Hypofractionated Stereotactic Radiotherapy vs. Single Fraction Stereotactic Radiosurgery to the Resection Cavity of Brain Metastases after Surgical Resection (SATURNUS trial): A Prospective, Randomized Phase III Trial

Abstract

The brain is a common site for metastases. Resection of large or symptomatic metastases is followed by stereotactic radiotherapy to prevent local recurrence. The optimal fractionation scheme is subject of ongoing research. Supported by emerging retrospective data, we hypothesize that hypofractionated stereotactic radiotherapy (HFSRT) is superior to single-fraction stereotactic radiosurgery (SRS) in terms of local control (LC). We designed the SATURNUS trial to prospectively demonstrate the superiority of HFSRT over SRS after resection of brain metastases in terms of LC. The SATURNUS trial is a prospective, randomized phase III trial, currently recruiting patients at a single institution. Patients are 1:1 allocated to HFSRT or SRS using permuted block randomization. Affiliation to the treatment arm is solely blinded to the neuroradiologist assessing therapy response. HFSRT will be delivered with 6 - 7 x 5 Gy and SRS with 1 x 12-20 Gy, prescribed to the surrounding isodose, depending on cavity size and proximity to structures at risk. For SRS, doses do not exceed the maximum doses according to RTOG 90-05. Case number calculation was based on own institutional data on HFSRT (mean LC rate of 88% at 12 months) and data from large phase III trials on SRS (pooled mean LC rate of 66% at 12 months). Using a Chi-squared test of equal proportions (odds ratio = 1), setting test significance level (α) to 0.05, and allocating an equal number of patients to both treatment arms, 114 patients are needed to detect the superiority of HFSRT in terms of LC at 12 months (primary endpoint) with a power of at least 80%. Estimating a dropout rate of 10%, the case number was set to 126. The trial was registered with clinicaltrials.gov (NCT05160818). The first patient was enrolled in May 2021 and recruitment is ongoing. Patients with up to three resected brain metastases are considered for study participation. Further eligibility criteria are histologically confirmed solid tumor disease, resection cavity diameter ≤ 4 cm, consent to perform adjuvant radiotherapy by an interdisciplinary tumor board, completed wound healing, resection within the last six weeks at the time of study inclusion, age ≥ 18 years, KPS ≥ 60%, adequate contraceptive measures for fertile women / men and written informed consent. Patients are followed up clinically and with MRI at 6 weeks and 3, 6, 9 and 12 months after treatment. LC is assessed according to RANO-BM. Toxicity (CTCAE v4.03) is assessed as a secondary endpoint. The rather broad dose corridors allowed within the trial do justice to clinical reality, however, may represent a limitation of the trial. They are therefore addressed with a predefined subgroup analysis, as will be cavity size, among others. Participation of further study centers is desired. To the best of our knowledge, the SATURNUS trial is the only randomized phase III trial adequately powered to detect the superiority of HFSRT over SRS with regard to LC for resected brain metastases. To be determined. To be determined.