Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617

Simple Summary Emerging evidence indicates that the immune system plays an important role in controlling tumors during radiotherapy, and radiation-induced immune toxicity such as lymphopenia is associated with poor survival. However, the immune system is not considered as a critical organ at risk in radiotherapy partially because the radiation dose to the immune system is difficult to compute. In this study, we developed a model to compute the radiation dose to the circulating blood, which contains the majority of active immune cells. We then validated this model by examining the correlations of the blood dose with treatment outcome for patients enrolled in the NRG/RTOG0617 phase III clinical trial. We demonstrated that the blood dose was significantly and independently associated with overall survival and local progression-free survival. This result suggests that radiation dose to circulating immune cells is critical for tumor control, and decreasing the dose to the immune system has the potential to improve survival. Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC-survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1-12.2 Gy) and 6.3 Gy (2.1-11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6-8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.