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We report a case of unresectable advanced esophageal cancer with an esophageal fistula that was treated with pembrolizumab plus CDDP plus 5-FU therapy and the fistula was closed. A 73-year-old male was diagnosed with cervical-upper thoracic esophageal cancer and esophago-bronchial fistula on CT and esophagogastroduodenoscopy. He underwent chemotherapy containing pembrolizumab. The fistula was closed after 4 cycles and oral intake became possible. Six months have passed since the first visit and chemotherapy is ongoing. The prognosis of esophago-bronchial fistula is extremely poor, and there is no established treatment, including fistula closure. Chemotherapy containing immune checkpoint inhibitors could considered to be expected not only for local control but also for long-term survival.

Background: The clinical significance of lymph node (LN) status determined by preoperative 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has not been investigated in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (NCRT) followed by surgery (trimodal therapy)., Methods: This study reviewed 132 consecutive patients with ESCC who had been preoperatively evaluated using FDG-PET before and after NCRT to analyze associations among LN status according to PET findings, pathologic LN metastasis, and prognosis of ESCC after trimodal therapy., Results: Lymph nodes that were PET-positive both before and after NCRT comprised significant predictive markers of pathologic LN metastasis in station-by-station analyses (sensitivity, specificity, and accuracy respectively 41.7%, 95.0%, and 92.7% before, and 12.0%, 99.4%, and 95.6% after NCRT; both p < 0.0001). The numbers of LNs evaluated using PET before and after NCRT were significantly associated with those of pathologic metastatic LNs. Uni- and multivariable analyses selected LN status determined by PET before NCRT as a significant independent predictor of both recurrence-free [LN-negative vs LN-positive: hazard ratio (HR) 1.90; 95% confidence interval (CI) 1.02-3.23; p = 0.045] and overall survival (HR 2.62; 95% CI 1.29-5.30; p = 0.01)., Conclusions: The status of LN determined by preoperative FDG-PET is significantly associated with pathologic LN status and the prognosis of ESCC with trimodal therapy. Thus, FDG-PET is a useful diagnostic tool for preoperative prediction of pathologic LN metastasis and survival among patients with ESCC.

Background: In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy., Methods: Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed., Results: The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group., Conclusions: Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options., (© 2013 Japanese Cancer Association.)

Background/aim: The status of each patient with advanced esophageal cancer varies widely, and the prognosis is generally poor. We aimed to determine which prognostic factors are involved in the management of locally advanced esophageal cancer with adjacent organ invasion., Patients and Methods: We retrospectively investigated the therapeutic outcomes of 74 patients with thoracic esophageal cancer and clinical evidence of adjacent organ invasion but without distant metastasis. The predictive factors for a chemoradiotherapeutic response and survival were evaluated., Results: Definitive chemoradiotherapy (CRT), bypass surgery and CRT, as well as CRT followed by esophagectomy were carried out in 48 (64.9%), 17 (23.0%), and 9 (12.2%) patients, respectively. The median survival time (MST) of patients overall was 11.3 months. The MST of patients after definitive CRT, bypass surgery plus CRT and CRT followed by esophagectomy was 10.4, 11.0 and 16.4 months, respectively; MST did not differ significantly between patients. MST of patients with a complete response (CR), a partial response (PR) and stable (SD)/progressive (PD) disease as clinical outcomes of CRT was 52.6, 11.3 and 6.7 months, respectively; the MST was considerably longer in patients with, than in those without CR (CR vs. SD/PD, p<0.0001; CR vs. PR, p=0.0004). In multivariate analysis, age <60 years [odds ratio (OR)=7.74; 95% confidence interval (CI)=1.85-32.41; p=0.005] and hemoglobin ≥13 g/dl (OR=11.54; 95% CI=1.29-103.21; p=0.03) were independently associated with CR as an outcome of CRT, and serum albumin level ≥3.5 g/dl (OR=2.11; 95% CI=1.09-4.10; p=0.03) was independently associated with prolonged survival., Conclusion: Pre-treatment hemoglobin and albumin levels were valuable predictors of the outcome of CRT and survival, respectively. A better response to CRT as well as improved nutritional status prolonged the survival of patients with advanced esophageal cancer.

5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the rate‑limiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus formation, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus formation induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.

Esophageal bypass surgery using a gastric tube prior to definitive chemoradiotherapy in preparation for the formation of esophago-tracheal or bronchial fistula is a possible strategy for esophageal cancer invading the airway. This report presents the case of a patient with esophageal cancer involving the left main bronchus who underwent esophageal bypass followed by definitive chemoradiotherapy and who has achieved long-term survival without deterioration of his quality of life, in spite of the development of a malignant esophago-bronchial fistula.

Purpose: We aimed to evaluate the safety, tolerability, and efficacy of combination preoperative chemoradiotherapy as first-line treatment in patients with advanced esophageal cancer., Methods: We performed a phase I dose-escalation trial of docetaxel at 25-40 mg/m(2) in four planned dose levels in 3-6 patient cohorts on days 1, 15, 29, and 43 administered in combination with cisplatin (70 mg/m(2) on days 1 and 29) and 5-fluorouracil (70 mg/m(2)/day on days 1-4 and 29-32) and concurrent radiation therapy (40 Gy). The tumors were resected during weeks 10-13., Results: This study included 7 patients with esophageal cancer. The dose-limiting toxicity was observed at a biweekly docetaxel dose of 30 mg/m(2) when patients developed grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 4 pain/esophagus, resulting in a maximum tolerated dose of 25 mg/m(2). Grade 3/4 hematological toxicity was observed in 71% of the patients and grade 3/4 non-hematological toxicity in 57%. The overall tumor response rate was 86% (complete, 57% and partial, 29%). All patients underwent surgery, and there were no deaths as a result of postoperative complications., Conclusions: This preoperative chemoradiotherapy regimen using triplets is feasible but results in moderate toxicity. It is noteworthy that this regimen was associated with a high rate of pathological complete remission.

Airway stenting is required for the palliative treatment of advanced esophageal cancer. This study retrospectively analyzes the outcomes of airway stenting for esophageal cancer at our institution. Data from nine patients who underwent airway stenting were reviewed. All patients had poor respiratory status due to esophagorespiratory fistula and/or respiratory stenosis. We retrospectively assessed the results of airway stenting as five grades of respiratory symptoms, regarding stent-related complications and clinical course and survival. Six silicone and six covered self-expandable metallic stents were deployed in five and six patients, respectively. Two types of airway stents were deployed in two patients, and double stents were positioned in the airway and in the esophagus of three other patients. The grade of respiratory symptoms improved in seven patients. The mean dyspnea grade was 3.0±0.9 and 1.3±1.3 before and after airway stenting, respectively. Stent-related complications comprised of chest pain, incomplete closure of the ERF, sputum retention and stent migration. The mean±SD survival of all patients was 103±108 (range, 0 to 325) days, and the survival of patients without relapsed cancer at the time of stenting, who underwent cancer-specific therapy after stenting, was prolonged. Although the airway should be stented according to the status and the prognosis of each patient individually stenting can relieve symptoms and improve the prognosis even when esophageal cancer is at very advanced stages. Airway stenting could play a role in the multidisciplinary management of advanced esophageal cancer.

Purpose: To evaluate the outcomes of colon interposition based on our surgical experience., Methods: We reviewed data from 40 patients who underwent esophagectomy with colon interposition using the terminal ileum and right colon, to treat esophageal cancer, between January 1990 and December 2009., Results: Transthoracic esophagectomy, transhiatal esophagectomy, and pharyngolaryngoesophagectomy were performed in 31 (77.5%), 8 (20.0%), and 1 (2.5%) patients, respectively. The routes of the colon interposition were posterior mediastinal in 30 (75.0%) patients, retrosternal in 5 (12.5%), and subcutaneous in 5 (12.5%). The median operative time was 450 min (range 320-760 min) and the median blood loss was 755 ml (range 180-3,000 ml). Overall postoperative morbidity involved 18 (45.0%) patients and included esophagoileostomy leakage in 7 (17.5%; minor, n = 4; major, n = 3) and necrosis of the colon conduit in 2 (5%) patients. The 30- and 90-day mortality rates were 0 and 2.5%, respectively. The 1-, 3-, and 5-year survival rates were 80, 66, and 66%, respectively., Conclusions: Our surgical outcomes were acceptable in relation to other published results and the prognosis was favorable. Thus, esophageal reconstruction using the ileum and right colon is useful for patients with esophageal cancer for whom the stomach is not available. We currently perform colon interposition with microvascular anastomoses for grafts via the subcutaneous route to increase the safety of this operation.

A 46-year-old man was referred to us after he presented to his local physician complaining of difficulty eating. Upper gastrointestinal endoscopy revealed a tumor at the esophagogastric junction (EGJ), and moderately differentiated adenocarcinoma was diagnosed from the biopsy findings. Computed tomography (CT) showed apparent enlargement of the pretracheal lymph nodes, the lymph nodes around the bilateral recurrent laryngeal nerves, and the lower thoracic paraesophageal lymph nodes, confirming metastasis. Since the disease was far advanced esophagogastric cancer with marked lymph node metastases throughout the mediastinum, curative resection would have been unlikely. Thus, he was commenced on systemic chemotherapy with cisplatin (90 mg/body, day 8) + S-1 (120 mg/body/day, given for 3 weeks, followed by a 2-week withdrawal). Even after six cycles of chemotherapy over 8 months, a complete response could not be achieved. Finally, we performed transthoracic subtotal esophagectomy with extensive lymph node dissection reconstructed using a gastric tube through a retrosternal route. The patient remains recurrence-free 7 years later.

We report a case of advanced esophageal cancer successfully treated with neoadjuvant chemoradiotherapy followed by esophagectomy in a 53-year-old man with situs inversus totalis. Upper gastrointestinal endoscopy in a clinical examination revealed a tumor in the lower third of the esophagus, and moderately differentiated squamous cell carcinoma was diagnosed from the biopsy findings. He was referred to us and the disease was diagnosed as esophageal cancer (clinical T3N1M0, cStage III) after further evaluation. According to the therapeutic strategy of our department, neoadjuvant chemoradiotherapy was commenced. The regimen was composed of radiotherapy (2 Gy/day, 5 days/week, 4weeks, total 40Gy) with cisplatin (70 mg/m2/day, day 1) and 5-FU (700 mg/m2/day, day 1-4). We performed a subtotal esophagectomy with radical lymph node dissection through a left thoracotomy because of the existence of situs inversus totalis. The thoracic operation could be performed with relatively safety because the organs were arranged in a mirror image of their normal positions. On the other hand, it was relatively difficult to construct a gastric tube. In particular, ligation of the gastrosplenic ligaments was difficult and this led to increased blood loss compared with usual operation. Histopathological examination revealed no residual carcinoma at the site of the primary focus. The patient has been followed up periodically on an outpatient basis and has remained free of recurrence for longer than 2 years 5 months after surgery.

Esophageal squamous cell carcinoma is often accompanied by intramural metastases, and it has been reported to carry a poor prognosis. Intramural metastasis from gastric cancer to the esophageal wall, however, has rarely been reported. We herein report a rare case of a 46-year-old man with an elevated esophageal lesion, resembling a 0-IIa-type esophageal cancer, which was discovered 13 months after a total gastrectomy performed for gastric cancer. The esophageal tumor, resected by endoscopic mucosal resection (EMR), was an adenocarcinoma with the same histology as the previously resected primary gastric cancer, and it showed massive lymphatic permeation. Soon after the EMR, other similar lesions emerged on the esophageal wall. We therefore considered the esophageal tumor to be a systemic expansion of the primary gastric cancer, and we administered the anticancer drug, S-1. Esophageal intramural metastases from a gastric cancer imply a systemic expansion of the gastric cancer, and portend a poor prognosis.