Roy J.J. Verhage

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial)

BackgroundFor esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.Methods/designThis is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.DiscussionThis is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.Trial registrationDutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790

How to define a positive circumferential resection margin in T3 adenocarcinoma of the esophagus.

A positive circumferential resection margin (CRM+) is associated with poor survival after esophagectomy for cancer. The Royal College of Pathologists (RCP) defines a CRM+ when tumor is found <1 mm of the lateral margin whereas the College of American Pathologists (CAP) defines CRM+ when tumor cells are located at the lateral margin. This study evaluates the clinical prognostic significance of CRM+ on overall survival (OS) and disease-free survival (DFS) in patients who underwent esophagectomy for T3 esophageal adenocarcinoma. Analysis included 132 patients. CRM+ was found in 26 cases (19.7%) corresponding to CAP criteria versus 89 cases (67.4%) corresponding to RCP criteria. Median OS using RCP criteria was 16.4 (95%CI, 8.5-24.2) months for CRM+ patients versus 21.0 (95%CI 16.3-25.6) months in CRM– patients (P=0.144). With CAP criteria, median OS in CRM+ and CRM– patients was 9.4 (95%CI, 7.6-11.2) months versus 21.6 (95%CI, 18.9-24.3) months, respectively (P=0.000). Median DFS using RCP criteria was 18.0 (95%CI, 11.5-24.6) months for CRM– patients versus 11.0 (95%CI, 8.1-14.0) months for CRM+ patients (P=0.257). Applying the CAP criteria, median DFS in CRM– and CRM+ patients was 16.3 (95%CI, 10.6-22.0) months versus 7.0 (95%CI, 6.3-7.8) months, respectively (P=0.000). Effects of a CRM+ according to CAP criteria remained significant after multivariate testing [OS: hazard ratio (HR), 2.43; 95%CI, 1.52-3.90; DFS: HR, 2.09; 95%CI, 1.32-3.30]. Only with the CAP criteria, CRM+ is an independent prognostic factor for survival and recurrence in patients with T3 adenocarcinoma of the esophagus. The circumferential margin should only be considered positive (ie, R1) if the tumor is found at the inked lateral margin of resection in accordance with the CAP criteria.

Cyclooxygenase Isoenzyme-2 and Vascular Endothelial Growth Factor are Associated with Poor Prognosis in Esophageal Adenocarcinoma

BackgroundCyclooxygenase isoenzyme-2 (COX-2) and vascular endothelial growth factor (VEGF) contribute to angiogenesis and are overexpressed in various malignancies. The aim of the study was to evaluate expression, prognostic value and correlation between COX-2 and VEGF expression in esophageal adenocarcinoma (EAC).MethodsSurgical specimens of 154 patients with EAC were used to construct a tissue micro array (TMA). TMA sections were immunohistochemically stained for COX-2 and VEGF and scored on intensity of staining.ResultsEstimated 5-year cancer specific survival was 37%. High COX-2 and VEGF expression was observed in 39 (26.5%) and in 77 (53.8%) tumors, respectively. Both markers were associated with poor cancer specific survival (p = .022 and p = .004, respectively, log rank). No significant correlation was found between VEGF and COX-2 expression (r = 063; p = .455). In multivariate analysis, high COX-2 expression (HR 1.65; 95% CI 1.04–2.61; p = .034) was associated with overall survival. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer specific survival (HR 1.81 95% CI 1.10–2.95; p = .019).ConclusionsThis is the first study that evaluated the prognostic value and correlation of COX-2 and VEGF expression in a large and homogenous population of patients with EAC. No correlation between COX-2 and VEGF expression was found. Both markers were expressed in EAC and were associated with poor prognosis. The findings support the use of COX-2 and VEGF inhibitors in future clinical studies.

A New Clinical Scoring System to Define Pneumonia following Esophagectomy for Cancer

Background: Pneumonia is a frequently observed complication following esophagectomy. The lack of a uniform definition of pneumonia leads to large variations of pneumonia rates in literature. This study was designed to develop a scoring system for diagnosing pneumonia following esophagectomy at the hospital ward. Methods: In a prospective cohort study of esophagectomy patients, known risk factors for pneumonia, temperature, leukocyte count, pulmonary radiography and sputum culture added were evaluated. Primary outcome was defined as the decision to treat suspected pneumonia. Multivariate Cox regression analysis with backward selection was used to identify predictors of pneumonia treatment. Results: The majority of postoperative pneumonia treatments (88.2%) occurred at the hospital ward, where treatment was observed in 67 (36.2%) of 185 patients. Independent diagnostic determinants for pneumonia treatment were temperature (hazard ratio (HR) = 1.283, p = 0.073), leukocyte count (HR = 1.040, p = 0.078) and pulmonary radiography (HR >11.0, p = 0.000). Sputum culture did not influence the decision to treat pneumonia. These findings were used to develop a scoring system which includes temperature, leukocyte count and pulmonary radiography. Conclusion: The decision to treat pneumonia is based on temperature, leukocyte count and pulmonary radiography findings. The proposed clinical scoring system for pneumonia following esophagectomy at the hospital ward has the potential to aid clinical practice and improve comparability of future research in esophageal cancer surgery.

Reduced local immune response with continuous positive airway pressure during one-lung ventilation for oesophagectomy

BACKGROUND Transthoracic oesophagectomy requires prolonged one-lung ventilation causing systemic and local inflammatory responses. Application of continuous positive airway pressure (CPAP) to the collapsed lung potentially reduces pulmonary damage, hypoxia, and consequent inflammation. This randomized controlled trial studied the influence of CPAP applied to the collapsed right lung during thoracoscopic oesophagectomy on local and systemic inflammatory response. METHODS Broncho-alveolar lavage fluid (BALF) from the right collapsed and left ventilated lung and serum samples were obtained during surgery from 30 patients undergoing thoracolaparoscopic oesophagectomy for cancer who were randomized for one-lung ventilation with or without CPAP applied to the collapsed right lung. Concentrations of cytokines and chemokines, in BALF and serum, were determined with Luminex. RESULTS Patients from the control (no CPAP) group had significantly increased concentrations of interleukin (IL)-1α, IL-1β, IL-10, tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-1α, pulmonary and activation-regulated chemokine (PARC), and IL-8 in the collapsed (right) lung when compared with patients from the CPAP group (P<0.05). The ventilated (left) lung of the control group showed increased concentrations of monocyte chemoattractant protein (MCP)-1 and MIP-1α (P<0.05). Serum concentrations of cytokines and chemokines increased during surgery, but did not differ between the control and CPAP groups. CONCLUSIONS A significantly lower local immune response was observed during one-lung ventilation when CPAP was applied to the collapsed lung. The findings suggest a beneficial effect of CPAP on the collapsed lung during oesophagectomy with one-lung ventilation.

Over-expression of phosphorylated mammalian target of rapamycin is associated with poor survival in oesophageal adenocarcinoma: a tissue microarray study

Background Protein kinase mammalian target of rapamycin (mTOR) is an important downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. In several tumour types, phosphorylated mTOR (p-mTOR) over-expression is an independent prognostic marker for poor survival. However, p-mTOR expression has not been assessed in oesophageal adenocarcinoma (OAC). Materials and methods Tumour cores of 154 patients with OAC were included in a tissue microarray (TMA). Scoring criteria were based on p-mTOR staining intensity. Results 147 (95.5%) patients were available for immunohistochemical evaluation. Over-expression of p-mTOR was detected in 29 (19.7%) tumours, whereas 118 (80.3%) patients showed negative expression. Over-expression was significantly associated with poor overall survival in univariate analysis (HR 1.648; 95% CI 1.019 to 2.664; p=0.042). Median survival was 21.2 months in patients with p-mTOR over-expression and 29.0 in the negative p-mTOR group (p=0.040). In addition, a trend towards p-mTOR over-expression and vasoinvasive growth was seen (p=0.057). In multivariate analysis, including clinical and pathological variables (p<0.10), only T-stage (HR 2.795; 95% CI 1.343 to 5.813; p=0.006) and differentiation grade (HR 2.198; 95% CI 1.353 to 3.570; p=0.001) were independent prognostic markers of poor survival. Conclusion p-mTOR over-expression was detected in 19.7% of patients with OAC and was associated with poor overall survival.

Fibrin-thrombin coated sealant increases strength of esophagogastric anastomoses in a rat model

BACKGROUND Anastomotic leakage is a feared complication after esophagectomy. The purpose of this study was to investigate whether the use of a fibrin-thrombin coated collagen patch (TachoSil; Nycomed, Zurich, Switzerland), applied as a sealant, would strengthen the esophagogastric anastomosis and stimulate anastomotic healing in a rat model. METHODS Hand sewn, end-to-side esophagogastric anastomoses were performed in 54 rats. Animals were randomized for an unsealed or sealed anastomosis. Rats were sacrificed on postoperative d 0, 3, 5, and 7. Primary parameter was bursting pressure. Secondary outcomes were complications, weight, and immunohistochemical staining for collagen formation and fibroblast activity. RESULTS Bursting pressure at d 0 and 3 was significantly increased when a sealant was used (55.1 ± 4.6 mmHg versus 102.4 ± 7.3 mmHg, P < 0.010; and 19.7 ± 3.3 mmHg versus 34.6 ± 4.9 mmHg, P < 0.050 respectively). There was no difference in bursting pressure at d 5 and 7 between unsealed and sealed anastomoses (60.9 ± 18.2 mmHg versus 53.4 ± 6.6 mmHg, P = 0.690; and 118.8 ± 20.2 mmHg versus 97.2 ± 8.3 mmHg, P = 0.374 respectively). Application of sealant independently influenced bursting pressure (P < 0.010). Increased fibroblastic activity was noticed at d 7 in sealed anastomoses (P < 0.050). There were no differences in weight gain between groups. CONCLUSIONS Additional sealing of the anastomosis increased anastomotic strength during early postoperative recovery when anastomotic strength is at its weakest. The findings indicate that sealing of the anastomosis has the potential to prevent leakage after esophagectomy in humans.

Barrett's esophagus: treatments of adenocarcinomas I

The following topics are explored in this collection of commentaries on treatments of adenocarcinomas related to Barretts esophagus: the importance of intraoperative frozen sections of the margins for the detection of high dysplasia; the preferable way for sentinel node dissection; the current role of robotic surgery and of video‐endoscopic approach; the value of the Siewerts classification of adenocarcinomas; the indications of two‐step esophagectomy; the evaluation of pathological complete response; the role of PET scan in staging and response assessment; the role of p53 in the selection of adenocarcinomas patients; chemotherapy regimens for adenocarcinomas; the use of monoclonal antibodies in the control of cell proliferation; he attempt to define a stage‐specific strategy, and the possible indications of selective therapy; and changes in mortality rates from esophageal cancer.

Barrett's esophagus: treatments of adenocarcinomas II: Barrett's esophagus: treatments of adenocarcinomas II

The following on the treatments of adenocarcinomas in Barretts esophagus contains commentaries on endo mucosal resection; choice between other ablative therapies; the remaining genetic abnormalities following stepwise endoscopic mucosal resection and possible recurrences; the Fotelo–Fotesi PDT; the CT TNM classification of early stages of Barretts carcinoma; the indications of lymphadenectomy in intramucosal cancer; the differences in lymph node yield in transthoracic versus transhiatal dissection; video‐assisted lymphadenectomy; and the importance of the length of proximal esophageal resectipon; and indications of sentinel node dissection.

Gastric Conduit Resection and Jejunal Interposition for Recurrent Esophageal Cancer

We describe the case of a 58-year-old man with recurrent adenocarcinoma at the site of an esophagogastrostomy that we treated by radical surgical resection and jejunal interposition. Oral intake was started on the 6th postoperative day and the patient was discharged on the 11th postoperative day. Seven months after the surgical procedure no signs of tumor recurrence were detected. Resection of localized (recurrent) esophageal cancer may well be a valuable treatment option and is therefore an interesting therapeutic option in patients with recurrent disease. However this needs to be investigated in a randomized controlled trial.