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Simple Summary: The N staging system for Nasopharyngeal Carcinoma (NPC) is constantly improving for better survival risk stratification with accumulating clinical evidence. Discovering new prognostic factors often depends on clinical observations, which often lack comprehensiveness and precision. This study aimed to propose new quantitative spatial characterizations of LN tumor and demonstrate their feasibility of improving N stage. Independent anatomical prognostic factors were discovered and achieved superior risk stratification performance when combined with N stage. This quantitative approach could be applied to other cancer sites to discover new prognostic or predictive factors and ultimately benefit precision medicine. This study aims to investigate the feasibility of improving the prognosis stratification of the N staging system of Nasopharyngeal Carcinoma (NPC) from quantitative spatial characterizations of metastatic lymph node (LN) for NPC in a multi-institutional setting. A total of 194 and 284 NPC patients were included from two local hospitals as the discovery and validation cohort. Spatial relationships between LN and the surrounding organs were quantified by both distance and angle histograms, followed by principal component analysis. Independent prognostic factors were identified and combined with the N stage into a new prognostic index by univariate and multivariate Cox regressions on disease-free survival (DFS). The new three-class risk stratification based on the constructed prognostic index demonstrated superior cross-institutional performance in DFS. The hazard ratios of the high-risk to low-risk group were 9.07 (p < 0.001) and 4.02 (p < 0.001) on training and validation, respectively, compared with 5.19 (p < 0.001) and 1.82 (p = 0.171) of N3 to N1. Our spatial characterizations of lymph node tumor anatomy improved the existing N-stage in NPC prognosis. Our quantitative approach may facilitate the discovery of new anatomical characteristics to improve patient staging in other diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]