Hippocampal-avoidance whole-brain radiotherapy with dose escalation on metastases: A prospective randomized trial (HIPPORAD).

2038 Background: The HIPPORAD trial aimed to evaluate a new method of whole brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) to the metastases, with versus without hippocampal avoidance in patients with brain metastases. Methods: We conducted a prospective, multicentre, randomised, double-blind trial (DRKS00004598). Patients with 4-10 brain metastases > = 5mm were randomised at 13 centres in Germany 1:1 between WBRT+SIB with hippocampus avoidance (HA-WBRT+SIB) (arm A) and WBRT+SIB (arm B). Patients and assessors of outcome were blinded to the randomised arm. All patients received WBRT with 30 Gy and SIB with 51 Gy or 42 Gy in 12 fractions, 5x/week. The primary endpoint was the change in neurocognitive function (assessed by the Verbal Learning and Memory Test [VLMT]) 3 months after treatment. Secondary endpoints included neurocognitive changes at 9 and 18 months, development of anxiety and depression, quality of life and measures of oncological outcome. Results: Between August 2 nd , 2016 and September 7 th , 2021, 170 patients were recruited and 136 were randomised between HA-WBRT+SIB (n = 67) and WBRT+SIB (n = 69). Of these, 38 patients in arm A and 42 in arm B were known to be alive 3 months after treatment and were included in the primary endpoint analysis. The change in overall learning performance at 3 months was not significantly different between arms (p = 0.83). VLMT-scores decreased after 3 months, but improved at 9 and 18 months, with HA-WBRT+SIB showing an overall superior trend over WBRT+SIB. At 18 months, VLMT-scores improved to values above baseline in both arms. Patients treated with HA-WBRT+SIB had significantly less depression compared to patients treated with WBRT+SIB at 3 (p = 0.047) and 18 months (p = 0.048). The 12-month-tumor control for boosted metastases was 96% in Arm A and 88% in Arm B, while for the WBRT area it was 78% in both arms. Time to hippocampal tumour progression was comparable between arms (p = 0.98). After 12 months, 4% of patients in arm A and 12% in arm B had suffered neurological death. Conclusions: To our knowledge, this is the first prospective trial to show that hippocampal avoidance during WBRT leads to significantly lower rates of depression. The development of VLMT values after HA-WBRT+SIB and WBRT+SIB with 30 Gy in 2.5 Gy-fractions was comparable and a good recovery was observed at 18 months in both arms. The method showed a considerably higher intracerebral tumour control with lower neurological mortality rates compared to historical cohorts. Clinical trial information: DRKS00004598 .