As molecular advances have improved the level of diagnosis and outcome prediction for LGG, treatment strategies need to be adjusted according to different molecular subtypes. This study aimed to determine the optimal radiation dose for IDHwt LGG. Survival analysis showed that high-dose radiotherapy independently prolonged patient survival. This finding may help tailor treatment strategies for IDHwt LGG.
The current multidisciplinary treatment strategies for glioma include surgery, radiotherapy, and chemotherapy. In recent decades, these treatments have been developed. Surgical techniques, including intraoperative electrical stimulations  and 5-aminolevulinic acid  reportedly elevated resection rate. Chemotherapy regimens, such as PCV (procarbazine, lomustine, and vincristine) and temozolomide, significantly improved the survival of gliomas [13, 14]. However, no novel treatment strategies have been proven effective for gliomas. Targeted therapy and immunotherapy have dramatically prolonged the survival of many tumors. For radiotherapy, the application of IMRT and proton therapy has significantly reduced the radiation dose to the surrounding brain tissue. This makes it possible for elevating does to tumors much safer. However, the effect of higher doses of treatment for LGG patients is still unclear.
Several clinical trials have investigated whether high-dose radiotherapy improved the prognosis of LGG. The EORTC study 22844 included 379 LGG patients and randomized them between a low-dose arm of 45 Gy and high-dose arm of 59.4 Gy . Meanwhile, the NCCTG study randomized 203 LGG patients between a low-dose arm of 50.4 Gy and high-dose arm of 64.8 Gy . Both studies failed to conclude that LGG patients benefitted from high-dose radiotherapy. This negative result may be attributed to the heterogeneity of LGG, especially across the different molecular subgroups. As an most important biomarker, IDH mutation status deeply influences the pathophysiology of LGG, from survival to therapy response [2, 17]. Tumors with IDH mutations, especially those accompanied by 1p/19q codeletion, may be sensitive to radiotherapy. Thus, a lower dose is sufficient, and complications from higher doses may adversely induce worse prognosis. In contrast, IDHwt LGG is more aggressive, like glioblastoma, and resistant to radiotherapy. In this subgroup, we examined if high-dose was a prognostic factor.
Since 45–54 Gy is the normal recommended dose for LGG , we declared doses > 54 Gy as high-dose. Univariate and multivariate survival analyses found that high-dose radiotherapy was significantly associated with better survival in IDHwt LGG. For glioblastoma, the Stupp regimen is the standard treatment , and 60 Gy is recommended. In our cohort, 54.4–61.2 (median = 57.6) Gy was administered in the high-dose group. This dose range was deemed reasonable for IDHwt LGG. As cIMPACT‑NOW update 3 pointed out that IDHwt LGG carried EGFR amplification, + 7/−10 or TERT promoter mutation was considered WHO grade IV . A higher dose, closer to 60 Gy, may bring more survival benefits for these patients.