Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients

Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients

G Model YDLD-3489; No. of Pages 8 ARTICLE IN PRESS Digestive and Liver Disease xxx (2017) xxx–xxx Contents lists available at ScienceDirect Digesti...

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G Model YDLD-3489; No. of Pages 8

ARTICLE IN PRESS Digestive and Liver Disease xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Liver, Pancreas and Biliary Tract

Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients Lu Hao a,1 , Xiang-Peng Zeng a,1 , Lei Xin a,b,1 , Dan Wang a , Jun Pan a , Ya-Wei Bi a , Jun-Tao Ji b , Ting-Ting Du a , Jin-Huan Lin a , Di Zhang a , Bo Ye c , Wen-Bin Zou a , Hui Chen a,b , Ting Xie d , Bai-Rong Li e , Zhao-Hong Zheng f , Teng Wang a,b , Hong-Lei Guo a , Zhuan Liao a,b , Zhao-Shen Li a,b,∗ , Liang-Hao Hu a,b,∗ a

Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China Digestive Endoscopy Center, Changhai Hospital, The Second Military Medical University, Shanghai, China c Department of surgery, Jinling Hospital, Nanjing, China d Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China e Department of Gastroenterology, Air Force General Hospital, Beijing, China f Department of Traditional Chinese Medicine, Jiangdu Hospital, Yangzhou, China b

a r t i c l e

i n f o

Article history: Received 25 February 2017 Received in revised form 5 July 2017 Accepted 7 July 2017 Available online xxx Keywords: Chronic pancreatitis Pancreatic cancer Risk factors

a b s t r a c t Background: Risk of pancreatic cancer may increase in chronic pancreatitis patients. Aims: This study aimed to identify the incidence of and risk factors for pancreatic cancer in chronic pancreatitis patients. Methods: Chronic pancreatitis patients admitted to our center from January 2000 to December 2013 were enrolled. Cumulative rates of pancreatic cancer and survival rates were calculated. The standardized incidence ratio was calculated based on the pancreatic cancer incidence in general population of China. Risk factors for pancreatic cancer were identified. Results: In a total of 1656 patients, the median follow-up duration was 8.0 years. Pancreatic cancer was detected in 21 patients (1.3%). The expected number of cases of pancreatic cancer was 1.039, yielding a standardized incidence ratio of 20.22. The standardized incidence ratios for patients with a >60 pack-year smoking history were much higher (145.82). Two risk factors for pancreatic cancer were identified: age at the onset of chronic pancreatitis (hazard ratio, 1.05) and a >60 pack-year smoking history (hazard ratio, 11.83). Conclusion: The risk of pancreatic cancer is markedly increased in chronic pancreatitis patients compared with the general population, especially in patients with an older age at onset and a >60 pack-year smoking history. The high-risk populations were suggested to be followed up closely. © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction The incidence of chronic pancreatitis (CP) in industrialized countries ranges from 3.5 to 10 people per 100,000 [1]. The damage to both the exocrine and endocrine compartments of the pancreas eventually results in severe maldigestion and diabetes. The histopathologic features of this disease include acinar atrophy,

∗ Corresponding authors at: Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, The Second Military Medical University, 168 Changhai Road, Shanghai 200433, China. Fax: +86 21 55621735. E-mail addresses: [email protected] (Z.-S. Li), [email protected] (L.-H. Hu). 1 The authors contributed equally to this study.

fibrosis, fatty replacement, chronic inflammation and abnormal ducts [1,2]. Chronic inflammatory conditions constitute predispositions to organ-specific cancers. CP patients reportedly represent a high-risk population for pancreatic cancer [3–10]. A recent meta-analysis that included 22 studies found an increased relative risk of developing pancreatic cancer of 13.3 in CP patients [11]. Pancreatic cancer is a severe clinical condition that is always diagnosed too late for surgical intervention. Moreover, the onset of pancreatic cancer is insidious in CP patients and the symptoms of pancreatic cancer may resemble the symptoms and clinical findings of CP [12]. Therefore, identifying risk factors for the development of pancreatic cancer in CP patients would be beneficial for early detection [13].

http://dx.doi.org/10.1016/j.dld.2017.07.001 1590-8658/© 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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Fig. 1. Flow diagram of patient enrolment and the study design.

This study was based on a retrospective–prospective cohort of 1656 CP patients with a long follow-up history after the onset of CP. We aimed to determine the incidence of pancreatic cancer in CP patients and identify the risk factors for this disease.

2. Materials and methods 2.1. Patients and database Since the 1990s, an electronic medical record system (GOODWILL Inc., Beijing, China) has been used in Changhai Hospital (Shanghai, China) and has facilitated several studies on CP [14–22]. To track changes consistently throughout the course of CP and facilitate the evaluation and the study of this disease, a dedicated database, the Changhai CP Database (version number 2.1, YINMA Information Technology Inc., Shanghai, China), was established in 2005 to collect the clinical data of CP patients who were admitted to Changhai Hospital. Data from January 2000 to December 2004 were retrospectively collected according to the electronic medical record system and were complemented through telephone, letter, and e-mail inquiries. Data were prospectively collected since January 2005. The following information was documented in detail: demographic data (age, sex, birthplace, etc.), the course of CP, medical history, history of other diseases, smoking and alcohol history, family history of pancreatic diseases and diabetes mellitus (DM), laboratory and imaging findings, and treatment strategy. The database system was set to remind the investigators to call patients for clinical check-ups. In addition to clinic visits due to complaints of discomfort related to CP, all patients were periodically (at least annually) called for clinical check-ups and investigations. Transabdominal ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT) was selected as the evaluation modality during each follow-up visit. Evaluations of each revisit or of telephone inquiries for patients who did not return to Changhai Hospital were added to the CP database. In December 2013, we contacted all the patients in our database for a final eval-

uation, except those who were lost to follow-up or had died. The duration of follow-up was defined as the duration from the onset of CP to the date of the last personal contact, death, or the end of follow-up (December 2013), whichever came first (Fig. 1). The exclusion criteria were as follows: groove pancreatitis (GP) and autoimmune pancreatitis (AIP) [23]. In the present study, cases of pancreatic cancer diagnosed within 2 years after the diagnosis of CP [16,24] and patients with a follow-up period of less than 2 years (CP diagnosed after December 2011) were excluded. The study was approved by the Ethics Committee of Changhai Hospital. Written informed consent was obtained from all participating patients. All of the diagnostic and therapeutic modalities were carried out in accordance with the approved guidelines.

2.2. Definitions The diagnosis of CP was established according to the Asia-Pacific consensus [25]. Alcoholic chronic pancreatitis (ACP) was considered when alcohol intake exceeded 80 g/day for men or 60 g/day for women for at least 2 years in the absence of other causes [17,26]. Hereditary CP refers to two first-degree relatives or ≥3 seconddegree relatives in ≥2 generations with recurrent acute pancreatitis and/or CP without any precipitating factors [27]. Although the abnormal anatomy of the pancreatic duct (including pancreas divisum and anomalous pancreaticobiliary junction) as a cause of CP remains controversial, we defined it as an etiology [28]. Patients were defined as having post-traumatic CP when there was a history of abdominal trauma with imaging evidence of pancreatic injury and subsequent ductal dilation. Hyperlipidemia is considered an etiology when blood triglycerides are >1000 mg/dL [29]. Patients with CP were considered idiopathic when none of the above causes were found. The diagnosis of pancreatic cancer was established according to the National Comprehensive Cancer Network (NCCN) guideline [30,31]. Once the patient was diagnosed with pancreatic

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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cancer, treatment was determined and performed by the multidisciplinary team. 2.3. Treatment strategy 2.3.1. Treatment strategy for CP Endoscopic treatment was the principle method of therapy, including extracorporeal shockwave lithotripsy (ESWL)/endoscopic retrograde cholangiopancreatography (ERCP) for stone removal and main pancreatic duct drainage [15,32–35]. Surgical treatment, such as pancreaticoduodenectomy, distal pancreatectomy, was considered when endoscopic treatment was ineffective, especially in CP patients with pancreatic pseudocysts or pseudoaneurysms [36]. For CP patients who did not experience pain, interventions were performed only when complications such as biliary stricture, infection, or pancreatic pseudocyst enlargement occurred [37]. DM and/or steatorrhea were not indications for invasive treatment of CP. 2.3.2. Treatment strategy for pancreatic cancer Pancreatic cancer was treated according to the NCCN and European Society for Medical Oncology guideline. Tumors that were considered localized and clearly resectable were treated by surgical resection. Neoadjuvant therapy was performed for tumors that were considered borderline resectable. Chemoradiation treatment was chosen for locally advanced or metastatic diseases. Palliative and supportive care was performed for tumors that were considered unresectable, such as pain control, expandable metal stent placement for duodenal obstruction, and biliary stenting for jaundice [30,31,38]. 3. Statistical methods The continuous variables are expressed as the mean ± standard deviation (SD) and were compared using an unpaired, 2-tailed t test or the Mann–Whitney test. The categorical variables were compared using the ␹2 test or the Fisher exact test. The cumulative rates of pancreatic cancer and the survival rate after the diagnosis of CP were calculated using the Kaplan–Meier method [39]. To determine the expected number of cases of pancreatic cancer in the cohort, we used age-stratified (according to a 10-year age interval) and sex-specific data on the incidence of cancer in China in 2012 provided by the National Central Cancer Registry of China [40]. The ratio of the observed number of cases of pancreatic cancer in the cohort of CP patients to the expected number of cases (the standardized incidence ratio, SIR) was calculated and used to estimate the relative risk for pancreatic cancer in this cohort. The 95% confidence interval (CI) for the SIR was calculated assuming that the observed cases of pancreatic cancer followed a Poisson distribution. The significance of each variable was assessed by a multivariate Cox regression analysis using SPSS (version 21.0) to investigate the independent risk factors for pancreatic cancer development after a diagnosis of CP.

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than 2 years, a total of 1656 patients with CP were finally enrolled in our study. The median duration of follow-up was 8.0 years (range 2.0–53.2 years). At the end of the follow-up, 21 patients (1.3%; 11 men, 10 women) had been diagnosed with pancreatic cancer. The final diagnosis of pancreatic cancer was confirmed in 17 patients by histological examination (10 surgical specimens, 3 CT-guided fineneedle biopsies and 4 endoscopic ultrasound-guided fine-needle aspirations). Histological examinations of the other 4 patients were negative. These 4 patients were diagnosed with pancreatic cancer by the multi-disciplinary team and the clinical course was consistent with their diagnosis. The median survival time of the 21 patients was 8.2 months (range 2.8–72.2 months). Two patients were still alive at the endpoint of the study (December 2013). One had been diagnosed with pancreatic cancer in December 2007 and the other in September 2011. Surgical resection was performed in both of these patients. The general characteristics of the 1656 patients with CP are presented in Table 1. Age at the onset of CP, smoking history, DM, morphology of the main pancreatic duct (MPD), the type of pain and the overall treatment were significantly different between the cancer and the no-cancer groups. The age at pancreatic stone diagnosis in pancreatic stone patients also differed between these two groups. 4.2. The cumulative rates of pancreatic cancer Pancreatic cancer was found in 1.3% (21/1656) of patients after 2 years of the diagnosis of CP the proportions were 1.0% (10/1152) in male patients and 2.0% (10/504) in female patients. The cumulative proportions of pancreatic cancer were 0.6% (95% CI: 0.02%–1.2%), 1.0% (95% CI: 0.2%–1.8%) and 1.3% (95% CI: 0.1%–2.4%) at 3, 5 and 10 years after the diagnosis of CP, respectively. Male and female patients showed no significant difference in the rate of pancreatic cancer (P = 0.085, Fig. 2). 4.3. Comparison of SIR of pancreatic cancer in CP patients After the exclusion of the patients with a follow-up period of less than 2 years, the total observation period was 16,357, yielding an expected number of cases of pancreatic cancer of 1.039 and an SIR of 20.22 (95% CI, 12.53–30.89). The cancer incidences were presented and duly corrected for age and gender in different alcohol and tobacco consumption patients. The total observation period for the 326 patients consuming >80 g/day alcohol was 3448 person–years and was 10,672 person–years for the 1120 nonalcoholics, yielding SIR values of 13.70 (95% CI, 2.76–38.80) and 26.56 (95% CI, 15.77–41.93), respectively. The total observation period for the 1,162 nonsmokers was 11,490 person–years, 4651 person–years for the patients smoking for <60 pack-years, and 216 person–years for those smoking for >60 pack-years, yielding SIR values of 24.67 (95% CI, 14.64–38.95), 3.39 (95% CI, 0.14–17.13), and 145.82 (95% CI, 16.63–501.01), respectively (Table 2). 4.4. Predictors for pancreatic cancer development after the diagnosis of CP

4. Results 4.1. General characteristics of the subjects As shown in Fig. 1, from January 2000 to December 2013, a total of 2287 CP patients were entered into the Changhai CP Database. After the exclusion of 118 patients, including 10 patients diagnosed with GP and 108 patients diagnosed with AIP, a cohort of 2169 patients with CP was established. After the further exclusion of 16 patients diagnosed with pancreatic cancer within 2 years after the diagnosis of CP and 513 patients with a follow-up period of less

A univariate analysis for pancreatic cancer development among the 1656 patients included in the study is shown in Table 3. Five variables showed a P value of less than 0.05: age at the onset of CP, age at the diagnosis of CP, a >60 pack-year smoking history, body mass index, and the morphology of the MPD. For the multivariate analysis, the 5 predictors above were included in the Cox proportional hazards regression model. Finally, 2 independent predictors for pancreatic cancer development were identified. The risk of developing pancreatic cancer was significantly higher in patients with an older age at the onset of CP (hazard

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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4 Table 1 General characteristics of 1656 patients with CP. Items

Overall

Cancer group N = 21

No cancer group N = 1635

P

Male sex Age at the onset of CP, ya Age at the diagnosis of CP, ya Adolescent Age at the onset of CP, y <30 30–40 40–50 50–60 >60 Smoking history Nonsmokers Smoking ≤60 pack-year Smoking >60 pack-year Alcohol consumption 0 g/d 0–20 g/d 20–80 g/d >80 g/d Body mass indexa Etiology ICP ACP Abnormal anatomy of pancreatic duct HCP Hyperlipidemic CP Post-traumatic CP Initial manifestations Abdominal pain Endocrine/exocrine dysfunction Others Pancreatic stonesb Age at pancreatic stone diagnosisa Time between onset and pancreatic stonea DM Age at diabetesa Time between onset and DMa Steatorrhea Age at steatorrheaa Time between onset and steatorrheaa Biliary stricture Age at CBD stenosisa Time between onset and CBD stenosisa Pancreatic pseudocyst Age at pseudocysta Time between onset and pseudocyst formationa Morphology of MPD Pancreatic stone alone MPD stenosis alone MPD stenosis and stone Complex pathologic changes Type of pain Recurrent acute pancreatitis Recurrent pain Recurrent acute pancreatitis and pain Chronic pain Without pain Severe acute pancreatitis Successful drainagec Overall treatment Endotherapy alone Surgery alone Both endotherapy and surgery Conservative treatment DM in first-/second-/third-degree relatives Pancreatic diseases in first-/second-/third-degree relatives (excluding hereditary CP)

1152 (69.6%) 38.866 ± 16.820 43.349 ± 15.740 217 (13.1%) – 336 (20.3%) 314 (19.0%) 463 (28.0%) 298 (18.0%) 245 (14.8%) – 1162 (70.0%) 473 (28.6%) 21 (1.3%) – 1120 (67.6%) 47 (2.8%) 163 (9.8%) 326 (19.7%) 24.800 ± 93.008 – 1249 (75.4%) 322 (19.4%) 47 (2.8%) 21 (1.3%) 9 (0.5%) 8 (0.5%) – 1384 (83.6%) 168 (10.1%) 104 (6.3%) 1257 (75.9%) 41.461 ± 14.938 6.021 ± 7.401 494 (29.8%) 45.826 ± 11.691 5.269 ± 7.273 398 (24.0%) 43.081 ± 11.986 6.074 ± 7.327 265 (16.0%) 51.202 ± 12.386 6.053 ± 8.673 268 (16.2%) 42.779 ± 17.315 4.811 ± 5.726 – 590 (27.4%) 598 (23.8%) 728 (33.8%) 237 (11.0%) – 536 (32.4%) 477 (28.8%) 449 (27.1%) 80 (4.8%) 114 (6.9%) 52 (3.1%) 1153 (69.6%) – 1172 (70.8%) 188 (11.4%) 118 (7.1%) 178 (10.7%) 68 (4.1%) 18 (1.1%)

11 (52.4%) 48.726 ± 14.633 49.918 ± 14.209 1 (4.8%) – 2 (9.5%) 5 (23.8%) 1 (4.8%) 11 (52.4%) 2 (9.5%) – 18 (85.7%) 1 (4.8%) 2 (9.5%) – 18 (85.7%) 0 0 3 (14.3%) 19.049 ± 2.787 – 14 (66.7%) 6 (28.6%) 0 1 (4.8%) 0 0 – 18 (85.7%) 2 (9.5%) 1 (4.8%) 13 (61.9%) 49.208 ± 9.126 3.723 ± 4.856 11 (52.4%) 45.136 ± 7.882 3.600 ± 4.047 6 (28.6%) 45.500 ± 10.485 2.200 ± 3.811 4 (19.0%) 50.400 ± 10.834 9.200 ± 2.211 4 (19.0%) 50.200 ± 8.302 3.525 ± 4.904 – 5 (23.8%) 12 (57.1%) 0 4 (19.0%) – 0 17 (81.0%) 0 0 4 (19.0%) 0 18 (85.7%) – 13 (61.9%) 2 (9.5%) 5 (23.8%) 1 (4.8%) 0 0

1141 (69.8%) 38.760 ± 16.813 43.265 ± 15.745 216 (13.2%) – 334 (20.4%) 309 (18.9%) 462 (28.3%) 287 (17.6%) 243 (14.9%) – 1144 (69.9%) 472 (28.9%) 19 (1.2%) – 1102 (67.4%) 47 (2.9%) 163 (10.0%) 323 (19.8%) 24.869 ± 93.560 – 1235 (75.5%) 316 (19.3%) 47 (2.9%) 20 (1.2%) 9 (0.6%) 8 (0.5%) – 1366 (83.5%) 166 (10.2%) 103 (6.3%) 1244 (76.1%) 41.380 ± 14.968 6.045 ± 7.421 483 (29.5%) 45.842 ± 11.768 5.307 ± 7.328 392 (24.0%) 43.062 ± 12.007 6.104 ± 7.342 261 (16.0%) 51.214 ± 12.426 6.005 ± 8.728 264 (16.1%) 42.657 ± 17.406 4.832 ± 5.745 – 585 (27.4%) 586 (27.5%) 728 (34.1%) 233 (10.9%) – 536 (32.8%) 460 (28.1%) 449 (27.5%) 80 (4.9%) 110 (6.7%) 52 (3.2%) 1135 (69.4%) – 1159 (70.9%) 186 (11.4%) 113 (6.9%) 177 (10.8%) 68 (4.2%) 18 (1.1%)

0.085 0.007 0.054 0.254 0.001 – – – – – <0.001 – – – 0.461 – – – – 0.816 0.550 – – – – – – 0.952 – – – 0.131 0.010 0.261 0.023 0.843 0.442 0.624 0.726 0.359 0.702 0.891 0.466 0.720 0.389 0.652 0.002 – – – – <0.001 – – – – – 0.406 0.107 0.025 – – – – 0.340 0.629

CP = chronic pancreatitis, DM = diabetes mellitus, ICP = idiopathic chronic pancreatitis, ACP = alcoholic chronic pancreatitis, HCP = hereditary chronic pancreatitis. a Mean ± SD. b Pancreatic calcifications were also regarded as stones that are located in branch pancreatic duct or ductulus. c Patients with successful main pancreatic duct (MPD) drainage are those whose CP was established after ERCP or pancreatic surgery or those who underwent successful MPD drainage during administration when CP diagnosis was established.

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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Table 2 Comparison of SIR of pancreatic cancer in 1,656 patients with CP: smokers versus nonsmokers and alcoholic versus nonalcoholics.

All Alcohol comsumption 0 g/d 0–20 g/d 20–80 g/d >80 g/d Smoking Nonsmokers Smoking ≤60 pack-year Smoking >60 pack-year

Cancer observed

Person–years

Cancer expected

SIR (O/E)

95% CI

21 – 18 0 0 3 – 18 1 2

16357 – 10672 600 1637 3448 – 11490 4651 216

1.039 – 0.678 – – 0.219 – 0.729 0.295 0.014

20.22 – 26.56 – – 13.70 – 24.67 3.39 145.82

12.53–30.89 – 15.77–41.93 – – 2.76–38.80 – 14.64–38.95 0.14–17.13 16.63–501.01

CP = chronic pancreatitis, SIR = standardized incidence ratio.

Fig. 2. The cumulative rates of pancreatic cancer. (A) The survival rates of pancreatic cancer patients; (B) the cumulative rates of pancreatic cancer after the diagnosis of CP. The figures in brackets indicate subjects at risk.

ratio [HR], 1.05, 95% CI, 1.01–1.09). Patients with a >60 pack-year smoking history were associated with a 9-fold increased risk of developing pancreatic cancer (HR, 11.83, 95% CI, 2.61–53.72). 5. Discussion This single-center, retrospective–prospective cohort study is the largest-sample study on pancreatic cancer in CP patients in Asia to

date, and also includes more comprehensive predictors in the risk analysis compared with previous studies. The results indicate that the risk of pancreatic cancer in CP patients is markedly increased compared with the general population, regardless of smoking or alcohol consumption status. The age at the onset of CP and a >60 pack-year smoking history were identified as the main risk factors for pancreatic cancer in CP patients. In the present study, the age at the onset of CP and smoking for >60 pack-years were risk factors for pancreatic cancer in CP patients. Smoking is reported as a risk factor for both pancreatic cancer and CP [13,41]. Smoking without consideration of the dose was not significantly different, but smoking for >60 pack-years showed a 12-fold increased risk of pancreatic cancer. It seems that tobacco use is associated with a dose-related increased risk for pancreatic cancer in CP patients. Heavy alcohol consumption was a recognized cause of CP, but it was not a risk factor for pancreatic cancer in CP patients in the present study, which is consistent with the results of some earlier studies [12,42,43]. However, Anderson et al. [41] reported that the dose and duration of alcohol consumption were correlated with pancreatic cancer in CP patients. The early detection of pancreatic cancer is very important. Pancreatic cancer reportedly requires 5 years to acquire metastatic ability, and patients die within an average of 2 years following diagnosis [44]. Patients with new symptoms, changes in the site or intensity of pain, and jaundice were suspected of having pancreatic cancer. Early-onset DM and deterioration of DM also suggest the presence of pancreatic cancer [45]. CP patients, especially those with an older onset age and a smoking history of >60 pack-years, were identified as a high-risk population for pancreatic cancer development in the present study. Therefore, these patient groups were suggested to be closely monitored, especially when presenting with the symptoms and the clinical findings described above. This may help in the early diagnosis of pancreatic cancer. Pancreatic cancer in CP patients is a big concern. Table 4 presents a comparison of several studies on this topic. The sample sizes range from 373 to 131,692, and the follow-up period from 6.0 to 10.0 years. The SIR of pancreatic cancer in CP patients was identified as 2.23–121.0 [3,16,43,46–48]. Age was identified as a risk factor for pancreatic cancer development in CP patients in all risk factor analyses. The present study, which had the largest sample size of all studies on this topic, proved markedly increased risk of pancreatic cancer development, and identified age as a risk factor. The predictors included in the present study were the most comprehensive of all the previously published risk factor analyses. Predictors, including general characteristics, family history, chronic pancreatitis course, and treatment history, were analyzed in this risk analysis of pancreatic cancer. Despite the stringent diagnostic criteria for CP, it is still challenging to differentiate pancreatic cancer and CP and some early-stage pancreatic cancers are often misdiagnosed as CP. However, pancreatic cancer is a rapidly progressing tumor with an overall 5-year survival rate of <5% [49]. Therefore, with longer periods of

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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Table 3 Predictive factors for pancreatic cancer development after the diagnosis of CP (1656 cases). Predictors

Age at the onset of CP, ya Age at the diagnosis of CP, ya Adolescent Age at the onset of CP, y <30 30–40 40–50 50–60 >60 Male sex Smoking history Smoking >60 pack-year Alcohol consumption 0 g/d 0–20 g/d 20–80 g/d >80 g/d Body mass indexa Etiology Idiopathic CP Acoholic CP Abnormal anatomy of pancreatic duct Hereditary CP Hyperlipidemic CP Post-traumatic CP Initial manifestations Abdominal pain Endocrine/exocrine dysfunction Others Pancreatic stonesb DM Steatorrhea Biliary stricture Pancreatic pseudocyst Morphology of MPD Pancreatic stone alone MPD stenosis alone MPD stenosis and stone Complex pathologic changes Type of pain Recurrent acute pancreatitis Recurrent pain Recurrent acute pancreatitis and pain Chronic pain Without pain Severe acute pancreatitis Successful drainagec Overall treatment Endotherapy alone Surgery alone Both endotherapy and surgery Conservative treatment DM in first-/second-/third-degree relatives Pancreatic diseases in first-/second-/third-degree relatives (excluding hereditary CP)

Univariate analysis

Multivariate analysis

P

HR (95%CI)

P

HR (95%CI)

0.005 0.021 0.237 0.005 Control 0.265 0.434 0.012 0.627 0.112 0.167 0.002 0.619 Control 0.988 0.819 0.183 0.017 0.774 Control 0.268 0.982 0.200 0.992 0.995 0.989 0.921 0.993 Control 0.077 0.101 0.681 0.472 0.547 0.255 0.189 0.786 0.719 Control 1.000 0.933 0.854 0.933 0.974 Control 0.578 0.160 0.092 0.539 0.594 0.089 Control 0.601 0.726

1.04 (1.01–1.07) 1.04 (1.01–1.07) 0.30 (0.40–2.22) –

0.009 0.151 – – – – – – – – – 0.001 – – – – – 0.827 – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

1.05 (1.01–1.09) – – – – – – – – – – 11.83 (2.61–53.72) – – – – –

2.54 (0.49–13.11) 0.383 (0.04–4.23) 6.883 (1.53–31.06) 1.627 (0.23–11.55) 0.499 (0.21–1.18) 0.422 (0.12–1.43) 10.163 (2.36–43.79) – 0.00 (0.00–) 0.84 (0.18–3.83) 0.36 (0.08–1.61) 0.85 (0.74–0.97) – 1.72 (0.66–4.47) 0.00 3.77 (0.50–28.69) 0.00 0.00 – 1.11 (0.15–8.30) 1.01 (0.09–11.16) 0.45 (0.19–1.09) 2.15 (0.86–5.35) 0.81 (0.30–2.21) 0.65 (0.20–2.09) 0.70 (0.22–2.25) – 0.41 (0.11–1.55) 1.17 (0.37–3.68) 0.00 (0.00–2.70E17) – 0.00 (0.00–9.82E124) 0.90 (0.30–2.68) 0.00 (0.00–6.30E124) 0.00 (0.00–) 0.05 (0.00–2202.61) 2.40 (0.71–8.15) – 1.89 (0.25–14.47) 1.92 (0.17–21.19) 6.43 (0.75–55.02) 0.05 (0.00–4317.59) 0.05 (0.00–1.03E6)

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

CP = chronic pancreatitis, DM = diabetes mellitus. a Mean ± SD. b Pancreatic calcifications were also regarded as stones that are located in branch pancreatic duct or ductulus. c Patients with successful main pancreatic duct (MPD) drainage are those whose CP was established after ERCP or pancreatic surgery or those who underwent successful MPD drainage during administration when CP diagnosis was established.

observation, the probability of misdiagnosing pancreatic cancer as pancreatitis would become less. In our study, the misdiagnosis bias was minimized by excluding CP patients with a follow-up period of less than 2 years and pancreatic cancer diagnosed within 2 years after the diagnosis of CP [24]. This policy led to the exclusion of more than two-fifths of the cases of pancreatic cancer in CP patients, further underlining the importance of this misdiagnosis bias. Our study had some limitations. First, the retrospectively acquired data collected between 2000 and 2004 may introduce a recall bias. Nevertheless, the statistical analysis showed that there were no significant differences between the clinical characteris-

tics of the patients admitted before and after January 2005. In this sense, the recall bias minimally influenced the results of the study. Second, the risk factor analysis did not include all potential factors related to the development of pancreatic cancer. Third, CP patients who had pancreatic cancer before admission were not included in this study, which may cause a survival bias. 6. Conclusions In conclusion, our study indicates that the risk of pancreatic cancer is markedly increased in CP patients. The age at the onset of

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

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Table 4 Researches on risks of pancreatic cancer in CP patients. Author

Design

Sample size

Duration of follow-upa (years)

SIR (95% CI)

Number of factors included

Risk factors

Lowenfels et al. [3] Bansal et al. [46]

Historical cohort Case control

9 NA

Age NA

Cohort Cohort Cohort Case control

18.5 (10–30) 26.7 (7.3–68.3) 22.8 (6.2–58.4) 6.9 (5.6–8.6) [HR]

7 NA 7 NA

Age NA Age NA

Midha et al. [43] Midha et al. [43]

Cohort Case control

7.4b Case: 8.2b Control: 9.0b 10.0c 9.2c 8.5c Case: 6.0b Control: 7.7b 9.87b NA

26.3 (19.9–34.2) 2.23 (1.43–3.49) [OR]

Talamini et al. [47] Malka et al. [48] Wang et al. [16] Bang et al. [12]

2015 Case: 2639 Control: 7774 715 373 420 Case: 11,972 Control: 119,720 402 Case: 249

121.0 (39.7–295.9) 97.7 (12.7–751.4) [OR]

NA 16

NA Age, family history of cancer, DM, nonvegetarian diet, smoking

Present study

Cohort

Control: 1000 1656

8.0c

20.22 (12.53–30.89)

24

Age, smoking

CP = chronic pancreatitis, CI = confidence interval, OR = odds ratio, DM = diabetes mellitus. a Duration of follow-up for cohort studies, and length of follow-up for pancreatitis for the case–control study. b Mean. c Median.

CP and a smoking history of >60 pack-years were identified as the risk factors for the development of pancreatic cancer in CP patients. Therefore, patients in these high-risk populations who present with new symptoms, changes in the site or intensity of pain, jaundice, early-onset DM, and deterioration of DM was suggested to be followed and inspected closely. Conflict of interest None declared. Funding This study was supported by the National Natural Science Foundation of China [Grant Nos. 81422010 (ZL), 81100316 (LHH), 81470883 (LHH) and 81300355 (LX)], Shanghai ChenGuang Program [Grant No. 12CG40 (LHH)], Shanghai Rising-Star Program [Grant No. 17QA1405500 (LHH)], Shanghai Outstanding Youth Doctor Training Program [Grant No. AB83030002015034 (LHH)], and Shanghai Youth Top-notch Talent Program [Grant No. HZW2016FZ67 (LHH)]. References [1] Witt H, Apte MV, Keim V, et al. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 2007;132:1557–73. [2] Braganza JM, Lee SH, McCloy RF, et al. Chronic pancreatitis. Lancet (Lond Engl) 2011;377:1184–97. [3] Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer: International Pancreatitis Study Group. N Eng J Med 1993;328:1433–7. [4] Ekbom A, McLaughlin JK, Karlsson BM, et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 1994;86:625–7. [5] Lin JT, Wang TH, Chen DS, et al. Pancreatic carcinoma associated with chronic calcifying pancreatitis in Taiwan: a case report and review of the literature. Pancreas 1988;3:111–4. [6] Farrow DC, Davis S. Risk of pancreatic cancer in relation to medical history and the use of tobacco, alcohol and coffee. Int J Cancer 1990;45:816–20. [7] La Vecchia C, Negri E, D’Avanzo B, et al. Medical history, diet and pancreatic cancer. Oncology 1990;47:463–6. [8] Haas O, Guillard G, Rat P, et al. Pancreatic carcinoma developing in chronic pancreatitis: a report of four cases. Hepatogastroenterology 1990;37:350–1. [9] Misra SP, Thorat VK, Vij JC, et al. Development of carcinoma in chronic calcific pancreatitis. Int J Pancreatol 1990;6:307–12. [10] Kalapothaki V, Tzonou A, Hsieh CC, et al. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control CCC 1993;4:375–82. [11] Raimondi S, Lowenfels AB, Morselli-Labate AM, et al. Pancreatic cancer in chronic pancreatitis: aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol 2010;24:349–58.

[12] Bang UC, Benfield T, Hyldstrup L, et al. Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study. Gastroenterology 2014;146:989–94. [13] Midha S, Chawla S, Garg PK. Modifiable and non-modifiable risk factors for pancreatic cancer: a review. Cancer Lett 2016;381:269–77. [14] Wang W, Liao Z, Li ZS, et al. Chronic pancreatitis in Chinese children: etiology, clinical presentation and imaging diagnosis. J Gastroenterol Hepatol 2009;24:1862–8. [15] Li ZS, Wang W, Liao Z, et al. A long-term follow-up study on endoscopic management of children and adolescents with chronic pancreatitis. Am J Gastroenterol 2010;105:1884–92. [16] Wang W, Liao Z, Li G, et al. Incidence of pancreatic cancer in chinese patients with chronic pancreatitis. Pancreatol 2011;11:16–23. [17] Wang W, Guo Y, Liao Z, et al. Occurrence of and risk factors for diabetes mellitus in Chinese patients with chronic pancreatitis. Pancreas 2011;40:206–12. [18] Xin L, He YX, Zhu XF, et al. Diagnosis and treatment of autoimmune pancreatitis: experience with 100 patients. Hepatobiliary Pancreatic Dis Int 2014;13:642–8. [19] Li BR, Pan J, Du TT, et al. Risk factors for steatorrhea in chronic pancreatitis: a cohort of 2,153 patients. Sci Rep 2016;6:21381. [20] Pan J, Xin L, Wang D, et al. Risk factors for diabetes mellitus in chronic pancreatitis: a cohort of 2011 patients. Medicine (Baltimore) 2016;95:e3251. [21] Yang YG, Hu LH, Chen H, et al. Target-controlled infusion of remifentanil with or without flurbiprofen axetil in sedation for extracorporeal shock wave lithotripsy of pancreatic stones: a prospective, open-label, randomized controlled trial. BMC Anesthesiology 2015;15:161. [22] Hao L, Pan J, Wang D, et al. Risk factors and nomogram for pancreatic pseudocysts in chronic pancreatitis: a cohort of 1998 patients. J Gastroenterol Hepatol 2017;32:1403–11. [23] Malde DJ, Oliveira-Cunha M, Smith AM. Pancreatic carcinoma masquerading as groove pancreatitis: case report and review of literature. JOP J Pancreas 2011;12:598–602. [24] Li BR, Hu LH, Li ZS. Chronic pancreatitis and pancreatic cancer. Gastroenterology 2014;147:541–2. [25] Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia–Pacific consensus report. J Gastroenterol Hepatol 2002;17:508–18. [26] Witt H, Sahin-Toth M, Landt O, et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 2006;38:668–73. [27] Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2:252–61. [28] Lu WF. ERCP and CT diagnosis of pancreas divisum and its relation to etiology of chronic pancreatitis. World J Gastroenterol 1998;4:150–2. [29] Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003;36:54–62. [30] Tempero MA, Malafa MP, Behrman SW, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw JNCCN 2014;12:1083–93. [31] Tempero MA, Arnoletti JP, Behrman SW, et al. Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Cancer Netw JNCCN 2012;10:703–13. [32] Li BR, Liao Z, Du TT, et al. Risk factors for complications of pancreatic extracorporeal shock wave lithotripsy. Endoscopy 2014;46:1092–100. [33] Sun XT, Hu LH, Xia T, et al. Clinical features and endoscopic treatment of Chinese patients with hereditary pancreatitis. Pancreas 2015;44:59–63. [34] Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2012;44:784–800.

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001

G Model YDLD-3489; No. of Pages 8 8

ARTICLE IN PRESS L. Hao et al. / Digestive and Liver Disease xxx (2017) xxx–xxx

[35] Li B-R, Liao Z, Du T-T, et al. Extracorporeal shock wave lithotripsy is a safe and effective treatment for pancreatic stones coexisting with pancreatic pseudocysts. Gastrointest Endosc 2015;84:69–78. [36] Schreyer AG, Jung M, Riemann JF, et al. S3 guideline for chronic pancreatitis — diagnosis, classification and therapy for the radiologist. RoFo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 2014;186:1002–8. [37] Ito T, Ishiguro H, Ohara H, et al. Evidence-based clinical practice guidelines for chronic pancreatitis 2015. J Gastroenterol 2016;51:85–92. [38] 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. [39] Ma Y, Zhou W, He S, et al. Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: identification of clinical and immunohistochemical biomarkers predicting survival. Int J Cancer 2016;139:1423–30. [40] Chen W, Zheng R, Zuo T, et al. National cancer incidence and mortality in China, 2012. Chin J Cancer Res Chung-kuo yen cheng yen chiu 2016;28:1–11. [41] Anderson MA, Zolotarevsky E, Cooper KL, et al. Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: a multicenter study. Am J Gastroenterol 2012;107:1730–9.

[42] Gold EB, Gordis L, Diener MD, et al. Diet and other risk factors for cancer of the pancreas. Cancer 1985;55:460–7. [43] Midha S, Sreenivas V, Kabra M, et al. Genetically determined chronic pancreatitis but not alcoholic pancreatitis is a strong risk factor for pancreatic cancer. Pancreas 2016;45:1478–84. [44] Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114–7. [45] Yamaguchi K, Okusaka T, Shimizu K, et al. EBM-based Clinical Guidelines for Pancreatic Cancer (2013) issued by the Japan Pancreas Society: a synopsis. Jpn J Clin Oncol 2014;44:883–8. [46] Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology 1995;109:247–51. [47] Talamini G, Falconi M, Bassi C, et al. Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999;94:1253–60. [48] Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–52. [49] Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2014. Ann Oncol 2014;25:1650–6.

Please cite this article in press as: Hao L, et al. Incidence of and risk factors for pancreatic cancer in chronic pancreatitis: A cohort of 1656 patients. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.07.001