The role of spleen radiomics model for predicting prognosis in esophageal squamous cell carcinoma patients receiving definitive radiotherapy.

BACKGROUND: The spleen plays an important role in systemic antitumor immune response, but whether spleen imaging features have predictive effect for prognosis and immune status was unknown. The aim of this study was to investigate computed tomography (CT)-based spleen radiomics to predict the prognosis of patients with esophageal squamous cell carcinoma (ESCC) underwent definitive radiotherapy (dRT) and to try to find its association with systemic immunity. METHODS: This retrospective study included 201 ESCC patients who received dRT. Patients were randomly divided into training (n = 142) and validation (n = 59) groups. The pre- and delta-radiomic features were extracted from enhanced CT images. LASSO-Cox regression was used to select the radiomics signatures most associated with progression-free survival (PFS) and overall survival (OS). Independent prognostic factors were identified by univariate and multivariate Cox analyses. The ROC curve and C-index were used to evaluate the predictive performance. Finally, the correlation between spleen radiomics and immune-related hematological parameters was analyzed by spearman correlation analysis. RESULTS: Independent prognostic factors involved TNM stage, treatment regimen, tumor location, pre- or delta-Rad-score. The AUC of the delta-radiomics combined model was better than other models in the training and validation groups in predicting PFS (0.829 and 0.875, respectively) and OS (0.857 and 0.835, respectively). Furthermore, some spleen delta-radiomic features are significantly correlated with delta-ALC (absolute lymphocyte count) and delta-NLR (neutrophil-to-lymphocyte ratio). CONCLUSIONS: Spleen radiomics is expected to be a useful noninvasive tool for predicting the prognosis and evaluating systemic immune status for ESCC patients underwent dRT.

Abdominal lymph node metastasis in non-surgical esophageal squamous cell carcinoma: prognostic significance and a novel staging strategy.

Purpose: This study aimed to evaluate the feasibility of a combination of abdominal lymph node (LN) metastasis and the number of LNs in esophageal squamous cell carcinoma (ESCC) patients to optimize its clinical nodal staging. Methods: A retrospective study, including a total of 707 ESCC patients treated with definitive radiotherapy, was conducted at two participating institutes. Different combinations of LN variables, including abdominal LN metastasis (R1: no-abdominal LN metastasis; R2: abdominal LN metastasis), were further analyzed to propose a potential revised nodal (rN) staging. Results: The multivariate analyses showed that the number of metastatic LN and abdominal LN metastasis were independent prognostic factors for the overall survival (OS). The results showed no significant differences in the OS between the N2 patients with abdominal LN metastasis and N3 patients. The OS of the stage III patients with abdominal LN metastasis was not significantly different from those with stage IVa. The N3R1 and N1-2R2 had similar hazard ratios (HRs). The N1R1 subset was defined as rN1, the N2R1 subset was defined as rN2, and the N3R1-2 and N1-2R2 subsets were defined as rN3. The HRs of OS of the rN2 and rN3 groups increased subsequently. The rN stage could identify the differences in the OS times of each subgroup based on the 8th AJCC cN staging or the 11th JES N staging. Conclusions: The rN staging, including the number of metastatic LNs and abdominal LN metastasis, might serve as a potential prognostic predictor for non-surgical patients with ESCC.

Lymph node metastasis is not associated with survival in patients with clinical stage T4 esophageal squamous cell carcinoma undergoing definitive radiotherapy or chemoradiotherapy.

Background: Clinical T4 stage (cT4) esophageal tumors are difficult to be surgically resected, and definitive radiotherapy (RT) or chemoradiotherapy (dCRT) remains the main treatment. The study aims to analyze the association between the status of lymph node (LN) metastasis and survival outcomes in the cT4 stage esophageal squamous cell carcinoma (ESCC) patients that underwent treatment with dCRT or RT. Methods: This retrospective study analyzed the clinical data of 555 ESCC patients treated with dCRT or RT at the Shandong Cancer Hospital and the Liaocheng People's Hospital from 2010 to 2017. Kaplan-Meier and Cox regression analyses was performed to determine the relationship between LN metastasis and survival outcomes of cT4 and non-cT4 ESCC patients. The chi-square test was used to evaluate the differences in the local and distal recurrence patterns in the ESCC patients belonging to various clinical T stages. Results: The 3-year survival rates for patients with non-cT4 ESCC and cT4 ESCC were 47.9% and 30.8%, respectively. The overall survival (OS) and progression-free survival (PFS) rates were strongly associated with the status of LN metastasis in the entire cohort (all P < 0.001) and the non-cT4 group (all P < 0.001) but not in the cT4 group. The local recurrence rates were 60.7% for the cT4 ESCC patients and 45.1% for the non-cT4 ESCC patients (P < 0.001). Multivariate analysis showed that clinical N stage (P = 0.002), LN size (P = 0.007), and abdominal LN involvement (P = 0.011) were independent predictors of favorable OS in the non-cT4 group. However, clinical N stage (P = 0.824), LN size (P = 0.383), and abdominal LN involvement (P = 0.337) did not show any significant correlation with OS in the cT4 ESCC patients. Conclusions: Our data demonstrated that the status of LN metastasis did not correlate with OS in the cT4 ESCC patients that received dCRT or RT. Furthermore, the prevalence of local recurrence was higher in the cT4 ESCC patients.

A nomogram for the predicting of survival in patients with esophageal squamous cell carcinoma undergoing definitive chemoradiotherapy.

BACKGROUND: Definitive chemoradiotherapy (dCRT) is widely accepted for esophageal squamous cell carcinoma (ESCC), although the outcomes can vary. Therefore, we aimed to develop a nomogram for the pre-treatment prediction of survival after dCRT for ESCC. METHODS: This retrospective study evaluated 204 patients (169 patients in a primary cohort and 35 patients in a validation cohort) who received dCRT for ESCC between July 2013 and June 2017. RESULTS: Pre-treatment parameters that predicted long-term survival in this setting were body mass index (BMI), absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), wall thickness, concurrent chemoradiotherapy, radiotherapy modality, and American Joint Committee on Cancer (AJCC) stage. The nomogram incorporated these factors and provided C-index values of 0.691 [95% confidence interval (CI): 0.641-0.740] in the primary cohort and 0.816 (95% CI: 0.700-0.932) in the validation cohort. The calibration curve analysis revealed that the nomogram had good ability to predict 2-year progression-free survival (PFS). The nomogram also performed better than the AJCC staging system by the C-index values (0.691 vs. 0.560) and the area under the curve values (0.702 vs. 0.576). Decision curve analysis (DCA) also indicated that the nomogram had better clinical utility. CONCLUSIONS: These results suggest that pre-treatment parameters may help predict the efficacy of dCRT for ESCC. Furthermore, as the nomogram provided better prognostic accuracy than the AJCC staging system, the nomogram may be useful in clinical practice for prognostication among patients who are going to receive dCRT for ESCC.

Clinical response to chemoradiotherapy in esophageal carcinoma is associated with survival and benefit of consolidation chemotherapy.

PURPOSE: Few studies have reported the impact of the clinical response of patients with Esophageal Carcinoma to chemoradiotherapy (CRT). Our study examines the association between clinical response and pretreatment variables, survival, patterns of failure, and benefit of consolidation chemotherapy in subjects with esophageal squamous cell carcinoma (ESCC) patients receiving CRT. METHODS: Data from ESCC patients treated at Shandong Cancer Hospital between January 2013 and December 2016 were analyzed retrospectively. By definition, we considered a poor response as progressive disease (PD) and stable disease (SD), while complete response (CR) and partial response (PR) were considered as a good response. Multivariate analyses were carried out using Cox proportional hazards models and patient survival was assessed using the Kaplan-Meier and log-rank test. RESULTS: After CRT, 136 (48.9%) patients responded well (good response) and 152 (51.1%) patients responded poorly (poor response). Overall survival (OS) and progression-free survival (PFS) differed significantly between patients responded well and those responded poorly. Patients with an early-stage or the upper location of the tumor were more likely to achieve a good response. Patients showing poor responses tended to experience local failure. The 3-year OS and PFS rates of patients showing poor response were 38.9% and 25.5%, respectively, for the CRT with consolidation chemotherapy (CRT + C) group, and 22.7% and 16.7%, respectively, for the CRT group. However, patients with a good response did not benefit from the consolidation chemotherapy. Primary tumor location, T category, N category, and clinical response to chemoradiotherapy were independent factors predicting OS and PFS in ESCC. CONCLUSION: Clinical response to CRT substantially improves patient survival and is associated with failure patterns in ESCC. Consolidated chemotherapy may benefit patients with a poor response.

Low Lymphocyte Count Is Associated With Radiotherapy Parameters and Affects the Outcomes of Esophageal Squamous Cell Carcinoma Patients.

Purpose: Lymphocytes are central players in systemic anti-tumor immune responses. In this study, we aimed to identify the relationship between absolute lymphocyte count (ALC) nadir during definitive radiotherapy (RT) and survival outcomes in patients with esophageal squamous cell carcinoma (ESCC), as well as evaluate the effect of RT parameters on ALC during RT. Materials and methods: We retrospectively reviewed 189 patients with stage I-IVA ESCC, who were treated with definitive RT at a single institution between 2012 and 2015. ALC values were assessed before, weekly during RT, and 1 month after the end of RT. Kaplan-Meier and Cox regression analyses were used to evaluate the relationship between ALC nadir during RT and patient outcomes. Predictors of low ALC nadir were assessed using univariate and multivariate logistic regression analyses. Results: The median ALC before treatment was 1.73 × 103 cells/µL. Fifty-eight (58.2) percent of the patients exhibited low ALC nadir (≤ 0.38 × 103 cells/µL) during RT. A low ALC nadir during RT was significantly associated with poor OS, PFS, and LRFS. The planning target volume (PTV) was larger in patients with low ALC nadir compared with patients with high ALC nadir (418.5 vs. 347.7 cm3, P = 0.023). Multivariate logistic regression analysis revealed that tumor stage III-IVA (P = 0.002), low ALC before treatment (P = 0.028), large Log10(PTV) (P = 0.01), high heart V10 (P = 0.003), and high heart V20 (P = 0.028) were associated with low ALC nadir during RT. Conclusions: In ESCC patients who received definitive RT, a low ALC nadir during RT was associated with large PTVs, and it was an independent prognostic factor of outcomes.

A review of radiation-induced lymphopenia in patients with esophageal cancer: an immunological perspective for radiotherapy.

Radiotherapy is a frequently utilized therapeutic modality in the treatment of esophageal cancer (EC). Even though extensive studies are carried out in radiotherapy for EC, the design of the clinical target volume and the radiation dose is not satisfactorily uniform. Radiotherapy acts as a double-edged sword on the immune system; it has both an immunostimulatory effect and an immunosuppressive effect. Radiation-induced lymphopenia and its potential association with tumor control and survival outcomes remain to be understood. The advent of immunotherapy has renewed the focus on preserving a pool of functioning lymphocytes in the circulation. In this review, we summarize the potential impact mechanisms of radiotherapy on peripheral blood lymphocytes and the prognostic role of radiation-induced lymphopenia in patients with EC. We also propose the concept of organs-at-risk of lymphopenia and discuss potential strategies to mitigate its effects on patients with EC. From an immunological perspective, we put forward the hypothesis that optimizing radiation modalities, radiation target volume schemes, and radiation doses could help to reduce radiation-induced lymphopenia risks and maximize the immunomodulatory role of radiotherapy. An optimized radiotherapy plan may further enhance the feasibility and effectiveness of combining immunotherapy with radiotherapy for EC.

The Prognostic Significance of Metastatic Nodal Size in Non-surgical Patients With Esophageal Squamous Cell Carcinoma.

Background: The present study aimed to determine the prognostic value of the size of metastatic lymph node (LN) in non-surgical patients with esophageal squamous cell carcinoma (ESCC). Methods: Three hundred seventy-six ESCC patients treated with definitive (chemo-) radiotherapy from January 2013 to March 2016 were reviewed. We analyzed potential associations of metastatic nodal size with responses, patterns of failure, and survival. Log-rank testing and Cox proportional hazards regression models were used to assess the impact of the clinical factors on survival. Results: The 3-years over survival (OS) rates following a median follow-up of 28.2 months were 53.2, 46.2, 35.5, and 22.7% for the N0 group, the >0.5 to ≤1 cm group, the >1 to ≤2 cm group, and the >2 cm group, respectively. The progression-free survival (PFS) rates for 2 years were 50.9, 44.2, 26.6, and 23.4% for the N0 group, the >0.5 to ≤1 cm group, the >1 to ≤2 cm group, and the >2 cm group, respectively. The objective response rates (ORR) for the 280 patients with metastatic LNs were 43.1% for the LN >0.5 to ≤1 cm group, 46.9% for the LN >1 to ≤2 cm group, and 25.5% for the LN ≥2 cm group. The LN >2 cm group had the worst ORR of the three groups with LNs. Gross tumor volume (GTV) failure was the most common failure pattern, followed by distant failure and out of GTV LN failure, with incidences of 47.9% (180 of 376), 42% (158 of 376), and 13.8% (52 of 376), respectively. Nodal size correlated statistically with GTV failure and distant failure but not with out-of-GTV nodal failure. After adjusting for age, sex, T category, Primary tumor location, and CRT, the size of metastatic LNs was an independent prognostic factor for OS and PFS in multivariate analyses. Conclusions: Nodal size is one of prognostic factors for non-surgical patients with ESCC and correlated statistically with GTV failure and distant failure.

Corrigendum: Low Lymphocyte Count Is Associated With Radiotherapy Parameters and Affects the Outcomes of Esophageal Squamous Cell Carcinoma Patients.

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The impact of the nodal status on the overall survival of non-surgical patients with esophageal squamous cell carcinoma.

BACKGROUND: The prognosis of N categories for patients with non-surgical esophageal carcinoma based on the number of metastatic lymph nodes is controversial. The present study analyzes prognostic implications of the number, extent, and size of metastatic lymph nodes for patients with esophageal squamous cell carcinoma (ESCC) treated with definitive (chemo-)radiotherapy to provide more information on treatment strategy. METHODS: We reviewed 357 ESCC patients treated with definitive radiotherapy between January 2013 and March 2016 retrospectively. We assessed potential associations between the involved extent (N0, 1 region, 2 regions, and 3 regions), number (N0, 1-2, 3-6, and ≥ 7), and size (N0, ≤2 cm, and > 2 cm) of metastatic lymph nodes and overall survival. Multivariate analyses of the clinicopathological factors were performed using the Cox proportional hazard model. RESULTS: 5-year survival rates were 43.6% for patients in the N0 group and 29.3% in the N+ group (p = 0.001). Kaplan-Meier analyses for all cases revealed that there were significant differences in survival based on the extent (the OS rates at 3 years were 53.3% for patients in the N0 group, 45.7% in the 1 region-involved group, 28.0% in the 2 regions-involved group, and 13.3% in the 3 regions-involved group, P < 0.001), number (the OS rates at 3 years were 49.0% for patients in the 1-2 LNs group, 27.8% in the 3-6 LNs group, 0 in the ≥7LNs group, P < 0.001), and size (the OS rates at 3 years were 41.6% for patients in the LNs ≤2 cm group and 20.7% in the LNs > 2 cm group, P = 0.001) of metastatic LNs. One hundred seventy-two patients (48.2%) had experienced GTV failure, 157 (43.1%) had distant failure, 49 (13.7%) had out-of-GTV nodal failure, and 70 patients (19.6%) had no evidence of disease at the last follow-up. Nodal status correlated statistically with GTV failure. Patients with LN metastases in the abdominal region had worse survival rates than those with metastases in the other regions. The extent and number of metastatic LNs, T category, Primary tumor location, and chemotherapy were independent prognostic factors of OS in multivariate analyses. CONCLUSIONS: For patients with ESCC who received definitive (chemo-)radiotherapy, the number, extent, and size of metastatic LNs were prognostic factors, particularly of the T2/3 disease. Patients with LN metastases in the abdominal region had worse survival.