Detection, Treatment and Survival of Pancreatic Cancer Recurrence in the Netherlands
Conditions: Pancreatic Ductal Adenocarcinoma, Pancreatic Cancer, Pancreas Cancer, PDAC
Sponsor: UMC Utrecht

STUDY PROPOSAL 
 
 
 
Detection, treatment and survival of pancreatic cancer 
recurrence in the Netherlands: a nationwide analysis 
L.A. Daamen1,2, I.W.J.M. van Goor1,2, V.P. Groot1,3, M. Intven2, N. Haj Mohammad4, L.A.A. Brosens5 … <<< other 
DPCG authors >>> *, I.Q. Molenaar, MD, PhD5# and H.C. van Santvoort, MD, PhD5# for the Dutch Pancreatic Cancer 
Group 
* author positions will be assigned as stated below (see ‘authorship’) 
# authors share senior authorship 
1 Dept. of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital 
Nieuwegein, the Netherlands 
2 Dept. of Radiation Oncology, University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands 
3 Dept. of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA 
4 Dept. of Oncology, University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands 
5 Dept. of Pathology, University Medical Center, Utrecht, The Netherlands 
 
Document date: 29-01-2017 
 
1. Introduction  
Pancreatic ductal adenocarcinoma (PDAC) is associated with a very poor prognosis, in part due to the development 
of disease recurrence in up to 80% of patients within two years after radical resection.1-4 Despite the high 
incidence of recurrent pancreatic cancer, current national guidelines do not contain specific recommendations for 
surveillance after resection of pancreatic ductal adenocarcinoma.5,6 The lack of Dutch or European guidelines 
regarding follow-up has led to different surveillance strategies among pancreatic surgeons in the Netherlands. A 
recent nationwide survey carried out under Dutch pancreatic surgeons showed that generally a symptomatic 
surveillance strategy is favored, consisting of regular outpatient visits without routine tumor marker testing or 
imaging.7 The impact of this current practice on the detection and treatment of recurrent pancreatic cancer and 
overall survival has not been well established.  
 

 
2. Aim 
The aim of this study is to evaluate current surveillance strategies after primary resection of pancreatic cancer in 
the Netherlands, with regard to the detection and treatment of recurrent disease. 
 
3. Intervention 
Not applicable. 
 
4. Sample size 
All patients undergoing resection for primary pancreatic ductal adenocarcinoma between 2011 and 2016. 
 
5. Study design  
A retrospective observational cohort study in all DPCG-affiliated centers.  
 
6. Primary outcome measures  
- 
Incidence of PDAC recurrence 
- 
Patterns of PDAC recurrence (asymptomatic vs. symptomatic; first site of recurrence; early vs. late recurrence) 
- 
Treatment of PDAC recurrence 
 
7. Secondary outcome measures  
- 
Symptoms at time of (suspected) recurrence 
- 
Performance score at time of recurrence detection 
- 
Use of imaging procedures during follow-up 
- 
Number of histologically confirmed recurrences 
- 
Recurrence-free survival 
- 
Post-recurrence survival 
- 
Overall survival 
 
8. Inclusion criteria  
- 
Patients with PDAC confirmed by pathological examination 
- 
Patients undergoing a pancreatic resection (PPPD, Whipple, distal pancreatectomy or total pancreatectomy)  
 
9. Exclusion criteria  
- 
Patients with 30-day postoperative mortality 
 

 
10. Participating centers 
All DPCG-affiliated hospitals.  
 
11. Data collection 
The following data will be collected: age, sex, BMI, ASA score, preoperative CA 19-9 level, operation procedure, 
resection margin status (R0/R1/R2), tumor differentiation, tumor size, TNM stage, total lymph nodes, positive 
lymph nodes, microscopic perineural invasion, microscopic perilymphatic invasion, adjuvant therapy, date start 
adjuvant treatment, time between surgery and start date adjuvant treatment, number of cycles adjuvant 
treatment received, use and type of imaging procedures, presence of recurrence, presence of histological evidence 
for recurrence and pathologic results, recurrence site, date of recurrence, symptomatic recurrence, asymptomatic 
recurrence, type of treatment after recurrence, date of operation, date of death, date of last follow-up.  
Asymptomatic recurrence is defined as recurrent pancreatic cancer detected as an incidental finding following 
additional examination for other reasons or by imaging requested by the patient. If recurrent pancreatic cancer is 
discovered due to a significant patient-initiated complaint that is new or has been increased in severity or 
frequency, disease recurrence will be defined as symptomatic. 
Patterns of recurrence are furthermore categorized using four categories: 1) isolated local recurrence: recurrence 
in the pancreatic remnant or in the surgical bed, such as soft tissue along the celiac or superior mesenteric artery, 
aorta or around the pancreatojejunostomy site; 2) isolated distant recurrence: recurrence restricted to a single 
organ or site; 3) local + distant recurrence: simultaneous occurrence of both isolated local recurrence and isolated 
distant recurrence; 4) multiple recurrence: recurrence at multiple distant sites and/or carcinomatosis. 
Early disease recurrence is defined as recurrence < 10 months after surgery, late disease recurrence is defined as 
recurrence ≥ 10 months after surgery. This cutoff point was found to be the most significant value for showing 
differences in post-recurrence survival. 
Overall survival (OS) and post-recurrence survival are defined as the time from the date of operation (OS) or the 
date of recurrence (post-recurrence survival) to either death from any cause or last follow-up. Recurrence-free 
survival (RFS) is defined as the time interval between the date of the operation and either date of recurrence or 
last follow-up if recurrence is not observed. 
 
12. Statistical analyses 
Descriptive statistics will be obtained. Continuous variables are expressed as median and range, unless specified 
otherwise, and categorical values as number (percentage). The proportion of patients receiving imaging 
procedures for each month of follow-up will be calculated by dividing the amount of patients receiving one or 
more imaging procedure(s) for the detection of recurrence by the amount of uncensored patients. Censoring 
occurs at date of recurrence, death, or last follow-up if recurrence does not occur. Kaplan-Meier curves are used to 

estimate median OS, RFS and post-recurrence survival with corresponding 95% confidence intervals. Univariable 
and multivariable analyses will be performed using Cox proportional hazard models to identify potential predictive 
factors for post-recurrence survival. A two-tailed P value of <0.05 is considered to indicate statistical significance. 
Statistical analysis will be performed with SPSS statistical software, version 23.0 (SPSS Inc., Chicago, IL). 
 
13. Co-authorships 
Authorship will be based on international ICMJE guidelines. Next to the study team (L.A. Daamen, I.W.J.M. van 
Goor, V.P. Groot, M. Intven, N. Haj Mohammad, L.A.A. Brosens, H.C. van Santvoort and I.Q. Molenaar), the number 
of authors per centre will be based on number of pancreatic resections in the study period (2011-2016): 1 author 
per centre performing up to 100 pancreatectomies; 2 authorships per centre performing >100 pancreatic 
resections. The study coordinators will be first and second authors (Daamen and Groot) where project leaders will 
be shared senior authors (Molenaar and van Santvoort). Other co-authorship places will be awarded in accordance 
to international guidelines.  
 
14. Quality control 
Not applicable. 
 
15. Study duration   
Not applicable since it is a retrospective study. 
 
16. Ethical approval 
It is confirmed by the MREC UMC Utrecht that an official approval of this study is not required under the Medical 
Research Involving Human Subject Act (WMO). The data will be handled confidentially and anonymously. The 
handling of personal data will comply with the Dutch Personal Data Protection Act (De Wet Bescherming 
Persoonsgegevens). A subject identification code list will be used to link the data to the subject. These codes will 
not be based on the patient initials and birth date. The coordinating investigator will safeguard the key to this 
code. The data will be kept for a minimum of 15 years. 
  
17. References 
1. Shibata K, Matsumoto T, Yada K, Sasaki A, Ohta M, Kitano S. Factors predicting recurrence after resection of 
pancreatic ductal carcinoma. Pancreas. 2005;31:69-73. 
2. Suenaga M, Fujii T, Kanda M, et al. Pattern of first recurrent lesions in pancreatic cancer: hepatic relapse is 
associated with dismal prognosis and portal vein invasion. Hepatogastroenterology. 2014;61:1756-1761. 

3. Parikh AA, Maiga A, Bentrem D, et al. Adjuvant Therapy in Pancreas Cancer: Does It Influence Patterns of 
Recurrence? J Am Coll Surg. 2016;222:448-456. 
4. Groot VP, Rezaee N, Wu W, et al. Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for 
Pancreatic Ductal Adenocarcinoma. Ann Surg. 2017. 
5. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v56-68. 
6. 15. IKNL. Landelijke richtlijn pancreascarcinoom (2.0). Available at: www.oncoline.nl. 
7. Groot VP, Daamen LA, Hagendoorn, J et al. Current Strategies for Detection and Treatment of Recurrence of 
Pancreatic Ductal Adenocarcinoma After Resection: A Nationwide Survey. Pancreas. 2017;46(9)-e75. 
8. Groot VP, Daamen LA, Hagendoorn J et al. Use of imaging during symptomatic follow-up after resection of 
pancreatic ductal adenocarcinoma. 2018;221:152-169.  
9. Fischer R, Breidert M, Keck T, et al. Early recurrence of pancreatic cancer after resection and during adjuvant 
chemotherapy. Saudi J Gastroenterol. 2012;18:118-121. 
10. Yamamoto Y, Ikoma H, Morimura R, et al. Optimal duration of the early and late recurrence of hepatocellular 
carcinoma after hepatectomy. World J Gastroenterol. 2015;21:1207-1215.