Mark I. van Berge Henegouwen

Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial

BACKGROUND Surgical resection is regarded as the only curative option for resectable oesophageal cancer, but pulmonary complications occurring in more than half of patients after open oesophagectomy are a great concern. We assessed whether minimally invasive oesophagectomy reduces morbidity compared with open oesophagectomy. METHODS We did a multicentre, open-label, randomised controlled trial at five study centres in three countries between June 1, 2009, and March 31, 2011. Patients aged 18-75 years with resectable cancer of the oesophagus or gastro-oesophageal junction were randomly assigned via a computer-generated randomisation sequence to receive either open transthoracic or minimally invasive transthoracic oesophagectomy. Randomisation was stratified by centre. Patients, and investigators undertaking interventions, assessing outcomes, and analysing data, were not masked to group assignment. The primary outcome was pulmonary infection within the first 2 weeks after surgery and during the whole stay in hospital. Analysis was by intention to treat. This trial is registered with the Netherlands Trial Register, NTR TC 2452. FINDINGS We randomly assigned 56 patients to the open oesophagectomy group and 59 to the minimally invasive oesophagectomy group. 16 (29%) patients in the open oesophagectomy group had pulmonary infection in the first 2 weeks compared with five (9%) in the minimally invasive group (relative risk [RR] 0·30, 95% CI 0·12-0·76; p=0·005). 19 (34%) patients in the open oesophagectomy group had pulmonary infection in-hospital compared with seven (12%) in the minimally invasive group (0·35, 0·16-0·78; p=0·005). For in-hospital mortality, one patient in the open oesophagectomy group died from anastomotic leakage and two in the minimally invasive group from aspiration and mediastinitis after anastomotic leakage. INTERPRETATION These findings provide evidence for the short-term benefits of minimally invasive oesophagectomy for patients with resectable oesophageal cancer. FUNDING Digestive Surgery Foundation of the Unit of Digestive Surgery of the VU University Medical Centre.

Incidence, risk factors, and treatment of pancreatic leakage after pancreaticoduodenectomy: drainage versus resection of the pancreatic remnant.

BACKGROUND Pancreatic leakage is a major cause of morbidity and mortality after pancreaticoduodenectomy, with incidences varying between 6-24% and a mortality rate up to 40%. Treatment is an issue of controversy. In this study we analyzed risk factors for pancreatic leakage and the results of early resection of the pancreatic remnant versus drainage procedures for leakage of the pancreaticojejunostomy. STUDY DESIGN From 1983 to 1995, 269 patients underwent pancreaticoduodenectomy, with pancreaticojejunostomy. Patients with manifestations of pancreatic leakage were compared with nonleakage patients to evaluate risk factors. Patients with leakage were divided into two treatment groups. One group comprised patients undergoing percutaneous or surgical drainage procedures; the other had patients undergoing resection of the pancreatic remnant. RESULTS Twenty-nine patients (11%) had clinical manifestations of pancreatic leakage, and the mortality in these patients was 28% (overall mortality: 3.7%). Leakage occurred after a median of 5 days (range 1-20). Age, preoperative bilirubin level, and albumin counts were not risk factors for pancreatic leakage. Small pancreatic duct size (< 2 mm) (p < 0.01) and ampullary carcinoma as histopathologic diagnosis (p < 0.05) were risk factors. The median number of relaparotomies was two (range 0-4) in the drainage group (n = 21), versus 1.5 (range 1-5) in patients who underwent resection (n = 8). The median hospital stay was 74 days (range 36-219), versus 55 days (range 22-107) for the drainage and resection groups, respectively (p < 0.05). Mortality was lower in patients who underwent resection, 38 versus 0% (p < 0.05). CONCLUSIONS Leakage of the pancreatic anastomosis is a severe complication after pancreaticoduodenectomy and carries a high mortality rate (28%). Completion pancreatectomy could be performed without additional mortality. In patients with severe and persistent leakage of the anastomosis, early completion pancreatectomy is the treatment of choice.

Delayed gastric emptying after standard pancreaticoduodenectomy versus pylorus-preserving pancreaticoduodenectomy: an analysis of 200 consecutive patients

BACKGROUND It has been suggested that pylorus-preserving pancreaticoduodenectomy (PPPD) is associated with a high incidence of delayed gastric emptying and consequently with a prolonged hospital stay compared with standard Whipples resection. The aim of this prospective study was to evaluate whether the incidence of delayed postoperative gastric emptying was different after both procedures. STUDY DESIGN From 1989 to 1996, 200 consecutive patients underwent pancreatic head resection (100 standard pancreaticoduodenectomy [PD]; 100 PPPD). The groups were compared with regard to patient characteristics, operative indices, postoperative morbidity, hospital stay, and mortality. Delayed gastric emptying was defined as nasogastric suction for > or = 10 days or delay of regular diet until > 14 days postoperatively. RESULTS Operative time and blood loss were higher for PD: 6 versus 4.8 hours (p < 0.0001) and 1,580 versus 1,247 mL (p < 0.001), respectively. Postoperative morbidity was 48% after PD and 44% after PPPD (not significant [NS]). Hospital mortality was 6% and 1% after PD and PPPD, respectively (NS). Delayed gastric emptying occurred in 34 patients after PD and in 37 after PPPD (NS). Median days of gastric suction was 3 versus 6 days for PD and PPPD (p < 0.0001). A regular diet was tolerated after a median of 10 and 11 days for PD and PPPD, respectively (NS). Postoperative hospital stay was shorter for patients who underwent PPPD: 20 versus 18 days (p < 0.03). Patients with intraabdominal complications (n = 52) showed a higher incidence of delayed gastric emptying (p < 0.0001). CONCLUSIONS Our results show that PPPD is a safe procedure associated with less operative time and blood loss than PD. After PPPD, patients require longer postoperative nasogastric intubation than after PD, suggesting some form of early postoperative gastric stasis. There is, however, no difference in the incidence of delayed gastric emptying or the first postoperative day on which a regular diet is tolerated between these surgical procedures. Intraabdominal complications are major risk factors for delayed gastric emptying.

Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials

PURPOSE To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Perioperative strategy in colonic surgery; LAparoscopy and/or FAst track multimodal management versus standard care (LAFA trial)

BackgroundRecent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track recovery programs. Both focus on a faster recovery and shorter hospital stay.The randomized controlled multicenter LAFA-trial (LAparoscopy and/or FAst track multimodal management versus standard care) was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients having segmental colectomy for malignant disease.Methods/designThe LAFA-trial is a double blinded, multicenter trial with a 2 × 2 balanced factorial design. Patients eligible for segmental colectomy for malignant colorectal disease i.e. right and left colectomy and anterior resection will be randomized to either open or laparoscopic colectomy, and to either standard care or the fast track program. This factorial design produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track program (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track program (d). Primary outcome parameter is postoperative hospital length of stay including readmission within 30 days. Secondary outcome parameters are quality of life two and four weeks after surgery, overall hospital costs, morbidity, patient satisfaction and readmission rate.Based on a mean postoperative hospital stay of 9 +/- 2.5 days a group size of 400 patients (100 each arm) can reliably detect a minimum difference of 1 day between the four arms (alfa = 0.95, beta = 0.8). With 100 patients in each arm a difference of 10% in subscales of the Short Form 36 (SF-36) questionnaire and social functioning can be detected.DiscussionThe LAFA-trial is a randomized controlled multicenter trial that will provide evidence on the merits of fast track perioperative care and laparoscopic colorectal surgery in patients having segmental colectomy for malignant disease.

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

BackgroundThis is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.MethodsThis trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.ResultsThere were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.ConclusionsPreoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.

Fluorodeoxyglucose Positron Emission Tomography for Evaluating Early Response During Neoadjuvant Chemoradiotherapy in Patients With Potentially Curable Esophageal Cancer

Background:Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. Methods:This clinical trial comprised serial FDG-PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. Results:In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60–0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. Conclusions:SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer.

Traditional invasive vs. minimally invasive esophagectomy: a multi-center, randomized trial (TIME-trial)

BackgroundThere is a rise in incidence of esophageal carcinoma due to increasing incidence of adenocarcinoma. Probably the only curative option to date is the use of neoadjuvant therapy followed by surgical resection. Traditional open esophageal resection is associated with a high morbidity and mortality rate. Furthermore, this approach involves long intensive care unit stay, in-hospital stay and long recovery period. Minimally invasive esophagectomy could reduce the morbidity and accelerate the post-operative recovery.Methods/DesignComparison between traditional open and minimally invasive esophagectomy in a multi-center, randomized trial. Patients with a resectable intrathoracic esophageal carcinoma, including the gastro-esophageal junction tumors (Siewert I) are eligible for inclusion. Prior thoracic surgery and cervical esophageal carcinoma are indications for exclusion. The surgical technique involves a right thoracotomy with lung blockade and laparotomy either with a cervical or thoracic anastomosis for the traditional group. The minimally invasive procedure involves a right thoracoscopy in prone position with a single lumen tube and laparoscopy either with a cervical or thoracic anastomosis. All patients in both groups will undergo identical pre-operative and post-operative protocol. Primary endpoint of this study are post-operative respiratory complications within the first two post-operative weeks confirmed by clinical, radiological and sputum culture data. Secondary endpoints are the operative data, the post-operative data and oncological data such as quality of the specimen and survival. Operative data include duration of the operation, blood loss and conversion to open procedure. Post-operative data include morbidity (major and minor), quality of life tests and hospital stay.Based on current literature and the experience of all participating centers, an incidence of pulmonary complications for 57% in the traditional arm and 29% in the minimally invasive arm, it is estimated that per arm 48 patients are needed. This is based on a two-sided significance level (alpha) of 0.05 and a power of 0.80. Knowing that approximately 20% of the patients will be excluded, we will randomize 60 patients per arm.DiscussionThe TIME-trial is a prospective, multi-center, randomized study to define the role of minimally invasive esophageal resection in patients with resectable intrathoracic and junction esophageal cancer.Trial registration (Netherlands Trial Register)NTR2452

Risk factors for development of benign cervical strictures after esophagectomy.

Objective:To identify independent risk factors for development of benign cervical anastomotic strictures in general and specifically for refractory strictures after esophagectomy in a large series of patients. Summary Background Data:Benign strictures develop frequently when a cervical anastomosis is performed after esophagectomy, causing burdensome symptoms and poor quality of life. Methods:From 1996 to 2006, all patients in the Academic Medical Center prospective database undergoing esophagectomy with a cervical anastomosis were included. Stricture was defined as dysphagia requiring endoscopic dilation of the anastomosis. Prediction of stricture was assessed using uni- and multivariate logistic regression analysis. Evaluation of risk factors was also performed for refractory strictures (>2 times the median number of dilations in all patients with stricture) in a similar fashion. Results:A total of 607 patients underwent potentially curative esophagectomy, with an in-hospital mortality of 2.5%. During follow-up, 253 (41.7%) patients developed a stricture after a median time of 74 days, requiring a median number of 5 dilations. Cardiovascular disease (P = 0.002), gastric tube compared with colonic interposition (P = 0.03), and anastomotic leakage (P = 0.002) were predictive for development of stricture in multivariate analysis. Development of stricture within 90 days after surgery (P = 0.001), chemoradiotherapy (P = 0.02), and anastomotic leakage (P = 0.03) were independent predictors for refractory strictures requiring over 10 dilations. Conclusions:The benign cervical stricture rate after esophagectomy was relatively high. Cardiovascular disease, gastric tube compared with colonic interposition and postoperative anastomotic leakage were independent predictors for development of benign anastomotic stricture. Anastomotic leakage, chemoradiotherapy and early development of stricture were independently associated with the development of refractory strictures, requiring a higher number of dilations. Prevention of anastomotic stricture formation should be focused on prevention of anastomotic leakage.

Do we still need EUS in the workup of patients with early esophageal neoplasia? A retrospective analysis of 131 cases

BACKGROUND EUS is often used for locoregional staging of early esophageal neoplasia. However, its value compared with that of endoscopic examination and diagnostic endoscopic resection (ER) may be questioned because diagnostic ER allows histological assessment of submucosal invasion and other risk factors for lymph node metastasis, eg, poor differentiation/lymphovascular invasion. OBJECTIVE To evaluate how often patients were excluded from endoscopic treatment of esophageal neoplasia based on EUS findings. DESIGN Retrospective cohort study. SETTING Tertiary care institution. PATIENTS Patients with early esophageal neoplasia. INTERVENTIONS EUS, diagnostic ER. MAIN OUTCOME MEASUREMENTS Number of patients excluded from endoscopic treatment based on EUS results. RESULTS A total of 131 patients were included (98 men, 33 women; age 66 ± 13 years). In 105 of 131 patients (80%), EUS findings were unremarkable. In 25 of 105 patients (24%), diagnostic ER showed submucosal invasion (n = 17), deep resection margins positive for cancer (n = 2, confirmed at surgery), or poor differentiation/lymphovascular invasion (n = 6). In 26 of 131 patients (20%), EUS findings raised the suspicion of submucosal invasion and/or lymph node metastasis. In the 14 of 26 patients (54%) with abnormal EUS findings, endoscopy results were unremarkable. Diagnostic ER showed submucosal invasion in 7 of 14 (50%) patients, whereas no lymph node metastasis risk factors were found in 7 of 14 patients (50%), who subsequently underwent curative endoscopic treatment. In 12 of 26 patients (46%) with abnormal EUS, endoscopy also raised doubts on whether curative endoscopic treatment could be achieved. After diagnostic ER, no risk factors for lymph node metastasis were found in 3 of 12 patients (25%). LIMITATION Retrospective study. CONCLUSIONS This study shows that EUS has virtually no clinical impact on the workup of early esophageal neoplasia and strengthens the role of diagnostic ER as a final diagnostic step.