ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit

Impact of time interval between multidisciplinary team meeting and intended pancreatoduodenectomy on oncological outcomes

Background: Dutch guidelines indicate that treatment of pancreatic head and periampullary malignancies should be started within 3 weeks of the multidisciplinary team (MDT) meeting. This study aimed to assess the impact of time to surgery on oncological outcomes. Methods: This was a retrospective population-based cohort study of patients with pancreatic head and periampullary malignancies included in the Netherlands Cancer Registry. Patients scheduled for pancreatoduodenectomy and who were discussed in an MDT meeting from May 2012 to December 2016 were eligible. Time to surgery was defined as days between the final preoperative MDT meeting and surgery, categorized in tertiles (short interval, 18 days or less; intermediate, 19–32 days; long, 33 days or more). Oncological outcomes included overall survival, resection rate and R0 resection rate. Results: A total of 2027 patients were included, of whom 677, 665 and 685 had a short, intermediate and long time interval to surgery respectively. Median time to surgery was 25 (i.q.r. 14–36) days. Longer time to surgery was not associated with overall survival (hazard ratio 0⋅99, 95 per cent c.i. 0⋅87 to 1⋅13; P = 0⋅929), resection rate (relative risk (RR) 0⋅96, 95 per cent c.i. 0⋅91 to 1⋅01; P = 0⋅091) or R0 resection rate (RR 1⋅01, 0⋅94 to 1⋅09; P = 0⋅733). Patients with pancreatic ductal adenocarcinoma and a long time interval had a lower resection rate (RR 0⋅92, 0⋅85 to 0⋅99; P = 0⋅029). Discussion: A longer time interval between the last MDT meeting and pancreatoduodenectomy did not decrease overall survival

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1):a multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

Performance with robotic surgery versus 3D-and 2D-laparoscopy during pancreatic and biliary anastomoses in a biotissue model: pooled analysis of two randomized trials

Background Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study assessed the impact of robotic surgery versus 3D- and 2D-laparoscopy on surgical performance and operative time using a standardized biotissue model for pancreatico- and hepatico-jejunostomy using pooled data from two randomized controlled crossover trials (RCTs). Methods Pooled analysis of data from two RCTs with 60 participants (36 surgeons, 24 residents) from 11 countries (December 2017-July 2019) was conducted. Each included participant completed two pancreatico- and two hepatico-jejunostomies in biotissue using 3D-robotic surgery, 3D-laparoscopy, or 2D-laparoscopy. Primary outcomes were the objective structured assessment of technical skills (OSATS: 12-60) rating, scored by observers blinded for 3D/2D and the operative time required to complete both anastomoses. Sensitivity analysis excluded participants with excess experience compared to others. Results A total of 220 anastomoses were completed (robotic 80, 3D-laparoscopy 70, 2D-laparoscopy 70). Participants in the robotic group had less surgical experience [median 1 (0-2) versus 6 years (4-12), p < 0.001], as compared to the laparoscopic group. Robotic surgery resulted in higher OSATS ratings (50, 43, 39 points, p = .021 and p < .001) and shorter operative time (56.5, 65.0, 81.5 min, p = .055 and p < .001), as compared to 3D- and 2D-laparoscopy, respectively, which remained in the sensitivity analysis. Conclusion In a pooled analysis of two RCTs in a biotissue model, robotic surgery resulted in better surgical performance scores and shorter operative time for biotissue pancreatic and biliary anastomoses, as compared to 3D- and 2D-laparoscopy.Surgical oncolog

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

The Dutch Pancreatic Cancer Project: Optimization of clinical research in pancreatic cancer

The Dutch Pancreatic Cancer Project (PACAP) has one goal: to improve the outcomes and quality of life of pancreatic cancer patients. PACAP is one of the largest national collaborations for the collection of clinical outcomes and biomaterials. It is estimated that by 2030, pancreatic cancer will be the second most common cause of cancer-related death in Europe. Without treatment, median survival of pancreatic cancer patients is only several months. The Dutch Pancreatic Cancer Group (DPCG, www.dpcg.nl) is the national multidisciplinary tumor working group for pancreatic cancer patients. Members include gastro-intestinal surgeons, gastroenterologists, medical oncologists, radiologists, pathologists, radiotherapists, dieticians, nurses and patient representatives. Within the DPCG, PACAP also functions as a platform to discuss all data, initiate translational research, initiate improvements, and develop strategies to test these improvements in clinical trials. All this is realized in a nationwide, multidisciplinary approach with strong patients’ involvement. In the Dutch Pancreatic Cancer Audit (DPCA) each patient undergoing pancreatic operation for pancreatic cancer is registered. The DPCA has been expanded with a registration for patients who cannot undergo surgery. All patients with pancreatic cancer are invited for a three-monthly, online questionnaire of patient-reported outcomes (‘quality of life’). The thesis also describes the first international collaborations of PACAP, and investigates several ‘hot topics’ within pancreatic cancer which may find their implementation within PACAP. PACAP provides the need for nationwide information on pancreatic cancer patients. The combination of a registration of treatment, quality of life and biomaterials on a nationwide scale provides information which will benefit many researchers, patients and other organizations in future