Effective Dose to Lymphocytes Predicts Lymphopenia and May Predict Survival in Patients Treated with CROSS Regimen in Patients with Squamous Cell Carcinoma of Esophagus

Abstract

We hypothesized that radiation induced lymphopenia can be predicted by the effective dose to the circulating immune cells (EDIC) which can be computed by modelling the doses of the total body, lung and heart in advanced squamous cell esophageal cancer treated with trimodality therapy according to the Dutch CROSS trial regimen. To test this hypothesis, we considered circulating immune cells as an organ at risk and examined the effect of EDIC on the degree of lymphocyte drop (lymphocyte nadir) . We further explored the relationship between EDIC, lymphocyte nadir and overall survival (OS) in this group of patients. Patients with advanced non-metastatic squamous esophageal carcinoma treated in one single tertiary cancer center from 2012-2018 were eligible for this study. All patients must have RT plan available for EDIC computation and received neoadjuvant chemoRT according to Dutch CROSS trial regimen (5 weeks of weekly carboplatin AUC=2 and paclitaxel 50mg/m2, radiation dose: 41.4 Gy in 23 fractions) before a radical esophagectomy. All had weekly blood test available during and 2 months after chemoRT. We made assumptions that circulating immune cells received uniform dose for rapidly circulating ones (in heart, lung, and blood vessels) and those slow circulating ones (in lymphatic system, veins, and capillaries) inside irradiated volume. The EDIC was calculated as a function to lung, heart and total body integral doses with a verified mathematical model. Association between EDIC and lymphocyte nadir was studied, and the relationships of OS with lymphocyte nadir and EDIC were assessed using multivariant Cox regression model. This analysis included 92 eligible consecutive patients with 77 males and 15 females. The median age was 65.5 years (range 40-82). There were 1, 84, and 7 patients with stage II, III, and IV diseases, respectively. The mean PTV was 529 cc (95% CI220.5-837.5). The baseline lymphocyte was normal in 79 (86%) patients, reduced in 13 (14%) patients. The mean EDIC was 2.8 Gy (range 0.6-4.4). EDIC was found to be highly correlated with lymphocyte nadir (Spearman coefficient -0.505 p< 0.01) which was found to significantly independently associated with shorter OS (HR =0.63 p<0.001). Lymphocyte nadir was also the most significant factor in determining OS among other clinical parameters. It remained significant after adjusting for clinically significant factors Age. Exploratory analysis showed there was significant OS difference between EDIC groups (<2Gy, 2-4Gy and >4Gy). The 2-year OS rates were 66.7%, 42.7% and 16.7% for EDIC <2Gy, 2-4Gy and >4Gy respectively. Radiation dose to circulating immune cells was significantly associated with survival and lymphocyte nadir which was also a significant factor for overall survival in patients with advanced non-metastatic squamous cell cancer of esophagus. The result may advise plan optimization and further prospective study is warranted.