In this study, we found stage, pretreatment NLR, ALC nadir, and V20 of TVB to be independent predictors of survival outcomes for the locally advanced ESCC patients who underwent definitive chemoradiotherapy.
As the marker of inflammation and immunosuppression, pretreatment NLR and ALC nadir during treatment have been determined as prognostic factors in various solid tumors, in particular lung cancer(14-16).
In 2014, Tang et al. reported a dataset of 711 NSCLC patients who were treated with definitive radiotherapy and found lower lymphocytes nadirs and larger GTVs predicting worse outcomes(10).
Ryoko Suzuki et al(14) retrospectively reviewed the clinicopathologic and treatment characteristics of 252 patients with ES-SCLC. Multivariate analysis identified low TLC and high NLR before the treatment as predicting inferior survival. In recent preclinical study, the grade 4 lymphopenia seemed to predict the worse progression-free and overall survival in esophageal cancer cohort(17). In this study, we demonstrated that pretreatment NLR and ALC nadir during definitive RT were significantly associated with worse outcomes.
How does radiation give rise to lymphopenia? Previous preclinical and clinical studies have revealed that the radiation interacting with the host immune system through activating innate and adaptive antitumor immune responses(18, 19). However, the mechanism of immunosuppression contributing to radiation-induced lymphopenia remains unresolved. It may seem due to the greater lymphocyte’s exposure of disease sites and larger radiation portals.
The radiation of thoracic malignancies are often close to the heart, such as esophageal, lung and left-sided breast cancers which are encompassed in the radiation portal. Therefore, the increasing dose of heart doses, lung and esophageal would result in strong lymphopenia(6, 10, 20). RTOG 0617, a randomized phase III clinical trial, has also revealed the potential for radiation acts as a relevant factor reducing immune function. From a survey of patients who received concurrent CRT of locally advanced NSCLC, heart V5 and heart V30 were indicated as being predictors of outcomes. On multivariate analysis, the higher cardiac dose was related to poorer survival(21).
Another retrospective study of 117 patients who underwent definitive treatment for stage III NSCLC found that the EDRIC was the independent prognosticator of outcomes(13). We take the model of EDRIC for reference but did not obtain the same conclusions. In our study, EDRIC shows the statistically significant differences in univariate analysis only, not in the multivariate Cox regression. We suppose that there are two possible reasons: (1)when variables of TVB and EDRIC entered into Cox regression simultaneously, an interaction existed between them, which interferes with the outcome; (2) the relative contribution of EDRIC to outcome is likely to be relatively small compared with that of TVB in ESCC.
In addition to the above standpoint, the unintentional RT to lymph node basins and secondary lymphoid organs like bone marrow, thymus and other potential organs may cause lymphopenia, as these sites and the tumor itself are the key organs induced by a direct hit of lymphocytes by RT. The bone marrow, pelvis, cervical vertebrae and thoracic vertebrae are the top three sites of hematopoiesis by activating the proliferating bone marrow(16). Therefore, RT doses to pelvic, cervical, and thoracic vertebrae are potential drivers of BM suppression.
Several studies have confirmed that RT dose contributes to BM suppression in the pelvis(22, 23). Recently, a study of 201 patients with NSCLC and SCLC received definitive chemoradiation demonstrated increasing mean TVB dose and V5-V20 of TVB were correlated with higher odds of grade ≥3 hematologic toxicities(13). However, only logistic analyses were performed to explore the correlation of TVB dose with HT3+ in this study without direct evidence of TVB dose and the overall survival of patients who received CRT.
We assumed in the procedure of chemoradiotherapy that thoracic vertebrae dose correlates with ALC nadir due to immunosuppression. In this study, multiple regression analysis confirmed this hypothesis(V20 of TVB< 80% reduced the risk of ALC nadir＜0.3*109/L), and multivariate COX analyses have shown that V20 of TVB is an independent predictor for ESCC patients in our cohort. To my knowledge, this is the first study between vertebral dose and prognosis in esophageal cancer.
The present study did have several limitations. First, the retrospective study enrolled from a single center in China, so there exists a risk of bias in selection and information. Second, our patient cohort comprised only 99 patients, and we counted several radiation parameters including the Dmean and V5-50 of heart and Dmean and V5-30 of lungs but did not enter them into the Cox regression due to the small patient cohort. Finally, identifing the cut-off values of categorical data by using ROC curve analysis may not provide the most accurate results.
Thus, a larger, multi-institutional study is necessary to verify our results.
In conclusion, our study demonstrated that Dmean and V20 of TVB might be clinically useful to help to predict severe lymphopenia of patients of locally advanced ECSS receiving definitive radiotherapy. Increased V20 of TVB, as well as pretreatment NLR and decreased ALC nadir were associated with poorer clinical outcomes. Dmean of TVB below 28.49Gy and TVB V20≤80% are correlated with lower ALC nadir. Optimizing prescription or treatment planning approaches to minimize mean dose and V20 of TVB may improve outcomes.