Vascular and Circulating Blood Exposure to Proton or Photon Irradiation: Differentials in Lymphocyte Subset Metrics in Cancer Patients

Background/Objectives: Radiation-induced lymphopenia is consistently associated with adverse outcomes across solid tumours, yet the vascular compartment that carries the irradiated lym-phocyte pool is not common delineated during treatment planning. The VASA project makes blood vessels an explicit, measurable structure in that process. We report Phase II, relating dose–volume metrics computed on MRI-segmented vessels to serial immunophenotyping in patients treated with protons or photons. Methods: Forty-three patients treated between March 2021, and May 2022 were studied prospectively (35 proton, 8 photon). Flow-contrast three-dimensional MRI with three velocity-encoding directions was added to simulation; the sum-of-magnitude recon-struction was used for semi-automated vessel segmentation, and vessel masks were imported into the treatment planning system to generate dose–volume histograms. The effective dose to circu-lating immune cells (EDIC), the integral dose to vessels (IDVe) and the integral dose to target were computed. Blood was sampled at the start, middle and end of irradiation for lymphocyte counts and B, T and NK immunophenotyping. Results: EDIC and IDVe were higher with photons than protons (6.10 vs. 1.22 Gy; 3.6 vs. 0.5 Gy·L) and higher in patients who became lymphopenic than in those who did not (4.2 vs. 1.1 Gy; 2.7 vs. 0.37 Gy·L). Within the proton cohort, EDIC and IDVe increased from brain to head-and-neck to thorax–abdomen targets (0.80, 1.11 and 1.89 Gy; 0.15, 0.26 and 1.31 Gy·L; p < 0.05). Lymphocyte counts fell from 1.81 to 1.42 × 10³/µL overall (p < 0.05), with the lowest nadir in thorax–abdomen targets (0.90 × 10³/µL). B, T and NK subpopula-tions all declined; T and NK losses were greatest in head-and-neck targets. Conclusions: Vascular dose can be measured patient by patient and tracks both irradiation modality and the magnitude of lymphocyte depletion. Treating vessels and circulating blood as an organ at risk is feasible and offers a route to immune-sparing radiotherapy plan optimisation.