Functional lung avoidance and response-adaptive escalation (FLARE) RT: Multimodality plan dosimetry of a precision radiation oncology strategy.

PURPOSE: Nonsmall cell lung cancer (NSCLC) patient radiation therapy (RT) is planned without consideration of spatial heterogeneity in lung function or tumor response. We assessed the dosimetric and clinical feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [99m Tc]MAA-SPECT/CT perfused lung while redistributing an escalated boost dose within [18 F]FDG-PET/CT-defined biological target volumes (BTV).
METHODS: Eight stage IIB-IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain < 20 Gy mean lung dose (MLD). Prescriptions included 60 Gy to the planning target volume (PTV) and concomitant boost of 74 Gy mean to biological target volumes (BTV = GTV + PET gradient segmentation) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial treatment planning systems via uptake threshold discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with volumetric modulated arc therapy (VMAT), proton pencil beam scanning (PBS) with 3%-3 mm robust optimization, and combination of PBS (avoidance) plus VMAT (escalation). The high boost dose region was evaluated within a standardized SUVpeak structure. FLARE RT plans were compared to reference VMAT plans. Linear regression between radiation dose to BTV and normalized FDG PET SUV at every voxel was conducted, from which Pearson linear correlation coefficients and regression slopes were extracted. Spearman rank correlation coefficients were estimated between radiation dose to lung and normalized SPECT uptake. Dosimetric differences between treatment modalities were evaluated by Friedman nonparametric paired test with multiple sampling correction.
RESULTS: No unacceptable violations of PTV and normal tissue objectives were observed in 24 FLARE RT plans. Compared to reference VMAT plans, FLARE VMAT plans achieved a higher mean dose to BTV (73.7 Gy 98195. 61.3 Gy), higher mean dose to SUVpeak (89.7 Gy vs. 60.8 Gy), and lower mean dose to highly perfused lung (7.3 Gy vs. 14.9 Gy). These dosimetric gains came at the expense of higher mean heart dose (9.4 Gy vs. 5.8 Gy) and higher maximum cord dose (50.1 Gy vs. 44.6 Gy) relative to the reference VMAT plans. Between FLARE plans, FLARE VMAT achieved higher dose to the SUVpeak ROI than FLARE PBS (89.7 Gy vs. 79.2 Gy, P = 0.01), while FLARE PBS delivered lower dose to lung than FLARE VMAT (11.9 Gy vs. 15.6 Gy, P < 0.001). Voxelwise linear dose redistribution slope between BTV dose and FDG PET uptake was higher in magnitude for FLARE PBS + VMAT (0.36 Gy per %SUVmax ) compared to FLARE VMAT (0.27 Gy per %SUVmax ) or FLARE PBS alone (0.17 Gy per %SUVmax ).
CONCLUSIONS: FLARE RT is clinically feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG PET dose escalation balanced target and normal tissue objective tradeoffs. These results provide a technical platform for testing of FLARE RT safety and efficacy within a precision radiation oncology trial.