Resected Esophageal Squamous Cell Carcinoma Research Articles

Induction of Kallikrein-Related Peptidase 13 and TET2/3 by Anticancer Drugs and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Preoperative Treatment.

Preoperative chemotherapy/chemoradiotherapy has been generally considered for the treatment of esophageal squamous cell carcinoma (ESCC) to improve prognosis. We examined the effects of anticancer drugs on the expression of kallikrein-related peptidase 13 (KLK13), a potential ESCC prognostic marker, and its clinical relevance in patients who received chemotherapy/chemoradiotherapy for ESCC. Overall, 105 patients with ESCC who received chemotherapy or chemoradiotherapy before esophagectomy were enrolled. The expression of KLK13 in biopsy samples obtained before chemotherapy/chemoradiotherapy and resected ESCC tumors was assessed by immunohistochemical staining. The effects of 5-fluorouracil (5-FU) and/or cisplatin (CDDP) exposure on the expressions of KLK13 and ten-eleven translocation dioxygenases (TET) in ESCC cells were examined by reverse transcription-polymerase chain reaction. Immunohistochemical staining of paired ESCC specimens before (biopsy samples) and after (resected specimens) chemotherapy/chemoradiotherapy demonstrated a change in KLK13 expression. KLK13 and TET2/3 transcriptions were induced when human ESCC cell lines were treated with 5-FU and/or CDDP. Among patients with KLK13-negative status before chemotherapy/chemoradiotherapy, those with KLK13-positive resected tumors had a significantly poorer prognosis than those with KLK13-negative resected tumors (p = 0.0477). By using tumor cells isolated from ESCC biopsy tissues obtained before chemotherapy/chemoradiotherapy, we established a primary culture system and detected the induction of KLK13 expression by anticancer drugs. Preoperative treatments alter KLK13 expression in ESCC. The conversion of KLK13 expression from a negative status in biopsy samples to a positive status in resected tumor samples is a predictor of poor prognosis. KLK13 status is a potential marker for decision making to avoid harmful chemotherapy/chemoradiotherapy in patients with ESCC.

1558P Preoperative pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma (ESCC): The phase II Keystone-001 trial

1558P Preoperative pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma (ESCC): The phase II Keystone-001 trial

Different Radiation Dose of Neoadjuvant Chemoradiation for Resectable Thoracic Esophageal Squamous Carcinoma: A Randomized Phase II Clinical Trial

Radiation dose used in the neoadjuvant chemoradiotherapy (nCRT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC) varies in clinical practice, no prospective studies have been conducted on this issue. The hypothesis of this study is that higher radiation dose in nCRT was associated with improved progression free survival in resectable ESCC. A phase II prospective randomized controlled trial was conducted from February 22, 2018 to February 22, 2021 in Zhejiang Cancer Hospital (NCT03381651). Patient with locally resectable advanced thoracic ESCC (cT2-T4aNxM0, T1-3N+M0) were randomized 1:1 to receive nCRT with different radiation doses of 50.4 Gy/28F and 41.4 Gy/23F, weekly TC regimen (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) was administered as concurrent chemotherapy. The primary endpoint was 2-year progression free survival (PFS), and the secondary endpoints included complete pathological response (pCR) rate, overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The last follow-up date was February 22, 2022 and data analysis was performed from May 1, 2022, to October 31, 2022. A total of 147 patients were enrolled in the prospective study, including 72 patients in 50.4 Gy/28F group and 75 patients in 41.4 Gy/23F group. Among all the patients, 101 patients finally underwent surgical resection, 23/46(50%) achieved pCR in the high-dose group, while 18/55(32.7%) achieved pCR in the low-dose group (P = 0.10). In intention-to-treat population analysis, 2-year PFS in the high-dose and low-dose groups were 53.5% (95% CI: 42.9-66.7%) and 45.5% (95% CI: 35.4%-58.5%), respectively, and hazard ratio (HR) was 0.72 (95% CI: 0.46-1.12, P = 0.14). Median PFS were 44.4 months (95% CI: 16-NA) versus 20.8 months (95% CI: 15-NA) in high and low dose groups. 2-year OS in the high and low-dose groups were 61.8% (95% CI: 51.2 -74.5%) and 60.5% (95% CI: 50.3 -72.8%), respectively, with a HR = 0.78(95% CI: 0.48-1.27, P = 0.32). Median OS were not arrived in both groups up to the last follow-up. In addition, 2-year LRFS were 87.9% (95% CI: 78.4-98.5%) and 74.8% (95% CI: 63.3-88.3%) in high and low-dose groups, while 2-year DMFS were 70.6% (95% CI: 58.3-85.5%) and 73.6% (95% CI: 61.7-87.8%), respectively. No significant statistical difference was observed between the two groups in terms of side effects during nCRT and postoperative complications. Our results showed that neoadjuvant high-dose radiotherapy failed to improve overall survival in ESCC. However, it was found that pCR and local tumor control rates tended to be increased at 50.4 Gy/28F, compared to 41.4 Gy/23F, although the trend was not statistically significant. There was no significant difference in treatment side effects between the two groups. Longer-term follow-up is required to verify our findings.

Comparison of Pathologic Response and Survival Outcomes between Neoadjuvant Immunochemotherapy (nICT) and Neoadjuvant Chemoradiotherapy (nCRT) in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: A Propensity Score-Matched Analysis

The neoadjuvant immunochemotherapy (nICT) is a novel treatment, which is likely to be safer for locally advanced, surgically resectable Esophageal squamous cell carcinoma (ESCC) that comparing with the traditional neoadjuvant therapy. However, the efficacy of nICT was controversial and the survival benefit remain unknown. This study included 313 patients with locally advanced ESCC who underwent surgery following neoadjuvant therapy at Sichuan Cancer Hospital from June 2017 and September 2021. The patients were divided into nICT group and neoadjuvant chemoradiotherapy (nCRT) group according to the neoadjuvant strategy. A 1:2 propensity score matching (PSM) was used to balance potential bias across several covariates between two groups with a caliper 0.05. Among the 146 patients after PSM, the baseline factors were comparable between two groups. Compared with the nCRT group, the nICT group shown a lower pathologic complete response(pCR) rate (11.54% vs 35.11%; P = 0.0039) and lymph nodes uninvolved rate (ypN0: 44.23% vs 62.77%; P = 0.0154), but a higher perineural invasion (32.69% vs 12.77%; P = 0.0075) and angioinvasion rate (40.38% vs 10.64%; P = 0.0001). However, the 2-year OS and DFS rates were similar between the nICT group and the nCRT group in overall study cohort, and these data were confirmed in the matched samples (2-year OS, 78.2% vs 77.2% [p = 0.95]; DFS, 56.9% vs 58.0% [p = 0.69]). Our preliminary findings indicate that, for individuals with locally advanced ESCC, nICT followed by surgery appears to be less effective in pathologic outcomes, while having a comparable survival rate to nRCT. These results imply a complicated and possibly multifaceted link between the kind of neoadjuvant therapy, the pathologic outcomes, and the final survival.

Chemoradiotherapy Combined with Nab-Paclitaxel plus Cisplatin in Patients with Locally Advanced Borderline Resectable or Unresectable Esophageal Squamous Cell Carcinoma: A Phase I/II Study

To evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-PTX) plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). Patients with locally advanced ESCC (cT3-4, Nany, M0-1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-PTX plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate and adverse events (AEs) were calculated. A total of 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1and 2 years were 81.5%, 86.6%, 64.3%, 73.2% and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6% and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patients and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95% CI, 1.10-23.94; P = 0.021). The OS rate at 1 and 2 years were 95.2% and 84.2% in resectable patients compared to 78.8% and 54.4% in unresectable patients (HR, 3.41; 95% CI, 1.10-10.61; P = 0.024). The toxicities during chemoradiotherapy were tolerated, the most common grade 3-4 toxicities were radiation esophagitis (15.6%). Nab-PTX plus cisplatin were effective and safe as the regimen of conversional chemoradiotherapy of ESCC. The patients receiving conversional chemoradiotherapy plus surgery (cCRT+S) were prone to have a better survival.

Postoperative serum squamous cell carcinoma antigen and carcinoembryonic antigen predict overall survival in surgical patients with esophageal squamous cell carcinoma.

Tumor markers are routinely used in clinical practice. However, for resectable patients with esophageal squamous cell carcinoma (ESCC), they are applied infrequently as their prognostic significance is incompletely understood. This historical cohort study included 2769 patients with resected ESCC from 2011 to 2018 in a high-risk area in northern China. Their clinical data were extracted from the Electronic Medical Record. Survival analysis of eight common tumor markers was performed with multivariable Cox proportional hazards regressions. With a median follow-up of 39.5 months, 901 deaths occurred. Among the eight target markers, elevated postoperative serum SCC (Squamous cell carcinoma antigen) and CEA (Carcinoembryonic antigen) predicted poor overall survival (SCC HRadjusted: 2.67, 95% CI: 1.70-4.17; CEA HRadjusted: 2.36, 95% CI: 1.14-4.86). In contrast, preoperative levels were not significantly associated with survival. Stratified analysis also demonstrated poorer survival in seropositive groups of postoperative SCC and CEA within each TNM stage. The above associations were generally robust using different quantiles of concentrations above the upper limit of the clinical normal range as alternative cutoffs. Regarding temporal trends of serum levels, SCC and CEA were similar. Their concentrations fell rapidly after surgery and thereafter remained relatively stable. Postoperative serum SCC and CEA levels predict the overall survival of ESCC surgical patients. More importance should be attached to the use of these markers in clinical applications.

Serum VEGF levels as a predictor of recurrence in patients with advanced‑stage esophageal squamous cell carcinoma following curative esophagectomy followed by chemotherapy or concurrent radiotherapy.

The present study evaluated serum levels of vascular endothelial growth factor (VEGF) as a predictor of recurrence in patients with advanced-stage esophageal squamous cell carcinoma (ESCC) following curative esophagectomy followed by chemotherapy or concurrent radiotherapy. Patients with locally advanced resectable ESCC underwent R0 esophagectomy followed by chemotherapy or concurrent radiotherapy as an adjuvant. Serum VEGF levels in 173 patients, including 57 patients with recurrent disease, and 183 healthy controls were determined using a Luminex assay. The results demonstrated that the serum VEGF levels were significantly higher in 57 patients with locally advanced resectable ESCC at recurrence compared with the levels at pre-treatment (P<0.001). The patients with recurrence exhibited significantly higher serum VEGF levels during chemotherapy or concurrent radiotherapy than patients with no recurrence (P<0.05). Patients with low serum VEGF levels had a significantly longer survival time than those with high serum VEGF levels prior to treatment (P<0.01). The median survival times were 70 and 25 months in patients with locally advanced resectable ESCC with serum VEGF levels <161.75 and ≥161.75 pg/ml following treatment, respectively (P<0.01). Compared with patients with VEGF levels <147 pg/ml following treatment, patients with locally advanced resectable ESCC with VEGF levels ≥147 pg/ml had a significantly higher risk of recurrence (P<0.01). Patients with low serum VEGF levels (<147 pg/ml) had significantly higher recurrence-free survival rates than those with high serum VEGF levels (≥147 pg/ml) following treatment (P<0.01). The findings of the present study demonstrate that serum VEGF levels are a potential predictor of recurrence and of the treatment outcomes of chemotherapy or concurrent radiotherapy in patients with locally advanced resectable ESCC.

Neoadjuvant Triplet Chemotherapy with Docetaxel, Cisplatin plus 5-Fluorouracil versus Docetaxel, Cisplatin plus S-1 for Advanced Esophageal Squamous cell Carcinoma: Propensity Score Matched Analysis

Introduction: This study examines whether neoadjuvant docetaxel, cisplatin plus S-1 (DCS) therapy is superior to docetaxel, cisplatin plus 5-fluorouracil (DCF) therapy for resectable advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients diagnosed with resectable advanced ESCC at our hospital between January 2010 and December 2019 underwent either neoadjuvant DCF therapy or DCS therapy, followed by radical esophagectomy. Prior to August 2014, we usually used neoadjuvant DCF therapy; we then completely transitioned to using neoadjuvant DCS therapy. Results: A total of 144 patients received one of these triplet regimens as neoadjuvant chemotherapy: DCF therapy to 67 patients and DCS therapy to 77 patients. After propensity score matching, 55 patients in each group were selected as matched cohorts. There was no significant difference between the groups in complete response (DCF = 7.3%, DCS = 9.1%) or in partial response (DCF = 45.4%, DCS = 52.7%). The pathological response rate was 23.8% for grade 2 and 18.2% for grade 3 in the DCF group, compared with 30.9% and 14.5% in the DCS group. Independent predictive factors for recurrence-free survival were poor clinical response and pathological response ≤1b. Independent prognostic factors for overall survival were poor clinical response, anastomotic leakage, and pathological response ≤1b. Duration of hospital stays in the DCS group was significantly shorter than those of the DCF group (6.0 vs. 15.0 days, p < 0.001). Expenses of drug and hospitalization for the neoadjuvant chemotherapy in the DCS group were also significantly lower than those of the DCF group (265.7 vs. 550.3 USD, p < 0.001). Conclusions: Neoadjuvant DCS therapy for resectable advanced ESCC did not result in significantly higher clinical and pathological response than neoadjuvant DCF therapy. However, neoadjuvant DCS therapy for resectable ESCC required comparatively shorter hospital stays and incurred lower costs, making it an attractive therapeutic option.

Perioperative immunotherapy for esophageal squamous cell carcinoma: Now and future.

Esophageal cancer (EC) ranks among the most prevalent malignant tumors affecting the digestive tract. Esophageal squamous cell carcinoma (ESCC) stands as the prevailing pathological subtype, encompassing approximately 90% of all EC patients. In clinical stage II-IVA locally advanced ESCC cases, the primary approach to treatment involves a combination of neoadjuvant therapy and surgical resection. Despite concerted efforts, the long-term outcomes for ESCC patients remain unsatisfactory, with dismal prognoses. However, recent years have witnessed remarkable strides in immunotherapy, particularly in the second- and first-line treatment of advanced or metastatic ESCC, with the development of monoclonal antibodies that inhibit programmed death 1 or programmed death ligand 1 demonstrating encouraging responses and perioperative clinical benefits for various malignancies, including ESCC. This comprehensive review aims to present the current landscape of perioperative immunotherapy for resectable ESCC, focusing specifically on the role of immune checkpoint inhibitors during the perioperative period. Additionally, the review will explore promising biomarkers and offer insights into future prospects.

Neoadjuvant camrelizumab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: A prospective, single-arm, open-label study.

Esophageal cancer (EC) is a major cause of cancer-related deaths worldwide, bringing tremendous pressure to the healthcare system and patients. Esophageal squamous cell carcinoma (ESCC) is the main subtype of EC in the Chinese population. This study aimed to extend the neoadjuvant therapy cycle to 4 cycles and evaluate the efficacy and safety of neoadjuvant camrelizumab combined with chemotherapy for the treatment of resectable ESCC. The enrolled patients received neoadjuvant camrelizumab (200 mg, day 1), nab-paclitaxel (260 mg/m2, day 1) and carboplatin (area under curve; 5 mg/mL/min) every 21 days for 4 cycles, and surgery was performed within 4-6 weeks after the first day of the 4th treatment cycle. The primary endpoint of the study was the pathological complete response (pCR) rate. From December 15, 2021, to October 1, 2022, a total of 35 patients were enrolled in the study. All patients completed the full 4-cycle treatment and were deemed fit for surgical intervention. Thirty-four (97.1%) patients achieved R0 resection, 18 (51.4%) showed a pCR rate, and 27 (77.1%) achieved a major pathological response (MPR). Tumor degradation was observed in 30 out of 35 patients (85.7%). Multivariate logistic regression analyses further confirmed that age (odds ratio (OR) = 6.710, 95% confidence interval (95% CI): 3.512-44.403) and programmed death-ligand 1 (PD-L1) (OR = 2.855, 95% CI: 1.181-3.079) were independent predictors of pCR. The most prevalent adverse event (AE) was leukopenia, which was experienced by 23 out of 35 patients (65.7%). Grade 3 or higher AEs included leukopenia in 2 cases (5.7%) and neutropenia in 12 cases (34.3%). No delays in surgery were observed. As demonstrated in this study, the 4 cycles of camrelizumab combined with nab-paclitaxel and carboplatin, which exhibited a relatively high pCR rate and acceptable safety, suggest a strong rationale for its further evaluation in resectable ESCC.

359. NFE2L2 MUTATIONS ARE PREDICTIVE AND PROGNOSTIC OF TREATMENT OUTCOME IN RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA PATIENTS

Abstract Background The poor prognosis of resectable esophageal squamous cell carcinoma (ESCC) poses an unmet need to identify genomic early predictive and prognostic biomarkers to improve treatment outcome and risk stratification. Methods Retrospective targeted sequencing was performed on 80 ESCC formalin-fixed, paraffin-embedded (FFPE) tumor specimens from 37 good responders and 43 poor responders receiving neoadjuvant treatment. Somatic mutations and copy number variations (CNVs) were detected in 130 cancer druggable genes with TOMA Os-seq. Kaplan Meier curve and COX regression analysis were used to estimate the risk of relapse and survival. Results Twelve patients (12/80, 15%) with hot spot NFE2L2 mutations occurred with significantly higher frequency in poor responders (p = 0.0003) and in patients with non-complete pathological response (p = 0.007) in resectable ESCC treated by chemo-radiotherapy (CRT). These patients also had poorer prognosis with higher risk of death (HR = 1.942, p = 0.039) and relapse (HR = 1.817, p = 0.063) by COX analysis. The independent prognostic role of hot spot NFE2L2 mutations was validated by the presence of recurrent plasma cell-free (ct)-DNA NFE2L2 mutations in an independent prospective cohort of resectable ESCC patients. Conclusions In summary, our study now demonstrates the clinical usefulness of hot spot NFE2L2 mutations, as a potential predictive and prognostic biomarker associated with pre-surgery CRT responses, and provides novel insights for future therapeutic options targeting the NRF signaling in resectable ESCC treated by neoadjuvant CRT. The novel prognostic role of hot spot NFE2L2 mutations may be useful markers to guide clinicians for treatment decisions in resectable ESCC patients following pre-surgery treatment.

401. THE ADJUVANT IMMUNOTHERAPY COMBINATIONS FOLLOWING ESOPHAGECTOMY FOR RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH NEOADJUVANT THERAPY

Abstract Background The potential benefits of postoperative adjuvant therapy for resectable esophageal squamous cell carcinoma (ESCC) following neoadjuvant therapy remain controversial. This study aims to evaluate the value of immunotherapy combinations as a potential adjuvant treatment for ESCC patients. Methods This retrospective study reviewed patients with ESCC who underwent neoadjuvant therapy following radical esophagectomy at West China Hospital, Sichuan University, between 2018 and 2021. The primary outcomes were overall survival (OS) and disease-free survival (DFS). The survival curves and independent prognostic factors were analyzed using the Kaplan–Meier method and Cox proportional hazards model, respectively. In the patients who received postoperative adjuvant therapy, the survival curves of postoperative adjuvant therapy options, including immunotherapy combinations, chemotherapy (CT), and chemoradiotherapy (CRT), were compared. Results Of the total 482 patients, 141 (29.3%) received adjuvant therapy with 58, 58, and 25 cases receiving immunotherapy combinations, CT and CRT, respectively. Immunotherapy combinations demonstrated both a significantly better OS and DFS compared to CT or CRT, with a mean OS of 34 months vs. 29 months (95% confidence interval [CI] 27.633–34.503, P &amp;lt; 0.05) and a mean DFS of 32 months vs. 24 months (95% CI 24.994–32.853, P &amp;lt; 0.05), respectively. However, immunotherapy combinations were not identified as an independent prognostic factor for OS (hazard ratio [HR] 0.677, 95% CI 0.293–1.564, P = 0.361) and DFS (HR 0.470, 95% CI 0.208–1.064, P = 0.070). Conclusion Although adjuvant immunotherapy combinations prolong OS and DFS compared with CT and CRT in ESCC, they cannot independently predict prognosis. Therefore, the efficacy of immunotherapy combinations in adjuvant therapy still needs further exploration.

343. T LYMPHOCYTE SUBSETS CHARACTERISTICS IN DIFFERENT CURATIVE EFFICACY OF NEOADJUVANT THERAPY FOR PATIENTS WITH ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background In patients with resectable esophageal squamous cell carcinoma(ESCC), neoadjuvant therapy increased the curative resection rate, disease-free survival, and overall survival. Up to 32% of patients with esophageal cancer show a pathological complete response after neoadjuvant therapy. However, the efficacy of neoadjuvant therapy varies among different patients. We aim to compare the differences in the characteristics of peripheral blood T lymphocyte subsets before and after neoadjuvant therapy in patients with different curative efficacy. Methods This study enrolled 269 ESCC patients who received neoadjuvant treatment followed by esophagectomy planned 4–6 weeks after preoperative therapy. The postoperative pathological results divided patients into the main pathological response (MPR) and non-MPR groups. Compare the differences in peripheral blood T lymphocyte subsets before neoadjuvant therapy, and analyze the trend of changes in T lymphocyte subsets before neoadjuvant therapy, before surgery, in the short term after surgery, and at the initial follow-up after surgery. Results Before receiving neoadjuvant therapy, the peripheral blood CD4/CD8(p = 0.001) and helper T cell rate (THrate)(p = 0.006) in the MPR group were significantly higher than those in the non-MPR group. In contrast, the suppressor T cell rate(TSrate) was lower(p = 0.029) in the MPR group. After neoadjuvant therapy, the CD4/CD8 in both groups reached similar classes, but the THrate decreased dramatically and TSrate increased more in the MPR group. At the first follow-up after surgery, the peripheral blood CD4/CD8, THrate, and TSrate of both groups of patients tended to be at the same level. Conclusion T lymphocyte subsets in the peripheral blood significantly differed among patients with different neoadjuvant treatment efficacy. High levels of CD4/CD8, THrate, and low levels of TSrate before receiving neoadjuvant therapy may have better curative efficacy.

325. CAMRELIZUMAB IN COMBINATION WITH CHEMOTHERAPY VERSUS CHEMORADIOTHERAPY FOR THE CONVERSION OF UNRESECTABLE ESOPHAGEAL CARCINOMA: A PROSPECTIVE CLINICAL STUDY PROTOCOL

Abstract Background Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 30% of patients still develop distant metastases and have a high incidence of treatment-related adverse events. Immunotherapy, as a new modality for anti-cancer treatment, has shown promising clinical benefits for patients with ESCC. The synergistic effects of immunotherapy and radiotherapy make their combination promising as neoadjuvant treatment for locally advanced ESCC. Methods All participants who meet the inclusion criteria will be enrolled after signing the informed consent form. Patients with thoracic segment esophageal cancer with clinical stage T2–3 N0 M0 or T2–3 N+ M0 will be included. They will be treated with radical surgery within 4–8 weeks after the completion of two cycles of neoadjuvant radiotherapy in combination with camrelizumab according to the study schedule. The primary endpoint is the major pathological remission rate of all per-protocol patients. The secondary endpoints are the R0 resection rate, pathological complete remission rate, and adverse events. The interim analysis will be conducted after half of the planned number of patients have been enrolled. The trials will be terminated when more than two treatment-related deaths occur or fewer than five patients have major pathological remission. Discussion We designed this prospective single-arm phase II clinical study to evaluate the combination of camrelizumab and standard radiotherapy as preoperative neoadjuvant therapy for patients with resectable ESCC as part of the quest for better treatment options for patients with locally advanced ESCC. Trial registration: This trial protocol has been registered on NIH Clinical Trials database (www.clinicaltrials.gov/, NCT05176002). The posted information will be updated as needed to reflect protocol amendments and study progress.

150. PATTERN OF LYMPH NODE RECURRENCE AFTER NEOADJUVANT CHEMORADIOTHERAPY AND MODIFIED EN BLOC ESOPHAGECTOMY

Abstract Background Esophageal cancer is an aggressive malignancy with high incidence of lymph node metastasis and recurrence rate even after neoadjuvant treatment and radical resection. Previous study has shown that modified en bloc esophagectomy (mEBE) improves survival for esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (nCRT). In this study, we aim to investigate the pattern of lymph node recurrence after nCRT+mEBE. Methods The data of patients who received nCRT followed by curative surgical resection for ESCC were retrospectively reviewed. The mEBE includes ‘mesophagus’ dissection and bilateral recurrent laryngeal nerve node dissection, whereas conventional esophagectomy (CE) only requires periesophageal tissues dissection that were close to the esophagus. The pattern of recurrence, especially lymph node recurrence (cervical, upper mediastinum, infra-carina, and abdominal), were compared between CE and mEBE, with stratification according to pathological stage (ypT0N0 or not.) Results A total of 221 (CE, n = 181; mEBE, n = 40) patients were included. Mediastinal lymph node recurrence was noted in 16.0% and 7.5% of patients after CE and mEBE, respectively (p = 0.166). In ypT0N0 patients who received CE, 6.0% had upper mediastinum recurrence, whereas no mediastinal recurrence was noted after mEBE (p = 0.329). In non-ypT0N0 stage patients who received CE, 15.3% and 8.2% had upper mediastinum and infra-carina recurrences, compared to 12.0% and 0% after mEBE (p = 0.283). There cervical/abdominal recurrences were noted in 6.6%/7.2% and 15.0%/5.0% after CE and mEBE, respectively (p = 0.080/0.618). Conclusion Although there was no significant difference in lymph node recurrence pattern between mEBE and CE, we observed that (1) 6% of ypT0N0 patients developed mediastinal lymph node recurrence after CE, implying the possibility of understaging after CE; (2) no patients developed infra-carina lymph node recurrence after mEBE, suggesting the necessity of mesoesophagus dissection, and (3) high incidence of cervical lymph node recurrence even after mEBE, indicating that cervical dissection should be considered in selected patients.

Preoperative serum bilirubin is an independent prognostic factor for curatively resected esophageal squamous cell carcinoma

PurposeThis study examines prognostic value of preoperative serum bilirubin, including unconjugated bilirubin (UCB), conjugated bilirubin (CB), and total bilirubin (TB), in esophageal squamous cell carcinoma (ESCC) patients who underwent curative resection.MethodsBetween May 2010 and December 2012, a total of 351 ESCC patients were retrospectively reviewed. All the patients underwent curative resection as their primary treatment. Clinicopathological features and overall survival (OS) rate were investigated. Kaplan-Meier curves were used to calculate the OS rate, and the prognostic factors were identified by Cox regression model. Besides, the potential inhibition effect of UCB on ESCC was investigated with both in vitro and in vivo models.ResultsThe higher-level groups of UCB, CB, and TB demonstrated longer OS than their low counterparts, with hazard ratio (HR) values of 0.567 (95% CI: 0.424–0.759), 0.698 (95% CI: 0.522–0.933), and 0.602 (95% CI: 0.449–0.807), respectively. All three forms of bilirubin were identified as independent prognostic factors for patients with ESCC, and they were found to effectively stratify the survival risk of patients at TNM stage III. In vivo and in vitro models further confirmed the inhibitory effect of unconjugated bilirubin (UCB) on the proliferation of ESCC.ConclusionThe findings of our study have shed new light on the prognostic value and biological functions of bilirubin in relation to ESCC. These results may contribute to a better understanding of the underlying mechanisms involved in ESCC tumorigenesis and provide potential therapeutic pathways for treating ESCC.

Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial

Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results of a phase 1b trial of neoadjuvant PD-L1 blockade with adebrelimab in resectable ESCC. Patients received two neoadjuvant doses of adebrelimab followed by surgery. The primary endpoints were safety and feasibility; secondary endpoints included pathologic complete response (pCR) and OS. Our data showed the primary endpoints of safety and feasibility had been met. Common treatment-related adverse events were anorexia (32%) and fatigue (16%), without grade 3 or more adverse events. Of the 30 patients enrolled in the trial, 25 underwent successful resection without surgery delay and 24% had major pathologic responses including a pCR rate of 8%. The 2-year OS was 92%. Responsive patients had an immune-enriched tumor microenvironment phenotype, whereas nonresponsive patients had greater infiltration of cancer-associated fibroblasts at baseline. Clonotypic dynamics of pre-existing intratumoral T cells was a hallmark of responsive patients. These findings provide a rational for neoadjuvant anti-PD-L1 monotherapy as a therapeutic strategy for patients with resectable ESCC. ClinicalTrials.gov identifier: NCT04215471.

High-dose chemotherapy sensitizes locally advanced esophageal squamous cell carcinoma to PD-1 blockade for a higher pathological complete response rate and survival

BackgroundPD-1 inhibitor and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as the first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). The present study aimed to evaluate the efficacy of PD-1 inhibitors plus different dose intensity neoadjuvant chemotherapy in the treatment of locally advanced ESCC. MethodsPatients with locally advanced but resectable thoracic ESCC, staged as T3 or T4a, N0–3, and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes), were enrolled in this study. The eligible patients received tislelizumab plus different dose intensity chemotherapy for a 21-day cycle with repeated 2–4 cycles before surgery. The primary endpoints are pathological complete response (pCR) and major pathological response (MPR), and the secondary endpoints are objective response rate (ORR), disease control rate (DCR), and disease-free survival (DFS). ResultsFrom November 2019 to February 2022, 122 cases received at least two cycles neoadjuvant chemoimmunotherapy and were evaluated by imaging examination. Subsequently, 99 patients underwent surgery and were evaluated by pathological evaluation. According to chemotherapy dose intensity, the patients were divided into three cohorts: cohort 1 (<80% dose intensity), cohort 2 (80–90% dose intensity), cohort 3 (90–100% dose intensity). All surgery patients underwent minimally invasive esophagectomy (MIE). The average pCR was identified in 22.22%; 16% had pCR in cohort 1, 17.65% had pCR in cohort 2, and 30.00% had pCR in cohort 3. MPR was observed in 9 (36.00%) patients in cohort 1, 18 (52.94%) patients in cohort 2, 22 (55.00%) patients in cohort 3. In univariable and multivariable analysis, dose intensity was significantly associated with MPR (p = 0.048) in patients who underwent esophagectomy. For surviving patients, the median follow-up was 13.76 months after esophagectomy. Compared to cohort 1, cohorts 2 and 3 had better DFS (p = 0.056). In addition, the prognosis of patients with MPR was better than that of patients without MPR (p = 0.014). ConclusionsThe robust antitumor activity of neoadjuvant chemoimmunotherapy for locally advanced but resectable thoracic ESCC was confirmed. More than 80% of chemotherapy dose intensity combined with immunotherapy resulted in a high pCR rate and prolonged DFS.

Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma.

Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.

Risk factors for the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma according to genetic polymorphisms related to alcohol and nicotine metabolism.

Multiple development of esophageal squamous-cell carcinoma is explained by field cancerization and is associated with alcohol consumption and smoking. We investigated the association between the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma and genetic polymorphisms related to alcohol and nicotine metabolism. The study group comprised 56 patients with esophageal squamous-cell carcinoma after endoscopic resection. The main variables were the following: (i) cumulative incidence and total number of second primary esophageal squamous-cell carcinoma according to genetic polymorphisms in alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6; and (ii) risk factors of second primary esophageal squamous-cell carcinoma identified using a multivariate Cox proportional-hazards model. The frequencies of alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6 genetic polymorphisms in the buccal mucosa were analyzed. The median follow-up was 92.8months (range: 2.7-134.2). Slow-metabolizing alcohol dehydrogenase 1B was associated with a higher 7-year cumulative incidence of second primary esophageal squamous-cell carcinoma (fast-metabolizing alcohol dehydrogenase 1B vs slow-metabolizing alcohol dehydrogenase 1B: 20.5% vs 71.4%, P=0.006). Slow-metabolizing alcohol dehydrogenase 1B (relative risk [95% confidence interval]: 3.17 [1.49-6.73]), inactive aldehyde dehydrogenase 2 (2.17 [1.01-4.63]) and poorly-metabolizing cytochrome P450 2A6 (4.63 [1.74-12.33]) had a significantly higher total number of second primary esophageal squamous-cell carcinoma per 100 person-years. In the multivariate Cox proportional-hazards model, slow-metabolizing alcohol dehydrogenase 1B was a significant risk factor of the development of second primary esophageal squamous-cell carcinoma (hazard ratio 9.92, 95% confidence interval: 2.35-41.98, P=0.0018). Slow-metabolizing alcohol dehydrogenase 1B may be a significant risk factor for the development of second primary esophageal squamous-cell carcinoma. In addition, inactive aldehyde dehydrogenase 2 and poorly-metabolizing cytochrome P450 2A6 may be important factors.