Neoadjuvant Chemotherapy or Adjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Chemotherapy and chemoradiation have become essential adjuncts to improve the survival of patients with resectable esophageal squamous cell carcinoma (ESCC) in the perioperative period. Although preoperative treatment plus surgery is commonly used, controversy remains regarding the optimal treatment strategy for patients with locally advanced ESCC. METHODS: A retrospective review of clinical stage II and III ESCC patients who underwent esophagectomy at Henan Cancer Hospital between October 2014 and October 2017 was performed. The patients were divided into a neoadjuvant chemotherapy (NAC) group and an adjuvant chemotherapy (AC) group. Propensity score matching (PSM) was used to exclude confounders. Survival was estimated using Kaplan‒Meier analysis and compared by the log-rank test. The Cox proportional hazards regression model was used for both the univariate and multivariate analyses. RESULTS: A total of 684 patients were enrolled, including 365 (53.4%) patients in the NAC group. After PSM, 294 pairs of patients were left. NAC prolonged the OS (not reached versus 57.3 months, P = 0.002) and DFS (57.2 vs. 36.4 months, P = 0.010) and decreased the total rate of recurrence (50.1% vs. 59.2%, P = 0.025) and local recurrence (27.9% vs. 36.7%, P = 0.022) compared with AC. The multivariable analyses showed that NAC plus surgery modality was an independent predictor for improved OS (HR: 0.582, 95% CI: 0.467-0.786, P = 0.001). CONCLUSION: NAC plus surgery prolonged OS and DFS, and significantly decreased the total rate of recurrence compared with surgery plus AC in patients with clinical stage II and III ESCC.

A multicenter randomized, controlled clinical trial of adjuvant sintilimab for esophageal squamous cell carcinoma.

No adjuvant treatment has been established for patients who remain at high risk of recurrence and incidental pathologic lymph node metastasis for esophageal squamous cell carcinoma (ESCC). In this open-label, multicenter, phase III, randomized controlled trial, ESCC patients who did not achieve pathologic complete response after neoadjuvant chemotherapy plus surgery and clinical T1-2 N0 patients with incidental pathologic lymph node metastasis following initial surgery were randomized at a 2:1 ratio to receive either a sintilimab regimen or observational management (NCT05495152). The primary end point was disease-free survival for all randomized patients. The results of this randomized controlled trial addressed controversy regarding the survival benefits of adjuvant sintilimab treatment for patients with resected locally advanced ESCC. Clinical Trial Registration: NCT05495152 (ClinicalTrials.gov).

Patterns and Influence of Lymph Nodal Metastases After Neoadjuvant Chemotherapy and Surgery for Thoracic Esophageal Squamous Cell Carcinoma.

PURPOSE: The purpose of this retrospective study was to define the pattern of lymph nodal metastases in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemotherapy (NCT) followed by esophagectomy and to evaluate its influence on prognosis. METHODS: A total of 398 patients with clinical stage T3N0 or T1-3N+ ESCC who underwent NCT and radical esophagectomy with two-field lymphadenectomy were included. The distribution and frequency of metastases were counted separately for each lymph node station. The ypN stage, number of positive lymph node stations and lymph node stations with a metastasis rate greater than 5% were analyzed by using univariate Cox regression, followed by separate multivariable Cox regression analyses after adjusting for various clinical factors. RESULTS: Lymph node metastases were most frequently observed in the right upper paratracheal (16.8%) and left gastric artery (13.1%) stations. Multivariable models controlling for clinical factors showed that ypN stage remained a significant independent predictor of survival (N1 vs. N0: hazard ratio [HR], 2.30, 95% confidence interval [CI] 1.38-3.83, P < 0.001; N2 vs. N0: HR, 3.76, 95% CI 2.21-6.38, P < 0.001; N3 vs. N0: HR, 7.14, 95% CI 3.78-13.48, P < 0.001). The model from the multivariable analysis with the highest c-index score, indicating superior discriminatory preference, was ypN stage (c-index, 0.72). CONCLUSIONS: The pattern and influence of lymph node metastases after NCT will provide guidance on the extent of lymphadenectomy. Common positive lymph node stations for thoracic ESCC after NCT include the paratracheal, subcarinal, paraesophageal, paracardial, and left gastric artery stations.

Initial experience with modified en bloc robot-assisted minimally invasive oesophagectomy for thoracic oesophageal squamous cell carcinoma.

BACKGROUND: The feasibility and safety of en bloc robot-assisted minimally invasive oesophagectomy (RAMIE) need to be verified. METHODS: Forty-seven patients who received conventional RAMIE and 31 who received modified en bloc RAMIE at Henan Cancer Hospital were included in the study cohort. We compared the perioperative outcomes of conventional RAMIE and modified en bloc RAMIE. RESULTS: Compared with the conventional RAMIE group, the en bloc RAMIE group yielded a higher total number of lymph nodes (p = 0.001), especially thoracic lymph nodes (p = 0.025) and left recurrent laryngeal nerve (RLN) lymph nodes (p = 0.005). No notable differences were found in the rate of total complications (p = 0.663) or RLN injury (p = 0.891) between the two groups. The preoperative and postoperative serological indicators were comparable between the two groups. CONCLUSIONS: Modified en bloc RAMIE was safe and feasible for patients with oesophageal squamous cell carcinoma and improved lymph node dissection, especially thoracic and left RLN lymph node dissection.

Survival impact of the number of lymph nodes dissection in patients receiving neoadjuvant chemotherapy for esophageal squamous cell carcinoma.

This study aimed to investigate the survival impact of the number of lymph nodes dissection (LND) in patients receiving neoadjuvant chemotherapy (NCT) for esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed the clinical pathological data and survival of 407 ESCC patients who underwent esophagectomy after NCT between January 2015 and December 2016. The relationship between the number of LNDs and 5-year overall survival (OS) or disease-free survival (DFS) was plotted by using restricted cubic spline analysis. A Cox proportional hazards regression model was used to identify prognostic factors of OS and DFS. We observed an obvious non-linear relationship between LND and the hazard ratios (HRs) for OS (P = 0.0015) and DFS (P < 0.001) of all the patients. In the multivariate analysis of OS and DFS, the number of LNDs (greater than 28 and less than 46) had a significant protective effect on survival (OS: HR: 0.61, 95% CI: 0.42-0.88, P = 0.007; DFS: HR: 0.50, 95% CI: 0.36-0.70, P < 0.001). For patients with nodal metastases, it was also an independent prognostic factor for OS (HR, 0.56, 95% CI, 0.35-0.90, P = 0.017) and DFS (HR, 0.42, 95% CI, 0.28-0.65, P < 0.001). Some degree of lymphadenectomy after NCT was beneficial in improving 5-year OS and DFS for ESCC patients with nodal metastases. For patients with nodal negativity, more extended lymphadenectomy did not improve patient survival.

Perioperative Outcomes and Learning Curve of Robot-Assisted McKeown Esophagectomy.

BACKGROUND: This study aimed to evaluate the perioperative outcomes of patients undergoing robot-assisted McKeown esophagectomy (RAME) and the learning curves of surgeons performing RAME at a single center. METHODS: Perioperative outcomes of RAME and video-assisted McKeown esophagectomy (VAME) were compared after eliminating confounding factors by propensity score matching (PSM). The cumulative sum (CUSUM) method was used to evaluate the learning curves of RAME for a single surgical team. RESULTS: In general, a total of 198 patients with esophageal cancer (RAME: 45 patients, VAME: 153 patients) were included in this study, and 43 pairs of patients receiving RAME or VAME were matched using 1:1 PSM analysis. Those in the RAME group had more lymph nodes dissected in the total lymph nodes (median 29.0 vs. 26.0, P = 0.011) and the upper mediastinum (median 8.0 vs. 6.0, P < 0.001), especially the left recurrent laryngeal nerve (RLN) lymph node (median 4.0 vs. 2.0, P = 0.001). According to the trend of the CUSUM plot, the learning curve was divided into two stages at the 20th RAME procedure. After mastering the learning curve, RAME harvested a significantly higher number of upper mediastinal lymph nodes (median 9.0 vs. 6.0, P = 0.001), left RLN lymph nodes (median 5.0 vs. 3.5, P = 0.003), and right RLN lymph nodes (median 4.0 vs. 2.0, P = 0.002). Meanwhile, the incidence of postoperative pneumonia in the proficiency phase was significantly lower than that in the learning phase (4.0% vs. 25.0%, P = 0.04). CONCLUSIONS: RAME improved left RLN lymph node dissection. Surgeons with extensive VAME experience need at least 20 cases to achieve early proficiency in RAME.

Adjuvant Chemotherapy for Node-positive Esophageal Squamous Cell Carcinoma Improves Survival.

BACKGROUND: The aim of this study was to evaluate the survival benefits of adjuvant chemotherapy in patients with positive lymph nodes after esophagectomy for esophageal squamous cell carcinoma. METHODS: Patients who underwent esophagectomy for esophageal cancer in the Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) in Zhengzhou, China from 2013 to 2017 were selected for this retrospective cohort study. Patients with positive lymph nodes were grouped into the surgery alone group or the adjuvant chemotherapy group. Propensity score matching (1:1) was used to minimize baseline differences. RESULTS: Among the 5118 patients who underwent esophagectomy, 792 patients were enrolled in the study. After matching, 253 (of 476) patients (adjuvant chemotherapy group) and 253 (of 316) patients (surgery alone group) were included. The median overall survival was significantly prolonged in the adjuvant chemotherapy group (54.0 months; 95% CI, 41.1-66.9 months) compared with the surgery alone group (28.0 months; 95% CI, 22.4-33.6 months) (P < .001). A significant difference was also observed in median disease-free survival between the 2 groups (adjuvant chemotherapy group, 33.0 months [95% CI, 20.8-45.2 months] compared with the surgery alone group, 22.0 months [95% CI, 17.0-27.0 months]; P = .007). In a multivariable analysis, receiving adjuvant chemotherapy (P < .001) was significantly associated with a reduced risk of death, and dissection of more than 6 lymph node stations (P = .05) was marginally associated with a reduced risk of death. CONCLUSIONS: Postoperative adjuvant chemotherapy improves the overall survival and disease-free survival of patients with resected esophageal squamous cell carcinoma with positive lymph nodes.

Application of four nutritional risk indexes in perioperative management for esophageal cancer patients.

PURPOSE: The Prognostic Nutritional Index (PNI), Nutritional Risk Index (NRI), Geriatric Nutritional Risk Index (GNRI), and Controlling Nutritional Status (CONUT) score were devised for quantifying nutritional risk. This study evaluated their properties in detecting compromised nutrition and guiding perioperative management of esophageal cancer patients. METHODS: A prospective institutional database of esophageal cancer patients was reviewed and analyzed. Compromised nutritional status was defined as PNI < 50, NRI < 97.5, GNRI < 92, or CONUT score ≥ 4, respectively. The malnutrition diagnosis consensus established by the European Society of Clinical Nutrition and Metabolism (ESPEN 2015) was selected as reference. Multivariable logistic regression and receiver operating characteristic curve analysis were used. External validation was conducted. RESULTS: After reviewing the 212-patient database, 192 patients were finally included. Among the four nutritional indexes, the GNRI < 92 showed highest sensitivity (72.0%), specificity (78.9%), and consistency (AUC 0.754, 95% CI 0.672-0.836) with malnutrition diagnosed by ESPEN 2015. The GNRI < 92 showed comparable performance with ESPEN 2015 in recognizing decreased fat mass, fat-free mass, and skeletal muscle mass (all P < 0.01). Both the GNRI < 92 and ESPEN 2015 showed good property in predicting major complications, infectious complications, overall complications and delayed hospital discharge (all P < 0.01), better than PNI < 50, NRI < 97.5, and CONUT score ≥ 4. Regarding the external validation, a retrospective analysis of 155 esophageal cancer patients confirmed the better performance of GNRI < 92 in predicting perioperative morbidities than other 3 nutritional indexes. CONCLUSION: The GNRI was optimal in perioperative management of esophageal cancer patients among the four nutritional indexes and was an appropriate alternative to ESPEN 2015 for simplifying nutritional assessment.

A phase III study on neoadjuvant chemotherapy versus neoadjuvant toripalimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: Henan Cancer Hospital Thoracic Oncology Group 1909 (HCHTOG1909).

BACKGROUND: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACR) are the standard treatments for esophageal squamous cell carcinoma (ESCC). However, the 5-year overall survival (OS) rate is still far from satisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in Henan Cancer Hospital. ICIs combined with NAC may usher in a new era and may benefit locally advanced, resectable ESCC patients. METHODS: A two-arm phase III trial was launched in April 2020 in Henan Cancer Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future. DISCUSSION: This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment. TRIAL REGISTRATION: NCT04280822 (https://www.clinicaltrials.gov/ct2/show/NCT04280822). Registered title: "A Phase III, Randomized Controlled Study of Neo-adjuvant Toripalimab (JS001) in Combination with Chemotherapy versus Neo-adjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma". Version 1.0/Nov. 21, 2019.

Highlighting sarcopenia management for promoting surgical outcomes in esophageal cancers: Evidence from a prospective cohort study.

BACKGROUND: Studies have provided controversial and limited knowledge regarding the impact of sarcopenia on surgical outcomes in esophageal cancers due to retrospective study designs and single muscle-mass assessment. This prospective cohort study aimed to resolve these issues. METHODS: Bioelectrical impedance analysis, handgrip strength measurement, and the 4-m walking test were conducted before surgery. Sarcopenia was diagnosed as low appendicular skeletal muscle mass index (<7.0 kg/m2 in men and <5.7 kg/m2 in women) plus low handgrip strength (<26 kg in men and <18 kg in women) and/or low gait speed (<0.8 m/s). Presarcopenia was diagnosed as either: (1) solely low muscle mass index; or (2) solely low handgrip strength and/or gait speed. Endpoints included perioperative biochemical indicators, postoperative complications, and the recovery of postoperative quality of life (QOL). RESULTS: In total, 212 patients were enrolled, including 55 (25.9%) and 60 (28.3%) patients diagnosed with sarcopenia and presarcopenia, respectively. The presarcopenic and normal patients showed a similar risk of postoperative complications and were combined. Despite similar baseline levels, sarcopenic patients (vs. non-sarcopenic) showed decreased prealbumin on postoperative day (POD) 1, decreased albumin on PODs 1, 3, and 5, and delayed recovery of lymphocyte counts (all P < 0.05). The levels of C-reactive protein in sarcopenic patients was lower than in non-sarcopenic patients on POD 1 (P = 0.010) but higher on POD 5 (P = 0.001). Multivariate analyses demonstrated the independent predictive value of sarcopenia for overall complications (P < 0.001), major complications (Clavien-Dindo grade ≥ III, P = 0.001), and delayed hospital discharge (>12 days, P < 0.001). Sarcopenia was demonstrated as a risk factor for deteriorated global QOL (P = 0.001), physical (P = 0.001) and role functions (P = 0.006), and severe fatigue (P = 0.004) at four weeks after surgery. CONCLUSIONS: Sarcopenia was associated with poor metabolic stress and immune responses surrounding esophagectomy and was a potential target for reducing complications and promoting recovery of QOL.

Clinical evaluation of right recurrent laryngeal nerve nodes in thoracic esophageal squamous cell carcinoma.

BACKGROUND: The accuracy of clinical N staging of esophageal squamous cell carcinoma is suboptimal. As an important station of lymph node metastasis, station C201 (right recurrent laryngeal nerve nodes) has rarely been evaluated alone. We aimed to explore an effective way to evaluate the right recurrent laryngeal nerve nodes in thoracic esophageal squamous cell carcinoma. METHODS: We retrospectively analyzed 628 thoracic esophageal squamous cell carcinoma patients who underwent radical resection without neoadjuvant therapy from two Chinese cancer centers. The diameter of the short axis of the largest right recurrent laryngeal nerve node (DC201) was measured on contrast-enhanced multi-slice computed tomography (MSCT). Right recurrent laryngeal nerve nodes were examined by postoperative pathologic results. The receiver operating characteristic (ROC) curve was generated to assess the diagnostic capabilities of DC201 to determine the right recurrent laryngeal nerve nodes status. RESULTS: ROC curve analysis revealed that the optimal cut-off point of DC201 was 6 mm, with an area under curve (AUC), sensitivity, specificity, and Youden index of 0.896, 71.9%, 88.8%, and 0.607 respectively. When the cut-off point of DC201 was set to 10 mm, sensitivity, specificity and the Youden index were 14.1%, 99.6% and 0.137 respectively. Among 128 patients with right recurrent laryngeal nerve node metastasis, 71 and 108 patients had the largest right recurrent laryngeal nerve node located above the suprasternal notch level and in the tracheoesophageal groove respectively. CONCLUSIONS: When DC201 ≥6.0 mm instead of DC201 ≥10 mm was used to dictate the right recurrent laryngeal nerve nodes metastasis, contrast-enhanced MSCT could evaluate the status of right recurrent laryngeal nerve nodes with high sensitivity and specificity. The largest right recurrent laryngeal nerve nodes were mainly located in the tracheoesophageal groove and/or above the suprasternal notch.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma: a single-Centre, open-label, randomized, controlled, clinical trial (HCHTOG1903).

BACKGROUND: Neoadjuvant therapy plus oesophagectomy has been accepted as the standard treatment for patients with potentially curable locally advanced oesophageal cancer. No completed randomized controlled trial (RCT) has directly compared neoadjuvant chemotherapy and neoadjuvant chemoradiation in patients with oesophageal squamous cell carcinoma (ESCC). The aim of the current RCT is to investigate the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiotherapy plus surgery on overall survival for patients with resectable locally advanced ESCC. METHODS: This open label, single-centre, phase III RCT randomized patients (cT2-T4aN + M0 and cT3-4aN0M0) in a 1:1 fashion to receive either the CROSS regimen (paclitaxel 50 mg/m2; carboplatin (area under the curve = 2), q1w, 5 cycles; and concurrent radiotherapy, 41.4 Gy/23 F, over 5 weeks) or neoadjuvant chemotherapy (paclitaxel 175 mg/m2; and cisplatin 75 mg/m2, q21d, 2 cycles). Assuming a 12% 5-year overall survival difference in favour of the CROSS regimen, 80% power with a two-sided alpha level of 0.05 and a 5% dropout each year for an estimated 3 years enrolment, the power calculation requires 456 patients to be recruited (228 in each group). The primary endpoint is 5-year overall survival, with a minimum 5-year follow-up. The secondary endpoints include 5-year disease-free survival, toxicity, pathological complete response rate, postoperative complications, postoperative mortality and quality of life. A biobank of pre-treatment and resected tumour tissue will be built for translational research in the future. DISCUSSION: This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies. TRIAL REGISTRATION: NCT04138212, date of registration: October 24, 2019.

Early oral feeding following esophagectomy.

Nutritional support for patients with esophagectomy is very important especially for patients with malnutrition. But there is significant variation in nutritional support between different hospitals. Traditionally, 5 to 7 days of nil by mouth is required to allow healing of the anastomosis after esophagectomy; a feeding tube (usually jejunostomy tube) placed before or during the operation provides enteral access for patients with esophagectomy. However, there is no consensus of the timing of oral intake after esophagectomy. We reviewed the published data about early oral feeding (EOF) after esophagectomy. At present, there were only four studies, including two randomized studies, investigating the feasibility and safety of EOF for patients with esophagectomy. The results of the current studies show that EOF after esophagectomy do not increase postoperative complications and motility. However, evidence from large multicenter randomized controlled clinical trials is still lacking. In the future, the long-term outcomes, including body weight loss, quality of life (QOL), laboratory nutritional markers and survival, should be investigated in the field of EOF protocols. EOF after esophagectomy may require the application of the most recent knowledge and the perioperative practice of multi-disciplinary team medical care, according to the situation of each medical center.

Impact of an Early Oral Feeding Protocol on Inflammatory Cytokine Changes After Esophagectomy.

BACKGROUND: The aim of the current study was to investigate the impact of early oral feeding (EOF) on inflammatory cytokine levels after McKeown minimally invasive esophagectomy (MIE) for cancer. METHODS: This study was based on a randomized controlled trial (NCT01998230). Patients with esophageal cancer who received McKeown MIE were randomly allocated into a group that started oral feeding on postoperative day (POD) 1 (EOF group) or a second group that received nil by mouth until 7 days after operation (late oral feeding [LOF] group). We chose 86 patients, 46 patients in the EOF group and 40 patients in the LOF group, in which to analyze inflammatory cytokine levels (interleukin [IL]-6, IL-8, tumor necrosis factor-a [TNF-α], and monocyte chemotactic protein-1 [MCP-1]). RESULTS: The EOF and LOF groups exhibited similar preoperative IL-6, IL-8 TNF-α, and MCP-1 levels. The levels of the four inflammatory cytokines at PODs 1 and 3 were significantly higher than the preoperative levels (all p < 0.001). At POD 5 the levels of all four inflammatory cytokines were decreased compared with those at PODs 1 and 3. At PODs 3 and 5 the levels of IL-6, IL-8, and TNF-α were significantly lower in the EOF group than in the LOF group (all p < 0.05). At POD 3 the MCP-1 levels in the EOF group were significantly lower than those in the LOF group (all p < 0.05). CONCLUSIONS: Compared with conventional rehabilitation programs the EOF protocol may decrease stress response after McKeown MIE.

Is laryngeal mask airway general anesthesia feasible for minimally invasive esophagectomy?

Minimally invasive esophagectomy (MIE) has been identified as an oncological method with lower mortality and morbidity. This procedure is usually performed under general anesthesia using double endotracheal tube intubation and one-lung ventilation for a good visualization like other video-assisted thoracoscopic surgery (VATS). However, it is difficult to differentiate weather the postoperative hoarseness is caused by intubation or by recurrent laryngeal nerve injury during operation, and some complications related to intubation also are the focus of thoracic surgeons. Recently, VATS without tracheal intubation were reported to be feasible and safe in a series of VATS procedures, including management of pneumothorax, wedge resection of pulmonary tumors, excision of mediastinal tumors, lung reduction surgery and lobectomy. However, there is no report about its use in MIE. In December of 2012, we successfully applied nonintubated laryngeal mask airway (LMA) general anesthesia in MIE for three patients with esophageal cancer. Here, we retrospectively report the tentative results.