Young children with medulloblastoma: important open questions and the high-risk dilemma

When choosing the postoperative therapy concept for young children with medulloblastoma, the question of whether or not to irradiate during primary treatment is key for all other therapeutic decisions. Craniospinal irradiation (CSI), a highly efficient treatment component for medulloblastoma, has detrimental effects on the developing brain and leads to significant impairment of neurocognitive functioning in surviving patients, especially in the youngest patients. Therefore, trial consortia recently investigated to avoid the use of CSI in these children by various chemotherapy strategies, (i) in combination with high-dose chemotherapy/autologous stem cell rescue (HDCT/ASCR) as described here by the Head-Start group, (ii) in combination with intraventricular methotrexate (MTX), and (iii) by conventional, systemic chemotherapy alone.^1–4 All of these trials confirmed the prognostic impact of histologic/molecular features, with sonic hedgehog (SHH)–activated desmoplastic/extensively nodular medulloblastoma (DMB/MBEN) representing a favorable risk group and rather infrequent need for radiotherapy, and non-SHH classic medulloblastoma/large cell anaplastic medulloblastoma (CMB/LCAMB) carrying a high risk of relapse.

Although sample sizes for these trials precluded randomized comparisons, results suggest that despite being low-risk, a substantial proportion of SHH-activated DMB/MBEN cannot be cured by conventional, systemic chemotherapy alone and therefore require treatment intensification either by HDCT/ASCT or by intraventricular MTX. Those trials that did not include such a component^3,4 reported progression-free survival (PFS) rates of 55% (5-y PFS in SJYC07-low risk stratum) and 52% (2-y PFS in ACNS-1221), and compare unfavorably to the 93% 5-year PFS in patients treated with intraventricular MTX² and 89% 5-year PFS for all DMB/MBEN patients (93% for M0 DMB/MBEN patients) treated with HDCT/ASCT in the series published in this edition.¹

However, important questions remain. One is the impact of histopathological features within biologically defined subgroups of medulloblastoma: Do patients with SHH-activated CMB carry a higher risk of relapse as suggested by retrospective analysis,⁵ and how frequent are those? If biology is primarily driving the prognosis, to which extent do the at least in part subjective histopathological features contribute to refine the genetically defined subtype? Unfortunately, the current study cannot contribute to answer this question, because information on genetically defined subgroups is unavailable. Another question is related to the role of germline mutations, as some groups have suggested a worse prognosis for children with Gorlin syndrome and SUFU (suppressor of fused homolog) mutations.⁶

Other questions are: What is the optimal therapy for young children with low-risk SHH-activated medulloblastoma, and what is the role of metastatic disease in this context? “Standard-dose” chemotherapy without additional intraventricular MTX and without HDCT/ASCT do not seem to confer sufficient event-free/radiotherapy-free survival rates for all infant SHH-MB,^1–4,7 but might be an option for patients with very-low-risk infant SHH-II medulloblastoma. However, the very positive outcome has only been described in one series so far,⁴ and was less clear in the other series with biological characterization available.^2,3 Although the long-term toxicities of both intraventricular MTX and HDCT/ASCT are less detrimental than CSI, they are related to different acute and long-term side effects, and survivors after either therapy show relevant neurocoginitve impairments.^1,2,8,9 Randomized comparisons of both therapeutic strategies including neurocognitive assessments are highly desirable but challenging to perform, given the low incidence of the disease and the complexity of such a trial.

Another very important question is: What can be offered to young children with medulloblastoma and biological high-risk features (non-SHH-MB)? The current 21% 5-year radiotherapy-free event-free survival reported for CMB/LCAMB patients in the series presented by Dhall et al¹ is similar to the 39% CSI-free survival in M0 CMB/LCAMB patients from the HIT-group² and the approximately 10% PFS for Group 3/Group 4 MB reported in the St Jude series.⁴ These data suggest that despite the intensive chemotherapy regimens used in these series, a very high proportion of children will require radiotherapy to survive their disease. In light of CSI-associated late effects, this is a critical tradeoff to be made by many affected families and treating physicians. Since most conventional chemotherapeutic regimens have failed so far to achieve substantial CSI-free survival rates, new approaches are urgently needed for these patients, as well as for older children with high-risk medulloblastoma. Some novel concepts are currently in preclinical or early-phase clinical trial development. In spite of the achieved improvements, there are still significant challenges remaining.

Conflict of interest statement

Stefan Rutkowski has received research funding from Riemser Pharma, Germany.