Survival and neurologic outcomes after re-irradiation in children with diffuse midline glioma and diffuse intrinsic pontine glioma

Background

Re-irradiation (reRT) is increasingly offered following progression in diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), though optimal patient selection remains a challenge. This study evaluated clinical outcomes after reRT in a contemporary cohort of patients with DIPG/DMG.

Methods

Patients < 26 years old with DMG/DIPG treated with radiation therapy between 2011-2025 were retrospectively reviewed. Primary endpoints included overall survival (OS2) and progression-free survival (PFS2), measured from first progression, and change in neurologic symptoms after reRT. Survival was estimated using Kaplan–Meier methods, with Cox proportional hazards modeling for prognostic factors.

Results

Fifty-eight patients were included; 37 (63.8%) underwent reRT. Tumors were predominantly pontine (74.1%). ReRT was associated with improvement in motor function (51.4% vs. 9.5%, p=0.002), cranial nerve function (29.7% vs. 4.8%, p=0.044), and gait ataxia (35.1% vs. 9.5%, p=0.059). Median OS2 and PFS2 were improved with reRT (OS2: 9.67 vs. 2.57 months, p <0.001; PFS2: 5.63 vs. 1.57 months, p <0.001). OS2 was independently associated with reRT (HR 0.27, p <0.0001), pontine location (HR 2.94, p =0.004), and steroid use at progression (HR 4.12, p =0.001). PFS2 was independently associated with reRT (HR 0.23, p <.0001) and distant pattern of failure (HR 2.83, p =.037). Among reRT patients, non-pontine location was associated with improved OS2 ( p =0.02), and local failure was associated with improved PFS2 ( p =0.003).

Conclusion

ReRT was associated with neurologic improvement and prolonged survival. Patients with non-pontine tumors or local-only failure might derive the greatest benefit. Prospective studies are warranted to define optimal dose/fractionation and refine patient selection.

Key Points

• Reirradiation in patients with DMG/DIPG improved overall survival and progression free survival

• Reirradiation improved neurologic outcomes

• Local-only failure and non-pontine tumor location may derive greatest benefit from reirradiation

Importance of the Study

In patients with diffuse intrinsic pontine glioma and diffuse midline glioma, progression after initial treatment remains nearly universal, and salvage therapies are limited. Re-irradiation (reRT) is increasingly offered, yet optimal patient selection and neurologic benefit remain unclear. Additionaly, prior studies exploring reRT lack a comparison cohort of patients that did not receive reRT and rarely integrate neurologic or molecular data. This study investigates the impact of reRT in a contemporary cohort of patients with molecular characterization and includes assessment of neurologic impact. We provide evidence that reRT can improve neurologic function and extend survival, particularly in patients with non-pontine tumors or local-only recurrence. By identifying factors associated with better outcomes, our findings help guide individualized decision-making for reRT.

Lay Summary

Pediatric patients with aggressive brain tumors, including diffuse intrinsic pontine glioma and diffuse midline glioma, often have tumor recurrence and neurologic decline despite initial treatment. Options when the tumor grows again are limited. This study shows that giving a second course of radiation, called re-irradiation, can help improve neurologic symptoms including movement and coordination, and extend survival. We also identify features like tumor location and site of tumor regrowth that help to predict who may benefit most. These findings can help physicians make informed decisions about using re-irradiation to improve quality of life and outcomes for those facing these challenging tumors.