Time to abandon single-site irradiation for inducing abscopal effects

Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether.