Lymph node metastatic patterns and the development of multidisciplinary treatment for esophageal cancer.

Abundant lymphatic flow and the anatomical location of the esophagus can result in the widespread distribution of lymph node metastasis of esophageal cancer from the cervical to the abdominal field. Historically, the Japan Esophageal Society and American Joint Committee on Cancer offer two different classifications of lymph node group location surrounding the esophagus. The location of sentinel lymph nodes in midthoracic esophageal cancer reflects the variety of lymphatic drainage routes. In fact, in cT1N0 esophageal cancer, pathological lymph node metastasis has been observed from the cervical to the abdominal field, and the locations were shown to be closely linked to the primary tumor location in advanced stages. While the impact of histology on the distribution of LN metastasis has been extensively debated, a recent prospective study on esophagogastric junction cancer found that metastatic patterns did not differ by histology. Thoracic duct lymph nodes were defined as one of the regional lymph node stations in the mediastinum. Although lymph node metastasis around the thoracic duct has occasionally been observed, the oncologic impact of thoracic duct lymph node dissection has not been fully elucidated. To eradicate tumors locoregionally, three-field lymph node dissection, a strategy for extended lymph node clearance, has been established. In esophagectomy, three-field lymph node dissection is defined as a procedure for complete regional cervico-thoraco-abdominal lymph node dissection. However, its therapeutic efficacy must be evaluated based on the balance between oncological outcomes and possible added surgical risk. To further improve survival, multidisciplinary treatment consisting of surgery, chemotherapy, and radiotherapy has been established worldwide as a standard treatment for esophageal cancer. Now that neoadjuvant therapy followed by esophagectomy is the standard, adding adjuvant therapy including immunotherapy could be a promising treatment option. The ideal combination of various multidisciplinary treatment approaches and extensive LN dissection need to be established to improve the oncological outcomes for EC patients.

Surgical outcomes and quality of life assessment of esophagectomy for cancer with colon conduit via retrosternal route.

PURPOSE: Colon conduit is an alternative to a gastric conduit for esophagectomy in patients that stomach is not available. Surgical technique is complex and has a high risk of morbidities and mortality. Outcomes of patients are still lacking in the literature, thus aims of this study are to evaluate the safety, feasibility and long-term functional outcomes of patients who underwent esophagectomy for cancer with colon conduit via retrosternal route. METHODS: Twenty-six patients underwent operation between August 2016 and June 2021 for malignancies. Minimally invasive esophagectomy and laparotomy were performed in accordance with the 2017 Japan Esophageal Society's guidelines. Colonic interposition was used for esophageal replacement. Outcomes were technical success, complications assessed using Clavien-Dindo classification, and patient's quality of life (QOL) based on EORTC-QOL-OES18 questionnaire. RESULTS: Mean age was 56.0 ± 9.9 years and 21 patients (80.8%) were men. Mean operating time was 432 ± 66 min. Technical success was 100%. The average number of resected lymph nodes was 26 ± 14. Twelve patients (46.2%) experienced postoperative complications: 7/12 were classified as grade I-II, 3/12 as grade III, 1/12 as grade IV, and 1/12 as grade V (death). Patient's QOL improved during the follow-up period with median (25-75th percentiles) global EORTC-QOL-OES18 score was 29 (17-34); 13 (9-21), and 9 (6-16) at 3, 6, and 12 months, respectively. During the follow-up period, there were 4 late complications, 3 lymphatic recurrences, 5 distant metastases, and 6 deaths. CONCLUSIONS: Colon conduit via retrosternal route after esophagectomy is feasible, safe, and could provide acceptable long-term functional outcomes.

Short- and long-term follow-up of patients with non-neoplastic esophageal perforation.

PURPOSE: Esophageal perforation is associated with high morbidity and mortality. In addition to surgical treatment, endoscopic endoluminal stent placement and endoscopic vacuum therapy (EVT) are established methods in the management of this emergency condition. Although health-related quality of life (HRQoL) is becoming a major issue in the evaluation of any therapeutic intervention, not much is known about HRQoL, particularly in the long-term follow-up of patients treated for non-neoplastic esophageal perforation with different treatment strategies. The aim of this study was to evaluate patients' outcome after non-neoplastic esophageal perforation with focus on HRQoL in the long-term follow-up. METHODS: Patients treated for non-neoplastic esophageal perforation at the University Hospital Cologne from January 2003 to December 2014 were included. Primary outcome and management of esophageal perforation were documented. Long-term quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI), the Health-Related Quality of Life Index (HRQL) for patients with gastroesophageal reflux disease (GERD), and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires for general and esophageal specific QoL (QLQ-C30 and QLQ-OES18). RESULTS: Fifty-eight patients were included in the study. Based on primary treatment, patients were divided into an endoscopic (n = 27; 46.6%), surgical (n = 20; 34.5%), and a conservative group (n = 11; 19%). Short- and long-term outcome and quality of life were compared. HRQoL was measured after a median follow-up of 49 months. HRQoL was generally reduced in patients with non-neoplastic esophageal perforation. Endoscopically treated patients showed the highest GIQLI overall score and highest EORTC general health status, followed by the conservative and the surgical group. CONCLUSION: HRQoL in patients with non-neoplastic esophageal perforation is reduced even in the long-term follow-up. Temporary stent or EVT is effective and provides a good alternative to surgery, not only in the short-term but also in the long-term follow-up.

QOLEC2: a randomized controlled trial on nutritional and respiratory counseling after esophagectomy for cancer.

BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.

Exploratory study of clinical effectiveness and safety of TJ-116 bukuryoingohangekobokuto for anxiety and postoperative water brash in esophageal cancer patients (TJ116E).

BACKGROUND: Patients with esophageal cancer suffer from anxiety in the perioperative period surrounding esophagectomy; this may increase the risk of postoperative complications. In particular, postoperative aspiration pneumonia carries a high risk of hospital mortality. Bukuryoingohangekobokuto (BRIHK) is a traditional Japanese medicine formula used to treat anxiety, the feeling of a foreign body in the esophagus, and water brash. We hypothesize that BRIHK might be effective for both anxiety and water brash in perioperative patients with esophageal cancer. The aim of this study is to evaluate the efficacy and safety of BRIHK compared to a placebo for anxiety and water brash in perioperative esophageal cancer patients. METHOD/DESIGN: This will be a single-center, single blind, placebo-controlled randomized clinical trial. Twenty-four patients with esophageal cancer undergoing radical resection surgery will be registered to participate, then randomly and blindly assigned to the BRIHK treatment group or control group. Patients will be administered BRIHK or the placebo from 2 weeks before to 6 weeks after surgery. Primary outcome measures will be anxiety and depression (assessed using the Hospital Anxiety and Depression Scale), and water brash (assessed using the 10-item Eating Assessment Tool, Esophagus and Stomach Surgery Symptom Scale, and videofluoroscopy swallowing measurement). Incidences of aspiration pneumonia will be noted and abdominal gas volume, inflammatory markers, and nutrition status will be evaluated. DISCUSSION: This investigative study will provide clinical evidence of BRIHK administration for anxiety and water brash, which might improve mental distress and reduce postoperative mortality. TRIAL REGISTRATION: The protocol and progress are registered on the Japan Registry of Clinical Trials (jRCT s021190001) and University Hospital Medical Information Network (UMIN000031330). The protocol was approved by the Japanese Ministry of Health, Labour and Welfare certified clinical research review board, Tohoku University (CRB2180001).

Esophagus and Gastrointestinal Junction Tumors.

Esophageal squamous cell carcinoma and adenocarcinoma account for 95% of all esophageal malignancies. The rates of esophageal adenocarcinoma have increased in Western countries, making it the predominant type of esophageal cancer. Treatment of both types of cancer has transformed to a more minimally invasive approach, with endoscopic methods being used for superficial cancers and more frequent use of video-assisted and laparoscopic modalities for locally advanced tumors. The current National Comprehensive Cancer Network guidelines advocate a trimodal approach to treatment, with neoadjuvant chemoradiation and surgery for locally advanced cancers.

Surgery Is Associated With Survival Benefit in T4a Esophageal Adenocarcinoma: A National Analysis.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend consideration of surgery for clinical T4a esophageal adenocarcinoma. There are limited data on the outcomes of patients with T4a adenocarcinoma treated with surgery vs definitive chemoradiation, however. METHODS: The National Cancer Database was used to identify patients from 2010-2015 with clinical T4aN0-3M0 esophageal adenocarcinoma, and grouped by receipt of surgery (with or without perioperative therapy) or definitive, concurrent chemoradiation. Patients receiving incomplete definitive therapy or with missing survival information were excluded. Overall survival was evaluated with Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Of 182 patients in the study, 85 (47%) underwent esophagectomy and 97 (53%) underwent chemoradiation. In the surgery cohort, 79 patients (93%) received perioperative chemotherapy. Unadjusted and multivariable analyses demonstrated a significant survival benefit associated with surgery compared with definitive chemoradiotherapy (adjusted hazard ratio 0.32; 95% confidence interval 0.21, 0.50). A 1:1 propensity score-matched analysis of 63 patient pairs also revealed a significant overall survival benefit with surgery compared with chemoradiotherapy alone (hazard ratio 0.26; 95% confidence interval 0.16, 0.43). CONCLUSIONS: In this national analysis, surgery for cT4a esophageal adenocarcinoma was associated with improved outcomes when compared with definitive chemoradiation. Surgery should be considered for medically fit patients with cT4aN0-3M0 esophageal adenocarcinoma.

A propensity-score matching analysis comparing long-term survival of surgery alone and postoperative treatment for patients in node positive or stage III esophageal squamous cell carcinoma after R0 esophagectomy.

BACKGROUND: Surveillance was recommended for patients after R0 esophagectomy by National Comprehensive Cancer Network (NCCN) guidelines. However, local failure was high in locally advanced patients (48-78%). The present study aimed to determine whether adjuvant treatment improved survival for stage IIb-III thoracic esophageal squamous cell carcinoma (TESCC). METHODS: A retrospective review of patients diagnosed as esophageal carcinoma at the Chinese Academy of Medical Sciences Cancer hospital, between January 2004 and December 2011, was performed. A database compiling 975 patents with node positive or stage III thoracic esophageal carcinoma after R0 surgery with or without postoperative radiation/chemoradiation was created. A 1:1 matched study group was generated by the Greedy method after propensity score matching (PSM) analysis. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were using the Cox proportional hazards regression model. RESULTS: 975 patients were enrolled in the study, 510 patients (52.3%) did not receive any postoperative treatment after R0 surgery and 465 patients had either postoperative chemoradiation or radiotherapy. Median follow-up was 69.2 months. After PSM, 222 well-balanced patients in each group demonstrated the same results. The 3-year, 5-year survival rates and median survival in surgery group (33.0%, 26.4%, 24.3 months) were inferior to those in postoperative treatment group (48.3%, 37.1% and 34.3 months), (P = 0.002). Compared with radiotherapy, postoperative chemoradiation did not improve DFS and OS (P = 0.692; P = 0.368). N stage and adjuvant treatment are independent prognostic factors. CONCLUSIONS: Adjuvant treatment could improve survival for patients with stage IIb-III TESCC.

Thyroid and Parathyroid Functions After Pharyngo-Laryngo-Esophagectomy for Cervical Esophageal Cancer.

BACKGROUND: Cervical esophageal cancer (CEC) patients whose larynx function cannot be preserved often undergo chemoradiotherapy, whereas those with residual or recurrent lesions undergo a pharyngo-laryngo-esophagectomy (PLE); however, some need to undergo a pharyngolaryngectomy with total esophagectomy (PLTE) for synchronous or metachronous esophageal cancer. We retrospectively evaluated the relationship between preoperative irradiation (or the extent of esophageal resection) and postoperative endocrine complications in CEC, including hypothyroidism and hypoparathyroidism. METHODS: The cancers of 35 (5.4%) of 678 esophageal cancer patients with esophagectomy treated in 2000-2017 were CECs. We also analyzed the 17 cases of CEC patients who underwent PLE with thyroid lobectomy-11 with irradiation before PLE and 6 without irradiation. Seven patients underwent a PLTE. RESULTS: Hypothyroidism and hypoparathyroidism occurred in 14 and 12 patients, respectively. The hypothyroidism rate was significantly higher in patients with irradiation versus those without irradiation (100% vs. 50%; p = 0.010), and the hypoparathyroidism rate was significantly higher in the PLTE versus non-PLTE patients (100% vs. 50%; p = 0.026). The mean levothyroxine dosage was 1.60 µg/kg/day in the PLE patients post-irradiation. CONCLUSIONS: Irradiation appears to be a risk factor for hypothyroidism after PLE with thyroid lobectomy, while PLTE might have some effect on hypoparathyroidism. Due to vocal function loss, PLE patients may experience symptoms from endocrine complications. Levothyroxine treatment soon after PLE for post-irradiation patients and patients requiring as-needed calcium or vitamin D supplementation based on biochemical hypocalcemia for PLE (especially PLTE), may be effective in preventing symptomatic endocrine complications.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial.

NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.

Perioperative enteral supplementation with glutamine, fiber, and oligosaccharide reduces early postoperative surgical stress following esophagectomy for esophageal cancer.

BACKGROUND: We clarified the effects of perioperative enteral supplementation with glutamine, fiber, and oligosaccharide (GFO) after an esophagectomy on preventing surgical stress. METHODS: Of 326 patients with esophageal cancer, 189 received GFO administration (GFO group) and 137 did not (control group). The propensity score matching method was used to identify 89 well-balanced pairs of patients to compare postoperative laboratory parameters and clinical and postoperative outcomes. RESULTS: The duration of the systemic inflammatory response syndrome (SIRS) was significantly shorter in the GFO group compared to the control group (p = 0.002). Moreover, the lymphocyte/neutrophil ratio (L/N ratio) had significantly recovered in the GFO group on postoperative day-3, and the CRP value was significantly lower in the GFO group than that in the control group on postoperative day-2. CONCLUSIONS: Perioperative use of enteral supplementation with glutamine, fiber, and oligosaccharide likely contributes to a reduction in early surgical stress after an esophagectomy. These beneficial effects can bring about early recovery from postoperative immunosuppressive conditions after radical esophagectomy.

Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial.

OBJECTIVES: Observational studies suggest an association between vitamin D deficiency and adverse outcomes of critical illness and identify it as a potential risk factor for the development of lung injury. To determine whether preoperative administration of oral high-dose cholecalciferol ameliorates early acute lung injury postoperatively in adults undergoing elective esophagectomy. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Three large U.K. university hospitals. PATIENTS: Seventy-nine adult patients undergoing elective esophagectomy were randomized. INTERVENTIONS: A single oral preoperative (3-14 d) dose of 7.5 mg (300,000 IU; 15 mL) cholecalciferol or matched placebo. MEASUREMENTS AND MAIN RESULTS: Primary outcome was change in extravascular lung water index at the end of esophagectomy. Secondary outcomes included PaO2:FIO2 ratio, development of lung injury, ventilator and organ-failure free days, 28 and 90 day survival, safety of cholecalciferol supplementation, plasma vitamin D status (25(OH)D, 1,25(OH)2D, and vitamin D-binding protein), pulmonary vascular permeability index, and extravascular lung water index day 1 postoperatively. An exploratory study measured biomarkers of alveolar-capillary inflammation and injury. Forty patients were randomized to cholecalciferol and 39 to placebo. There was no significant change in extravascular lung water index at the end of the operation between treatment groups (placebo median 1.0 [interquartile range, 0.4-1.8] vs cholecalciferol median 0.4 mL/kg [interquartile range, 0.4-1.2 mL/kg]; p = 0.059). Median pulmonary vascular permeability index values were significantly lower in the cholecalciferol treatment group (placebo 0.4 [interquartile range, 0-0.7] vs cholecalciferol 0.1 [interquartile range, -0.15 to -0.35]; p = 0.027). Cholecalciferol treatment effectively increased 25(OH)D concentrations, but surgery resulted in a decrease in 25(OH)D concentrations at day 3 in both arms. There was no difference in clinical outcomes. CONCLUSIONS: High-dose preoperative treatment with oral cholecalciferol was effective at increasing 25(OH)D concentrations and reduced changes in postoperative pulmonary vascular permeability index, but not extravascular lung water index.

Combination of preoperative pulmonary and nutritional preparation for esophagectomy.

PURPOSE: To compare pulmonary and nutritional parameters before and after inspiratory muscle training (IMT) and enteral feeding support in patients with esophageal disease undergoing preoperative outpatient follow-up. METHODS: Thirty patients with a mean age of 55.83 years, 16 men and 14 women, were included. Pulmonary assessment consisted of the measurement of MIP, MEP, and spirometry. Anthropometric measurements and laboratory tests were performed for nutritional assessment. After preoperative evaluation, inspiratory muscle training and enteral nutrition support were started. A p<0.05 was considered statistically significant. RESULTS: After an outpatient follow-up period of 4 weeks, a significant increase in MIP (-62.20 ± 25.78 to -81.53 ± 23.09), MEP (73.4 ± 31.95 to 90.33 ± 28.39), and FVC (94.86 ± 16.77 to 98.56 ± 17.44) was observed. Regarding the anthropometric variables, a significant increase was also observed in BMI (20.18 ± 5.04 to 20.40 ± 4.69), arm circumference (23.38 ± 3.28 to 25.08 ± 4.55), arm muscle circumference (21.48 ± 3.00 to 22.07 ± 3.36), and triceps skinfold thickness (5.62 ± 2.68 to 8.33 ± 6.59). CONCLUSION: Pulmonary and nutritional preparation can improve respiratory muscle strength, FVC and anthropometric parameters. However, further studies are needed to confirm the effectiveness of this preoperative preparation.

Combination of preoperative pulmonary and nutritional preparation for esophagectomy

Abstract Purpose: To compare pulmonary and nutritional parameters before and after inspiratory muscle training (IMT) and enteral feeding support in patients with esophageal disease undergoing preoperative outpatient follow-up. Methods: Thirty patients with a mean age of 55.83 years, 16 men and 14 women, were included. Pulmonary assessment consisted of the measurement of MIP, MEP, and spirometry. Anthropometric measurements and laboratory tests were performed for nutritional assessment. After preoperative evaluation, inspiratory muscle training and enteral nutrition support were started. A p<0.05 was considered statistically significant. Results: After an outpatient follow-up period of 4 weeks, a significant increase in MIP (-62.20 ± 25.78 to -81.53 ± 23.09), MEP (73.4 ± 31.95 to 90.33 ± 28.39), and FVC (94.86 ± 16.77 to 98.56 ± 17.44) was observed. Regarding the anthropometric variables, a significant increase was also observed in BMI (20.18 ± 5.04 to 20.40 ± 4.69), arm circumference (23.38 ± 3.28 to 25.08 ± 4.55), arm muscle circumference (21.48 ± 3.00 to 22.07 ± 3.36), and triceps skinfold thickness (5.62 ± 2.68 to 8.33 ± 6.59). Conclusion: Pulmonary and nutritional preparation can improve respiratory muscle strength, FVC and anthropometric parameters. However, further studies are needed to confirm the effectiveness of this preoperative preparation.

Comparison of neoadjuvant chemotherapy versus upfront surgery with or without chemotherapy for patients with clinical stage III esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) and chemoradiotherapy have been shown to extend postoperative survival, and preoperative therapy followed by esophagectomy has become the standard treatment worldwide for patients with esophageal squamous cell carcinoma (ESCC). The Japan Clinical Oncology Group 9907 study showed that NAC significantly extended survival in advanced ESCC, but the survival benefit for patients with clinical stage III disease remains to be elucidated. We compared the survival rates of NAC and upfront surgery in patients with clinical stage III ESCC. Consecutive patients histologically diagnosed as clinical stage III (excluding cT4) ESCC were eligible for this retrospective study. Between September 2002 and April 2007, upfront transthoracic esophagectomy was performed initially and, for patients with positive lymph node (LN) metastasis in a resected specimen, adjuvant chemotherapy using cisplatin and 5-fluororouracil every 3 weeks for two cycles was administered (Upfront surgery group). Since May 2007, a NAC regimen used as adjuvant chemotherapy followed by transthoracic esophagectomy has been administered as the standard treatment in our institution (NAC group). Patient characteristics, clinicopathological factors, treatment outcomes, post-treatment recurrence, and overall survival (OS) were compared between the NAC and upfront surgery groups. Fifty-one and 55 patients were included in the NAC and upfront surgery groups, respectively. The R0 resection rate was significantly lower in the NAC group than in the upfront surgery group (upfront surgery, 98%; NAC, 76%; P = 0.003). In the upfront surgery group, of 49 patients who underwent R0 resection and pathologically positive for LN metastasis, 22 (45%) received adjuvant chemotherapy. In the NAC group, 49 (96%) of 51 patients completed two cycles of NAC. In survival analysis, no significant difference in OS was observed between the NAC and upfront surgery groups (NAC: 5-year OS, 43.8%; upfront surgery: 5-year overall surgery, 57.5%; P = 0.167). Patients who underwent R0 resection showed significantly longer OS than did those who underwent R1, R2, or no resection (P = 0.001). In multivariate analysis using age, perioperative chemotherapy, depth of invasion, LN metastasis, surgical radicality, postoperative pneumonia, and anastomotic leakage as covariates, LN metastasis [cN2: hazard ratio (HR), 1.389; P = 0.309; cN3: HR, 16.019; P = 0.012] and surgical radicality (R1: HR, 3.949; P = 0.009; R2 or no resection: HR, 2.912; P = 0.022) were shown to be significant independent prognostic factors. In clinical stage III ESCC patients, no significant difference in OS was observed between NAC and upfront surgery. Although potential patient selection bias might be a factor in this retrospective analysis, the noncurative resection rate was higher after NAC than after upfront surgery. The survival benefit of more intensive NAC needs to be further evaluated.

Review of chemotherapeutic approaches for operable and inoperable esophageal squamous cell carcinoma.

The predominant histological types of esophageal cancer are adenocarcinoma and squamous cell carcinoma. Since these two histological types present as different diseases in terms of their epidemiology, pathologenesis, and tumor biology, separate therapeutic approaches should be developed against each type. While surgical resection remains the dominant therapeutic intervention for patients with operable esophageal squamous cell carcinoma (ESCC), their high rates of tumor recurrence have prompted investigation of multimodality therapies that combine surgery with chemotherapy, radiotherapy, and chemoradiotherapy. In Japan, preoperative chemotherapy with cisplatin (CDDP) plus 5-fluorouracil (5-FU) followed by radical esophagectomy has been accepted as the standard therapeutic approach for resactable clinical Stage II/III ESCC. Similarly, the CDDP and 5-FU regimen has been accepted as the first-line treatment for metastatic and unresectable ESCCs in Japan. Thus, in Japan chemotherapy is an indispensable component of therapy for both resectable and unresectable ESCCs. This review discusses the current knowledge, rationale, and available data regarding chemotherapy for resectable and unresectable ESCCs.

Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend sampling 15 or more lymph nodes during esophagectomy. The proportion of patients meeting this guideline is unknown, as is its influence on overall survival (OS). METHODS: Univariate analysis and logistic regression were performed to identify variables associated with sampling 15 or more lymph nodes among patients undergoing esophagectomy in the National Cancer Data Base (NCDB). The NCCN guideline was evaluated in Cox proportional hazards modeling, along with alternative lymph node thresholds. Positive to examined node (PEN) ratios were calculated, and OS was compared using Kaplan-Meier analysis. RESULTS: From 2006 to 2012, only 6,961 of 18,777 (37.1%) patients undergoing esophagectomy had sampling of 15 or more lymph nodes. Variables associated with sampling 15 or more lymph nodes included income greater than or equal to $38,000, procedure performed in an academic facility, and increasing clinical T and N stages. Induction therapy was associated with a decreased likelihood of 15 or more lymph nodes being sampled. The largest decrease in mortality hazard in patients undergoing upfront esophagectomy was detected when 25 lymph nodes or more were sampled (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67-0.89; p < 0.001), whereas for patients undergoing induction therapy, sampling of 10 or 15 or more lymph nodes was associated with optimal survival benefit (HR, 0.81; 95% CI, 0.74-0.90; p < 0.001). PEN ratios of 0 to 0.10 were associated with maximum survival benefit among all patients undergoing esophagectomy. For patients with a PEN ratio of 0, increases in OS were detected with higher lymph node sampling (85.3 months for sampling of 20 or more lymph nodes versus 52.0 months for sampling 1-9 lymph nodes; p < 0.001). CONCLUSIONS: For patients undergoing upfront esophagectomy, there may be an increased survival benefit for examining 20 to 25 lymph nodes, which is higher than current recommendations. However, only a minority of patients are meeting current guidelines.

Minimally Invasive Versus Open Esophagectomy for Esophageal Cancer: A Population-Based Analysis.

BACKGROUND: The objective of this study was to evaluate outcomes of minimally invasive approaches to esophagectomy using population-level data. METHODS: Multivariable regression modeling was used to determine predictors associated with the use of minimally invasive approaches for patients in the National Cancer Data Base who underwent resection of middle and distal clinical T13N03M0 esophageal cancers from 2010 to 2012. Perioperative outcomes and 3-year survival were compared between propensity-matched groups of patients with esophageal cancer who underwent minimally invasive esophagectomy (MIE) or open esophagectomy (OE). A subgroup analysis was performed to evaluate the impact of using robotic-assisted operations as part of the minimally invasive approach. RESULTS: Among 4,266 patients included, 1,308 (30.6%) underwent MIE. It was more likely to be used in patients treated at academic (adjusted odds ratio [OR], 10.1; 95% confidence interval [CI], 4.2-33.1) or comprehensive cancer facilities (adjusted OR, 6.4; 95% CI, 2.6-21.1). Compared with propensity-matched patients who underwent OE, patients who underwent MIE had significantly more lymph nodes examined (15 versus 13; p = 0.016) and shorter hospital lengths of stay (10 days versus 11 days; p = 0.046) but similar resection margin positivity, readmission, and 30-day mortality (all p > 0.05). Survival was similar between the matched groups at 3 years for both adenocarcinoma and squamous cell carcinoma (p > 0.05). Compared with MIE without robotic assistance, use of a robotic approach was not associated with any significant differences in perioperative outcomes (p > 0.05). CONCLUSIONS: The use of minimally invasive techniques to perform esophagectomy for esophageal cancer is associated with modestly improved perioperative outcomes without compromising survival.

Resection of a Submucosal Tumor-Like Superficial Carcinoma in Middle Thoracic Esophagus Concomitant with Mucosal Adenocarcinoma and Submucosal Squamous Cell Carcinoma: A Case Report and Review of Literature.

A 67-year-old man was pointed out mucosal irregularity on health check-up and was referred to our institution. Diagnostic examinations were performed and an aggregated type 0-IIa lesion having 3 small protrusions was recognized in the middle thoracic esophagus. Endoscopic biopsy led to diagnosis of esophageal cancer concomitant with adenocarcinoma and squamous cell carcinoma. Thoracic esophagectomy with 3-fields lymph node dissection was performed via a right thoracoabdominal approach and reconstructed with stomach roll. Three submucosal tumors like small protrusions were recognized in resected specimen. One of them was well differentiated tubular adenocarcinoma which occupied in mucosal layer. The other two were moderately differentiated squamous cell carcinoma. They existed very near but no connection was recognized by serial section. The adenocarcinoma existing in middle esophagus is very rare. Almost all of them were submucosal or advanced cancers. When we searched with the ICHUSHI database (a domestic medical literature database service provided by the NPO Japan Medical Abstracts Society) and the PubMed database, there was no report of mucosal adenocarcinoma occurred in middle thoracic esophagus in the past 10 years. Then this report was thought to be the first report of mucosal adenocarcinoma in middle thoracic esophagus in the world.