Omission of Upfront Craniospinal Irradiation in Patients with Low-Risk WNT-Pathway Medulloblastoma Is Associated with Unacceptably High Risk of Neuraxial Failure

Medulloblastoma is the commonest primary malignant tumor of the central nervous system (CNS) in children (1). Novel biological insights gained during the last decade have improved our fundamental understanding of various pediatric barin tumors including medulloblastoma with potential to transform therapy (2, 3). It is now widely accepted that medulloblastoma is a heterogeneous disease (4) comprising four distinct molecular subgroups–wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 respectively with unique developmental origins, distinct molecular genetics, diverse phenotypes, and varying clinical behavior (4, 5) which has also been incorporated in the revised World Health Organization (WHO) classification (6). WNT-pathway medulloblastoma is associated with the best outcomes, while group 3 tumors generally have the worst survival (3, 7).

The contemporary standard-of-care for noninfantile medulloblastoma comprises maximal safe resection followed by risk-stratified postoperative radiotherapy and adjuvant systemic chemotherapy (37). Traditionally, children (≥3 years of age) with good surgical resection (residual tumor <1.5 cm²) and no evidence of leptomeningeal metastases (M0) were classified as average-risk disease (8) with more than 80% long-term survival (9); while younger age (<3 years), large residue (≥1.5 cm²), and presence of leptomeningeal metastases (M+ disease) either alone or in combination were considered high-risk features (8) yielding much worse 5-year survival (30%–60%) despite aggressive multi-modality therapy (10). This traditional risk-stratification has been further refined by incorporating molecular/genetic information in the molecular era (11). Given the high propensity of neuraxial spread via cerebrospinal fluid (CSF) pathways, craniospinal irradiation (CSI) to a dose of 23.4 to 36 Gy plus posterior fossa/tumor-bed boost (18–30.6 Gy) for total primary-site dose of 54 Gy remains the cornerstone of adjuvant radiotherapy in medulloblastoma (8–10). Such treatment however, results in significant dose-dependent long-term toxicity (12), particularly in children, as younger age is associated with higher therapy-related late-effects. Herein, we report early results of our prospective study of omission of upfront CSI in WNT-pathway medulloblastoma.

All patients with newly-diagnosed WNT-pathway medulloblastoma registered at a single tertiary-care comprehensive cancer center were screened for eligibility. Children with low-risk WNT-pathway medulloblastoma defined as aged between 3 to 16 years at diagnosis, with residual tumor less than 1.5 cm² on postoperative MRI, and no evidence of leptomeningeal metastases (M0 status) on rigorous neuraxial staging (spinal MRI and CSF cytology) were included. All imaging was interpreted by dedicated neuro-radiologists and suspicious findings, if any, were discussed in a multi-disciplinary joint clinic for decision-making. Adjuvant radiotherapy was scheduled to start within 6 weeks of surgery. Molecular subgroup assignment was based on a validated assay combining differential expression of 12 protein-coding genes and 9 microRNAs (13). Molecular diagnosis of WNT-pathway medulloblastoma was further confirmed in all 7 included patients through supplementary orthogonal techniques such as CTNNB1 mutation (Sanger sequencing) and/or monosomy 6 (FISH) as appropriate in accordance with international recommendations (11). The study was approved by Institutional Ethics Committee that functions in accordance with the Declaration of Helsinki and is registered with the Clinical Trials Registry of India (CTRI/2017/12/010767). Written informed consent (from parents) and assent (from children as applicable) was obtained prior to study participation. The sponsors had no role in the study design, conduct, data collection, statistical analysis, interpretation, or reporting of results.

Following surgery, focal radiotherapy was delivered to the tumor-bed only (54 Gy/30 fractions over 6 weeks) using image-guided intensity modulated radiation therapy (IMRT). Resection cavity and residual tumor, if any, was delineated as initial clinical target volume (CTV). An isotropic margin of 15 to 20 mm was applied to initial CTV and edited away from natural anatomic barriers (bone, tentorium) to generate final CTV. An isometric margin of 3 mm was applied to final CTV to create planning target volume (PTV) to account for daily set-up errors. 4 weeks later, patients were started on standard adjuvant systemic chemotherapy comprising six cycles of cisplatin (75 mg/m² intravenously on day 1 in alternate cycles 2, 4, 6); cyclophosphamide (1,000 mg/m² intravenously on days 1–2 in cycles 1, 3, 5 and days 2–3 in cycles 2, 4, 6); and vincristine (1.5 mg/m² i.v. on days 1 and 8 in all six cycles) administered at 4-weekly intervals with requisite dose modifications as appropriate. Following adjuvant therapy, patients were periodically followed up clinico-radiologically. All children underwent neuro-cognitive, endocrine, and audiologic assessments at baseline and periodically on follow-up.

The study was designed according to group-sequential methods specifically the triangular test (14) with an early stopping rule if the rate of relapse exceeded 15% at 2 years to ensure safety of participants. Triangular test is one way of analyzing group-sequential trials and uses straight line stopping boundaries. It involves analyzing the data as they accumulate, with points being plotted relative to a triangular region and stopping when the upper or lower boundary of the region is crossed. By using S plus module of sequence trial analysis software we got a total sample size of 60 patients for our study. Sequential analyses were planned after every 15 assessable patients (minimum 12-month follow-up) with decision to stop prematurely if 5 of 15, 6 of 30, 7 of 45, or 8 of 60 assessable patients relapsed. Any documented relapse (local and/or neuraxial) on surveillance neuro-imaging was defined as event for recurrence-free survival (RFS) while death from any cause was considered as event for overall survival (OS). Any recurrence or mortality (whichever occurred earlier) was counted as event for event-free survival (EFS). All time-to-event outcomes were calculated from date of surgery till the defined event of interest (with December 31, 2021 as cut-off date) using Kaplan–Meier methods and reported as survival probabilities at 2 years with 95% confidence intervals (CI). All statistical analyses was done on R^TM Version 4.03 (R Corporation).

All data generated in this study are available within the article itself; additional individual patient data can be made available on reasonable request without any patient-identifying information.

The principal investigator and corresponding author (T. Gupta) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Between June 2017 to January 2019, 17 patients with newly-diagnosed WNT-pathway medulloblastoma were screened for eligibility, 10 of whom were deemed screen failures due to older age (>16 years, n = 1), large residue (>1.5 cm², n = 3), leptomeningeal metastasis at presentation (M+ disease, n = 2), and delay in molecular subgrouping (>6 weeks, n = 4). Supplementary genetic testing using orthogonal techniques demonstrated presence of either CTNNB1 mutation (in 4 of 5 samples tested, uninterpretable in 1) and/or monosomy 6 (in all 6 samples tested) confirming the diagnosis of WNT-pathway medulloblastoma (Table 1). 7 children were identified as having low-risk WNT-pathway medulloblastoma and treated with focal IMRT to the tumor-bed (54 Gy/30 fractions) followed by six cycles of standard adjuvant chemotherapy after written informed consent/assent. Median time to initiation of radiotherapy (from surgery) was 37 days (interquartile range 30–39 days). All children completed fractionated IMRT uneventfully and were started on adjuvant chemotherapy. 6 children completed all planned six cycles, while 1 child (case 3) succumbed to neutropenic sepsis and multi-organ dysfunction after first cycle of chemotherapy. Three children (cases 1, 2, 4) were detected with neuraxial failure (supratentorial brain and/or spine) including 1 with synchronous local recurrence on surveillance neuro-imaging at 21, 15, and 23 months from index diagnosis following which the study was terminated prematurely (Table 1). At relapse, all 3 children were treated with tomotherpay-based CSI with conformal avoidance of previously-treated tumor-bed (as appropriate) plus boost irradiation of metastatic deposits followed by second-line salvage chemotherapy. 2 children (cases 1, 4) continue to be in remission (32 and 26 months after first relapse) while 1 child (case 2) developed a second relapse (involving tumor-bed and spine) 28 months after first relapse and was further treated with salvage chemotherapy and craniospinal reirradiation resulting in excellent clinico-radiologic response. Representative images of a patient with neuraxial relapse and complete response to salvage therapy is illustrated in Fig. 1. Imaging patterns of first relapse of the other 2 patients are also presented in online supplementary file (Supplementary Fig. S1). 3 patients (cases 5, 6, 7) are relapse-free at 42, 35, and 35 months from index diagnosis. Patient, disease, and treatment-related characteristics with survival outcomes for individual patients are summarized in Table 1. At a median follow-up of 42 months, 2-year Kaplan–Meier estimates of EFS, RFS, and OS with 95% CI were 42.9% (95% CI, 18.2–100), 50% (95% CI, 22.5–100), and 85.7% (95% CI, 63.3–100) respectively (Fig. 2). The current analysis was unplanned and not part of the original study design wherein first interim analysis was scheduled to be done after 15 evaluable patients. However, unacceptably high risk of neuraxial failure prompted us to terminate our study prematurely without formal statistical analysis.

Novel biological insights have led to classification of medulloblastoma into four distinct molecular subgroups (4, 5), prompting prospective testing of subgroup-specific treatment paradigms for optimization of adjuvant therapy (15). We hypothesized that focal IMRT to primary-site avoiding upfront CSI would significantly reduce radiotherapy-related late toxicity without compromising survival in low-risk WNT-pathway medulloblastoma. We also postulated that salvage CSI plus boost irradiation of metastatic sites followed by further systemic chemotherapy would provide sustained disease control for any neuraxial relapse. Unfortunately, three children relapsed within 2 years of initial diagnosis necessitating early termination of our study. Limited patient numbers and relatively short follow-up can be considered limitations of our study. Inferences and conclusions of the current analyses are not based on formal early stopping rules as originally planned reducing statistical rigor.

Cohen and colleagues (16) explored a primary chemotherapy only approach eliminating upfront radiotherapy completely following surgery in children with low-risk WNT-pathway medulloblastoma. First 2 patients on their study relapsed (both local and disseminated) at 3 and 6 months after completion of planned adjuvant systemic chemotherapy comprising of Children's Oncology Group (COG) ACNS0331 AAB-AAB-AAB (A = cisplatin/lomustine/vincristine; B = cyclophosphamide/vincristine) backbone following which further accrual was halted on the study. Of the remaining 4 subjects, 2 were in remission after completion of primary chemotherapy while other 2 were in midst of protocol therapy (at time of reporting). Additional therapy in the form of radiotherapy and/or intensification of chemotherapy was recommended for these 4 children to reduce their risk of relapse. An updated analysis (17) reconfirmed that primary chemotherapy approach omitting upfront CSI/radiotherapy is insufficient treatment for WNT-activated medulloblastoma. The first 2 relapsed patients were successfully salvaged with CSI plus focal boost followed by systemic chemotherapy. 2 patients who had completed primary chemotherapy at time of study closure received consolidation CSI plus focal boost and remain in remission 1 year from completion of treatment. Of the remaining two children on treatment, one aborted protocol therapy and transitioned to Head Start type regimen and remains in remission at 10 months. The final subject who recently completed primary chemotherapy developed new areas of restricted diffusion suspicious of early recurrence necessitating salvage CSI plus boost, but experienced further relapse and is receiving salvage chemotherapy. Findings from both these studies should inform and guide neuro-oncology researchers as well as practicing clinicians to tread cautiously and plan for controlled deintensification of therapy in even in good-biology disease. The physical, mental, and emotional suffering endured by patients and care-givers after early relapse due to deintensification of therapy to mitigate toxicity in a disease setting with high cure rates can be devastating thereby mandating strict stopping rules. Despite using stringent criteria for patient selection, both studies had to be terminated prematurely due to unacceptably high risk of neuraxial failures suggesting that radiotherapy, particularly CSI remains an integral component of treatment even in low-risk WNT-pathway medulloblastoma.

Various platforms exist for robust molecular subgrouping of medulloblastoma including IHC panel, gene expression profiling, microRNA profiling, and DNA methylation array (4, 13). DNA methylation is considered gold-standard and method of choice for molecular classification (18); however, there remain issues with its availability, accessibility, and affordability. It is generally recommended to use complementary orthogonal techniques such as nuclear β-catenin staining, CTNNB1 mutation, or monosomy 6 to molecularly confirm the diagnosis of WNT-pathway medulloblastoma before planning deescalation of therapy (11). Using our assay (13), we have previously accurately classified all 34 medulloblastoma samples from an external dataset (based on NanoString) excepting for one group 4 tumor that was misclassified as group 3 medulloblastoma providing an accuracy rate of 97%. NanoString assay has recently been reported to have 100% concordance with DNA methylation array for WNT-pathway medulloblastoma (18). Heatmap illustration of our assay used to define WNT-pathway medulloblastoma is provided as online supplementary file (Supplementary Fig. S2).

The optimal dose of CSI in WNT medulloblastoma is currently being explored in several prospective clinical trials (15) such as the SJMB-12 (NCT01878617), COG ACNS1422 (NCT02724579), and PNET-5 (NCT02066220). Previous data has shown that deferral of radiotherapy (19) or reduction of CSI dose (20) in younger children (aged between 3 to <8 years) with molecularly unselected medulloblastoma results in inferior survival. We are now recruiting children with low-risk WNT-pathway medulloblastoma in a successor study (NCT04474964) using 18 Gy CSI plus 36 Gy tumor-bed boost for total primary-site dose of 54 Gy followed by six cycles of standard adjuvant chemotherapy. Low-dose CSI (15–18 Gy) as being tested in ongoing clinical trials or current standard-dose CSI (23.4 Gy) as being used in routine clinical practice in the upfront adjuvant setting are likely to be associated with decreased neuro-cognitive toxicity compared with full-dose CSI (35–36 Gy) delivered upfront or in the salvage setting at neuraxial relapse. The potential of using lower doses of CSI in the salvage setting for relapsed medulloblastoma after deintensified therapy remains unexplored. For children with isolated local recurrence in the index tumor-bed, lower doses of CSI (23.4 Gy) might suffice; however, for disseminated disease, full-dose CSI would be warranted for durable disease control.

Over the last two decades, a number of molecular players and associated signaling pathways involved in metastases from medulloblastoma have been described (21). However, given the excellent long-term survival (5-year survival >90%) with very low risk of relapse in adequately treated WNT-pathway medulloblastoma, prognostic factors affecting outcomes, patterns of failure, and drives of metastatic dissemination have not been described well in this subgroup. Recently, Nobre and colleagues (22) have reported on a retrospective multi-institutional clinically annotated cohort of 93 patients with WNT-pathway medulloblastoma using an integrated genomic approach. 15 patients with relapse were identified, 12 in metastatic compartment including 1 with extra-neuraxial metastases, and 3 in the surgical cavity. Interestingly, 8 of 11 neuraxial relapses were in lateral ventricles (6 confined to frontal horns). Maintenance systemic chemotherapy (P = 0.032) specifically the cumulative dose of cyclophosphamide/ifosfamide (<12 mg/m²) and male gender (0.033) were associated with significantly increased risk of relapse (P = 0.033). Age at diagnosis, extent of resection, metastatic status at presentation, dose of CSI, and additional molecular/genetic alterations did not predict the risk of relapse in WNT-pathway medulloblastoma. All children in our study (excepting 1 who succumbed to chemotherapy-related complications after first cycle) had received 12 mg/m² of cumulative cyclophosphamide dose. All three relapses in our cohort occurred in the female gender in contrast to the findings from retrospective multi-institutional analysis (22); remaining 3 children (2 boys and 1 girl) continue to be relapse-free and in sustained remission on follow-up. All 3 children with failure experienced metastatic relapse in the neuraxis including two in and around the lateral ventricles (one each in frontal horn and juxta-ventricular region) reinforcing the view that ependymal lining of lateral ventricles possibly provides unique micro-environment conducive to homing and growth of WNT-medulloblstoma tumor cells (22).

Treatment of the tumor-bed alone with postoperative focal conformal radiotherapy avoiding upfront CSI in children with low-risk WNT-pathway medulloblastoma followed by six cycles of standard adjuvant systemic chemotherapy is associated with an unacceptably high risk of neuraxial failure and should not be tested any further even in the context of prospective trials.

T. Gupta reports grants from Tata Memorial Centre, SOHN Conference Foundation, and Daivesh Doshi - Brain Tumor Foundation (BTF) Endowment Fund during the conduct of the study. A. Dasgupta reports grants from Tata Memorial Centre Intramural Research Grant, SOHN Conference Foundation, and Daivesh Doshi - BTF Endowment Fund during the conduct of the study. No disclosures were reported by the other authors.

T. Gupta: Conceptualization, data curation, formal analysis, supervision, funding acquisition, investigation, methodology, project administration, writing–review and editing. S. Pervez: Data curation, formal analysis, writing–original draft. A. Dasgupta: Formal analysis, writing–original draft. A. Chatterjee: Formal analysis, writing–review and editing. S. Epari: Data curation, writing–review and editing. G. Chinnaswamy: Data curation, writing–original draft. R. Jalali: Conceptualization, writing–review and editing.

Intramural Research Grant-Tata Memorial Centre, SOHN Conference Foundation, and Daivesh Doshi - BTF Endowment Fund. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.