Neoadjuvant ultrahypofractionated radiotherapy with simultaneous integrated boost for glioblastoma: study protocol for a phase I multicenter clinical trial.

Background: The Stupp protocol standardized adjuvant radiotherapy (RT) with temozolomide as the best treatment after glioblastoma (GBM) resection. Later phase III trials found that moderate hypofractionation and ultrahypofractionation were not inferior in elderly or frail patients. As most recurrences occurred near the tumor bed, RT margins could be reduced, favoring ultrahypofractionated RT (UHRT). Neoadjuvant UHRT might provide additional benefits by allowing better margin selection and lowering radionecrosis risk through the surgical removal of the irradiated tissue. Methods: This is a phase I, single-arm, multicenter clinical trial having as primary endpoint the identification of maximum tolerated dose in operable GBM patients. A total dose of 30 Gy delivered in 5 fractions will be prescribed to planning target volume, with a simultaneous integrated boost dose escalation to gross tumor volume from 35 to 50 Gy, with 5 patients at each dose level. Dose to the next patient group will be escalated if toxicity target is met. The assumption is that not more than 30% of patients would present cumulative ≥G3 toxicity (CTCAE v5.0 scale) one month after the end of UHRT. A 30-patient sample size is predicted to result in a 2-sided 95% confidence interval with a width of 0.328 (0.136–0.464) when the sample proportion is 0.300. Four weeks after the end of UHRT, following a brain MRI, the lesion will be surgically removed. A peripheral blood sample will be taken before and after UHRT, up to 6 months, for immunophenotyping. Discussion: The study aims at evaluating MRI-guided dose escalation neoadjuvant UHRT-related toxicity along with potential improvements in overall- and disease-free survival. Other goals are to identify prognostic factors and monitor radiation-treatment related immune effects. An important expected benefit of the neoadjuvant UHRT is that it will shorten treatment time, improving patients’ quality of life, and facilitate access to specialized treatment centers. Neoadjuvant RT represents a paradigm shift in GBM, and implications for the scientific community should be significant. The study may help identify distribution patterns of aggressive radioresistant areas with a higher probability of recurrence, counteract intrinsic radioresistance, and identify immune correlates of therapeutic efficacy and/or biomarkers of treatment response/toxicity. Trial registration: The study was prospectively registered at clinicaltrials.gov (NCT06551909, 13/08/2024). Protocol version: Version 1.0, 17/06/2024.