OligoCare TwiCs (Trials Within Cohorts) Trial Comparing Acute Toxicity in Single-fraction vs Multiple-fraction SBRT for Metastasis-directed Treatment (SPRINT)

The goal of this clinical trial is to evaluate single-fraction metastases-directed SBRT in the broader radiation oncology community and to compare its safety and efficacy profile with the current Standard of Care (SoC) of multiple-fraction SBRT in patients with oligometastatic disease of primary breast, prostate, NSCLC and colorectal cancer having all lesions that will be treated with radical radiotherapy amenable to single-fraction SBRT. The main question/hypothesis this clinical trial aims to answer is: \- Single-fraction SBRT has comparable outcomes as those obtained with multiple fraction SBRT, both in terms of safety and efficacy. Patients from the OligoCare cohort will be randomized to receive either single-fraction SBRT or the current SoC of multiple-fraction SBRT.

As a consequence of improved survival of metastatic cancer patients due to more effective systemic therapy, focused radiotherapy in the form of stereotactic body radiotherapy (SBRT) has become a standard of care in many clinical situations to achieve durable symptom and / or metastasis control: treatment of brain metastases, of painful bone or spinal metastases and especially as local treatment in a multimodality treatment strategy for oligometastatic disease. These indications are supported by international practice guidelines, e.g. ESMO guidelines for NSCLC and colorectal cancer; and NCCN guidelines for NSCLC, prostate cancer, renal cell cancer, colorectal cancer and sarcoma. However, despite the universal use of SBRT in the local treatment of oligometastases, the level of evidence supporting stereotactic radiotherapy is low, apart from few small prospective clinical trials showing a very favourable toxicity profile of SBRT and promising efficacy data. In this context, the OligoCare research project, a prospective observational cohort study, has been developed within the E²-RADIatE platform. The aim of this project is to collect real-world data on SBRT treatment of patients with oligometastatic disease of primary breast, prostate, lung and colorectal cancer, with no limit on the maximum number of treated metastases. Yet, the local treatment of multiple metastases poses several challenges. One of them is the integration of local metastases-directed SBRT into a systemic treatment strategy: in an interim analysis of the OligoCare cohort, almost all patients were treated with fractionated SBRT and the median number of SBRT fractions was 5. This would result in a total of 50 SBRT fractions in a patient with 10 metastases. Considering that several drugs are paused before and after SBRT, the systemic therapy free interval could last for almost 2 months, which one could consider as unacceptably long in metastatic cancer patients. One solution to this problem would be the delivery of radiotherapy in a smaller number of SBRT fractions, preferably as single-fraction SBRT. Single-fraction SBRT has been described since the 90's for treatment of liver metastases, lung metastases or vertebral metastases. A recent randomized phase II trial compared multiple-fraction vs single-fraction SBRT for pulmonary oligometastases (n=90) and did not observe differences in toxicity or any oncological outcome parameter. Nevertheless, single-fraction SBRT still lacks adoption in the radiation oncology community. Likely reasons are the experience of single-fraction SBRT restricted to small, highly specialized centers, the small number of patients treated with single-fraction SBRT in the literature and the concerns of potentially increased toxicity and / or decreased efficacy. There is consequently a strong rationale to implement and evaluate single-fraction metastases-directed SBRT in the broader radiation oncology community and to compare its safety and efficacy profile with the current SoC of multiple-fraction SBRT. This question will be addressed in the current Trials within Cohorts (TwiCs) study, in which patients from the OligoCare cohort will be randomized to receive either single-fraction SBRT or the current SoC of multiple-fraction SBRT. The main hypothesis is that single-fraction SBRT has comparable outcomes as those obtained with multiple fraction SBRT, both in terms of safety and efficacy.