P11.29.B WHOLE-BRAIN RADIATION THERAPY WITH DOSE ESCALATION ON MULTIPLE METASTASES, WITH AND WITHOUT HIPPOCAMPAL AVOIDANCE (HIPPORAD TRIAL)

Abstract BACKGROUND The HIPPORAD trial investigated a novel method of whole brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) with and without hippocampal avoidance in patients with multiple brain metastases. MATERIAL AND METHODS This was a prospective, multicenter, randomized, double-blind phase II clinical trial (DRKS00004598), conducted across 13 German centers. Patients with 4 to 10 brain metastases (≥5 mm in size) were randomly assigned (1: 1) to receive either hippocampal avoidance WBRT with SIB (HA-WBRT+SIB, Arm A) or standard WBRT with SIB without hippocampal sparing (Arm B). Treatment comprised WBRT with 30 Gy combined with SIB of 51 Gy directed at the metastases (42 Gy for lesions in the brainstem or surgical cavities), administered over 12 daily fractions. The primary outcome was the change in neurocognitive performance in the Verbal Learning and Memory Test (VLMT), assessed three months post-therapy. Secondary endpoints included neurocognitive function at 9 and 18 months, emotional wellbeing, quality of life, and oncological efficacy. RESULTS Between 02.08.2016-07.09.2021, 170 patients were enrolled and 136 randomized: 67 to HA-WBRT+SIB and 69 to WBRT+SIB. At the three-month evaluation, 38 patients in Arm A and 42 in Arm B were alive, treated per protocol, and included in the primary analysis. No significant difference in overall learning ability was observed between groups (p = 0.83). Both arms experienced a decline in VLMT scores at three months. At the nine-month mark, cognitive scores improved, with Arm A trending more favorably than Arm B. Notably, depression rates were significantly lower in the HA-WBRT+SIB group at both 3 (p = 0.047) and 18 months (p = 0.048). Arm A also exhibited a trend towards lower anxiety and higher emotional functioning. One year after treatment, the rate of distant intracranial progression was 22% in both groups, whereas local progression occurred in 4% of patients in Arm A and 12% in Arm B. Time to hippocampal metastases did not differ significantly (p = 0.98). Median overall survival was 9.1 months in the HA-WBRT+SIB arm und 6.6 months in the WBRT+SIB arm (p = 0.44). Neurological mortality at one year was 4% in arm A and 12% in arm B. Serious adverse events related to treatment were observed in 3% of Arm A patients and 6% of Arm B patients. CONCLUSION This is the first randomized trial to prove feasibility of HA-WBRT+SIB and suggest that it may reduce depressive symptoms in patients with multiple brain metastases. Verbal memory performance showed no significant difference, although patients receiving HA-WBRT+SIB exhibited a trend toward better recovery. HA-WBRT+SIB was well tolerated, maintained strong intracranial control, and was associated with very low neurological mortality.