Prediction of radiotherapy benefit using genomic-adjusted radiation dose in pediatric low grade gliomas and ependymomas

Radiotherapy (RT) in pediatric cancer: Radiotherapy is a critical component of cure for many pediatric malignancies. However, there is often hesitation to prescribe RT for children out of concern for late effects of treatment, particularly for central nervous system tumors. For some malignancies, such as low grade gliomas, the most common brain tumor in children, radiotherapy while highly efficacious 1 2  3 is often a last resort or comes after progressing through multiple lines of chemotherapy due to concerns related to late toxicities 1 4 2 3. For other malignancies, such as ependymoma or medulloblastoma, the optimal dose for enhancing local control while minimizing toxicity is not clear 5, although some studies suggest higher doses may optimize control and survival outcomes 6.
Optimizing RT Dose with Tumor Genomics: Radiation Therapy (RT) is prescribed using a one-size fits all approach that is based on clinical factors including disease site and stage 7. However, cancer is a highly heterogenous biological disease and this approach is likely not optimal for each individual patient. In recent studies, we have developed the gene expression-based radiosensitivity index (RSI) a clinically-validated molecular signature of tumor radiosensitivity and the genomic-adjusted radiation dose (GARD), a radiation-specific metric that quantifies the clinical effect of a given dose of RT8-26. Combined, RSI/GARD transforms radiation oncology into a biologic discipline by providing the first approach to optimize RT prescription dose using tumor genomics. In a pan-cancer analysis of 1615 patients, GARD was associated with OS and risk of recurrence outperforming RT dose as a prescription parameter. In addition, GARD predicted and quantified the therapeutic benefit of RT providing the first approach to optimize clinical outcome by individualizing RT dose 19. Three prospective clinical trials are currently underway testing the effectiveness of this platform as a prescription parameter in adult patients with non-small cell lung (NCT0587343), sarcoma (NCT05301283) and triple negative breast cancer (NCT05528133). In solid adult tumors, we have demonstrated that current standard of care (SOC) practice to deliver uniform doses of RT potentially under/overdoses up to 75% of patients and significantly under-realizes the clinical potential of RT 20. GARD in pediatric brain tumors:  In this study we hypothesize that GARD is a predictive biomarker for RT benefit in gliomas and ependymoma pediatric patients that receive RT, marking the first time we test RSI/GARD in childhood cancers. Ependymomas are a type of central nervous system tumor arising from the ependymal cells in the brain and spine. Cranial ependymomas are treated with surgery followed by radiation therapy and in some cases, chemotherapy. The optimal dose of radiation is unclear and no randomized studies exist to this end 5. Low grade gliomas are the most common brain tumor in children. Although many of these patients have very good survival, treatment-related morbidity is a major clinical issue.  A subset of patients require RT either in the post-operative setting or as primary therapy for unresectable tumors and RT has been prescribed using a one-size fits all (50-54 Gy) with no previous attempt at biological optimization of RT prescription dose. Treatment of both pediatric glioma and ependymoma are already particularly vulnerable to central nervous system RT-based toxicities, and with higher doses of radiation, the risk of brainstem necrosis 27, hearing loss 28, neurocognitive deficits 29 30, and endocrinopathies increases, even with modern radiation techniques including proton therapy.
This study will test a novel hypothesis: the therapeutic benefit of RT is quantifiable and is heterogenous among pediatric patients with ependymoma and glioma that receive RT.  If successful, this could open the opportunity for the genomic-based optimization of RT dose for glioma and ependymoma pediatric patients. This could lead to both improved clinical outcomes and reduced RT-related long-term sequelae.