The 8 edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of non-anatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with non-metastatic NPC treated with radical IMRT +/- chemotherapy based on the 8 edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma EBV DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. 5-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066, and p = 0.002 respectively). RPA derived 4 new stages: RPA-I (T1-T4N0-N2 & EBV DNA <500 copies/ml) (PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4N0-N2 & EBV DNA ≥500 copies/ml) (PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2N3) (PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4N3) (PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2N0-N2; II: T3-T4N0-N2 or T1-T2N3, and III: T3-T4N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the 8 edition TNM and the AHR stage groups. This article is protected by copyright. All rights reserved.

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Purpose We hypothesized that radiation-induced lymphopenia could be predicted by the effective dose to the circulating immune cells (EDIC) in advanced esophageal squamous cell carcinoma treated with trimodality therapy according to the Dutch ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial regimen. To test this hypothesis, we examined the effect of EDIC on the degree of lymphocyte drop (lymphocyte nadir). Methods and Materials Patients with advanced nonmetastatic esophageal squamous cell carcinoma treated in a single tertiary cancer center from 2012 to 2018 were eligible for this study. All patients had to have a radiation therapy plan available for EDIC computation and received neoadjuvant chemoradiation according to the Dutch CROSS trial regimen before radical esophagectomy. The EDIC was calculated as a function of integral doses to the lung, heart, and total body with a verified mathematical model. The association between EDIC and lymphocyte nadir was studied, and the relationships of overall survival (OS) with lymphocyte nadir and EDIC were assessed using multivariable Cox regression model. Results This analysis included 92 eligible consecutive patients (77 men and 15 women). The mean EDIC was 2.8 Gy (range, 0.6-4.4). EDIC was significantly correlated with lymphocyte nadir (Spearman coefficient = –0.505; P < .01), and lymphocyte nadir was a significant independent factor for shorter OS (hazard ratio = 0.63; P < .001). Lymphocyte nadir was also the most significant factor in determining OS among other clinical parameters. Exploratory analysis showed significant OS differences between EDIC groups (<2, 2-4, and >4 Gy). The 2–year OS rates were 66.7%, 42.7%, and 16.7% for EDIC <2, 2 to 4, and >4 Gy, respectively. Conclusions There was a significant correlation between radiation dose to circulating immune cells and lymphocyte nadir, which in turn affected OS in patients with advanced nonmetastatic esophageal squamous cell carcinoma treated by trimodality therapy.