Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET
Authors: Olson Robert , Abraham Hadassah , Leclerc Curtis , Benny Alexander , Baker Sarah , Matthews Quinn , Chng Nick , Bergman Alanah , Mou Benjamin , Dunne Emma M. , Schellenberg Devin , Jiang Will , Chan Elisa , Atrchian Siavash , Lefresne Shilo , Carolan Hannah , Valev Boris , Tyldesley Scott , Bang Andrew , Berrang Tanya , Clark Haley , Hsu Fred , Louie Alexander V. , Warner Andrew , Palma David A. , Howell Doris , Barry Aisling , Dawson Laura , Grendarova Petra , Walker Debra , Sinha Rishi , Tsai Jillian , Bahig Houda , Thibault Isabelle , Koul Rashmi , Senthi Sashendra , Phillips Iain , Grose Derek , Kelly Paul , Armstrong John , McDermott Ronan , Johnstone Candice , Vasan Srini , Aherne Noel , Harrow Stephen , Liu Mitchell 
Published: February 2024

Abstract
Background
Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience.

Methods
This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival.

Discussion
This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone.

Trial registration
Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.