Risk-stratification for treatment de-intensification in WNT-pathway medulloblastoma: finding the optimal balance between survival and quality of survivorship.

INTRODUCTION: Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups - wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4 respectively. Traditionally, children > 3-years of age, with no/minimal residual tumor (<1.5 cm2) and lack of metastasis were classified as average-risk disease with > 80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm2), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30-60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials. AREAS COVERED: We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma including molecular subgrouping. Based on previously published data including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship. EXPERT OPINION: Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.

Clinico-Radiological Outcomes in WNT-Subgroup Medulloblastoma.

Medulloblastoma (MB) comprises four broad molecular subgroups, namely wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively, with subgroup-specific developmental origins, unique genetic profiles, distinct clinico-demographic characteristics, and diverse clinical outcomes. This is a retrospective audit of clinical outcomes in molecularly confirmed WNT-MB patients treated with maximal safe resection followed by postoperative standard-of-care risk-stratified adjuvant radio(chemo)therapy at a tertiary-care comprehensive cancer centre. Of the 74 WNT-MB patients registered in a neuro-oncology unit between 2004 to 2020, 7 patients accrued on a prospective clinical trial of treatment deintensification were excluded, leaving 67 patients that constitute the present study cohort. The median age at presentation was 12 years, with a male preponderance (2:1). The survival analysis was restricted to 61 patients and excluded 6 patients (1 postoperative mortality plus 5 without adequate details of treatment or outcomes). At a median follow-up of 72 months, Kaplan-Meier estimates of 5-year progression-free survival and overall survival were 87.7% and 91.2%, respectively. Traditional high-risk features, large residual tumour (≥1.5 cm2), and leptomeningeal metastases (M+) did not significantly impact upon survival in this molecularly characterized WNT-MB cohort treated with risk-stratified contemporary multimodality therapy. The lack of a prognostic impact of conventional high-risk features suggests the need for refined risk stratification and potential deintensification of therapy.

Institutional Patterns of Care of Diffuse Intrinsic Pontine Glioma.

Background and Aim: Despite recent advances, the outcomes of diffuse intrinsic pontine glioma (DIPG) remain dismal. This is a retrospective study to understand the pattern of care and its impact on DIPG patients diagnosed over 5 years in a single institute. Subjects and Methods: DIPGs diagnosed between 2015 and 2019 were retrospectively reviewed to understand the demographics, clinical features, patterns of care, and outcomes. The usage of steroids and response to treatment were analyzed as per the available records and criteria. The re-irradiation cohort was propensity matched with patients with a progression-free survival (PFS) >6 months treated with supportive care alone based on PFS and age as a continuous variable. Survival analysis was performed using the Kaplan-Meier method, and Cox regression model was used to identify any potential prognostic factors. Results: One hundred and eighty-four patients were identified with demographic profiles similar to western population-based data in the literature. Of them, 42.4% were residents from outside the state of the institution. About 75.2% of patients completed their first radiotherapy treatment, of which only 5% and 6% had worsening clinical symptoms and persistent need for steroids 1 month posttreatment. On multivariate analysis, Lansky performance status <60 (P = 0.028) and cranial nerve IX and X (P = 0.026) involvement were associated with poor survival outcomes while receiving radiotherapy with better survival (P < 0.001). In the cohort of patients receiving radiotherapy, only re-irradiation (reRT) was associated with improved survival (P = 0.002). Conclusion: Many patient families still do not choose radiotherapy treatment, although it has a consistent and significant positive association with survival and steroid usage. reRT further improves outcomes in the selective cohorts. Involvement of cranial nerves IX and X needs improved care.

WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go?

Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of molecular/genetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma. Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm2 and no evidence of metastases. This systematically excludes adolescents and young adults who have been perceived to have worse outcomes. We have previously reported long-term survival of our adolescent and young adult cohort that were largely comparable to childhood medulloblastoma. We now report on molecularly characterized WNT-subgroup patients treated between 2004-2020 with risk-stratified multi-modality therapy to identify differences between childhood (<15 years) versus adolescent and young adults (>15 years). Despite modest differences in disease status at presentation and treatment modality, there were no significant differences in patterns of failure or survival between childhood versus adolescent and young adult WNT-pathway medulloblastoma. Two de-intensification trials in low-risk WNT-pathway medulloblastoma - first testing omission of upfront craniospinal irradiation and second a primary chemotherapy approach after surgery - had to be terminated prematurely due to unacceptably high relapse rates suggesting that craniospinal irradiation remains an integral component of treatment. The presence of TP53 mutations and OTX2 gains have recently been reported as independent negative prognostic factors in a multi-institutional cohort of WNT-pathway medulloblastoma raising questions on eligibility of such patients for de-escalation trials. The definition of low-risk WNT-pathway medulloblastoma may need to be refined in light of recent clinical data and newer biological information.