Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial.

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

Patients' preferences for treatment after neoadjuvant chemoradiotherapy for oesophageal cancer.

BACKGROUND: After neoadjuvant chemoradiotherapy (nCRT) plus surgery for oesophageal cancer, 29 per cent of patients have a pathologically complete response in the resection specimen. Active surveillance after nCRT (instead of standard oesophagectomy) may improve health-related quality of life (HRQoL), but patients need to undergo frequent diagnostic tests and it is unknown whether survival is worse than that after standard oesophagectomy. Factors that influence patients' preferences, and trade-offs that patients are willing to make in their choice between surgery and active surveillance were investigated here. METHODS: A prospective discrete-choice experiment was conducted. Patients with oesophageal cancer completed questionnaires 4-6 weeks after nCRT, before surgery. Patients' preferences were quantified using scenarios based on five aspects: 5-year overall survival, short-term HRQoL, long-term HRQoL, the risk that oesophagectomy is still necessary, and the frequency of clinical examinations using endoscopy and PET-CT. Panel latent class analysis was used. RESULTS: Some 100 of 104 patients (96·2 per cent) responded. All aspects, except the frequency of clinical examinations, influenced patients' preferences. Five-year overall survival, the chance that oesophagectomy is still necessary and long-term HRQoL were the most important attributes. On average, based on calculation of the indifference point between standard surgery and active surveillance, patients were willing to trade off 16 per cent 5-year overall survival to reduce the risk that oesophagectomy is necessary from 100 per cent (standard surgery) to 35 per cent (active surveillance). CONCLUSION: Patients are willing to trade off substantial 5-year survival to achieve a reduction in the risk that oesophagectomy is necessary.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Comparison of a low Hartmann's procedure with low colorectal anastomosis with and without defunctioning ileostomy after radiotherapy for rectal cancer: results from a national registry.

AIM: This study used a national registry to compare the outcome after a low Hartmann's procedure (LHP), defined as removal of most of the rectum to leave a short anorectal stump and an end colostomy, and low anterior resection (LA) with or without a diverting ileostomy (DI) in rectal cancer patients all of whom had received preoperative neoadjuvant radiotherapy (RT). METHOD: Patients who underwent LHP or LA with or without DI for rectal cancer after RT between 2009 and 2013 were identified from the Dutch Surgical Colorectal Audit. The postoperative outcome was compared between the three groups and risk of complications, reoperation and mortality were analysed in a multivariable model. RESULTS: The study included 4288 patients were included, of whom 27.8% underwent LHP, 20.2% LA and 52.0% LA with DI. Thirty-day mortality was higher after LHP (3.2% vs 1.3% and 1.3% for LA with or without DI, P < 0.001), but LHP was not an independent predictor of mortality in multivariable analysis. LHP and LA with DI were associated with a lower rate of abdominal infective complications (6.5% and 10.1% vs 16.2%, P < 0.001) and reoperation (7.3% and 8.1% vs 16.5%, P < 0.001). In multivariable analysis, LHP (OR 0.35, 95% CI 0.26-0.47) and LA with DI (OR 0.43, 95% CI 0.33-0.54) were associated with a lower risk of reoperation than LA alone. LHP was associated with a lower risk of any postoperative complication than LA with or without DI (OR 0.81, 95% CI 0.66-0.98). CONCLUSION: LHP and LA with DI were associated with fewer infective complications and reoperations than LA alone. The rate of any complication was less after LHR than LA with or without DI.

What patients and surgeons should know about the consequences of appendectomy for acute appendicitis after long-term follow-up: factors influencing the incidence of chronic abdominal complaints.

INTRODUCTION: Abscess formation and perforation are complications of acute appendicitis that lead to localized or generalized peritonitis. The long-term implications of complicated appendectomy remain largely unknown. MATERIALS AND METHODS: In the present study, it was investigated whether patients with complicated appendicitis experienced more abdominal complaints after long-term follow-up when compared to uncomplicated cases. In addition, the influence of operation technique (open versus laparoscopic) was studied. A retrospective analysis of 1,481 appendectomies for acute appendicitis was performed in two centers from January 2000 until January 2006. Demographic data, operative reports, intraoperatively adhesions and complications, abdominal pain, and satisfaction were monitored. In total, 1,433 patients were invited to fill out a questionnaire with a median follow-up of 7.1 years. Questionnaires of 526 (37 %) patients were suitable for analysis. RESULTS: Perforation, abdominal abscesses, or adhesions at initial operation did not result in more abdominal complaints when compared to appendectomy for uncomplicated acute appendicitis. Additionally, no significant differences in abdominal complaints were seen between laparoscopic and open techniques. CONCLUSION: In conclusion, the results of our study show that after follow-up of 7 years, the incidence of abdominal complaints was not influenced by operative technique or whether acute appendicitis was complicated or not. This finding does not support a causative role for adhesions with regard to chronic abdominal complaints. Our data enables surgeons to inform their patients about the long-term results of appendectomy, whether it was complicated or not.

Long-term survival after perforated diverticulitis.

AIM: Short-term survival after emergency surgery for perforated diverticulitis is poor. Less is known about long-term survival. The aims of this study were to evaluate long-term survival after discharge from hospital and to identify factors associated with prognosis. METHOD: All patients who underwent emergency surgery for perforated diverticulitis in five hospitals in Rotterdam, the Netherlands, between 1990 and 2005, were included. The association between type of surgery (Hartmann's procedure or primary anastomosis) and long-term survival was analysed using multivariate Cox regression analysis, taking into account age American Society of Anesthesiology (ASA) classification, Hinchey score, Mannheim Peritonitis Index (MPI) and surgeon's experience. In addition, survival of the patients was compared with that of the matched general Dutch population. RESULTS: Of 340 patients included in the study, 250 were discharged alive from hospital. The overall 5-year survival was 53%. Survival was significantly impaired compared with the expected matched gender-, age- and calendar time-specific survival. Overall survival was significantly related to age and ASA classification. Hinchey score, MPI, number of re-interventions, the surgeon's experience and type of procedure did not influence long-term survival, although a trend was found for Hartmann's procedure to be a risk factor for poorer survival compared with primary anastomosis (hazard ratio for mortality: 1.88; 95% confidence interval, 0.96-3.67; P = 0.07). CONCLUSION: Long-term survival of patients after perforated diverticulitis is limited and mainly caused by the poor general condition of the patients, rather than by the severity of the primary disease or calendar-time and type of procedure.

Restoration of bowel continuity after surgery for acute perforated diverticulitis: should Hartmann's procedure be considered a one-stage procedure?

OBJECTIVE: Hartmann's procedure (HP) still remains the most frequently performed procedure in acute perforated diverticulitis, but it results in a end colostomy. Primary anastomosis (PA) with or without defunctioning loop ileostomy (DI) seems a good alternative. The aim of this study was to assess differences in the rate of stomal reversal after HP and PA with DI and to evaluate factors associated with postreversal morbidity in patients operated for acute perforated diverticulitis. METHOD: All 158 patients who had survived emergency surgery for acute perforated diverticulitis in five teaching hospitals in The Netherlands between 1995 and 2005 and underwent HP or PA with DI were retrospectively studied. Age, gender, ASA-classification, severity of primary disease, delay of stoma reversal, surgeon's experience, surgical procedure and type of anastomosis were analysed in relation to outcome after stoma reversal. RESULTS: Of the 158 patients, 139 had undergone HP and 19 PA with DI. The reversal-rate was higher in patients with DI (14/19; 74%) compared to HP (63/139; 45%) (P = 0.027) Delay between primary surgery and stoma reversal was shorter after PA with DI compared with HP (3.9 vs 9.1 months; P < 0.001). Cumulative postreversal morbidity after HP was 44%. Early surgical complications occurred in 22 of 63 patients. Morbidity after DI reversal was 15% (P < 0.001). Three patients died after HP reversal, none died after DI reversal. Anastomotic leakage was observed in 10 patients after HP reversal. This was less frequently observed when the operation was performed by a specialist colorectal surgeon (10%vs 33%; P = 0.049) and when a stapled anastomosis was performed (4%vs 24%; P = 0.037). CONCLUSIONS: Reversal of HP should only be performed by an experienced colorectal surgeon, preferably performing a stapled anastomosis, or probably not be performed at all, as it is accompanied by high postoperative morbidity and even mortality. It is important that these findings are taken in account for when performing primary emergency surgery for acute perforated diverticulitis.

Herniation of the gall bladder through the abdominal wall.

We present a case of an 81-year-old woman, without medical history, with a swelling in the right lateral abdominal wall. Ultrasound and multislice CT were sufficient to confirm the diagnosis of a herniated gall bladder through the abdominal wall. This is the first case in which MRI proved to be a useful modality to exclude malignant characteristics and revealed an accurate differentiation between the gall bladder and the different layers of the abdominal wall. The gall bladder, including three stones, was removed laparoscopically. Histopathological research revealed signs of a chronic cholecystitis. Herniation of the gall bladder through the abdominal wall is rare. It was previously described in a few cases, but they were associated with the presence of an incisional hernia or carcinoma infiltration.

Primary closure of the skin after stoma closure. Management of wound infections is easy without (long-term) complications.

BACKGROUND AND AIMS: Whether or not the skin can be closed primarily after stoma closure is still debated in the existing literature. Therefore, this present study was undertaken to compare the complications and consequences between primary or delayed closure of the skin after stoma closure. PATIENTS AND METHODS: All consecutive stoma closures between January 2001 and August 2004 were included. In 25 patients (group I), the skin at the stoma site was closed primarily. In 37 patients (group II), the skin was left open. Patient characteristics, comorbidity, medication use, hospital stay and long-term complications were recorded and retrospectively compared between the two groups. RESULTS: In group I, wound infection rate was 36% versus 5% in group II (p = 0.005). Infected wounds were mostly found after ileostomy closure with primary closure of the skin (p = 0.018). The occurrence of a wound infection was not related to the use of corticosteroids, diabetes mellitus, fistula formation, anastomotic leakage, or primary disease and did not lead to a prolonged hospital stay or an increased number of incisional hernias. conclusion: In our opinion, it is safe to close the skin after stoma closure, but patients should be informed carefully about the advantages and disadvantages of this strategy, especially in case of ileostomy closure.