Childhood medulloblastoma, which has the highest incidence as a malignant tumor in the central nervous system, has shown considerable improvement in treatment outcomes over the last 5 decades. The introduction of multimodal therapies, which include risk-adapted craniospinal irradiation (CSI) followed by chemotherapy, has resulted in increased survival rates with over 80% of patients living beyond 5 years. However, there still remains significant worries with regards to the long-term neurocognitive functioning and overall quality of life of long-term survivors. As pointed by Papini et al.,1 adult survivors of medulloblastoma who were diagnosed during childhood have up to a fivefold increased prevalence of neurocognitive deficits when compared with siblings in terms of memory, attention, and processing speed. Although modulation of CSI dose and addition of chemotherapy has been implemented, contemporary therapies have not changed the rate of functional nonindependence, which remains at 42% in survivors. This situation gets further compounded by chronic health conditions including sensorimotor deficits, hearing loss, and seizures, which indicates a great need for intervention to lessen the lifetime consequences that stem from the treatment of this disease.
The study by Papini et al. symbolizes a remarkable contribution to the understanding of long-term effects of evolving therapies. The authors’ analysis of 505 survivors diagnosed between 1970 and 1999 revealed that risk-adjusted therapies were no more beneficial neurocognitively than the older ones. Such a finding casts doubt on the notion that lesser doses of CSI will result in better functional outcomes. Furthermore, employing latent class analysis2 to examine functional independence provided unique perspectives into the heterogeneity of survivorship experience. It was found that neurosensory and neurologic conditions significantly influenced functional independence. More significantly, the study demonstrates the increased burden that chronic health conditions place on neurocognitive functioning and therefore proposes the need for comprehensive survivorship care. These findings make a persuasive case for longitudinal surveillance and set the stage for more refined clinical guidelines. Overall, we consider this study one of the most innovative and important investigations compared with other ongoing similar trials3,4 because the authors managed to put together treatment modalities, chronic health problems, and neurocognitive dysfunctions into one holistic model that explains the plights of adult survivors (Table 1). Nevertheless, it is also important to note that from different viewpoints, this study could be further enhanced.
Table 1.
Similar Clinical Trials on Neurocognitive Outcomes of Medulloblastoma Treatment
| Recent similar clinical trials | Description |
|---|---|
| COG ACNS1422 (NCT02724579, Ongoing) | Reduced CSI (18 Gy) + chemotherapy for WNT-activated medulloblastoma. Neurocognitive Focus: Longitudinal assessments of intellectual and adaptive functioning. First trial to de-escalate therapy for a molecular subgroup (WNT), aiming to reduce neurotoxicity while maintaining survival. But long-term adult neurocognitive data (eg, memory, task efficiency) are pending. Also there are limited data on functional independence outcomes. |
| SJMB12 (NCT01878617, Not ongoing) | Risk-adapted therapy (CSI dose, chemotherapy) based on molecular subgroups (WNT, SHH, Group 3/4). Neurocognitive Focus: Annual neuropsychological testing, including processing speed and executive function. This trial integrates molecular profiling to personalize treatment, potentially sparing neurocognitive function. But survivors remain at risk for late-emerging deficits (eg, organization impairment) as they age into adulthood. |
| SIOP PNET5 MB (NCT02066220, Ongoing) | Reduced CSI (18 Gy) + chemotherapy for standard-risk medulloblastoma. Neurocognitive Focus: IQ, memory, and processing speed via standardized batteries. This trial collaborating with EU validates reduced CSI efficacy, with early data showing preserved IQ in childhood. But there are no published data on adult functional outcomes (eg, employment, independent living). |
| Sodium Thiosulfate for Oto-protection (NCT02997189, Ongoing) | Prevent cisplatin-induced hearing loss in children with medulloblastoma. Neurocognitive Focus: Indirectly addresses cognitive deficits linked to hearing loss (eg, task efficiency). This trial shows significant reduction in severe hearing loss, which may mitigate downstream neurocognitive risks. But it does not directly target neurocognitive rehabilitation, also long-term social outcomes for adulthood unstudied. |
As we all know, it has been extremely challenging to develop prognostic models for childhood medulloblastoma. Despite careful investigation of treatment exposures and chronic health conditions, the study by Papini et al. did not consider tumor molecular biomarkers5 in prognostic models. Medulloblastoma is divided into 4 molecular subgroups (WNT, SHH, Group 3, Group 4), all of which possess distinct biological behavior and clinical features. For instance, WNT tumors are linked with favorable outcomes, while Group 3 tumors are considered neurocognitively aggressive and poor in profiles. As noted by Tsimberidou et al.,6 the absence of molecular data reduces the capacity to differentiate between survivors based on their inherent tumor biology, which may conceal fundamental differences in sensitivity to neurotoxicity or specific chronic health conditions in a subgroup. Thus, it seems that further studies need to be conducted in which genomic profiling is incorporated with the objective of understanding how molecular subtypes combined with specific treatment exposures influence long-term functioning and cognition.
Another issue that should not be neglected is the confounding factor of disease severity, since the analysis fails to compare treatment effects within disease-severity groups.7 Participants defined as having high-risk features were perhaps intensively treated, which may inflate the relationship between treatment intensity and neurocognitive impairment. For example, the use of high-risk therapies such as CSI ≥ 30 Gy is associated with a 50% increased risk of organizational impairment compared with standard-risk approaches, but this finding may reflect baseline disease severity rather than treatment effect alone.8 Subgroup analyses stratified by tumor stage or metastatic status, coupled with multivariate models adjusting for baseline risk factors, could clarify the independent contribution of therapeutic exposures. Such approaches would enhance the validity of comparisons between historical and contemporary regimens.
It also should be noted that although Papini et al. acknowledged psychosocial challenges such as depression, their study still lacks granular data on social support, coping mechanisms, or mental health factors which could be additional determinants known to mediate functional outcomes.9 For example, depression and social isolation may amplify the impact of neurocognitive deficits on employment or independent living. Prospective studies should employ validated tools, such as the PROMIS Psychosocial Illness Impact scales, to quantify these variables and assess their interaction with biologic and treatment-related risks. This would provide more holistic views of the determinants of long-term outcomes in medulloblastoma survivors. In the future, perhaps more personalized psychological interventions can be integrated into the health management of childhood medulloblastoma survivors.
Lastly, the authors heavily rely on cross-sectional neurocognitive assessments while ignoring longitudinal neurocognitive testing.10 Usually, having information from longitudinal neurocognitive assessment from childhood to adolescence can inform how/where cognitive decline/improvement occurs. It also aids in understanding when/how certain neurocognitive deficits present themselves and if there are particular times suitable for intervention. For example, early declines in processing speed may predict later impairments in executive function, providing a time-sensitive window for cognitive rehabilitation. Recent longitudinal studies have demonstrated that processing speed deficits often emerge within the first 5-year posttreatment period, while memory impairments may develop more gradually. The absence of longitudinal neurocognitive data may limit causal inferences about the trajectory of deficits. Thus, longitudinal designs, with repeated assessments from diagnosis through adulthood, are needed to identify critical periods of decline and evaluate the efficacy of interventions.
In conclusion, the study by Papini et al. provides a sobering reminder that advancements in medulloblastoma therapy have not yet translated to proportional improvements in long-term neurocognitive/functional outcomes. While their work illuminates the roles of chronic health conditions and treatment era in shaping survivorship, critical gaps remain in molecular stratification, confounding adjustment, psychosocial integration, and longitudinal assessment. Addressing these limitations will require policy makers, researchers, and clinicians to work together. As precision medicine reshapes front-line therapies, parallel innovations in survivorship research—rooted in biomarker-driven stratification and holistic care models—are imperative to safeguard the quality of life for generations of survivors.
Contributor Information
Sijia Liu, School of Law, Sun Yat-sen University, Guangzhou, China; School of Law and Intellectual Property, Guangdong Polytechnic Normal University, Guangzhou, China.
Jialao Ma, School of Public Health, Guangzhou Medical University, Guangzhou, China; The Affiliated Guangzhou Twelfth People’s Hospital, Guangzhou Medical University, Guangzhou, China.
Author contributors
Sijia Liu (Conceptualization, Writing, Revising, Refinement—original draft) and Jialao Ma (Writing, Suggestion)
Conflict of interest statement
We declare no competing interests.
Ethical approval statement
Not required being a theoretical paper.
Patient consent for publication
Not applicable.
References
- 1. Papini C, Mirzaei S, Xing M, et al. Neurocognitive outcomes and functional independence in adult survivors of childhood medulloblastoma diagnosed over 3 decades. Neuro Oncol. 2025; 27(1):254–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Furuta H, Mizuno K, Unai K, et al. Functional independence measure subtypes among inpatients with subacute stroke: classification via latent class analysis. Prog Rehabil Med. 2022;7:20220021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Khan RB, Patay Z, Klimo P, et al. Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol. 2021;23(9):1586–1596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Mynarek M, Milde T, Padovani L, et al. SIOP PNET5 MB trial: history and concept of a molecularly stratified clinical trial of risk-adapted therapies for standard-risk medulloblastoma. Cancers (Basel). 2021;13(23):6077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Das S, Dey MK, Devireddy R, Gartia MR.. Biomarkers in cancer detection, diagnosis, and prognosis. Sensors (Basel). 2023;24(1):37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Tsimberidou AM, Kahle M, Vo HH, et al. Molecular tumour boards — current and future considerations for precision oncology. Nat Rev Clin Oncol. 2023;20(12):843–863. [DOI] [PubMed] [Google Scholar]
- 7. Andrews JS, Desai U, Kirson NY, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimers Dement (N Y). 2019;5(1):354–363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Turcas A, Homorozeanu B, Gheara C, et al. Dynamics and predictors of hematologic toxicity during cranio-spinal irradiation. Rep Pract Oncol Radiother. 2024;29(3):362–372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Carriedo N, Rodríguez-Villagra OA, Moguilner S, et al. Cognitive, emotional, and social factors promoting psychosocial adaptation: a study of latent profiles in people living in socially vulnerable contexts. Front Psychol. 2024;15:1321242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Anokhin AP, Luciana M, Banich M, et al. Age-related changes and longitudinal stability of individual differences in ABCD neurocognition measures. Dev Cogn Neurosci. 2022;54:101078. [DOI] [PMC free article] [PubMed] [Google Scholar]