Background: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance... Show moreBackground: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance with this guideline during six years after publication.Materials and methods: Nationwide guideline compliance was investigated for three subsequent time periods (2012-2013 vs. 2014-2015 vs. 2016-2017) in patients with pancreatic cancer using five quality indicators in the Netherlands Cancer Registry: 1) discussion in multidisciplinary team meeting (MDT), 2) maximum 3-week interval from final MDT to start of treatment, 3) preoperative biliary drainage when bilirubin >250 mu mol/L, 4) use of adjuvant chemotherapy, and 5) chemotherapy for inoperable disease (non-metastatic and metastatic).Results: In total, 14 491 patients were included of whom 2290 (15.8%) underwent resection and 4561 (31.5%) received chemotherapy. Most quality indicators did not change over time: overall, 88.8% of patients treated with curative intent were discussed in a MDT, 42.7% were treated with curative intent within the 3-week interval, 62.7% with a resectable head tumor and bilirubin >250 mu mol/L underwent preoperative biliary drainage, 57.2% received chemotherapy after resection, and 36.6% with metastatic disease received chemotherapy. Only use of chemotherapy for non-metastatic, non-resected disease improved over time (23.4% vs. 25.6% vs. 29.7%).Conclusion: Nationwide compliance to five quality indicators for the guideline on pancreatic cancer management showed little to no improvement during six years after publication. Besides critical review of the current quality indicators, these outcomes may suggest that a nationwide implementation program is required to increase compliance to guideline recommendations. (C) 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved. Show less
Roessel, S. van; Strijker, M.; Steyerberg, E.W.; Groen, J.V.; Mieog, J.S.; Groot, V.P.; ... ; Besselink, M.G. 2020
Background: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of... Show moreBackground: The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer.Methods: We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement.Results: Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3 -year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001).Conclusions: This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www pancreascalculaior. corn may facilitate use in daily practice and future trials. (C) 2019 Elsevier Ltd, BASO The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
BackgroundPancreatic 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... Show moreBackgroundPancreatic 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/designPACAP-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.DiscussionThe 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 registrationClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018. Show less
Background Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor... Show moreBackground Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor characteristics. Such prediction models for patients with resected pancreatic cancer are lacking and therefore conditional survival was assessed and a nomogram predicting 5-year survival at a predefined period after resection of pancreatic cancer was developed. Methods This population-based study included patients with resected pancreatic ductal adenocarcinoma from the Netherlands Cancer Registry (2005-2016). Conditional survival was calculated as the median, and the probability of surviving up to 8 years in patients who already survived 0-5 years after resection was calculated using the Kaplan-Meier method. A prediction model was constructed. Results Overall, 3082 patients were included, with a median age of 67 years. Median overall survival was 18 months (95% confidence interval 17-18 months), with a 5-year survival of 15%. The 1-year conditional survival (i.e. probability of surviving the next year) increased from 55 to 74 to 86% at 1, 3, and 5 years after surgery, respectively, while the median overall survival increased from 15 to 40 to 64 months at 1, 3, and 5 years after surgery, respectively. The prediction model demonstrated that the probability of achieving 5-year survival at 1 year after surgery varied from 1 to 58% depending on patient and tumor characteristics. Conclusions This population-based study showed that 1-year conditional survival was 55% 1 year after resection and 74% 3 years after resection in patients with pancreatic cancer. The prediction model is available via to inform patients and caregivers. Show less
Background: In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact... Show moreBackground: In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact hereof has not been assessed in nationwide cohort studies. This population-based study aimed to investigate nationwide trends in incidence, treatment and survival of PDAC.Materials and methods: Patients with PDAC (1997-2016) were included from the Netherlands Cancer Registry. Results were categorised by treatment and by period of diagnosis (1997-2000, 2001-2004, 2005-2008, 2009-2012 and 2013-2016). Kaplane-Meier survival analysis was used to calculate overall survival.Results: In a national cohort of 36,453 patients with PDAC, the incidence increased from 12.1 (1997-2000) to 15.3 (2013-2016) per 100,000 (p < 0.001), whereas median overall survival increased from 3.1 to 3.8 months (p < 0.001). Over time, the resection rate doubled (8.3% -16.6%, p-trend<0.001), more patients received adjuvant chemotherapy (3.0%-56.2%, p-trend<0.001) and 3-year overall survival following resection increased (16.9%-25.4%, p < 0.001). Over time, the proportion of patients with metastatic disease who received palliative chemotherapy increased from 5.3% to 16.1% (p-trend<0.001), whereas 1-year survival improved from 13.3% to 21.2% (p < 0.001). The proportion of patients who only received supportive care decreased from 84% to 61% (p-trend<0.001).Conclusion: The incidence of PDAC increased in the past two decades. Resection rates and use of adjuvant or palliative chemotherapy increased with improved survival in these patients. In all patients with PDAC, however, the survival benefit of 3 weeks is negligible because the majority of patients only received supportive care. (C) 2019 The Authors. Published by Elsevier Ltd. Show less
In this thesis the additional value of targeted Next-Generation Sequencing was described in order to optimize the diagnostic process of patients with a suspect pancreatic lesion. Furthermore,... Show moreIn this thesis the additional value of targeted Next-Generation Sequencing was described in order to optimize the diagnostic process of patients with a suspect pancreatic lesion. Furthermore, several imaging techniques are described to visualize pancreatic cancer or colorectal liver metastases prior to surgery and during surgery. By better visualization of the tumor extent optimal treatment plans can be proposed and radical resections can be accomplished. Show less
Christodoulou, E.; Visser, M.; Potjer, T.P.; Stoep, N. van der; Rodriguez-Girondo, M.; Doorn, R. van; Gruis, N. 2019
Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of... Show moreCarriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients' surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR - 0.703 [95% CI - 1.201 to - 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined. Show less
Surgical exploration in patients with pancreatic or periampullary cancer is often performed without intraoperative image guidance. Although intraoperative ultrasound (IOUS) may enhance... Show moreSurgical exploration in patients with pancreatic or periampullary cancer is often performed without intraoperative image guidance. Although intraoperative ultrasound (IOUS) may enhance visualization during resection, this tool has not been investigated in detail until now. Here, we performed a prospective cohort study to evaluate the effect of IOUS on surgical strategy and to evaluate whether vascular involvement and radicality of the resection could be correctly assessed with IOUS. IOUS was performed by an experienced abdominal radiologist during surgical exploration in 31 consecutive procedures. IOUS affected surgical strategy by either (i) having no effect, (ii) determining tumor localization, (iii) evaluating vascular involvement or (iv) waiving surgery. Radicality of the resections and vascular contact were determined during pathologic analysis and compared with preoperative imaging and IOUS findings. Overall, IOUS influenced surgical strategy in 61% of procedures. In 21 out of 27 malignant tumors, a radical resection was achieved (78%). Vascular contact was assessed correctly using IOUS in 89% compared with 74% of patients using preoperative imaging. IOUS can help the surgical team to assess the resectability and to visualize the tumor and possible vascular contact in real time during resection. IOUS may therefore increase the likelihood of achieving a radical resection. (C) 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Show less
Leede, N. de; Bastiaannet, E.; Geest, L. van der; Egan, K.; Velde, C. van de; Balducci, L.; ... ; Extermann, M. 2019
Objectives: A significant proportion of patients with pancreatic cancer are over the age of 70 years. The aim was to compare treatment and survival for older patients with pancreatic cancer treated... Show moreObjectives: A significant proportion of patients with pancreatic cancer are over the age of 70 years. The aim was to compare treatment and survival for older patients with pancreatic cancer treated throughout the Netherlands or Moffitt Cancer Center (Tampa, Florida).Methods: All age-eligible patients with pancreatic adenocarcinoma (2008-2012) were identified. Results were stratified by stage. Treatment (neoadjuvant, surgery, adjuvant and palliative treatment) and short-term survival were compared, and where appropriate adjusted (sex, age, grade, year) or stratified according to age or hospital (Netherlands-academic, teaching, non-teaching).Results: In total, 2728 patients were included. Neo-adjuvant chemoradiation was more often administered at Moffitt (non-metastatic stages), as was adjuvant chemoradiation and chemotherapy (p <.001). The proportion surgery was not significantly different. In patients with advanced disease, more patients at Moffitt underwent palliative chemotherapy (64.5% versus 17.4%; p < .001). Short-term survival was better among Moffitt patients (HR 0.30 (95%CI 0.11-0.82), HR 0.56 (0.41-0.72), HR 0.43 (0.36-0.52) for early, T3 or node positive and advanced). Differences were less pronounced comparing Dutch academic hospitals to Moffitt.Conclusion: In the present comparison, a treatment regimen as delivered at Moffitt was associated with prolonged short-term survival. Further detailed analyses of selection criteria for systemic treatment could lead to tailored treatment and improved outcomes. (C) 2019 Elsevier Ltd. All rights reserved. Show less
For years, pancreatic cancer had a dismal prognosis with a long term survival of around 5%. Since the centralization of pancreatic cancer surgery and the introduction of systemic chemotherapy... Show moreFor years, pancreatic cancer had a dismal prognosis with a long term survival of around 5%. Since the centralization of pancreatic cancer surgery and the introduction of systemic chemotherapy with FOLFIRINOX, the median overall survival increased to around 20%. Radical tumor-margin free resection provides the patient with the best potential chance for cure. However, due to late onset of symptoms, the majority of patients present with inoperable disease. These patients can benefit from neoadjuvant therapy, or palliative chemotherapy. During clinical practice, this means that decision-making before and during surgery is critical to select the most optimal primary treatment modality. Currently, conventional imaging modalities lack sensitivity to detect small metastatic lesions, and are unable to visualize treatment response on neoadjuvant therapy. Tumor-specific molecular imaging in the form of fluorescence and photoacoustic imaging aids the surgeon to accurately recognize and resect malignant tissues in real-time during surgery. This thesis focuses on the challenges a surgeon faces during pancreatic cancer treatment, and the potential improvements that could be achieved by the use of tumor-specific imaging. In addition, the regulatory aspects of clinical translation of tumor-specific optical imaging agents are addressed. Show less
In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection... Show more In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection of breast cancer and pancreatic cancer. The status of breast cancer screening by proteomic profiling is discussed. Which steps have already been made? What is essential to implement this techniques in a clinical setting? Furthermore, the new protein profiling screening methods for pancreatic cancers are evaluated. Future studies will be suggested that are needed to translate this promising biomarker into a clinical application. Show less
Houweling, A.C.; Fukata, K.; Kubota, Y.; Shimada, H.; Rasch, C.R.N.; Ohno, T.; ... ; Horst, A. van der 2016
Background and purpose: We evaluated the robustness of carbon ion therapy for pancreatic cancer patients by investigating the impact of interfractional anatomical changes on the accumulated dose... Show moreBackground and purpose: We evaluated the robustness of carbon ion therapy for pancreatic cancer patients by investigating the impact of interfractional anatomical changes on the accumulated dose when using bony anatomy- and fiducial marker-based position verification.Material and methods: Carbon ion treatment plans were created for 9 patients in this retrospective planning study. The planning CT was deformably registered to each daily cone-beam CT (CBCT). The gastrointestinal gas volume visible on each CBCT was copied to these deformed CT images. Subsequently, the fraction doses were calculated by aligning the treatment plan according to a bony anatomy- and a fiducial marker-based registration.We compared the accumulated fraction doses with the planned dose using dose-volume histograms (DVHs) of the internal gross tumour volume (iGTV), internal clinical target volume (iCTV), duodenum, stomach, liver, spinal cord and kidneys.Results: iCTV coverage (D-98%) was on average reduced from 98.6% as planned to 81.9% and 88.6% for the bony anatomy- and marker-based registrations, respectively. DVHs of the duodenum showed large differences between the planned and accumulated dose.Conclusions: Severe reductions in dose coverage of the target due to interfractional anatomical changes were observed in both position verification methods. (C) 2016 Elsevier Ireland Ltd. All rights reserved. Show less
In deze studie is het gedrag van pancreas-tumorcellen onderzocht om meer zicht te krijgen op de impact die verschillende behandelingen hebben. Omdat de incidentie van pancreaskanker stijgt, is er... Show moreIn deze studie is het gedrag van pancreas-tumorcellen onderzocht om meer zicht te krijgen op de impact die verschillende behandelingen hebben. Omdat de incidentie van pancreaskanker stijgt, is er sterke vraag naar therapeutica. Het publieke bewustzijn en de kennis ten aanzien van kwaadaardige tumoren van de alvleesklier zijn relatief laag, in vergelijking tot bijvoorbeeld borstkanker. Ook wetenschappelijk onderzoek naar de oorzaken en effecten van alvleesklierkanker zijn summier wanneer vergeleken met de aanwezige kennis over tumoren van andere herkomst. Dit is vooral opvallend omdat de totale overlevingstijd van alvleesklierkanker zeer kort is. Om deze redenen is het van groot belang om essentiële eigenschappen te identificeren en mechanismen op te helderen die verantwoordelijk zijn voor deze slechte prognose. In het eerste deel van de thesis is de verandering in gedrag ten gevolge van het uitschakelen van genen bestudeerd. In het tweede deel zijn de effecten van diverse experimentele stoffen geanalyseerd op het moment dat ze bij de cellen gevoegd werden. Alvleesklier kanker kan alleen terug gedrongen worden als er een drastische verandering van de leefstijl doorgevoerd wordt. Het veranderen van de omgeving van de tumor door andere voeding in te nemen, kan resulteren in afname van de celmassa, zoals eerder werd aangetoond. Show less
