survival of patients receiving CT who were diagnosed between 2010 and 2018 was better than that of previous patients. The subgroup analysis showed that there were interaction effects between CT and sex. CT improved CSS for adult patients with MB. With therapeutic advances, adult patients with MB might benefit from the use of CT.

Extra-axial adult cerebellopontine angle medulloblastoma

A purely extra-axial position of medulloblastoma in adults at cerebellopontine (CP) angle is extremely rare. To the best of our knowledge, only ten cases have been reported till date. The authors report a case of extra-axial medulloblastoma in a 30-year-old female located at right CP angle. It was surgically treated with a provisional diagnosis of meningioma. Histopathological diagnosis of desmoplastic/nodular medulloblastoma was made with the routine hematoxylin eosin (HE) stain and immunohistochemical markers. This case report highlights the fact that, although extremely rare, the possibility of an extra-axial CP angle mass being a medulloblastoma still needs to be considered in the differential diagnoses, even in adults.

The Alliance AMBUSH Trial: Rationale and Design.

Simple SummaryMedulloblastoma, the most common embryonal tumor in children, can also arise in older patients. Clinical studies in children with medulloblastoma have increased our understanding of molecular pathways and improved treatment strategies. We now know that medulloblastoma has at least four subtypes and each maybe best suited to specific therapies. The sonic hedgehog (SHH) pathway is altered in a significant proportion of older patients with medulloblastoma. The Alliance for Clinical Trials in Oncology cooperative group is developing the AMBUSH trial: Comprehensive Management of Adolescent and Young Adult (AYA) and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors With A Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). The trial gives treatment directions for all patients and randomizes patients with average risk SHH-activated medulloblastoma to maintenance sonidegib, a hedgehog signaling pathway inhibitor, or placebo. This trial will establish a baseline for future trial comparison and investigate the benefit of a novel targeted agent.Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Simple SummaryIn the last decade, medulloblastoma entered the molecular era, with progressive advances in the knowledge of the molecular biology of this rare tumor. These expanding data have allowed the recognition of four distinct molecular subgroups, and, subsequently, the design of novel clinical trials to update the treatment protocols adopted so far, with the introduction of new molecular targeted drugs.Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

The Molecular Landscape of Medulloblastoma in Teenagers and Young Adults.

Simple SummaryMedulloblastoma is a malignant primary brain tumour that commonly occurs in children but also occurs in teenagers and young adults (TYA, aged 13–24 years) frequently enough to warrant attention. While remarkable progress has been made with paediatric tumours, TYAs with medulloblastoma represents an understudied population, lacking dedicated studies. The study aims to comprehensively characterise medulloblastoma in TYAs using data obtained from genomic technologies. It highlights that TYA medulloblastoma constitutes heterogenous molecular subgroups with distinct epigenetic and transcriptomic characteristics. Additionally, the prognostic gene signature-based score stratifies TYA patients into low- and high-risk groups and associates significantly with the outcomes. These results demonstrate unique molecular characteristics of TYA medulloblastoma that may contribute to the clinical differences at presentation between TYAs and other age groups. A better understanding of the TYA-specific biology might impact the treatment of those patients in the future.Medulloblastoma (MB) is a childhood malignant brain tumour but also occurs in teenagers and young adults (TYA). Considering that MB is heterogeneous, this study aimed to define the molecular landscape of MBs in TYAs. We collated more than 2000 MB samples that included 287 TYA patients (13–24 years). We performed computational analyses consisting of genome-wide methylation and transcriptomic profiles and developed a prognostics model for the TYAs with MB. We identified that TYAs predominantly comprised of Group 4 (40%) and Sonic Hedgehog (SHH)-activated (33%) tumours, with Wingless-type (WNT, 17%) and Group 3 (10%) being less common. TYAs with SHH tumours displayed significantly more gene expression alterations, whereas no gene was detected in the Group 4 tumours. Across MB subgroups, we identified unique and shared sets of TYA-specific differentially methylated probes and DNA-binding motifs. Finally, a 22-gene signature stratified TYA patients into high- and low-risk groups, and the prognostic significance of these risk groups persisted in multivariable regression models (P = 0.001). This study is an important step toward delineating the molecular landscape of TYAs with MB. The emergence of novel genes and pathways may provide a basis for improved clinical management of TYA with MB.

Dosimetric study of Rapid Arc therapy during Craniospinal Irradiation in Adult patients

Context: Adult medulloblastomas are very rare and constitute only 1% of the central nervous system tumors in adults. CSI treatment is challenging in adults due to the long, irregular target volume, critical structures, and field matchings due to multiple fields. Aims: This retrospective dosimetric study of adult patients who underwent Craniospinal irradiation was done to get insight into the challenges in the treatment and advantages of using RapidArc technique. Materials and Methods: The computed dosimetric rapid arc planning data of 3 adult cases who underwent Craniospinal irradiation between November 2018 and June 2021 were studied. Results: In our study mean conformity index (range) was 0.95 (0.91–1) and Mean homogeneity index (range) was 0.11 (0.06–0.15). Mean dose to the lenses, lungs, heart, and kidneys was 6.4 Gy, 9.4 Gy, 5 Gy, and 7 Gy, respectively. Conclusions: Volumetric modulated arc therapy technique for Craniospinal irradiation gives conformal dose distribution within the target, better normal tissue sparing, and more homogeneous dose distribution in the field junctions without the need to move the junction.

A Rare Case of Adult Medulloblastoma Associated with Multiple Sclerosis: Case Report and Literature Review

Medulloblastomas are the most common primary malignant brain tumors in childhood. They are responsible for around 20–40% of all brain tumors in children. They rarely occur in adulthood, but here they only make up less than 1% of all brain tumors. The standard therapy consists of an operation in combination with radiation and chemotherapy, which are individually determined for the patient. In this article, we discuss a case of 47 years old female patient diagnosed with primary progressive multiple sclerosis since 1 year. After 3 months of the diagnosis, she deteriorated and became unable to walk. MRI showed a large patchy enhancing midline cerebellar mass with evolving hydrocephalus. Tumor expressed positive reaction with synaptophysin immunohistochemical stain rendering medulloblastoma diagnosis.

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< 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.

Medulloblastoma in adults: an analysis of clinico-pathological, molecular and treatment factors.

Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features. We retrospectively investigated 44 adults (age 17-48 years) with a histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identify the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival). We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent gross total or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients. Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.