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

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.

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.

Pediatric versus Adult Medulloblastoma: Towards a Definition That Goes beyond Age

Medulloblastoma is a rare malignant brain tumor that predominantly affects children but also occurs in adults. The incidence declines significantly after age 15, and distinct tumor molecular features are seen across the age spectrum. Standard of care treatment consists of maximal safe surgical resection followed by adjuvant radiation and/or chemotherapy. Adjuvant treatment decisions are based on individual patient risk factors and have been informed by decades of prospective clinical trials. These trials have historically relied on arbitrary age cutoffs for inclusion (age 16, 18, or 21, for example), while trials that include adult patients or stratify patients by molecular features of disease have been rare. The aim of this literature review is to review the history of clinical trials in medulloblastoma, with an emphasis on selection criteria, and argue in favor of rational and inclusive trials based on molecular features of disease as opposed to chronological age. We performed a scoping literature review for medulloblastoma and clinical trials and include a summary of those results. We also discuss some of the significant advances made in understanding the molecular biology of medulloblastoma within the past decade, most notably the identification of four distinct subgroups based on gene expression profiling. We will also cite the recent experiences of childhood leukemia and the emergence of tissue-agnostic therapies as examples of successes of rationally designed, inclusive trials translating to improved clinical outcomes for patients across the age spectrum. Despite the prior trial history and recent molecular advances outcomes remain poor for ~30% of medulloblastoma patients. We believe that defining patients by the specific molecular alterations their tumors harbor is the best way to ensure they can access potentially efficacious therapies on clinical trials.

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

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.

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

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.

Adult Medulloblastoma Demographic, Tumor and Treatment Impact since 2006: A Canadian University Experience

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006–2012 and 2013–2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006–2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

Clinical Characterization of Adult Medulloblastoma and The Effect of First-line Therapies on Outcome; The MD Anderson Cancer Center Experience

Background Adult medulloblastoma (MB) is rare, and management guidelines are largely based on pediatric clinical trials and retrospective series. Limited data exist with respect to clinical characteristics, prognostic factors, and outcomes based on first-line treatments. Methods 200 adults with MB seen at a single institution from January 1978 to April 2017 were identified and followed for a median of 8.4y (7.1, 10.3). Results Patient’s median age at diagnosis was 29y (18, 63). One hundred eleven (55.5%) were standard-risk, 59 (29.5%) were high-risk, and 30 (15.0%) were indeterminate. Most received post-operative radiation (RT) (184 [92.0%]), and 105 (52.5%) received first-line chemotherapy . Median overall survival (OS) was 8.8y (7.2, 12.2) and median progression-free survival (PFS) was 6.6y (4.9, 11.2). High-risk patients had inferior OS (Hazard ratio [HR]=2.5 [1.5, 4.2], p=0.0006) and PFS (HR=2.3 [1.3, 3.9], p=0.002) compared to standard-risk patients. Age, sex, and metastatic disease were not associated with survival. After adjusting for risk status, those who received RT plus adjuvant chemotherapy had superior PFS compared to RT plus neoadjuvant chemotherapy [HR=0.46 (0.22, 0.95), p=0.0357]. Within a subgroup for whom detailed clinical data were available, those who received RT plus adjuvant chemotherapy had improved PFS compared to RT only [HR = 0.24 (0.074-0.76), p = 0.016]. The substitution of cisplatin for carboplatin and the elimination of vincristine did not negatively affect outcomes. Conclusion This is the largest single-institution retrospective study of adult MB to our knowledge and identifies standard-risk status, first-line RT and adjuvant chemotherapy as factors associated with improved outcomes.