Highlight
The International Benchmarking of Childhood Cancer Survival by Stage (BENCHISTA) study represents a landmark collaborative effort involving 73 population-based cancer registries across 27 countries to standardize the reporting of tumor stage using the Toronto guidelines.
Key findings indicate that while stage at diagnosis accounts for survival variation in some cancers, such as neuroblastoma in the UK and Ireland, significant disparities remain for Ewing sarcoma and medulloblastoma in several European regions even after adjusting for stage and age.
The study underscores that improving childhood cancer outcomes requires more than just early diagnosis; it necessitates addressing systemic factors including treatment protocol adherence, access to multidisciplinary expertise, and post-relapse care infrastructure.
Background: The Challenge of International Benchmarking
Disparities in childhood cancer survival have been documented for decades across different high-income and middle-income countries. While overall survival for pediatric malignancies has improved dramatically, a persistent gap remains between various geographical regions. Historically, it has been hypothesized that these differences are primarily driven by the stage of the disease at the time of diagnosis. If children in certain regions are diagnosed later, when the disease is more advanced, their prognosis is naturally poorer.
However, verifying this hypothesis has been challenging due to the lack of standardized staging data across population-based cancer registries (CRs). Most adult staging systems are not directly applicable to pediatric oncology, and until recently, there was no international consensus on how CRs should record stage for childhood tumors. The Toronto Childhood Cancer Stage Guidelines were developed to bridge this gap, providing a uniform framework for registries. The BENCHISTA study was designed to implement these guidelines and determine whether survival probabilities by tumor stage vary internationally, using six childhood solid tumors as exemplars.
Study Design: The BENCHISTA Methodology
The BENCHISTA project is a population-based retrospective cohort study. It included all incident cases of six specific solid tumors: neuroblastoma, Wilms tumor, medulloblastoma, osteosarcoma, Ewing sarcoma of bone, and rhabdomyosarcoma. The study period covered diagnoses made between January 1, 2014, and December 31, 2017, with a minimum of three years of follow-up for survival.
The dataset was comprised of 9883 cases from 73 cancer registries across 27 countries, including 23 European nations, Australia, Brazil, Canada, and Japan. To facilitate meaningful comparisons, countries were grouped into five predefined European areas: Central Europe (the reference group), Southern Europe, Eastern Europe, Northern Europe, and the UK and Ireland. The primary outcome measure was three-year overall survival (OS) by stage for each tumor type.
Multivariable Cox and logistic models were employed to estimate the hazard ratios (HR) or odds ratios of death. The analysis was conducted in stages: first adjusting for age, and then adding an adjustment for tumor stage to see if the geographical variation persisted or was mitigated.
Key Findings: A Granular Look at Survival and Stage
Overall Survival and Stage Completeness
One of the most significant achievements of the BENCHISTA study was the high level of stage completeness, which reached 93% (9199 of 9883 cases). This demonstrates the feasibility of using Toronto guidelines in a registry setting. The overall three-year survival rates across the entire cohort were as follows:
- Wilms tumor: 95% (95% CI, 94%-96%)
- Neuroblastoma: 83% (95% CI, 81%-84%)
- Medulloblastoma: 79% (95% CI, 77%-81%)
- Ewing sarcoma: 78% (95% CI, 75%-80%)
- Rhabdomyosarcoma: 77% (95% CI, 74%-79%)
- Osteosarcoma: 75% (95% CI, 73%-77%)
Geographical Variation and the Role of Stage
The study found significant geographical variations in age-adjusted OS for neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdomyosarcoma. When the researchers further adjusted for stage at diagnosis, the results varied by tumor type and region.
For neuroblastoma in the UK and Ireland, the survival difference compared to Central Europe disappeared after adjusting for stage, suggesting that the initial survival gap was largely due to a different distribution of disease stages at diagnosis. Similarly, the survival gap for rhabdomyosarcoma in Eastern Europe was no longer significant after stage adjustment.
However, the most striking findings concerned Ewing sarcoma and medulloblastoma. For Ewing sarcoma, survival variation was not mitigated by stage adjustment in the UK and Ireland (HR, 2.06; 95% CI, 1.39-3.04) or in Eastern Europe (HR, 1.87; 95% CI, 1.22-2.86). This indicates that children with Ewing sarcoma in these regions had a higher risk of death regardless of whether they were diagnosed early or late. A similar pattern was observed for medulloblastoma in Eastern Europe (HR, 1.68; 95% CI, 1.13-2.49) and Southern Europe (HR, 1.42; 95% CI, 1.03-1.94).
Clinical and Policy Implications: Moving Beyond Stage
The finding that stage adjustment does not eliminate survival disparities in several regions is a critical insight for clinicians and health policy experts. It suggests that the “stage at diagnosis” is only one piece of the puzzle. When survival remains lower despite similar stage distributions, other factors must be at play.
Treatment and Protocol Adherence
Variation in survival for tumors like Ewing sarcoma may be linked to differences in treatment intensity, adherence to international protocols, or the availability of specialized multidisciplinary teams. Ewing sarcoma requires complex management, including intensive chemotherapy, high-quality surgery, and precise radiotherapy. Disparities in the delivery of these components can lead to inferior outcomes even in localized disease.
Healthcare Infrastructure and Expertise
For medulloblastoma, survival is heavily dependent on the quality of neurosurgery and the subsequent delivery of craniospinal irradiation. The persistent survival gap in Eastern and Southern Europe, even after stage adjustment, might reflect variations in surgical resection completeness or delays in starting radiotherapy. These are systemic issues that go beyond early detection programs.
The Importance of Toronto Guidelines
The BENCHISTA study validates the use of Toronto guidelines as a powerful tool for cancer registries. By providing a common language, these guidelines allow for more accurate benchmarking and help identify specific areas where national health systems are underperforming. Sustaining this collaboration between clinicians and registries is essential for ongoing monitoring and improvement.
Expert Commentary and Limitations
While the BENCHISTA study provides high-quality data, it is not without limitations. The retrospective nature of the study means that detailed information on molecular subtypes, which are increasingly important for prognosis in tumors like neuroblastoma and medulloblastoma, was not consistently available across all registries. Furthermore, while the study adjusted for stage, it could not fully account for all socioeconomic factors or the specific details of the treatment received by each patient.
Experts suggest that the next phase of research should focus on “process indicators.” This includes measuring the time from the first symptom to diagnosis, the time from diagnosis to the start of treatment, and the level of adherence to standard-of-care protocols. Understanding why some regions have a more advanced stage distribution (as seen in neuroblastoma in the UK/Ireland) can help refine early diagnosis strategies, while understanding why stage-matched survival is lower (as seen in Ewing sarcoma) can lead to improvements in treatment delivery.
Conclusion
The BENCHISTA study confirms that international variation in childhood cancer survival is a complex phenomenon. While differences in tumor stage distribution explain some of the variation, they do not account for all of it. The persistent survival gaps in Ewing sarcoma and medulloblastoma serve as a call to action for health systems to look beyond early diagnosis and investigate the quality and equity of treatment delivery. By continuing to use the Toronto guidelines and fostering international collaboration, the pediatric oncology community can move closer to the goal of ensuring that every child, regardless of where they live, has the best possible chance of survival.
Funding and References
The BENCHISTA study was supported by various national and international funding bodies, including the European Union’s Health Programme and participating national cancer registries.
Botta L, Didonè F, Lopez-Cortes A, et al. Stage at Diagnosis and International Survival Variation in Childhood Tumors in the BENCHISTA Study. JAMA Netw Open. 2026;9(2):e2556747. doi:10.1001/jamanetworkopen.2025.56747
Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5—a population-based study. Lancet Oncol. 2014;15(1):35-47.
Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37,513,025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391(10125):1023-1075.
