BACKGROUND:The current study was aimed at investigating the feasibility of hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost (HA-WBRT+SIB) for metastases and at assessing tumor control in comparison with conventional whole-brain radiation therapy (WBRT) in patients with multiple brain metastases. METHODS: Between August 2012 and December 2016, 66 patients were treated within a monocentric feasibility trial with HA-WBRT+SIB: hippocampus-avoidance WBRT (30 Gy in 12 fractions, dose to 98% of the hippocampal volume ≤ 9 Gy) and a simultaneous integrated boost (51 or 42 Gy in 12 fractions) for metastases/ resection cavities. Intracranial tumor control, hippocampal failure, and survival were subsequently compared with a retrospective cohort treated with WBRT via propensity score matching analysis. RESULTS: After 1:1 propensity score matching, there were 62 HA-WBRT+SIB patients and 62 WBRT patients. Local tumor control (LTC) of existing metastases was significantly higher after HA-WBRT+SIB (98% vs 82% at 1 year; P = .007), whereas distant intracranial tumor control was significantly higher after WBRT (82% vs 69% at 1 year; P = .016); this corresponded to higher biologically effective doses. Intracranial progression-free survival (PFS; 13.5 vs 6.4 months; P = .03) and overall survival (9.9 vs 6.2 months; P = .001) were significantly better in the HA-WBRT+SIB cohort. Four patients (6.5%) developed hippocampal metastases after hippocampus avoidance. The neurologic death rate after HA-WBRT+SIB was 27.4%. CONCLUSIONS: HA-WBRT+SIB can be an efficient therapeutic option for patients with multiple brain metastases and is associated with improved LTC of existing metastases, higher intracranial PFS, a reduction of the neurologic death rate, and an acceptable risk of radiation necrosis. The therapy has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicenter, phase 2 HIPPORAD trial. Cancer 2020;126: 2694-2703.

Background: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). Methods: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging

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