BACKGROUND:Optimal timing for surgery after neoadjuvant chemoradiotherapy (NCRT) remains controversial, necessitating reliable preoperative indicators. This study examines how sarcopenia and surgical timing affect prognosis in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). PATIENTS AND METHODS:This retrospective study analyzed patients with LA-ESCC who underwent NCRT and surgery at three institutions in China from 2014 to 2023. The skeletal muscle area at the third lumbar vertebra was measured to calculate the skeletal muscle index (SMI). Prognostic analysis was performed using Cox proportional hazards models and propensity score matching (PSM), with survival curves generated using the Kaplan-Meier method and statistical significance set at p<0.05. RESULTS:A total of 415 patients were analyzed, with a median follow-up of 39.1 months. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 59.3% and 53.1%, respectively. Malnutrition and time to surgery (TTS) were independent prognostic factors for both OS and PFS (p < 0.05). Patients with long TTS showed better OS [hazard ratio (HR) = 0.62, p = 0.01] and PFS (HR = 0.68, p = 0.02) compared with those with short TTS. Among patients with sarcopenia, long TTS significantly improved OS (HR = 0.56; p = 0.01) and PFS (HR = 0.62; p = 0.02), while no survival benefit was observed for TTS in patients who were nonsarcopenic (p > 0.05). CONCLUSIONS:Sarcopenia does not independently impact OS or PFS. Patients with sarcopenia benefit from a longer surgical time interval after NCRT. In addition, preoperative evaluation of muscle quality may aid in optimizing surgical timing to improve outcomes.

BACKGROUND:The method of lymph node (LN) irradiation for locally advanced esophageal squamous cell carcinoma (LA-ESCC) is still a topic of debate. We investigated the efficacy, toxicity, and rate of out-of-field LNs in irradiation across different target areas in patients with LA-ESCC undergoing neoadjuvant chemoradiotherapy (nCRT). METHODS:We retrospectively reviewed patient records from June 2017 to August 2022 and divided patients into elective nodal irradiation (ENI) and involved-field irradiation (IFI) groups. The differences in hematological and non-hematological toxicities of the out-of-field LNs were analyzed between the two groups. The log-rank test was used to evaluate the Kaplan-Meier curves for overall and progression-free survival. RESULTS:Among the 306 included patients, 202 (66.0%) received ENI and 104 (34.0%) received IFI. At the 3-year follow-up, the survival rate did not differ significantly between the groups (p > 0.05). Although the occurrence of radiation-induced pneumonia did not differ (p > 0.05), the incidence of radiation-induced esophagitis and the degree of leukopenia differed significantly (p < 0.05). While the average heart irradiation dose or heart V20, V30, and V40 did not differ significantly (p > 0.05), we observed significant differences in the clinical target volume, average lung irradiation dose, and lung V20, V30, and V40 (p < 0.05). Among all patients, 29 cases (9.5%) experienced out-of-field LNs with 26 (93.1%) in abdominal LNs, whereas only 3 cases (6.9%) with out-of-field LNs were in the upper esophagus. There was no statistical significance between out-of-field LNs and LN irradiation methods (p = 0.724). CONCLUSIONS:Under similar prognostic conditions, IFI resulted in mild toxicity compared to ENI. Therefore, for patients with ESCC undergoing nCRT, IFI is the preferred irradiation approach for the lymphatic drainage area.

The administration of second-line or subsequent immune checkpoint inhibitors (ICIs) in previously treated patients with advanced solid cancers has been clinically investigated. However, previous clinical trials lacked an appropriate primary endpoint for efficacy assessment. This systematic review aimed to explore the most optimal early efficacy endpoint for such trials. Phase 2 or 3 clinical trials involving patients with advanced solid cancers with disease progression following standard first-line therapy receiving second-line or subsequent ICI administration, with adequate survival outcome data, were included from PubMed, Embase, Web of Science, and Cochrane Library databases before February 2023. Quality assessment was conducted using the Cochrane tool and Newcastle–Ottawa Quality Assessment Scale for Cohort Studies for randomized controlled trials (RCTs) and non-randomized trials, respectively. Objective response rate (ORR) and progression-free survival (PFS) at 3, 6, and 9 months were investigated as potential early efficacy endpoint candidates for 12-month overall survival (OS), with a strong correlation defined as Pearson’s correlation coefficient r ≥ 0.8. A total of 64 RCTs comprising 22,725 patients and 106 non-randomized prospective trials involving 10,608 participants were eligible for modeling and external validation, respectively. RCTs examined 15 different cancer types, predominantly non-small-cell lung cancer (NSCLC) (17, 28

Zhou, Xiaoding MD; Yue, Hailin MD; Zheng, Zhunhao MD; Zhang, Wencheng MD; Wang, Jianxin MD; Peng, Lin MD; Wang, Qifeng MD Author Information

The optimal treatment for patients with pretreatment T3N0M0 (pre-T3N0M0) esophageal squamous cell carcinoma (ESCC) remains controversial. This study evaluated the impact of neoadjuvant chemoradiotherapy (NCRT) on the survival outcomes of individuals diagnosed with pre-T3N0M0 ESCC. A total of 443 patients with pre-T3N0M0 ESCC who underwent either NCRT plus surgery (NCRT + S) or surgery alone were included in the study. In the surgery group, patients with post-operative staging of pathological T3N0M0 (pT3N0M0) were classified as pre-T3N0M0. In the NCRT + S group, due to tumor downstaging after NCRT, patients with pre-treatment clinical T3 and post-operative pathology indicating lymph nodes without evidence of tumor involvement or regression were considered to have pre-T3N0M0. Univariate and multivariate Cox analyses were conducted to identify independent prognostic factors influencing overall survival (OS) in pre-T3N0M0 patients. Kaplan–Meier curves were employed to assess disparities in OS and disease-free survival (DFS) between the two groups. Compared to surgery alone, NCRT + S significantly enhanced the OS (Hazard ratio [HR] = 0.572, 95% Confidence interval [CI] = 0.407 – 0.804; P = 0.0059); however, it did not show a significant benefit in DFS (HR = 0.784, 95% CI = 0.564 – 1.09; P = 0.17). Compared with the surgery group, patients who achieved a pathologically complete response (pCR) after NCRT showed significantly improved OS (HR = 0.522, 95% CI = 0.339 – 0.804; P = 0.019). The overall and locoregional recurrence rates were significantly lower in the NCRT + S group than in the surgery group. Compared with surgery alone, NCRT + S significantly improved OS in patients with pre-T3N0M0 stage disease, especially in those who achieved pCR after NCRT.

e13601 Background: The drug approval and clinical use of immune checkpoint inhibitors (ICIs) were different among de novo and previously treated cancer patients. The purpose of this study is to investigate progression-free survival (PFS) and objective response rate (ORR) as earlier primary endpoints in previously treated advanced or metastatic solid cancers in immunotherapy era. Methods: This systematic review included phase 2 and 3 clinical trials in previously treated advanced or metastatic solid cancers receiving ICIs, through literature search on databases up to 2022. Quality control was performed, where studies with high risk of bias were excluded. Prediction models were first established using randomized controlled trials (RCTs), and then externally validated in the phase 2 non-randomized trials. Trial-level surrogacy analysis was conducted by correlating PFS hazard ratio (HR) and overall survival (OS) HR. Correlation analysis within checkpoint inhibitor arms was performed between ORR, 3-, 6-, and 9-month PFS rates and 12-month OS rate. The correlation was evaluated using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. High, medium strength, and low correlation was defined as r ≥ 0.85, 0.7 < r < 0.85, and r ≤ 0.7, respectively. Sensitivity analyses were performed to assess the consistency of predictive model by leaving trials of one cancer type out at a time. Results: A total of 64 phase 2 or 3 RCTs with 22,011 patients and 96 phase 2 non-randomized trials with 10,288 patients were included in modeling and validation, respectively. The most common primary endpoint in RCTs and non-randomized trials was OS (38 [59%]) and ORR (72 [75%]). The mostly used endpoint assessment criteria were RECIST v1.1 in both RCTs (59 [92%]) and non-randomized trials (88 [92%]). In trial-level surrogacy, PFS HR showed a low correlation with OS HR ( r, 0.52; 95% confidence interval [CI], 0.23–0.78). Within the checkpoint inhibitor treatment arms in RCTs, there was a high correlation between 6-month PFS and 12-month OS ( r, 0.85; 95% CI, 0.76–0.90), and 9-month PFS and 12-month OS ( r, 0.85; 95% CI,0.80–0.90), with a medium strength correlation between 3-month PFS and 12-month OS ( r, 0.79; 95% CI, 0.65–0.89) and a low correlation between ORR and 12-month OS ( r, 0.13; 95% CI, 0.10–0.76). In external validation, when 6-month PFS was used to predict 12-month OS, there was a good calibration between actual and predicted 12-month OS. Sensitivity analysis demonstrated reasonable overall consistency. Conclusions: For phase 2 non-randomized, observational checkpoint inhibitor trials enrolling previously treated advanced or metastatic solid cancers, we recommended 6-month PFS rate as primary surrogate endpoint. For RCTs, gold standard endpoint OS should be persistently used and should not be replaced by earlier endpoints PFS or ORR.