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

T M Mackay, F J Smits, A E J Latenstein, A Bogte, B A Bonsing, H Bos, K Bosscha, L A A Brosens, L Hol, O R C Busch, G J Creemers, W L Curvers, M den Dulk, S van Dieren, L M J W van Driel, S Festen, E J M van Geenen, L G van der Geest, D J A de Groot, J W B de Groot, N Haj Mohammad, B C M Haberkorn, J T Haver, E van der Harst, G J M Hemmink, I H de Hingh, C Hoge, M Y V Homs, N C van Huijgevoort, M A J M Jacobs, E D Kerver, M S L Liem, M Los, H Lubbinge, S A C Luelmo, V E de Meijer, L Mekenkamp, I Q Molenaar, M G H van Oijen, G A Patijn, R Quispel, L B van Rijssen, T E H Römkens, H C van Santvoort, J M J Schreinemakers, H Schut, T Seerden, M W J Stommel, A J Ten Tije, N G Venneman, R C Verdonk, J Verheij, F G I van Vilsteren, J de Vos-Geelen, A Vulink, C Wientjes, F Wit, F J Wessels, B Zonderhuis, C H van Werkhoven, J E van Hooft, C H J van Eijck, J W Wilmink, H W M van Laarhoven, M G Besselink, Dutch Pancreatic Cancer Group, T M Mackay, F J Smits, A E J Latenstein, A Bogte, B A Bonsing, H Bos, K Bosscha, L A A Brosens, L Hol, O R C Busch, G J Creemers, W L Curvers, M den Dulk, S van Dieren, L M J W van Driel, S Festen, E J M van Geenen, L G van der Geest, D J A de Groot, J W B de Groot, N Haj Mohammad, B C M Haberkorn, J T Haver, E van der Harst, G J M Hemmink, I H de Hingh, C Hoge, M Y V Homs, N C van Huijgevoort, M A J M Jacobs, E D Kerver, M S L Liem, M Los, H Lubbinge, S A C Luelmo, V E de Meijer, L Mekenkamp, I Q Molenaar, M G H van Oijen, G A Patijn, R Quispel, L B van Rijssen, T E H Römkens, H C van Santvoort, J M J Schreinemakers, H Schut, T Seerden, M W J Stommel, A J Ten Tije, N G Venneman, R C Verdonk, J Verheij, F G I van Vilsteren, J de Vos-Geelen, A Vulink, C Wientjes, F Wit, F J Wessels, B Zonderhuis, C H van Werkhoven, J E van Hooft, C H J van Eijck, J W Wilmink, H W M van Laarhoven, M G Besselink, Dutch Pancreatic Cancer Group

Abstract

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.

Keywords: Best practices; Biliary drainage; Chemotherapy; Implementation; Pancreatic cancer; Pancreatic enzyme replacement therapy; Quality of life; Registry; Stepped-wedge cluster randomized controlled trial; Survival.

Conflict of interest statement

Judith de Vos-Geelen has received non-financial support from Servier and has received institutional research funding from Servier, all outside the submitted work. Other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Guideline compliance among 2564 patients treated for pancreatic or periampullary cancer in the Netherlands in 2010 and 2012. MDT multidisciplinary team. Adjuvant chemotherapy, percentage of patients receiving adjuvant chemotherapy after tumor resection for pancreatic carcinoma. Discussed in MDT meeting, percentage of patients discussed within a MDT meeting. Waiting time, percentage of patients who started curative treatment within three weeks of final MDT meeting. * Not available for 2010
Fig. 2
Fig. 2
Type of palliative chemotherapy given to 345 patients with metastasized pancreatic cancer in 2015 in the Netherlands in pancreatic and non-pancreatic centers (NCR data). CAPOX capecitabine and oxaliplatin, 5FU 5-fluorouracil, FOLFIRINOX folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin
Fig. 3
Fig. 3
Schedule of enrolment, interventions, and assessments of PACAP-1 according to SPIRIT guidelines
Fig. 4
Fig. 4
Schematic representation of PACAP-1 stepped-wedge cluster randomized controlled trial. DPCG Dutch Pancreatic Cancer Group
Fig. 5
Fig. 5
Schematic representation of 17 Dutch Pancreatic Cancer Group centers (large dots) and their respective referral networks and centers (smaller dots) per color. Note that referral centers may refer patients to more than one pancreatic center and therefore this figure is only for illustration
Fig. 6
Fig. 6
Schematic representation of PACAP-1 best practices. PERT pancreatic enzyme replacement therapy, EPI exocrine pancreatic insufficiency, POC postoperative conclusion, PALGA nationwide network and registry of histo- and cytopathology of the Netherlands, WHO World Health Organization performance status

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