Paediatric H3K27/H3G34 mutant diffuse midline gliomas are high grade gliomas that arise in midline structures/cerebral hemispheres and are known to have dismal outcomes. Standard treatment includes definitive radiation therapy to primary site along with concurrent temozolomide chemotherapy following histological confirmation with a biopsy. Studies have shown poorer outcomes in the paediatric age group compared to that of adults and an increased risk to fail/recur in the leptomeninges(covering of brain and spinal cord). The following study is planned in order to assess the benefit of craniospinal irradiation(delivering radiotherapy to brain, spinal cord and its covering membrane in this high risk population. Thereby the investigator aim to improve survival in newly diagnosed histone mutant pediatric midline gliomas in the upfront setting. Patterns of disease failure, treatment related toxicities and quality of life will also be assessed as a part of this study. If proven beneficial, this study will influence how patients with this diagnosis will be treated in the future.

Introduction: Paediatric H3K27/H3G34 mutant diffuse midline gliomas (DMGs) are aggressive high-grade gliomas predominantly affecting midline structures and cerebral hemispheres. Despite aggressive therapy including radiation and chemotherapy, these tumors carry a poor prognosis, particularly in children, with frequent recurrence and high risk of leptomeningeal spread. Current standard treatment involves definitive radiation therapy to the primary site and concurrent temozolomide chemotherapy following histological confirmation via biopsy. However, outcomes remain suboptimal, prompting exploration of more intensive therapeutic strategies.

Primary objective:

To study if the addition of craniospinal irradiation to standard practice improves outcomes in pediatric diffuse midline glioma.

Secondary objectives:

• Estimate median time to leptomeningeal dissemination and compare with historical control
• Study patterns of failure
• Early and late toxicities
• Study quality of life indices
• To estimate QTWiST (Quality of life without symptoms or toxicity)

Primary endpoint: Overall survival at 12 months

Secondary endpoints:

• Time to leptomeningeal dissemination in months
• Incidence of different failure patterns from clinico-radiological assessment
• Toxicity assessment with the NCI Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) during CSI(weekly), at conclusion of radiotherapy , post completion of 6 cycles adjuvant temozolomide, and in subsequent follow-ups at 3, 6, 9 and 12 months.
• Quality of life indices using the EORTC QLQC- 30 and its BN -20 module at baseline, after completion of radiotherapy, post completion of 6 cycles adjuvant temozolomide and in subsequent follow-up visits at 3, 6, 9 and 12 months.
• Quality of life without symptoms or toxicity in three health states TOX (toxicity), TWIST (time without symptoms) and REL (relapse) at baseline, after completion of radiotherapy, post completion of 6 cycles adjuvant temozolomide and in subsequent follow-up visits at 3, 6, 9 and 12 months.

Study setting: The study will be conducted in the department of Radiation Oncology, Neuro Oncology Disease management group

Inclusion Criteria:

1. Newly diagnosed biopsy proven histone altered diffuse midline glioma
2. Age- ≥3 to <18 years at time of diagnosis
3. Karnofsky/Lansky Performance Score more than or equal to 70
4. Has provided written informed consent/ assent form
5. No prior therapy except debulking surgery or biopsy

Exclusion Criteria:

1. Recurrent or progressive disease
2. Clinical features or family history suggestive of Inherited Cancer Predisposition such as Constitutional Mismatch Repair Deficiency (CMMRD)
3. Previous history of malignancy
4. Not willing /unlikely to comply with proposed therapy and follow up