Developing a CBCT-Guided Online Adaptive Radiotherapy Approach for Isotoxic Delivery of Ultra-High Dose to Oligometastatic Disease in Combination with Immunotherapy

Abstract

<h3>Purpose/Objective(s)</h3> A Phase I trial combining stereotactic body radiotherapy (SBRT), 45Gy in 3 fractions(fx), with pembrolizumab was safe (9% grade 3 toxicity) with promising local control and overall survival. Whether SBRT dose escalation can improve outcomes is uncertain. A subsequent planning study showed feasibility of ultra-high SBRT dose, 90Gy in 3fx, while respecting organ at risk (OAR) tolerances. However, due to patient anatomy interfractional uncertainty, online adaptation may enhance safety/efficacy. This work develops a CBCT-guided adaptive radiotherapy approach for isotoxic treatment with ultra-high doses using retrospective data and simulated online adaptation. <h3>Materials/Methods</h3> Patient data from 15 subjects of the original Phase I trial were used (gross tumor volume (GTV) mean volume 177cc; range 67-390cc). Disease sites were liver(n=8), pelvis(n=4), abdomen(n=2), lung(n=1). Clinical prescriptions were to 65cc subvolumes of the GTV (SubGTV). In the adaptive setting, rather than define a specific sub volume, OAR expansions based on tolerance and achievable dose gradients were cropped from GTV so that the SubGTV receiving ultra-high dose adapts to changing anatomy. Initial 6 arc VMAT plans used a clinical goal based automated plan optimization platform. High priority was given to critical OAR Dmax goals, medium priority was given to GTV coverage (V90Gy) and OAR volumetric constraints. SubGTV core was defined with further contraction away from OARs with low priority goals to ensure a centralized GTV hot spot. For a subset of patients (8 total: 3 liver, 2 abdomen, 2 pelvis, 1 lung), an online adaptive session using clinical CBCTs was simulated with anatomy recontoured for plan reoptimization/evaluation and comparison of adapted (ADP) vs. scheduled (SCH) plans. <h3>Results</h3> For initial plans, all OAR goals were satisfied. The average GTV V90Gy was 80.8cc/57.3% (range: 53.8-144.5cc/24.4-99.1%). In online adaptive sessions, the ADP plan was preferred over the SCH plan in 7 of 8 cases. ADP plans generally had superior coverage (average GTV V90Gy of 86.3cc (ADP) vs. 77.9cc (SCH)). ADP plans nearly always met OAR tolerances (one minor exception: skin D0.03cc (tolerance of 11.0Gy/fx) was 11.5Gy (ADP) vs. 11.9Gy (SCH)). In contrast, SCH plans often did not meet OAR constraints, with critical violations to bowel (n=2), stomach(n=3), duodenum(n=1), inferior vena cava(n=1) as well as violations to skin(n=3) and bone(n=2). <h3>Conclusion</h3> This work develops a paradigm for true isotoxic radiotherapy treatment maximizing ablative target doses using CBCT-guided online adaptive SBRT. A forthcoming phase I trial will investigate potential clinical benefit from escalation to ultra-high doses. As adaptive technologies evolve, the OAR-guided isotoxic approach developed here may be an important future direction for radiation oncology. NCT02608385