An International Consensus on the Design of Prospective Clinical–Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer

SIMPLE SUMMARY: Spatially fractionated radiation therapy (SFRT) delivers intentionally heterogenous dose to tumors. This is a major departure from current radiation therapy, which strives for uniform dose. Early pilot experience suggests promising treatment outcomes with SFRT in patients with challenging bulky tumors, including gynecologic cancer. Well-conducted prospective multi-institutional clinical trials are now needed to further test SFRT as a treatment modality. However, clinical trial development is hampered by the variabilities in SFRT approach and the overall unfamiliarity with heterogeneous dosing. A broad consensus among SFRT experts, potential investigators, and the wider radiation oncology community is needed so that clinical trials in SFRT can be successfully designed and carried out. We developed an international consensus guideline for the design parameters of clinical/translational trials in SFRT for gynecologic cancer. High-to-moderate consensus was achieved, and harmonized fundamental design parameters for SFRT trials in advanced gynecologic cancer were defined. ABSTRACT: Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.