Prognostic significance of PET/CT and its association with immuno-genomic profiling in oesophageal squamous cell carcinoma treated with immunotherapy plus chemoradiotherapy: results from a phase II study.

BACKGROUND: A phase II trial (EC-CRT-001) demonstrated the promising efficacy of combining toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) for locally advanced oesophageal squamous cell carcinoma (ESCC). Biomarkers are key to identifying patients who may benefit from this therapeutic approach. METHODS: Of the 42 patients with ESCC who received toripalimab combined with definitive CRT, 37 were included in this analysis. Baseline assessments included PET/CT metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG), RNA sequencing of tumour biopsies to quantify the tissue mutational burden (TMB), and multiplex immunofluorescence staining to estimate immune cell infiltration in the tumour microenvironment (TME). Frozen neoplastic samples were procured for RNA sequencing to further explore the immune-related TME. RESULTS: Among the 37 patients, high baseline SUVmax (≥12.0; OR = 6.5, 95% CI 1.4-48.2, p = 0.032) and TLG (≥121.8; OR = 6.8, 95% CI 1.6-33.5, p = 0.012) were significantly correlated with lower complete response rates. All five PET/CT parameters were notably associated with overall survival; only SUVmax and TLG were associated with a significantly worse progression-free survival. A trend towards an inverse correlation was observed between SUVmax and TMB (R = -0.33, p = 0.062). PD-1 + CD8 + T cell infiltration was negatively correlated with MTV (R = -0.355, p = 0.034) and TLG (R = -0.385, p = 0.021). Moreover, RNA sequencing revealed that the high TLG subgroup exhibited low immune cell infiltration, indicating an immunosuppressive landscape. CONCLUSIONS: High baseline SUVmax and TLG might predict poorer treatment response and worse survival in patients with ESCC undergoing immunotherapy combined with CRT. In addition, high PET/CT metabolic parameters, particularly TLG, were correlated with an immunosuppressive TME, which warrants further exploration.

Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial.

BACKGROUND: Toripalimab is a PD-1 inhibitor that is approved for the treatment of advanced oesophageal squamous cell carcinoma, but its efficacy in locally advanced disease is unclear. We administered toripalimab with definitive chemoradiotherapy to patients with unresectable locally advanced oesophageal squamous cell carcinoma, and aimed to investigate the activity and safety of this regimen, and potential biomarkers. METHODS: EC-CRT-001 was a single-arm, phase 2 trial done at Sun Yat-sen University Cancer Center (Guangzhou, China). Patients aged 18-70 years with untreated, unresectable, stage I-IVA oesophageal squamous cell carcinoma, with an ECOG performance status of 0-2, and adequate organ and bone marrow function were eligible for inclusion. Patients received concurrent thoracic radiotherapy (50·4 Gy in 28 fractions), chemotherapy (five cycles of weekly intravenous paclitaxel [50 mg/m2] and cisplatin [25 mg/m2]), and toripalimab (240 mg intravenously every 3 weeks for up to 1 year, or until disease progression or unacceptable toxicity). The primary endpoint was the complete response rate at 3 months after radiotherapy by investigator assessment. Secondary endpoints were overall survival, progression-free survival, duration of response, quality of life (not reported here), and safety. All enrolled patients were included in the activity and safety analyses. The trial is registered with ClinicalTrials.gov, NCT04005170; enrolment is completed and follow-up is ongoing. FINDINGS: Between Nov 12, 2019, and Jan 25, 2021, 42 patients were enrolled. The median age was 56 years (IQR 53-63), 39 (93%) of 42 patients had stage III or IVA disease, and 32 (76%) patients were male and 10 (24%) were female. 40 (95%) of 42 patients completed the planned chemoradiotherapy and 26 (62%; 95% CI 46-76) of 42 had a complete response. The median duration of response was 12·1 months (95% CI 5·9-18·2). After a median follow-up of 14·9 months (IQR 11·9-18·4), 1-year overall survival was 78·4% (95% CI 66·9-92·0) and 1-year progression-free survival was 54·5% (41·3-72·0). The most common grade 3 or worse adverse event was lymphopenia (36 [86%] of 42). One (2%) patient died from treatment-related pneumonitis. INTERPRETATION: Combining toripalimab with definitive chemoradiotherapy provided encouraging activity and acceptable toxicity in patients with locally advanced oesophageal squamous cell carcinoma, and this regimen warrants further investigation. FUNDING: National Natural Science Foundation of China and Sci-Tech Project Foundation of Guangzhou. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy.

BACKGROUND: To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT. PATIENTS AND METHODS: Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/µL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir. RESULTS: Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC. CONCLUSIONS: The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.

Efficacy and Dose-Response Relationship of Stereotactic Body Radiotherapy for Abdominal Lymph Node Metastases from Hepatocellular Carcinoma.

BACKGROUND: The objective of this study was to investigate the treatment efficacy of stereotactic body radiotherapy (SBRT) and evaluate the influence of radiation dose on local control and survival in patients with abdominal lymph node metastases (LNM) from hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Between 2010 and 2020, data of 148 patients with HCC with abdominal LNM, including 114 who underwent SBRT and 34 who received conventional fractionation radiation therapy (CFRT), were collected. A total radiation dose of 28-60 Gy was delivered in 3-30 fractions, with a median biologic effective dose (BED) of 60 Gy (range, 39-105 Gy). Freedom from local progression (FFLP) and overall survival (OS) rates were analyzed. RESULTS: With a median follow-up of 13.6 months (range, 0.4-96.0 months), the 2-year FFLP and OS rates of the entire cohort were 70.6% and 49.7%, respectively. Median OS of the SBRT group was longer than the CFRT group (29.7 vs. 9.9 months, P = .007). A dose-response relationship was observed between local control and BED in either the entire cohort or the SBRT subgroup. Patients who received SBRT with a BED ≥60 Gy had significantly higher 2-year FFLP and OS rates than those who received a BED <60 Gy (80.1% vs. 63.4%, P = .004; 68.3% vs. 33.0%, P < .001). On multivariate analysis, BED was an independent prognostic factor for both FFLP and OS. CONCLUSIONS: SBRT achieved satisfactory local control and survival with feasible toxicities in patients with HCC with abdominal LNM. Moreover, the findings of this large series suggest a dose-response relationship between local control and BED.

Clinical and Dosimetric Predictors for Postoperative Cardiopulmonary Complications in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Chemoradiotherapy and Surgery.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). This study explored correlations of clinical factors and dose-volume histogram (DVH) parameters with postoperative cardiopulmonary complications and predicted their risk by establishing a nomogram model. METHODS: Clinical and DVH parameters of ESCC patients who underwent trimodality treatment from 2002 to 2020 were collected. Postoperative cardiopulmonary complications were recorded. Logistic regression analysis was applied, and a nomogram model was constructed. Area under the receiver operating characteristic (AUC) curve, calibration curve, and decision curve analyses were performed to evaluate the performance of the nomogram. RESULTS: Of the 307 ESCC patients enrolled in this study, 65 (21.2%) experienced pulmonary complications and 57 (18.6%) experienced cardiac complications. The following six risk factors were identified as independent risk factors for pulmonary complications by multivariate logistic regression analyses in the integrated model: male sex (odds ratio [OR], 3.26; 95% confidence interval [CI], 1.27-9.70; P = 0.021), post-radiation therapy (RT) forced expiratory volume in 1 s (FEV1) (OR, 0.51; 95% CI 0.28-0.90; P = 0.023), mean lung dose (MLD) (OR, 1.13; 95% CI 1.01-1.28; P = 0.041), and pre-RT monocyte (OR, 8.36; 95% CI 1.23-11.7; P = 0.03). The AUC of this integrated model was 0.705 (95% CI 0.64-0.77). The paclitaxel and cisplatin (TP) concurrent chemotherapy regimen was the independent predictor of cardiac complication (OR, 2.50; 95% CI 1.22-5.55; P = 0.016). CONCLUSIONS: For ESCC patients who underwent trimodality treatment, male sex, post-RT FEV1, MLD, and pre-RT monocyte were confirmed as significant predictors of postoperative pulmonary complications. A nomogram model including six risk factors was further established. The independent predictor of cardiac complication was TP concurrent chemotherapy.

Comparative efficacy and safety of immunotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma: a systematic review and network Meta-analysis.

BACKGROUND: The study aimed to compare efficacy and safety of various immune checkpoint inhibitors for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). METHODS: We searched Medline, Web of Science, Cochrane Central Register of Controlled Trials, Embase, Clinical Trials.gov and several international conference databases from January 1, 2000 to December 19, 2021. We conducted Bayesian network meta-analysis to assess the relative effects among treatments. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate and adverse events. RESULTS: Ten eligible trials with 5250 patients were included. Toripalimab and Camrelizumab plus chemotherapy were preferred to rank first on OS (probability, 61%) and PFS (probability, 37%) in the first-line setting, respectively. In refractory patients, Sintilimab and Camrlizumab were most likely to be ranked first on OS (probability, 37%) and PFS (probability, 94%). The toxicity related to immunotherapy was manageable in clinical trials. Camrelizumab and Nivolumab had the less adverse events of grade 3 or higher in the first and refractory setting, respectively. CONCLUSIONS: This study found that Toripalimab and Camrelizumab plus chemotherapy were likely to be the best option in terms of OS and PFS in the first-line setting for patients with advanced or metastatic ESCC respectively. Sintilimab and Camrelizumab were the preferred options for OS and PFS in refractory patients respectively. The toxicity of immunotherapy was different from conventional chemotherapy, but manageable in patients with ESCC. TRIAL REGISTRATION: PROSPERO registration number: (CRD 42021261554).

Risk factors and prognosis for esophageal fistula in patients with esophageal squamous cell carcinoma during radiotherapy.

PURPOSE: To determine risk factors, treatment outcomes, and prognostic factors for esophageal fistula (EF) in patients with esophageal squamous cell carcinoma (ESCC) during radiotherapy. METHODS: Between 2010 and 2018, 109 patients with EF during radiotherapy were retrospectively collected. A controlled cohort including 416 patients who received definitive chemoradiotherapy without EF was used to compare risk factors and survival outcomes. Univariate and multivariate logistic regression analyses were performed to identify predictors of EF. Propensity score matching (PSM) was applied to adjust for potential confounding factors. RESULTS: Multivariate analysis demonstrated that sex, body mass index, alcohol history, esophageal ulceration, primary tumor length, T stage, and absolute lymphocyte count were independent risk factors for EF. After PSM, patients with EF showed remarkably worse prognosis than those without EF (median overall survival: 13.0 versus 20.5 months; P = 0.009). For patients with EF, serum albumin level (≥ 35 g/L), subsequent radiotherapy, and fistula closure were associated with significantly prolonged survival. In addition, esophageal-mediastinum fistula and subsequent radiotherapy were positive predictors for fistula closure. CONCLUSIONS: We identified risk factors for radiotherapy-related EF and its unfavorable prognosis in patients with ESCC. Of them, patients with serum albumin level of ≥ 35 g/L, subsequent radiotherapy after EF, and fistula closure had a more favorable survival.

Lymphopenia During Definitive Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Association with Dosimetric Parameters and Patient Outcomes.

BACKGROUND: The objective of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (CRT). MATERIALS AND METHODS: Clinical characteristics and dosimetric parameters were collected from 436 patients with ESCC who received definitive CRT from 2010 through 2017. Absolute lymphocyte counts (ALCs) were obtained before, during, and 1 month after CRT. Grade 4 (G4) lymphopenia was defined as ALC <0.2 × 109 /L during CRT. Logistic regression analysis was used to evaluate the effect of each factor on predicting G4 lymphopenia. The relationship between lymphopenia and overall survival (OS) was examined, and a nomogram was developed to predict OS. RESULTS: G4 lymphopenia was observed in 103 patients (23.6%) during CRT. Multivariate analysis indicated that planning target volume (PTV), lung V10 , heart V10 , performance status, and pretreatment lymphopenia were significant risk factors for G4 lymphopenia. Patients with G4 lymphopenia had significantly worse survival than those without. Based on multivariate analysis, clinical TNM stage, radiotherapy modality, pretreatment ALC, and G4 lymphopenia were predictive of OS and were incorporated into the nomogram, yielding a concordance index of 0.71. CONCLUSIONS: G4 lymphopenia during definitive CRT was associated with larger PTVs, higher lung V10 and heart V10 , and worse survival. IMPLICATIONS FOR PRACTICE: The purpose of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in 436 patients with esophageal squamous cell carcinoma who received definitive chemoradiotherapy. Grade 4 (G4) lymphopenia was observed in 23.6% of patients during radiotherapy. G4 lymphopenia was associated with larger planning target volumes, higher lung V10 and heart V10 , and worse survival. Then, a nomogram was built based on multivariate analysis, yielding excellent performance to predict overall survival. Prospective studies are needed to investigate potential approaches for mitigating severe lymphopenia, which may ultimately convert into survival benefits.

Modeling the risk of radiation pneumonitis in esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

BACKGROUND: To develop and validate a nomogram for the prediction of symptomatic radiation pneumonitis (RP) in patients with esophageal squamous cell carcinoma (ESCC) who received definitive concurrent chemoradiotherapy. METHODS: Clinical factors, dose-volume histogram parameters, and pulmonary function parameters were collected from 402 ESCC patients between 2010 and 2017, including 321 patients in the primary cohort and 81 in the validation cohort. The end-point was the occurrence of symptomatic RP (grade ≥ 2) within the first 12 months after radiotherapy. Univariate and multivariate logistic regression analyses were applied to evaluate the predictive value of each factor for RP. A prediction model was generated in the primary cohort, which was internally validated to assess its performance. RESULTS: In the primary cohort, 31 patients (9.7%) experienced symptomatic RP. Based on logistic regression model, patients with larger planning target volumes (PTVs) or higher lung V20 had a higher predictive risk of RP, whereas the overall risk was substantially higher for three-dimensional conformal radiotherapy (3DCRT) than intensity-modulated radiotherapy. On multivariate analysis, independent predictive factors for RP were smoking history (P = 0.035), radiotherapy modality (P < 0.001), PTV (P = 0.039), and lung V20 (P < 0.001), which were incorporated into the nomogram. The areas under the receiver operating characteristic curve of the nomogram in the primary and validation cohorts were 0.772 and 0.900, respectively, which were superior to each predictor alone. CONCLUSIONS: Non-smoking status, 3DCRT, lung V20 (> 27.5%), and PTV (≥ 713.0 cc) were significantly associated with a higher risk of RP. A nomogram was built with satisfactory prediction ability.

Weekly Chemotherapy of 5-Fluorouracil plus Cisplatin Concurrent with Radiotherapy for Esophageal Squamous Cell Carcinoma Patients with Postoperative Locoregional Recurrence: Results from a Phase II Study.

LESSONS LEARNED: Weekly treatment with 5-fluorouracil and cisplatin, concurrent with radiotherapy, achieved promising response rates in patients with postoperative recurrent esophageal squamous cell carcinoma. Superior toxicity results were also found. BACKGROUND: Concurrent chemoradiotherapy (CCRT) is one of the treatment strategies for patients with esophageal squamous cell carcinoma (ESCC) with postoperative locoregional recurrence. However, the once every 3 weeks chemotherapy regimen causes a high incidence of toxicity. The aim of this study was to evaluate the efficacy and toxicity of weekly 5-fluorouracil (5-FU) and cisplatin concurrent with radiotherapy in postoperative locoregional recurrent ESCC. MATERIALS AND METHODS: Patients received four weekly chemotherapy cycles of cisplatin (25 mg/m2 , day 1) plus 5-FU (1,176 mg/m2 , day 1-3), and concurrent with radiotherapy (50.4-60 Gy). The primary endpoint was objective response rate (ORR). Secondary objectives were toxicity, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Between January 2013 and December 2015, 48 patients were enrolled. The ORR was 68.8% (12 patients with complete response, 21 patients with partial response), with DCR 68.8%. No treatment-related grade 4 adverse events occurred. Grade 3 hematologic toxicities were observed in eight (17%) patients. Grade 3 vomiting or esophagitis occurred in four (8%) patients each. The median PFS and OS were 13.94 months (95% confidence interval [CI], 0.75-51.05) and 27.43 months (95% CI, 5.278-49.58; Fig. 1). CONCLUSION: Weekly 5-FU and cisplatin concurrent with radiotherapy achieved a promising response rate and improved toxicity in patients with postoperative locoregional recurrent ESCC.

Multi-institutional Analysis of Recurrence and Survival After Neoadjuvant Chemoradiotherapy of Esophageal Cancer: Impact of Histology on Recurrence Patterns and Outcomes.

OBJECTIVE: To determine the impact of histology on pathologic response, survival outcomes, and recurrence patterns in patients with esophageal cancer (EC) who received neoadjuvant chemoradiotherapy (CRT). SUMMARY OF BACKGROUND DATA: There is a paucity of data regarding comparative outcomes after neoadjuvant CRT between esophageal squamous cell carcinoma (SCC) and adenocarcinoma. METHODS: Between 2002 and 2015, 895 EC patients who underwent neoadjuvant CRT followed by esophagectomy at 3 academic institutions were retrospectively reviewed, including 207 patients with SCC (23.1%) and 688 patients with adenocarcinoma (76.9%). Pathologic response, survival, recurrence pattern, and potential prognostic factors were compared. RESULTS: Pathologic complete response (pCR) rate was significantly higher for SCC compared with adenocarcinoma (44.9% vs 25.9%, P < 0.001). After a median follow-up of 52.9 months, 71 patients (34.3%) with SCC versus 297 patients (43.2%) with adenocarcinoma had recurrent disease (P = 0.023). For patients who achieved a pCR, no significant differences were found in recurrence pattern, sites, or survival end-points between the 2 histology groups. For non-pCR patients, the SCC group demonstrated significantly higher regional and supraclavicular recurrence rates but a lower hematogenous metastasis rate than adenocarcinoma patients, whereas the adenocarcinoma patients had a more favorable locoregional failure-free survival (P = 0.005) and worse distant metastasis-free survival (P = 0.024). No differences were found in overall survival (P = 0.772) or recurrence-free survival (P = 0.696) between groups. CONCLUSIONS: SCC was associated with a significantly higher pCR rate than adenocarcinoma. Recurrence pattern and survival outcomes were significantly different between the 2 histology subtypes in non-pCR patients.

Treatment-Related Lymphopenia Predicts Pathologic Complete Response and Recurrence in Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Chemoradiotherapy.

PURPOSE: To investigate the relationship between treatment-related lymphopenia and pathologic response to neoadjuvant chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Between 2002 and 2016, 220 ESCC patients treated with neoadjuvant CRT followed by surgery were retrospectively analyzed. Absolute lymphocyte count was determined before, during, and 1 month after neoadjuvant CRT. Treatment-related lymphopenia was graded using Common Terminology Criteria for Adverse Events version 4.0. Relationship between lymphopenia with pathologic complete response (pCR) and recurrence were evaluated. RESULTS: Ninety-five patients (43.2%) achieved a pCR after neoadjuvant CRT and 71 patients (32.3%) developed recurrences. The incidence of grade 0, 1, 2, 3, and 4 lymphopenia during CRT were 1.8%, 6.8%, 31.4%, 38.2% and 21.8%, respectively. Patients with grade 4 lymphopenia had a significantly lower pCR rate than those with grade 0-3 lymphopenia (22.9% vs. 48.8%, P = 0.001). Moreover, grade 4 lymphopenia was significantly associated with a higher risk of recurrences (45.8% vs. 28.5%, P = 0.023). Multivariable analysis identified that primary tumor length, tumor location, and radiation dose were independent predictors for grade 4 lymphopenia. CONCLUSIONS: ESCC patients with grade 4 lymphopenia during neoadjuvant CRT were associated with a significantly lower pCR rate and a higher recurrence risk.

Recurrence Risk Stratification After Preoperative Chemoradiation of Esophageal Adenocarcinoma.

OBJECTIVE: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT). BACKGROUND: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce. METHODS: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients. RESULTS: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort. CONCLUSIONS: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories.

Recurrence Risk Based on Pathologic Stage After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Implications for Risk-Based Postoperative Surveillance Strategies.

BACKGROUND: This study aimed to investigate the association between pathologic stage and recurrence risk and survival for patients with esophageal squamous cell carcinoma (SCC) after neoadjuvant chemoradiotherapy (CRT). METHODS: This retrospective analysis consisted of two patient cohorts who had esophageal SCC treated with neoadjuvant CRT and esophagectomy at two major academic institutions between 2002 and 2015. The study included 174 patients in the training cohort and 51 patients in the validation cohort. Recurrence pattern, frequency, and survival according to pathologic stage were analyzed. RESULTS: After surgery, patients in the training cohort had the following pathologic categories: stage 0 (44.8%, n = 78), stage 1 (6.9%, n = 12), stage 2 (35.6%, n = 62), and stage 3 (12.6%, n = 22). During a median follow-up period of 53.9 months, recurrences developed in 59 patients. The recurrence rates were 22.2% for stages 0 and 1, 38.7% for stage 2, and 68.2% for stage 3 (stages 0 and 1 vs. stage 2 [P = 0.028], stages 0 and 1 vs. stage 3 [P < 0.001], and stage 2 vs. stage 3 [P = 0.017]). More than 20% of patients with stages 0 and 1 or 2 disease experienced late relapses after 3 years of follow-up evaluation, whereas all the patients with pathologic stage 3 had recurrences within 2 years. The 5-year recurrence-free survival rate was 74.7% for the patients with pathologic stage 0 or 1, 61.4% for those with stage 2, and 20.9% for those with stage 3 disease (P < 0.001). These major findings were successfully reproduced in the Western validation cohort. CONCLUSIONS: Patients with a higher pathologic stage were associated with a significantly higher risk of recurrences and worse survival. Multicenter and prospective validation is warranted.

Preoperative Nomogram to Risk Stratify Patients for the Benefit of Trimodality Therapy in Esophageal Adenocarcinoma.

PURPOSE: To develop a nomogram that estimates 1-year recurrence-free survival (RFS) after trimodality therapy for esophageal adenocarcinoma and to assess the overall survival (OS) benefit of esophagectomy after chemoradiotherapy (CRT) on the basis of 1-year recurrence risk. METHODS: In total, 568 consecutive patients with potentially resectable esophageal adenocarcinoma who underwent CRT were included for analysis, including 373 patients who underwent esophagectomy after CRT (trimodality therapy), and 195 who did not undergo surgery (bimodality therapy). A nomogram for 1-year RFS was created using a Cox regression model. The upper tertile of the nomogram score was used to stratify patients in low-risk and high-risk groups for 1-year recurrence. The 5-year OS was compared between trimodality and bimodality therapy in low-risk and high-risk patients after propensity score matching, respectively. RESULTS: Median follow-up for the entire cohort was 62 months. The 5-year OS in the trimodality and bimodality treatment groups was 56.3% (95% confidence interval [CI] 47.9-64.7) and 36.9% (95% CI 31.4-42.4), respectively. The final nomogram for the prediction of 1-year RFS included male gender, poor histologic grade, signet ring cell adenocarcinoma, cN1, cN2-3, and baseline SUVmax, with accurate calibration and reasonable discrimination (C-statistic: 0.66). Trimodality therapy was associated with improved 5-year OS in low-risk patients (p = 0.003), whereas it showed no significant survival benefit in high-risk patients (p = 0.302). CONCLUSIONS: The proposed nomogram estimates early recurrence risk. The addition of surgery to CRT provides a clear OS benefit in low-risk patients. The OS benefit of surgery in high-risk patients is less pronounced.

Failure pattern of elective nodal irradiation for esophageal squamous cell cancer treated with neoadjuvant chemoradiotherapy.

OBJECTIVE: To analyze the failure pattern and clinical efficacy of elective nodal irradiation in patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy. METHODS: We retrospectively analyzed 173 esophageal squamous cell carcinoma patients who received neoadjuvant chemoradiotherapy including elective nodal irradiation from 2002 to 2015. Failure pattern, survival and recurrence sites were analyzed. For patients with regional recurrences, the recurrence sites were analyzed in relation to an imaginary field of involved field irradiation. RESULTS: After a median follow-up of 55.5 months, 58 patients (33.5%) developed recurrences. Among 22 patients with regional recurrences, infield failure occurred in 19 patients (86.4%) and outfield failure occurred in 3 patients (13.6%), of whom only 1 patient had an outfield failure without synchronous distant metastasis. Compared with the involved field irradiation field, 6 patients' failure sites (27.3%) were located in the involved field irradiation field and 13 patients' failure sites (59.1%) were out of the involved field irradiation field but within the elective nodal irradiation field. CONCLUSIONS: Since only a minority of patients had outfield regional recurrences, neoadjuvant chemoradiotherapy with elective nodal irradiation yields satisfactory infield control. More than half of the regional recurrences occurred within the elective nodal irradiation field but out of the involved field irradiation field. Prospective evaluation of whether elective nodal irradiation could lead to an improved survival outcome is necessary.

Prognosis of Fibrosarcoma in Patients With and Without a History of Radiation for Nasopharyngeal Carcinoma.

PURPOSE: To determine whether radiation-induced fibrosarcoma (RIF) in patients with a history of radiotherapy for nasopharyngeal carcinoma (NPC) was associated with an inferior prognosis compared to sporadic fibrosarcoma of the head and neck. METHODS: Forty-two patients with RIF who previously received radiotherapy for NPC and 124 patients with sporadic fibrosarcoma of the head and neck were identified between January 1965 and December 2013 at our institution. Information on clinicopathologic characteristics and treatment was abstracted from medical records. The primary end point was disease-specific survival (DSS). RESULTS: The median latency from NPC diagnosis to RIF diagnosis was 9.9 years (range 3.1-36.8 years). RIF was diagnosed at an older age than sporadic fibrosarcoma. Treatment modality was significantly different between the two groups, with only 64.3 % of the RIF group receiving surgery ± adjuvant treatment versus 91.1 % in the sporadic fibrosarcoma group (P < 0.001). Patients with RIF had poorer 5-year DSS compared to the sporadic fibrosarcoma group (36.2 vs. 50.4 %; P = 0.026). Multivariate analysis of the combined group indicated that patient group (P = 0.032), tumor, node, metastasis classification system stage (P = 0.019), histologic grade (P = 0.046) and treatment modality (P < 0.001) were independent variables affecting DSS. CONCLUSIONS: Compared to patients with sporadic fibrosarcoma, NPC survivors who develop RIF are older at diagnosis of fibrosarcoma and have an inferior prognosis.

Comparing docetaxel plus cisplatin versus fluorouracil plus cisplatin in esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy.

OBJECTIVE: The optimal neoadjuvant chemoradiotherapy (CRT) regimen in esophageal cancer has not yet been defined. This study was aimed to compare the differences in pathologic response and survival between docetaxel/cisplatin and fluorouracil/cisplatin as neoadjuvant CRT in locally advanced esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively analyzed patients with thoracic esophageal SCC who received neoadjuvant CRT followed by esophagectomy from 2000 to 2014. After adjusting for sex, age, performance status, tumor length, tumor location and clinical TNM stage, 32 docetaxel/cisplatin-treated patients were matched to 62 patients who received fluorouracil/cisplatin at a ratio of 1:2. Treatment toxicity, pathologic complete response (pCR) and survival outcomes were compared between groups. RESULTS: Baseline characteristics were well balanced between groups. The pCR rate in the docetaxel/cisplatin group was higher than that in the fluorouracil/cisplatin group but without significant difference (40.6% vs. 30.6%, P = 0.333). The 3-year overall survival rate in the docetaxel/cisplatin group was 64.9% versus 46.0% in the fluorouracil/cisplatin group (P = 0.039). There were no significant differences in incidence of treatment toxicity during CRT or surgical complications between groups, with the exception of Grade 3-4 hematologic toxicity (37.5% vs. 17.7%, P = 0.035), which was more frequent in the docetaxel/cisplatin group. CONCLUSIONS: Docetaxel/cisplatin might be associated with more favorable survival than fluorouracil/cisplatin in esophageal SCC treated with neoadjuvant CRT. Prospective validation is warranted.