Average-risk Medulloblastoma Research Articles

MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (>75% or <75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received <75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.

QOL-13. Impact of hearing loss on neuropsychological functioning in children treated for medulloblastoma: A report from the Children’s Oncology Group (COG)

BACKGROUND/OBJECTIVE: We prospectively examined neuropsychological outcomes and ototoxicity in children with average-risk medulloblastoma. METHODS: Eligible patients included those treated on COG protocol ACNS0331 who completed audiograms at end of therapy or one-year off-therapy, and neuropsychological assessments between 2- and 5-years post-diagnosis. Conventional pure-tone audiometric evaluations (0.25-8kHz) were assigned an ototoxicity grade based on the International Society of Pediatric Oncology (SIOP) grading scale. Grade for the better hearing ear was used for analyses. Participants were divided into two groups: SIOP grade≥3 hearing loss (HL) versus SIOP grade<3. Cutoff score of 60 on BASC-2 was used to dichotomize parent-reported anxiety and depression scores as ‘low’ or ‘high’. RESULTS: Data were available for 113 children (66% male; 86% white), aged 3.0-18.5 at diagnosis (Mean=9.1). One-quarter (24.8%, n=28) had at least moderate HL (≥ SIOP grade 2), and 12.3% (n=14) had severe HL (≥ SIOP grade 3). After controlling for radiation exposure and age, children with severe HL showed significantly higher levels of anxiety (OR=5.9, 95%CI 1.3-26.0, p=0.0195) and borderline differences in depression (OR=4.0, 95%CI 1.0-16.5, p=0.0563), but no differences in cognitive functioning when compared to other participants. When moderate and severe HL were combined in exploratory analyses, significantly greater anxiety (OR=9.0, 95%CI 2.1-37.4, p=.0027) and depression (OR=4.6, 95%CI 1.3-15.7, p=.0165) were observed. CONCLUSIONS: Survivors of pediatric medulloblastoma with moderate to severe HL evidenced greater psychosocial, but not neurocognitive, difficulties compared to those with no or mild HL. It may be that modern treatment protocols generally preserve cognitive functioning such that associations between HL and cognitive impairment are no longer significant. It is also possible that neurocognitive risk associated with HL may not manifest until survivors are further from diagnosis. In contrast, survivors with HL may be at greater risk for negative psychosocial adjustment, suggesting that increased monitoring of mental health outcomes is warranted.

Neurocognitive function and survival in children with average-risk medulloblastoma treated with hyperfractionated radiation therapy alone: Long-term mature outcomes of a prospective study.

The purpose of this study was to report long-term neurocognitive and clinical outcomes in children treated for average-risk medulloblastoma with hyperfractionated radiation therapy (HFRT) alone. Between 2006 and 2010, 20 children with rigorously staged average-risk medulloblastoma were treated on a prospective study with HFRT without upfront adjuvant systemic chemotherapy after written informed consent. HFRT was delivered as twice-daily fractions (1 Gy/fraction, 6-8 hours apart, 5 days/week) to craniospinal axis (36 Gy/36 fractions) plus conformal tumor-bed boost (32 Gy/32 fractions). Neurocognitive function was assessed at baseline and periodically on follow-up using age-appropriate intelligence quotient (IQ) scales. Median age was 8 years (range 5-14 years) with 70% being males. Mean and standard deviation (SD) scores at baseline were 90.5 (SD = 17.08), 88 (SD = 16.82) and 88 (SD = 17.24) for Verbal Quotient (VQ), Performance Quotient (PQ), and Full-Scale IQ (FSIQ) respectively. Mean scores remained stable in the short-to-medium term but declined gradually beyond 5 years with borderline statistical significance for VQ (P = .042), but nonsignificant decline in PQ (P = .259) and FSIQ (P = .108). Average rate of neurocognitive decline was <1 IQ point per year over a 10-year period. Regression analysis stratified by age, gender, and baseline FSIQ failed to demonstrate any significant impact of the tested covariates on longitudinal neurocognitive function. At a median follow-up of 145 months, 10-year Kaplan-Meier estimates of progression-free survival and overall survival were 63.2% and 74.1% respectively. HFRT alone without upfront adjuvant chemotherapy in children with average-risk medulloblastoma is associated with modest decline in neurocognitive functioning with acceptable long-term survival outcomes and may be most appropriate for resource-constrained settings.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.

PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

Expertise is crucial to prolong survival in average risk medulloblastoma: long-term results of a retrospective study

Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated. Patients included in our study were ⩾16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification. We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5-178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p = 0.05; OS: HR, 0.187, p = 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p = 0.008; OS: HR, 0.295, p = 0.038). Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy.

MBCL-14. A STUDY OF LOW-DOSE CRANIOSPINAL RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED AVERAGE-RISK MEDULLOBLASTOMA

INTRODUCTIONMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy.METHODSWe performed a single-arm, multi-institution study, seeking to reduce the late effects of treatment in patients with average-risk medulloblastoma prior to advances in molecular subgrouping. To do so, we reduced the dose of craniospinal irradiation by 25% to 18 gray with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.RESULTS28 patients aged 3–30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 78.6% (95% CI 58.4% to 89.8%) and 92.9% (95% CI 74.4% to 98.2%), respectively. The 5-year RFS and OS were 71.4% (95% CI 50.1% to 84.6%) and 85.7% (95% CI 66.3% to 94.4%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.CONCLUSIONSGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from reduced craniospinal radiation dose of 18 gray without impacting relapse-free or overall survival.

MBCL-15. IMPACT OF MOLECULAR SUBGROUPS ON OUTCOMES FOLLOWING RADIATION TREATMENT RANDOMIZATIONS FOR AVERAGE RISK MEDULLOBLASTOMA: A PLANNED ANALYSIS OF CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331

The COG conducted a randomized trial for average-risk medulloblastoma (AR-MB). Patients age 3–21 years were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT) after receiving CSI. Patients age 3–7 years were also randomized to standard dose CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). 464 evaluable patients were available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI. 380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; 12 inconclusive. Molecular subgrouping confirmed the following representation amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%), 66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively (p=0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for LDCSI and SDCSI, respectively (p=0.028). EFS distributions differed significantly by subgroup (p<0.0001). Group 3 had the worst outcome, while WNT had the best outcome. There was a significant difference in EFS by RT group among SHH patients; SHH patients receiving IFRT arm had better EFS compared to PFRT (p=0.018). There was a significant difference in EFS distributions by CSI group in Group 4 patients; young Group 4 patients treated with SDCSI had better EFS compared to LDCSI (p=0.047). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB but LDCSI is worse than SDCSI in younger children. Significant differences in outcome by study randomization and molecular subgroup are observed.

LINC-07. PREVALENCE AND SPECTRUM OF EARLY ENDOCRINE DISORDERS IN SURVIVORS OF PEDIATRIC EMBRYONAL BRAIN TUMORS (PEBT): EXPERIENCE FROM INDIA

BACKGROUNDSurvivors of pediatric brain tumors are at high risk of developing endocrine disorders, potentially impacting growth,development and quality of life.METHODSetrospective audit of 2-year survivors of PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypical teratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI; 35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cyclophosphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT.RESULTSOf 249 PEBT treated during this period,88 are alive in remission >2 years (69-MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a median follow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one endocrine disorder,26(29.%)≥2 hormonal deficiencies. The most common endocrine disorders were central hypothyroidism(57%),growth hormone deficiency(40%), central hypogonadism(5%)and central hypoadrenalism (3.5%).The median time to develop hypothyroidism was 2.8 years(range 5months to 8.5 years) from CSI. Growth hormone replacement therapy began after a median period of 4.2 years(range-1.5 to 11.5years) from CSI. Higher dose of CSI was associated with development of endocrine disorder (odds ratio [OR] 2.71; 95% CI, 1.03 to 7.04,p-0.04).CONCLUSIONSThe high incidence of endocrine deficits in survivors of PEBT necessitates early and lifelong monitoring. Early and appropriate management is crucial to achieve full growth potential.

MBCL-36. HOW TO INCREASE SURVIVAL IN 7 TO 10% OF PATIENTS WITH AVERAGE-RISK MEDULLOBLASTOMA WITHOUT NEW THERAPIES: EARLY PROSPECTIVE NEURORADIOLOGY SCREENING EXPERIENCE FROM THE CHILDREN’S ONCOLOGY GROUP

BACKGROUNDPrevious Children’s Oncology Group (COG) average-risk medulloblastoma studies retrospectively identified that 7 to 10% of patients were wrongly staged; either due to the presence of unequivocal residual disease greater than 1.5cm2 or metastatic disease. Notably, these patients had an inferior survival. The current COG front-line average-risk study for WNT-driven medulloblastoma patients, ACNS1422, is a reduced-intensity therapeutic protocol. Given the potentially devastating consequences of dose reduction in a wrongly staged patient, ACNS1422 is utilizing optimized MRI sequences, including thin slices with no gap and post contrast T2 FLAIR sequences, combined with a rapid central neuroradiology review.RESULTSThe study opened on October 2 2017. As of 31 December 2019, a total of 34 patients have undergone central neuroradiology review. In 27/34 (79%) repeat scans were requested due to technically inadequate sequences (majority due to missing post contrast T2 FLAIR, slice thickness and gap issues). Of 19 repeat scans received, four patients (12%) were wrongly staged as average-risk; three patients were identified with residual disease >1.5cm2 (in 2 residual disease was confirmed at second resection) and one patient had widespread spinal metastases previously obscured by motion. In addition, metastatic disease was excluded in another patient, reported as having metastatic disease.CONCLUSIONOur data is consistent with previous reports revealing that approximately 10% of patients are wrongly staged as average-risk. The early experience of ACNS1422 reveals that the optimized MRI sequences combined with a rapid central neuroradiology review are very valuable in a cooperative group setting to more accurately stage patients.

Impact of Molecular Subgroups on Outcomes Following Radiation Treatment Randomizations for Average Risk Medulloblastoma: A Planned Analysis of Children’s Oncology Group (COG) ACNS0331

The COG conducted a randomized trial for average-risk medulloblastoma (AR-MB). Patients age 3-21 years were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT) after receiving CSI. Patients age 3-7 years were also randomized to standard dose CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). A total of 464 evaluable patients were available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI. 380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; and 12 inconclusive. Molecular subgrouping confirmed the following representation amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%), 66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively (p = 0.44). Five-year overall survival (OS) estimates were 84.6±2.5% and 85.2±2.4% for the IFRT and PFRT regimen, respectively (p = 0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for LDCSI and SDCSI, respectively (p = 0.028). Five-year estimates of OS were 77.5±4.0% and 85.6±3.5% for the LDCSI and SDCSI regimens, respectively (p = 0.049). EFS distributions differed significantly by molecular subgroup (p<0.0001). Group 3 had the worst outcome, while WNT had the best outcome. There was a significant difference in EFS by RT group among SHH patients; SHH patients receiving IFRT arm had better EFS compared to PFRT (p = 0.018). There was a significant difference in EFS distributions by CSI group in Group 4 patients; young Group 4 patients treated with SDCSI had better EFS compared to LDCSI (p = 0.047). There were differences in EFS by the presence of specific mutations and/or copy number variations (CNVs). Among SHH patients, chromosome 14q loss (p<0.001) and chromosome 10q loss (p = 0.012) were associated with worse EFS. SHH patients with GLI2 amplification had inferior outcome, though not statistically significant (p = 0.056); there were only 3 SHH patients with amplified GLI2 however. Group 3 patients with MYC amplification and/or isochromosome 17 had inferior EFS. For group 4 patients none of the mutations or CNVs showed statistically significant differences in EFS at the nominal 0.05 level. These included presence of isochromosome 17 (p = 0.48), chromosome 11 loss (p = 0.056), chromosome 17 gain (p = 0.84), and chromosome 11 loss and/or chromosome 17 gain (p = 0.32). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB but LDCSI is worse than SDCSI in younger children. Significant differences in outcome by study randomization and molecular subgroup are observed.

Brain tumors: Medulloblastoma, ATRT, ependymoma.

Children with medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and ependymoma are treated with a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Lower doses of craniospinal irradiation and tumor bed boost together with chemotherapy are the current standard of care for average-risk medulloblastoma in the Children's Oncology Group (COG). The International Society of Pediatric Oncology (SIOP) is examining the role of hyperfractionated craniospinal irradiation and chemotherapy in high-risk patients. The recent stratification of medulloblastoma into specific molecular risk groups has prompted both COG and SIOP to reexamine the role of these modalities in these different risk groups to maximize cure rates and minimize long-term complications. Proton therapy has shown lower rates of neurocognitive and endocrine complications compared with photons. Ependymomas are treated with maximal surgical resection and adjuvant radiation therapy. The role of chemotherapy in ependymoma is currently being studied in both COG and SIOP. Likewise, for ATRT the role of different high-dose chemotherapy regimens together with local radiation therapy in infants, or craniospinal radiation in older children, is the current focus of research.

The Effect of Absorbed Dose to Organs at Risk Following Craniospinal Irradiation Using Different Radiotherapy Techniques

Introduction: In medulloblastoma patients craniospinal irradiation is an important element the treatment. Our study aimed to evaluate the effect of absorbed dose to organs at risk using the hybrid intensity-modulated radiation therapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) for craniospinal irradiation (CSI) in average risk medulloblastoma patients. Materials and Methods: In this study, thirteen medulloblastoma patients were included. The prescribed total dose to the planning target volume (PTV) was 23, 40 Gy in 13 fractions. Two radiotherapy techniques, three dimensional conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (IMRT) were used to treat these patients. The coverage of the Target was evaluated using the D mean, D95%, D2%, D98% and V95%. Other parameters were also compared such as Integral dose (ID), Homogeneity index (HI) and doses to the organs at risk (OARs). Results: There was no significant difference in the mean dose received by the PTV-Brain or the dose received by 95% and 98% of PTV volume using the two techniques. For PTV-Spine, the percentage volume receiving 95% of the total dose increased significantly in the hybrid IMRT technique compared to the conformal technique. So, hybrid IMRT plan achieved the best coverage for PTV spine. Lower dose for OAR was delivered by 3DCRT, except the heart and thyroid, hybrid IMRT achieved better sparing. All plans resulted in the same dose homogeneity index (DHI) for PTV-Brain. For PTV-Spine, hybrid IMRT technique achieved better dose homogeneity compared to 3DCRT technique (1.09 vs. 1.12; p > 0.05). Conclusions: hybrid IMRT technique can be realized on conformal technique because it achieved better dose coverage for the (PTV) and organ at risk (OAR). 3DCRT reduced mean dose to most OARS, except the heart and thyroid. Therefore, the hybrid IMRT technique may be a CSI treatment alternative to 3DCRT.

Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children's Oncology Group

Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children's Oncology Group

Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients?

The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age >16years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide±cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9%) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5cm) and delay in RT. After a median follow up time of 10years (range: 8-13), median survival was 18years (95% CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15years were 100%, 78.6% (95% CI 60.0-97.2%) and 60.2% (95% CI 36.9-83.5%), in patients treated with RT alone, and 100, 100 and 100%, in patients treated with RT plus chemotherapy (p=0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).

Abstract B01: MicroRNAs as novel therapeutic adjuvants to treat high-risk medulloblastoma.

Abstract Medulloblastoma is the most common malignant brain tumor in children, accounting for 18% of newly diagnosed brain tumors and 10% of all children cancer-related deaths. Despite improvement in the 5-year survival rate of medulloblastoma in recent years, only a small percentage of patients survive high-risk metastatic disease. The quality of life for those who do survive is often substantially reduced due to the toxicity associated with radiation and chemotherapy. Vincristine is a microtubule-destabilizing antimitotic drug, which is routinely administered in higher dosages to both high and average risk medulloblastoma patients. As a result, these patients suffer from devastating neurotoxic effects that include but not limited to: sensorimotor and autonomic neuropathy, hearing loss, mononeuropathy, and seizures. Using high-throughput microRNA mimic library screens, we identified a group of microRNAs that may improve the efficacy of vincristine against c-MYC amplified medulloblastoma as well as re-sensitize vincristine-resistant medulloblastoma. Our findings revealed that these microRNAs may act as tumor suppressors since their overexpression inhibited colony formation, migration and invasion ability of medulloblastoma cells. Furthermore, these microRNAs suppressed stem cell renewal/proliferation of c-MYC amplified medulloblastoma cells. Expression analysis, gene enrichment analysis and target prediction algorithms revealed that these microRNAs exert their vincristine sensitizing and tumor suppressor effect by targeting genes involved in microtubule organization, cell cycle regulation, DNA damage repair and mRNA translation. One of our most interesting targets is EIF4E3, which is a translation initiation factor. Our preliminary findings indicate that EIF4E3 may regulate medulloblastoma cell growth, progression and vincristine sensitivity by modulating c-MYC translation. Further experiments are underway to test the potential of candidate miRNA and EIF4E3 as vincristine sensitizer in vivo. In conclusion, this study may identify novel factors that have potential not only to decrease the current therapeutic dose of vincristine and therefore eliminate its side effects, but also have potential to multiply the efficacy of lower doses in order to overcome hard to treat high-risk tumors. Citation Format: Nourhan Abdelfattah, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Subapriya Rajamanickam, Hung-I Harry Chen, Manjeet Rao. MicroRNAs as novel therapeutic adjuvants to treat high-risk medulloblastoma.. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B01.

Impacts of radiation dose on survival in 72 patients with average-risk medulloblastoma

Objective To retrospectively analyze the impacts of a craniospinal radiation dose ≤24 Gy or>24 Gy on the prognosis of patients with average-risk medulloblastoma. Methods Average-risk medulloblastoma was defined as non-metastatic cancer in children more than 3 years old with complete or near-complete (residual tumor ≤1.5 cm3) resection of tumor. A total of 72 children and adolescents with newly diagnosed average-risk medulloblastoma were enrolled as subjects from 2003 to 2013. After radical resection of the tumor, all patients received craniospinal plus local tumor bed radiotherapy and 8 cycles of adjuvant chemotherapy using cisplatin-, semustine-, or plus vincristine-based regimens. Patients exposed to a radiation dose ≤24 Gy were enrolled into Group A (n=20), while patients exposed to a radiation dose>24 Gy were enrolled into Group B (n=52). The recurrence rate and survival rate were compared between the two groups. The recurrence rate and survival rate were calculated using the Kaplan-Meier method and the differences between the two groups were analyzed using the log-rank test. Results Patients in Group A and Group B received craniospinal radiotherapy with a dose of 19.2-24.0 Gy and 24.1-30.6 Gy, respectively. After radiotherapy, 66 patients (92%) completed all adjuvant chemotherapy. A total of 11 patients were recurrence. In all patients, the 3-year sample size was 48; the 3-year event-free survival (EFS) and overall survival (OS) rates were 83% and 86%, respectively. There were no significant differences in the 3-year EFS and OS rates between Group A and Group B (84% vs. 83%, P=0.609; 85% vs. 87%, P=0.963). Conclusions The standard comprehensive therapy achieves satisfactory treatment outcomes for average-risk medulloblastoma, in which a craniospinal radiation dose decreased to 19.2-24.0 Gy has no impacts on treatment outcomes. Key words: Medulloblastoma, average-risk/radiotherapy; Medulloblastoma, average-risk/chemotherapy; Prognosis

Prospective longitudinal assessment of sensorineural hearing loss with hyperfractionated radiation therapy alone in patients with average-risk medulloblastoma.

To report on sensorineural hearing loss (SNHL) in a cohort of patients treated with hyperfractionated radiation therapy (HFRT) without upfront platinum-based chemotherapy in average-risk medulloblastoma. Hearing thresholds were assessed by ear-specific pure-tone audiograms at stimulus frequencies of 0.25, 0.5, 1, 2, 4, and 8 kilohertz. Audiometric assessments were done serially longitudinally at baseline, between 6-12 months after HFRT, and annually thereafter. Pure-tone audiograms were analyzed and graded according to Brock pediatric ototoxicity grading criteria. Five of 20 (25%) children had communicatively and developmentally significant SNHL (Brock grade 2 or worse) even before starting radiotherapy. On follow-up, new-onset Brock grade 2 or worse ototoxicity was documented in 6 previously normal ears. Eleven patients had preserved hearing in both ears on last audiometric follow-up. Compared with baseline testing, post-HFRT audiometry at 2-3 years showed modest decline in hearing threshold across all frequencies. Age at diagnosis and sex did not significantly impact hearing, while higher cochlear doses trended towards worse hearing outcomes. Tumors that extended more towards one side expectedly showed significant worsening in the ipsilateral ear. There was a differential impact of treatment on the right and left ears with the right ear (and not the left ear) showing significantly worse hearing thresholds in the low-to-intermediate speech frequency range over time. The use of HFRT for craniospinal irradiation and conformal tumor bed boost without upfront platinum-based chemotherapy in children with average-risk medulloblastoma results in preserved hearing in a large proportion of patients in the audible speech range.

Advances in managing medulloblastoma and intracranial primitive neuro-ectodermal tumors.

Medulloblastoma and central nervous system (CNS)-primitive neuro-ectodermal tumors (PNETs) are a diverse group of entities which encompasses different pathological and clinical pictures. Initially divided based on histology and location, molecular insight is leading to new definitions and a change in the borders delineating these diseases, such that they become more divergent. Current treatment approaches consist of surgical resection, radiotherapy and intensive chemotherapy, dependent on age. Stratification is one risk factor shown to be prognostic and is divided into high- and average-risks. Outcomes with modern treatment regimens are good, particularly in average-risk medulloblastoma patients, but the cost of cure is high, with high rates of neurocognitive, endocrine and social dysfunction. The changing biological landscape, however, may allow for clearer prediction of tumor behavior, to better identify “good” and “bad” players within these groups. Discovery of subgroups with changes in dependent molecular pathways will also lead to the development of new specific targeted therapies. Presenting exciting opportunities, these advances may transform the treatment for some patients, revolutionizing therapy in the future. Several challenges, however, are yet to be faced and caution is needed not to abandon previously defined prognostic factors on the strength of thus far retrospective evidence. We are witnessing a new era of trials with biological stratification involving multiple subgroups and treatment arms, based on specific tumor-related targets. This review discusses the changing face of medulloblastoma and CNS-PNETs and how we move molecular advances into clinical trials that benefit patients.

Can average-risk medulloblastoma adult patients be treated with radiotherapy and plus chemotherapy?

2022 Background: The standard treatment in children with average-risk medulloblastoma (MB) is chemotherapy after reduced-dose radiotherapy (23.4 Gy of craniospinal irradiation and a posterior fossa...

Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of CNS oncology

Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of CNS oncology