Prognostic impact of semantic MRI features on survival outcomes in molecularly subtyped medulloblastoma.

PURPOSE: Imaging features are known to reflect inherent disease biology in various cancers including brain tumors. We report on the prognostic impact of magnetic resonance imaging (MRI) features on survival in patients with medulloblastoma treated between 2007 and 2018 at our institute. METHODS: Sixteen semantic imaging features (with predefined categories) were extracted from pre- and postcontrast T1-weighted and T2-weighted MRI by consensus. Univariate analysis and multivariate Cox regression analysis were performed to assess the correlation of semantic features with relapse-free survival (RFS) and overall survival (OS). RESULTS: The study cohort comprised 171 medulloblastoma patients (median age 9 years) treated with maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. A total of 55 patients experienced recurrent/progressive disease (commonly neuraxial metastases) resulting in 44 deaths, including one treatment-related death. At a median follow-up of 45 months (interquartile range 19-65 months), 5­year Kaplan-Meier estimates of RFS and OS were 64% and 71%, respectively. Semantic MRI features such as non-central tumor location on vertical axis, absence of brainstem involvement, ≤ 80% solid tumor area with contrast uptake, heterogenous pattern of contrast enhancement, necrosis, calcification, and T2-weighted heterogeneity were associated with significantly worse RFS and/or OS in univariate analysis. Cox regression analysis identified tumor location on the vertical axis, brainstem involvement, and calcification as independent prognostic factors impacting outcomes. Distinctive MRI features correlated with survival even within individual molecular subgroups of medulloblastoma. CONCLUSION: Distinctive semantic MRI features correlate significantly with survival outcomes in medulloblastoma, also within individual molecular subgroups, reflecting their prognostic impact.

Magnetic Resonance Imaging in the Contemporary Management of Medulloblastoma: Current and Emerging Applications.

Medulloblastoma, the most common malignant primary brain tumor in children, is now considered to comprise of four distinct molecular subgroups-wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4 medulloblastoma, each associated with distinct developmental origins, unique transcriptional profiles, diverse phenotypes, and variable clinical behavior. Due to its exquisite anatomic resolution, multiparametric nature, and ability to image the entire craniospinal axis, magnetic resonance imaging (MRI) is the preferred and recommended first-line imaging modality for suspected brain tumors including medulloblastoma. Preoperative MRI can reliably differentiate medulloblastoma from other common childhood posterior fossa masses such as ependymoma, pilocytic astrocytoma, and brainstem glioma. On T1-weighted images, medulloblastoma is generally iso- to hypointense, while on T2-weighted images, the densely packed cellular component of the tumor is significantly hypointense and displays restricted diffusion on diffusion-weighted imaging. Following intravenous gadolinium, medulloblastoma shows significant but variable and heterogeneous contrast enhancement. Given the propensity of neuraxial spread in medulloblastoma, sagittal fat-suppressed T1-postcontrast spinal MRI is recommended to rule out leptomeningeal metastases for accurate staging. Following neurosurgical excision, postoperative MRI done within 24-48 h confirms the extent of resection, accurately quantifying residual tumor burden imperative for risk assignment. Post-treatment MRI is needed to assess response and effectiveness of adjuvant radiotherapy and systemic chemotherapy. After completion of planned therapy, surveillance MRI is recommended periodically on follow-up for early detection of recurrence for timely institution of salvage therapy, as well as for monitoring treatment-related late complications. Recent studies suggest that preoperative MRI can reliably identify SHH and Group 4 medulloblastoma but has suboptimal predictive accuracy for WNT and Group 3 tumors. In this review, we focus on the role of MRI in the diagnosis, staging, and quantifying residual disease; post-treatment response assessment; and periodic surveillance, and provide a brief summary on radiogenomics in the contemporary management of medulloblastoma.

Multidisciplinary Management of Medulloblastoma: Consensus, Challenges, and Controversies.

Medulloblastoma is a highly aggressive "small round blue cell tumor" of the posterior fossa predominantly seen in children. Historically aggressive multimodality regimens have achieved encouraging outcomes with the caveat of severe long-term toxicities. The last decade has unleashed a revolution in terms of evolved understanding of this heterogeneous disease entity in terms of molecular biology. Medulloblastoma as of today is grouped into one of four canonical molecular subgroups (WNT, SHH, Group 3, and Group 4) each characterized by different putative cells of origin, characteristic aberrations at the molecular level, radiogenomics, and outcomes. Our understanding continues to grow in this regard. The future promises much in terms of personalized medicine in tailoring therapy to the needs of individual patients based on their clinical and molecular profile in order to maximize individual and population based outcomes at the cost of minimizing toxicity.

Clinical Audit of Survival Outcomes and Prognostic Factors in Adolescents and Adults with Medulloblastoma.

Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much rarer in adulthood. Disease biology varies substantially across different age groups; however, owing to rarity, adults with medulloblastoma are traditionally treated using pediatric protocols. This is a retrospective audit of adolescent and adult medulloblastoma from a comprehensive cancer center. Methods: Data regarding demography, clinical presentation, imaging characteristics, histopathological features, molecular profiling, risk stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event outcomes were analyzed using Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analysis of relevant prognostic factors was done with p value <0.05 being considered statistically significant. Results: A total of 162 patients ≥15 years of age with medulloblastoma were included. The median age was 25 years (range: 15-59 years) with leptomeningeal metastases seen in 31 (19%) patients at initial diagnosis. Following surgery, patients were treated with appropriate risk-stratified adjuvant therapy comprising of craniospinal irradiation plus boost with or without systemic chemotherapy. At a median follow-up of 50 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 53.5% and 59.5%, respectively. The addition of adjuvant systemic chemotherapy did not impact upon survival in standard-risk medulloblastoma. High-risk (HR) disease and anaplastic histology emerged as significant and independent predictors of poor survival on multivariate analysis. Conclusion: Medulloblastoma is a rare tumor in adolescents and adults with key differences in disease biology and resultant outcomes compared with the pediatric population. Contemporary management comprising maximal safe resection followed by appropriate risk-stratified adjuvant therapy provides acceptable survival outcomes.

Hippocampal radiotherapy dose constraints for predicting long-term neurocognitive outcomes: mature data from a prospective trial in young patients with brain tumors.

BACKGROUND: Hippocampus is considered to be the seat for neurocognitive functions. Avoidance of hippocampus during radiotherapy to brain may serve to preserve various domains of neurocognition. We aimed to derive radiotherapy dose constraints to hippocampi for preserving neurocognition in young patients with brain tumors by measuring various neurocognitive parameters. METHODS: Forty-eight patients with residual/progressive benign or low-grade brain tumors treated with stereotactic conformal radiotherapy (SCRT) to a dose of 54 Gy in 30 fractions underwent prospective neuropsychological assessments at baseline before SCRT and at 6 months and 2, 3, 4, and 5 years. Hippocampi were drawn as per the Radiation Therapy Oncology Group atlas. Longitudinal change in intelligence quotient scores was correlated with hippocampal doses. RESULTS: Mean volume of bilateral hippocampi was 4.35 cc (range: 2.12-8.41 cc). Craniopharyngioma was the commonest histologic subtype. A drop of >10% in mean full-scale intelligence quotient (FSIQ) scores at 3 and 5 years post SCRT was observed in patients in whom left hippocampus received a mean dose of 30.7 Gy (P = 0.04) and 31 Gy (P = 0.04), respectively. Mean performance quotient (PQ) scores dropped > 10% at 5 years when the left hippocampus received a dose of > 32 Gy (P = 0.03). There was no significant correlation of radiotherapy doses with verbal quotient, or with doses received by the right hippocampus. Multivariate analysis revealed young age (<13 y) and left hippocampus dose predicted for clinically relevant decline in certain neurocognitive domains. CONCLUSIONS: A mean dose of ≤30 Gy to the left hippocampus as a dose constraint for preserving intelligence quotient is suggested. KEY POINTS: 1. Children and young adults with benign and low-grade gliomas survive long after therapy.2. Higher dose to the hippocampi may result in long-term neurocognitive impairment.3. Mean dose of <30 Gy to left hippocampus could be used as a pragmatic dose constraint to prevent long-term neurocognitive decline.

Extent of re-excision, sequence/timing of salvage re-irradiation, and disease-free interval impact upon clinical outcomes in recurrent/progressive ependymoma.

PURPOSE: To report clinical outcomes of salvage re-irradiation (re-RT) in recurrent/progressive ependymoma. METHODS: Medical records of patients treated with curative-intent re-RT as multi-modality management for recurrent/progressive ependymoma were analyzed retrospectively. The linear-quadratic model was used to provide estimates of biologically effective dose (BED) of irradiation using an α/ß value of 2 for late CNS toxicity for each course of irradiation and summated to derive cumulative BED without correcting for the assumed recovery. RESULTS: A total of 55 patients (median age 10 years at index diagnosis) treated with curative-intent re-RT between 2010 and 2018 were included. Median time to first recurrence was 29 months with an inter-quartile range (IQR) of 16-64 months. Majority (n = 46, 84%) of patients underwent surgical re-excision of recurrent disease. Median interval from first course of irradiation (RT1) to second course (RT2) was 35 months (IQR = 26-66 months) with a median re-RT dose of 54 Gy in 30 fractions (range 40-60 Gy), resulting in median cumulative equivalent dose in 2 Gy fraction (EQD2) of 106.2 Gy (range 92.4-117.6 Gy). Volume of re-RT was based on location and pattern of relapse, comprising uni-focal (n = 49, 89%), multi-focal (n = 3, 5.5%), or craniospinal irradiation (CSI) in 3 (5.5%) patients respectively. Thirty-six (66%) patients received platinum-based salvage chemotherapy either before or after RT2. At a median follow up of 37 months (range 6-80 months), the Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) for the entire study cohort were 40% and 51% respectively. Gross total resection at recurrence; early salvage re-RT (prior to chemotherapy, if any); and longer (> 2 years) disease-free interval (DFI) were associated with better survival outcomes. Salvage re-RT was generally well tolerated with only 3 (5.5%) patients developing symptomatic radiation necrosis necessitating corticosteroids. CONCLUSION: Extent of re-excision, sequence/timing of re-RT, and DFI impact upon outcomes in curative-intent, multi-modality salvage therapy for recurrent ependymoma.

68Ga-prostate-specific membrane antigen PETCT-based response to androgen deprivation therapy in patients with prostate cancer.

OBJECTIVE: To assess the response of castration-naïve prostate cancer to androgen deprivation therapy (ADT) in Ga-PSMA PETCT, and test the hypothesis of differential response in primary, nodal and metastatic lesions. MATERIALS/METHODS: Patients with adenocarcinoma prostate with baseline Ga-prostate-specific membrane antigen (PSMA) PETCT scan, and response scan after 3-12 months of ADT from 2014 to 2017 were analyzed. Change in radiotracer uptake in the prostate, involved regional nodes and distant metastasis was semiquantitatively assessed in paired scans using maximum standardized uptake value (SUVmax). Response was categorized into complete or partial response (CR, PR) or stable disease or progressive disease (SD, PD), and correlated with known prognostic factors. RESULTS: Total 86 scans of 43 patients (17 metastatic, M+) were analyzed. After median 6 months of ADT, 0% primary, 23.3% nodes and 17.6% metastases showed CR; 18.6% primary, 8.3% nodes and 35% metastases showed PD. Prostate response was not significantly associated with any prognostic factor. Nodal response was higher in M0 than in M+ disease (CR 37 vs 4%, P = 0.003). Oligometastases responded better than polymetastases (CR/PR 62.5 vs 11.1%, P = 0.05). Decline in SUVmax of primary tumor correlated with decline in serum prostate-specific antigen (PSA) (90% of partial responders showed >80% decline in serum PSA vs 50% with PD, P = 0.06). CONCLUSION: Primary prostatic tumor seems less likely to respond to ADT than nodal or metastatic lesions. Residual primary uptake may guide patient selection for local therapy in (oligo) metastatic prostate cancer.

Outcomes of salvage re-irradiation in recurrent medulloblastoma correlate with age at initial diagnosis, primary risk-stratification, and molecular subgrouping.

PURPOSE: To report outcomes of salvage re-irradiation (re-RT) in recurrent/progressive medulloblastoma (MB). METHODS: Medical records of patients treated with curative-intent re-RT as multi-modality management for recurrent/progressive MB between 2008 and 2018 were analyzed retrospectively. RESULTS: A total of 28 patients (median age 18 years at index diagnosis) were included. Molecular subgrouping was done using real-time reverse transcriptase polymerase chain reaction (RT-PCR) based on the differential expression of select set of 12 protein coding genes and 9 microRNAs. Fifteen of 17 (88%) patients with sonic hedgehog (SHH)-MB developed isolated local recurrence within the index tumor-bed, while 5 of 7 (72%) patients with Group 4 MB developed localized relapse outside the posterior fossa. Diffuse neuraxial dissemination was seen in 2 patients with SHH-MB, and one each of Group 4 and wingless (WNT)-MB. Molecular subgrouping was not known in 3 patients. The dose and volume of re-RT was based on site and patterns of relapse, comprising unifocal in 18 (64%), multi-focal in 3 (11%), and repeat craniospinal irradiation (re-CSI) in 7 (25%) patients. Median interval from primary irradiation to re-RT was 49.5 months (range 24-98 months) with median cumulative biologically effective dose of 117 Gy (range 78-132 Gy). All patients received platinum-based salvage chemotherapy either before or after re-RT. One patient developed symptomatic radiation necrosis following re-CSI. At a median follow-up of 24 months (range 6-84 months), 2-year post-re-RT progression-free survival (PFS) and overall survival (OS) was 46% and 51% respectively. Younger age (< 18 years) at index diagnosis, primary risk stratification (standard-risk) and molecular subgrouping (Group 4) were associated with significantly better post-re-RT outcomes. CONCLUSION: Salvage re-RT provides good local control and encouraging survival outcomes with acceptable toxicity in selected patients with recurrent/progressive MB.

Dose-Constraint Model to Predict Neuroendocrine Dysfunction in Young Patients With Brain Tumors: Data From a Prospective Study.

PURPOSE: We report on a possible dose-constraint model to predict long-term neuroendocrine dysfunction after cranial irradiation in children and young adults with benign and low-grade brain tumors treated with stereotactic conformal radiation therapy (RT) in a prospective clinical trial. METHODS AND MATERIALS: Patients treated with stereotactic conformal RT (54 Gy in 30 fractions) were included for analysis if their co-registered planning computed tomography and magnetic resonance imaging scans were available, along with baseline and post-RT endocrine assessment for at least 2 years. The hypothalamus-pituitary axis (HPA) was contoured on the fused computed tomography-magnetic resonance imaging data set. Worsening of endocrine function was defined biochemically as a new onset endocrine deficit or worsening of preexisting endocrine deficit. Dosimetric indices of HPA, extracted using cumulative dose-volume histograms, were correlated with worsening endocrine function using logistic regression analysis. RESULTS: A total of 51 patients (median age: 13 years; range, 5-25 years) were included. Worsening post-RT endocrine levels were seen in 27 of 51 patients (47%). Growth hormone was the most commonly affected (70%), followed by cortisol (44%), gonadotropin (40%), and thyroxine (7%). The mean of the maximum and minimum doses to HPA was 42.1 Gy and 35.7 Gy, respectively. For patients with worsening endocrine levels, the mean maximum dose to HPA was 46.6 Gy compared with 36.5 Gy in patients with stable functions. The mean minimum dose to HPA was also higher (40.5 Gy vs 29.6 Gy) in patients with endocrine dysfunction. Logistic regression analysis identified the volume of HPA receiving 50% of the prescribed dose as the only statistically significant parameter predicting endocrine dysfunction. A dose of ≥27 Gy to any volume of HPA was associated with a 4-fold increase in risk of endocrine dysfunction (odds ratio: 4.05; 95% confidence interval, 1.07-15.62; P = .038). CONCLUSIONS: Our prospective longitudinal study demonstrates the feasibility of HPA avoidance using modern, high-precision, conformal RT techniques and correlates HPA dosimetry with neuroendocrine dysfunction. We suggest restricting HPA doses to <27 Gy to minimize the risk of post-RT neuroendocrine deficits.