What have we learnt from previous phase II trials to help in the management of childhood brain tumours?
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Published on: December 28, 2017
P Chastagner1, E Bouffet, J Grill
1Department of Paediatric Oncology, Hôpital d'Enfants, CHU Nancy, 54500, Vandoeuvre, France. p.chastagner@chu-nancy.fr
Abstract:
Contrary to major advances in cure rates observed for almost all childhood cancers, progress in reducing brain tumour survival rates remains very limited. Although new drug development in oncology is founded on principles outlined in the organised methodology of phase I, II, and III trials, based on rigorous study design using standardised criteria, this approach has been applied very slowly in the field of neuro-oncology. There are multiple explanations for the paucity of well-conducted prospective clinical trials, such as the rarity and the heterogeneity of these tumours, and the reluctance of some investigators to enroll their patients in constraining trials. Data from the past two decades shows that several methodological problems preclude the drawing of any definite conclusions for the majority of drugs assessed. Among them, the necessity of a central neuropathological and neuroradiological review has been highlighted in, at least, two multicentric studies. Changes in histological diagnosis and grade have been reported in a proportion as high as 20%, and changes in response rate in 14% of the cases. This review of phase II trials for brain tumours reveals a wide array of sometimes arbitrary response definitions, that is if response is defined at all, and most series have enrolled small numbers of patients. We report on the different problems encountered in childhood brain tumours in these phase II trials, and their impact on phase III trials.
Insights
Childhood brain tumor survival rates have seen limited progress due to methodological issues in clinical trials. Improving trial design and central reviews are crucial for advancing treatment for pediatric brain tumors.
Area of Science:
- Neuro-oncology
- Pediatric Oncology
- Clinical Trial Methodology
Background:
- Significant advances in childhood cancer cure rates contrast with limited progress in pediatric brain tumor survival.
- The application of rigorous clinical trial methodologies (Phase I, II, III) has been slow in neuro-oncology.
Purpose of the Study:
- To review the methodological challenges in Phase II clinical trials for childhood brain tumors.
- To analyze the impact of these challenges on Phase III trial outcomes.
Main Methods:
- Review of Phase II clinical trials for pediatric brain tumors over the past two decades.
- Analysis of methodological problems including tumor rarity, heterogeneity, and trial design constraints.
- Examination of the necessity for central neuropathological and neuroradiological review.
Main Results:
- Methodological problems frequently preclude definitive conclusions for assessed drugs.
- Central review identified diagnostic changes in up to 20% of cases and response rate changes in 14%.
- Phase II trials often suffer from small patient numbers and inconsistent or arbitrary response definitions.
Conclusions:
- Paucity of well-conducted prospective trials hinders progress in pediatric neuro-oncology.
- Standardization of trial design, response criteria, and central review is essential for reliable results.
- Addressing these issues is critical for improving the efficacy of future Phase III trials and ultimately, patient outcomes.
