Constraints, Cumulative Doses, and Toxicity Outcomes in Glioma Reirradiation: A Systematic Review and Radiobiological...

There remains considerable uncertainty regarding normal tissue tolerances to reirradiation for recurrent brain tumours. This systematic review aimed to collate reirradiation constraints, planned cumulative organ at risk (OAR) doses and corresponding toxicity outcomes for adults treated with reirradiation for recurrent glioma. The Medline, Embase, Cochrane, Web of Science and Scopus databases were searched for studies published up to 1^st July 2025. To allow comparison between constraints, where necessary, equivalent doses in 2Gy fractions (EQD2Gy) were calculated. In total, 27 studies were included. Most patients had glioblastoma. Of the 24 studies that reported constraints, 17 employed flat constraints (i.e. applied to the reirradiation treatment alone), and 11 employed cumulative constraints (i.e. applied across the original and reirradiation treatments), without the use of tissue recovery factors (TRFs). None of the included studies used TRFs. Constraints were highly heterogenous. Planned cumulative doses were reported in seven studies and were also heterogeneous. No serious optic pathway, eye or brainstem toxicities were reported. Radionecrosis was infrequently reported, but severe cases did occur. No clear patterns emerged between cumulative constraints or planned cumulative doses and the occurrence of radionecrosis. Given the heterogeneity, it is not possible to recommend definitive OAR constraints for glioma reirradiation. That said, in patients with recurrent glioblastoma, for optic pathways and brainstem, candidate cumulative maximum or near-maximum EQD2Gy limits (α/β=2Gy) of 75-80Gy and 85-100Gy, respectively, are suggested as being associated with <5% risk of severe toxicity. For normal brain, 100-110Gy might be reasonable though larger volume constraints are likely relevant but, as yet, are undefined. In conclusion, there is heterogeneity in glioma reirradiation constraints. The lack of data on larger volume normal brain constraints and toxicity outcomes from centres using cumulative constraints with TRFs represent substantial gaps. Trials and standardisation of reporting are means to better define dose-toxicity relationships.