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Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study

Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A... Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Hepatobiliary Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study a,b c d e f g h NICOLE BRIGHI, FRANCESCO PANZUTO, ROBERTA MODICA, FABIO GELSOMINO, MANUELA ALBERTELLI, SARA PUSCEDDU, SARA MASSIRONI, a,i c k e f g GIUSEPPE LAMBERTI, MARIA RINZIVILLO, ANTONGIULIO FAGGIANO, ANDREA SPALLANZANI, DIEGO FERONE, NATALIE PRINZI, h c d a,j ROBERTA ELISA ROSSI, BRUNO ANNIBALE, ANNA MARIA COLAO, DAVIDE CAMPANA NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy; Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, c d Meldola, Italy; Digestive Disease Unit, Sant’Andrea University Hospital, ENETS Center of Excellence, Rome, Italy; Clinical Medicine and Surgery Department - Federico II University, Naples, Italy; Department of Oncology and Hematology, University Hospital of Modena, f g Modena, Italy; Endocrinology Department (DiMi), San Martino University Hospital, Genova, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy; Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; Departments of Experimental, Diagnostic and Specialty j k Medicine and Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Neuroendocrine neoplasms � Gallstones � Adverse events � Prophylactic cholecystectomy � Ursodeoxycholic acid ABSTRACT Background. Somatostatin analogs (SSAs) are the mainstay biliary stone disease were excluded; 478 patients were of neuroendocrine tumor (NET) treatment. Biliary stone dis- included. Among them, 118 patients (24.7%) received pro- ease is reported as a common side effect of SSAs, with a phylactic ursodeoxycholic acid (UDCA). During the study frequency ranging from 10% to 63%. Studies on SSA-treated period, 129 patients (27.0%) developed biliary stone dis- patients for acromegaly report an increased incidence of ease; of them, 36 (27.9%) developed biliary complications. biliary stone disease compared with the general population, On multivariate analysis, primary gastrointestinal (GI)-NET whereas data on patients with NETs are few. Guidelines are (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were based on weak evidence, thus resulting in conflicting rec- independent risk factors for biliary stone disease. ommendations. The aim of the study is to evaluate biliary Conclusion. We report a high incidence of biliary stone dis- stone disease incidence, complications, and risk factors in a ease particularly in GI-NET or GI surgery. UDCA prophylaxis large population of SSA-treated patients with NETs. does not seem to have a protective role. Our data suggest Materials and Methods. A retrospective analysis of a pro- that all patients with primary GI-NET or undergoing abdom- spectively collected database was performed. Patients with inal surgery should be considered for prophylactic cholecys- a diagnosis of NET in seven dedicated centers from 1995 to tectomy; no conclusion could be drawn on the indication of 2017 were included at the time of SSA start. prophylactic cholecystectomy in patients with primary pan- Results. A total of 754 SSA-treated patients were evaluated. creatic or thoracic NET for whom abdominal surgery is not Patients with history of cholecystectomy or with known planned. The Oncologist 2020;25:259–265 Implications for Practice: The results of this study confirm an increased rate of gallstones development and related compli- cations in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointesti- nal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease. Correspondence: Davide Campana, M.D., Ph.D., Department of Medical and Surgical Sciences – University of Bologna, S. Orsola-Malpighi University Hospital, Via Massarenti 9, Bologna 40138, Italy. Telephone: 390516363067; e-mail: [email protected] Received May 27, 2019; accepted for publication October 3, 2019; published Online First on November 6, 2019. http://dx.doi.org/10.1634/ theoncologist.2019-0403 The Oncologist 2020;25:259–265 www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 260 Biliary Stone Disease in SSA-Treated NET Patients INTRODUCTION Somatostatin analogs (SSAs) represent the backbone of neu- development of biliary complications, death, or SSAs with- roendocrine tumor (NET) treatment. SSAs (octreotide long- drawal; the database was closed in September 2018. acting release [LAR] and lanreotide Autogel) act by binding to The histological specimens were examined by a NEN- somatostatin receptors, variously expressed on neuroendo- dedicated pathologist at each center. When required, an crine cells, resulting in both antisecretive and antip- additional centralized revision of the tumor specimen was roliferative activity [1]. Thus, SSAs are used in patients with performed. Tumors were classified according to the 2010 advanced gastro-entero-pancreatic or thoracic NETs to con- World Health Organization (WHO) classification (gastro- trol not only hormones hypersecretion in functionally active entero-pancreatic neuroendocrine tumors) [14] or 2004 NETs but also tumor growth. WHO classification (thoracic neuroendocrine tumors) [15] SSAs are usually well tolerated and side effects are mostly and the ENETS grading system [1]. Ki-67 proliferation index mild [2, 3]. One of the most severe side effects of SSA is bili- was expressed as a percentage based on the count of Ki- ary stone disease; its occurrence is clinically relevant because 67-positive cells in 2,000 tumor cells in the areas of the it may lead to treatment discontinuation or to medical or sur- highest immunostaining. gical procedures to treat complications [2]. SSA treatment and clinical follow-up have been conducted Several studies reported an increased gallstone inci- according to the most recent ENETS guidelines [1, 16, 17]. dence in patients receiving SSAs if compared with the gen- Due to the few and conflicting recommendations, UDCA eral population, although with very variable data; however, prophylaxis was prescribed on a case-by-case evaluation most of these studies have been conducted among patients according to physicians’ discretion [1, 12]. with acromegaly [2–6]. In fact, only few studies are specifi- The following data were collected: gender, age at the time cally focused in patients with NETs, and all are retrospective of SSAs start, primary NEN site, WHO classification, grade, in nature; the observed incidence of biliary stone disease in functionality, presence of multiple endocrine neoplasia type 1 this specific population ranges from 36% to 63% [7–11]. (MEN 1) syndrome, surgery of primary tumor or hepatic The European Association for the Study of the Liver metastases, type, dose and duration of treatment with SSAs, (EASL) guidelines identify SSA-treated patients as a high-risk and prophylactic treatment with UDCA. Unconventional SSAs group for developing gallstone disease; thus, the use of pro- dose was defined as an increased frequency of drug adminis- phylactic ursodeoxycholic acid (UDCA) is weakly suggested, tration (lanreotide Autogel 120 mg or octreotide LAR 30 mg despite low-quality evidence [12]. On the other hand, both every 21 days) [18]. European Neuroendocrine Tumor Society (ENETS) and North American Neuroendocrine Tumor Society (NANETS) guide- Definitions lines result in weak clinical recommendations only on pro- Incidence of biliary stone disease was defined as the identi- phylactic cholecystectomy, and UDCA prophylaxis is not fication, on ultrasound (US) or cross-sectional imaging, of taken into consideration [1, 13]. suspected findings and subsequent confirmation of gall- The aim of our study was to evaluate the incidence of stones with a dedicated US evaluation. The occurrence of biliary stone disease in a large population of patients with any condition related to biliary stone disease, such as biliary NETs treated with SSAs; we also assessed risk factors for colic, acute cholecystitis, cholangitis, biliary pancreatitis, or stone incidence and for biliary complications, with a partic- obstructive jaundice, was classified as a biliary complication. ular focus on debated issues such as the role of UDCA Biliary stone disease-free survival (BsDFS) was defined as prophylaxis. the interval between the start of SSAs and the time of bili- ary stone disease occurrence. Biliary complications disease- free survival (BcDFS) was defined as the interval between the start of SSAs and the time of biliary complications occurrence (only in patients with biliary stone disease). MATERIALS AND METHODS All patients or their legal representatives provided writ- ten informed consent for anonymous review of their data for Study Design research purpose. The study protocol was approved by a A retrospective analysis of a multicenter prospectively col- local institutional review board (Comitato Etico Indipendente, lected database was performed. All consecutive patients S. Orsola-Malpighi University Hospital, Bologna, Italy) and with NETs starting SSA treatment at seven Italian dedicated was conducted in accordance with the principles of the Dec- centers from 1995 to 2017 were analyzed. All data were laration of Helsinki (6th revision, 2008). prospectively retrieved at the center where the patient had been enrolled and then collected in a single computerized data sheet. Statistical Analysis Study inclusion criteria were as follows: histological diagno- The distribution of the continuous variables was reported as sis of neuroendocrine neoplasms (NENs) of any grade and site, median (range); categorical variables were described as num- and treatment start with SSAs for metastatic or nonresectable ber (percentage). Risk factors for biliary stone disease and disease at conventional or unconventional dose between related complications were evaluated by univariate and mul- January 1995 and December 2017. Patients with a history of tivariate analysis using the Cox proportional hazards method cholecystectomy or biliary stone disease at the time of SSA and expressed as hazard ratio (HR) and 95% confidence inter- start were excluded. Included patients were followed up until val (CI). The multivariate model was designed using the © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Brighi, Panzuto, Modica et al. 261 forward stepwise method after including all variables. Analy- Table 1. Baseline characteristics of the study population sis A included also the variable SSA type (lanreotide Autogel Patients vs. octreotide LAR); thus, patients sequentially treated with Characteristic (n = 478) both octreotide and lanreotide Autogel have been censored. Demographic Analysis B was conducted in order to include all patients in Gender (male), n (%) 263 (55.0) the multivariate model; therefore, the limiting variable Median age (range) at SSA start, years 61 (18–87) (SSA type, lanreotide Autogel vs. octreotide LAR) has been Primary tumor site excluded. BsDFS and BcDFS were measured using the Kaplan- Gastrointestinal tract, n (%) 211 (44.1) Meier method, and the results were compared using the Pancreas, n (%) 184 (38.5) log-rank test. Lung, n (%) 47 (9.8) The p value was considered significant when inferior to Unknown, n (%) 36 (7.5) .05. Statistical analysis was performed using a dedicated soft- WHO classification ware (IBM – SPSS Statistics v. 22.0; IBM Corp., Armonk, NY). G1 or typical carcinoid, n (%) 280 (58.6) G2 or atypical carcinoid, n (%) 156 (32.6) RESULTS Missing data, n (%) 42 (8.8) MEN 1 syndrome, n (%) 38 (7.9) Study Population Functioning tumors, n (%) 87 (18.2) Seven hundred fifty-four patients treated with SSAs for advanced disease were included. Among them, 225 patients Carcinoid syndrome, n 59 with a history of cholecystectomy and 51 with known biliary Zollinger-Ellison syndrome, n 10 stone disease were excluded from the analysis. Finally, 478 Insulinoma syndrome, n 8 patients were evaluated; baseline characteristics are described PTH-rP hypercalcemia, n 5 in Table 1. Cushing syndrome, n 2 Two hundred sixty-three patients (55.0%) were male. Glucagonoma syndrome, n 2 Median age at SSA start was 61 years (range 18–87). Primary tumor site was gastrointestinal (GI) tract in 211 patients VIPoma syndrome, n 1 (44.1%), pancreas in 184 (38.5%), lung in 47 (9.8%), and Surgery unknown in 36 (7.5%). As for WHO classification, 280 Primary tumor surgery, n (%) 218 (45.6) patients (58.6%) had a NET G1 or typical lung carcinoid and Pancreatic surgery, n 48 156 (32.6%) a NET G2 or atypical lung carcinoid; data were Gastrointestinal surgery, n 133 missing in 42 cases (8.8%). Thoracic surgery, n 37 MEN 1 syndrome was present in 38 patients (7.9%). Eighty-seven patients (18.2%) had a functioning tumor. Liver metastases surgery, n (%) 51 (10.7) Among them, 59 presented with carcinoid syndrome, 10 Medical treatment Zollinger-Ellison syndrome, 8 insulinoma syndrome, 5 parathy- SSAs treatment characteristics roid hormone-related peptide hypercalcemia, 2 glucagonoma Octreotide LAR, n (%) 276 (57.7) syndrome, 2 Cushing syndrome, and 1 VIPoma syndrome. Lanreotide Autogel, n (%) 144 (30.1) Primary tumor surgery was performed in 218 (45.6%) patients: of them, 133 underwent resection of GI tract (gas- Both, n (%) 58 (12.1) tric or ileal resection or partial or total colectomy), 48 pan- Conventional doses, n (%) 438 (91.6) creatic surgery, and 37 thoracic surgery. Fifty-one patients Unconventional doses, n (%) 40 (8.4) (10.7%) underwent hepatic surgery for liver metastases. UDCA prophylaxis 118 (24.7) As for SSA treatment, 276 patients (57.7%) received Abbreviations: LAR, long-acting release; MEN 1, multiple endocrine octreotide LAR 30 mg every 28 days, 144 (30.1%) lanreotide neoplasia type 1; PTH-rP, parathyroid hormone-related peptide; SSA, Autogel 120 mg every 28 days, and 58 (12.1%) both, sequen- somatostatin analogs; UDCA, ursodeoxycholic acid; WHO, World Health Organization. tially. Forty patients (8.4%) received SSAs at unconventional doses (lanreotide Autogel 120 mg or octreotide LAR 30 mg every 21 days). Median duration of SSAs was 31.5 months (range 1–263 months). One hundred eighteen patients GI primary tumor (HR 2.36, p < .001) and related surgery (24.7%) received prophylactic UDCA (with variable dosing (HR 2.33, p < .001). Gender, age, MEN 1 syndrome, func- schedules based on local clinical practice). tionality of primary tumor, hepatic metastases surgery, SSA type, and dose were not related to biliary stone disease Biliary Stone Disease Frequency and Risk Factors development. Patients were followed up for a median of 31.5 (1–263) Multivariate Analysis A (performed after exclusion of 58 months. During the study period, 129 patients (27.0%) devel- patients sequentially treated with both lanreotide Autogel oped gallstones. and octreotide LAR, 420 patients) identified only GI primary Risk factors for biliary stone disease are reported in tumor (HR 1.89, p = .012) as an independent risk factor for Table 2. At univariate analysis, significant risk factors were biliary stone disease development. Multivariate Analysis B www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 262 Biliary Stone Disease in SSA-Treated NET Patients Table 2. Risk factors for biliary stone disease a b Univariate analysis Multivariate analysis A Multivariate analysis B Characteristic HR 95% CI p value HR 95% CI p value HR 95% CI p value Male (gender) 1.00 0.70–1.42 .998 —— — — — — Age 1.01 0.99–1.02 .182 —— — — — — MEN 1 syndrome 0.82 0.43–1.57 .549 —— — — — — Gastrointestinal 2.36 1.64–3.39 <.001 1.89 1.15–3.09 .012 1.76 1.10–2.82 .018 primary tumor Functioning tumor 1.14 0.75–1.72 .547 —— — — — — Gastrointestinal surgery 2.33 1.64–3.30 <.001 1.59 0.98–2.58 .058 1.58 1.003–2.49 .049 Liver metastases surgery 1.26 0.77–2.05 .357 —— — — — — UDCA prophylaxis 0.99 0.67–1.47 .952 —— — — — — c c c Lanreotide vs. octreotide LAR 1.44 0.95–2.17 .082 1.49 0.99–2.25 .059 — — — Unconventional dose SSA 1.32 0.79–2–21 .281 —— — — — — Analysis A: Analysis performed on 420 patients (excluding 58 patients sequentially treated with both lanreotide Autogel and octreotide LAR). Analysis B: Analysis performed on the entire population of 478 patients. Parameter not included in analysis. Significant risk factors at multivariate analysis are marked in bold. Abbreviations: CI, confidence interval; HR, hazard ratio; LAR, long-acting release; MEN 1, multiple endocrine neoplasia type 1; SSA, somatostatin analogs; UDCA, ursodeoxycholic acid. Figure 2. Kaplan-Meier estimates of biliary stone disease-free survival according to the site of primary tumor: gastrointestinal Figure 1. Kaplan-Meier estimates of biliary stone disease-free tract (dotted line) versus other sites (continuous line); p < .001. survival in patients with neuroendocrine tumors treated with somatostatin analogs. (performed on the entire population of 478 patients) identi- Figure 3 shows Kaplan-Meier curves for BsDFS comparing fied both GI primary (HR 1.76, p = .018) and related GI sur- patients who underwent GI primary tumor surgery versus all gery (HR 1.58, p = .049) as independent risk factors for other patients (median 65 months, 95% CI: 51.3–78.7 months biliary stone disease development. vs. 165 months, 95% CI: 106.6–223.4 months; p <.001). No difference was observed when correlating BsDFS to gender (median in male: 120 months, female: 102 months; Biliary Stone Disease-Free Survival p = .998), MEN 1 syndrome (median with MEN 1 syndrome: Figure 1 shows Kaplan-Meier curve for BsDFS; median BsDFS 93 months, without MEN 1 syndrome: 120 months; p =.547), was 120 months (95% CI: 87.7–152.3 months). Significant dif- hormone secretion syndrome (median in patients with ferences in BsDFS were observed according to primary tumor syndrome: 120 months, without syndrome: 136 months; site; in particular, Figure 2 shows Kaplan-Meier curves for p = .545), hepatic metastases surgery (median yes: 124 BsDFS according to primary GI tumor versus other primary months, no: 120 months; p = .355), UDCA prophylaxis tumor sites (median 73 months, 95% CI: 62.7–83.3 months (median with prophylaxis: 120 months, without prophylaxis: vs. 214 months, 95% CI: 101.3–326.6 months; p <.001). 124 months; p = .952), SSA type (median octreotide LAR: 136 © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Brighi, Panzuto, Modica et al. 263 biliary complications (Table 3). Kaplan-Meier curves analysis did not identify any correlation with BcDFS. DISCUSSION To the best of our knowledge, we conducted the largest study specifically dealing with biliary stone disease in patients with NENs treated with SSAs and observed a high frequency (27%) of biliary stone disease occurrence. As stated by EASL guidelines, we agree that SSA-treated patients with NENs should be considered a high-risk popula- tion for biliary stone disease [12]. Based on our results, this population has a higher frequency of biliary stone disease compared with the general population, where the preva- lence is 10%–20%. As for complications, in the general popu- lation, 0.7%–2.5% of patients with asymptomatic gallstones develop gallstone-related symptoms yearly; the annual inci- dence of complications is 0.1%–0.3% [12, 19–21]. Thus, our study population can be considered at high risk not only for Figure 3. Kaplan-Meier estimates of biliary stone disease-free gallstone developments but also for related complications. survival according to surgery of gastrointestinal primary tumor Data from CLARINET and PROMID trials showed a sensi- (dotted line) versus other patients (continuous line); p < .001. bly lower frequency (10%–14%), probably due to a shorter period of exposure to SSAs (with a median of 14 months in PROMID and 24 months in the CLARINET study vs. 31.5 in our analysis) and a shorter follow-up [10, 11]. Table 3. Risk factors for biliary complications A previous single-center analysis from our institute Univariate analysis reported a comparably high frequency of biliary stone dis- Characteristic HR 95% CI p value ease (36.6%) [7]. Other retrospective studies based on Male (gender) 0.78 0.39–1.53 .467 patients with NENs reported a prevalence of 52%–63%, but studies on this specific population are few [8, 9]. On the con- MEN 1 syndrome 0.70 0.21–2.35 .563 trary, many studies on patients receiving SSAs to treat acro- Gastrointestinal primary tumor 2.06 0.97–4.36 .060 megaly are available, reporting a very variable biliary stone Functioning tumor 0.61 0.27–1.38 .239 frequency (3%–56% in the first 2 years of treatment) [2, 4, Gastrointestinal surgery 1.11 0.57–2.16 .764 6]. However, patients with acromegaly are not comparable to Liver metastases surgery 0.31 0.07–1.29 .108 those with NETs, because acromegaly has already been iden- UDCA prophylaxis 0.58 0.25–1.34 .206 tified as a risk factor for gallstones occurrence per se [3]. The role of SSAs in the pathogenesis of gallstone disease Lanreotide vs. octreotide LAR 0.78 0.33–1.83 .570 is related to several factors. First, SSAs tend to inhibit meal- Unconventional dose SSAs 0.47 0.14–1.55 .217 stimulated cholecystokinin release, resulting in reduced Abbreviations: CI, confidence interval; HR, hazard ratio; LAR, gallbladder motility [4, 6]. In addition, SSAs slow intestinal long-acting release; MEN 1, multiple endocrine neoplasia type 1; SSAs, somatostatin analogs; UDCA, ursodeoxycholic acid. transit, allowing intestinal bacteria to increase the amounts of deoxycholate, which favors the aggregation of cholesterol crystals into stones. Finally, SSAs inhibit postprandial Oddi’s months, median lanreotide Autogel: 76 months; p =.079), sphincter relaxation, further increasing bile stasis [22, 23]. and SSA dose (median conventional dose: 136 months, We identified GI-NET and surgery for primary GI-NET as unconventional dose: 71 months; p =.278). independent risk factors for biliary stone disease develop- ment. Despite the fact that studies on cholesterol and bile Biliary Stone Disease Complications and Risk Factors acids metabolism in patients with GI-NET are lacking, it has During the study period, 36 patients (7.5% of the entire been previously reported that patients who underwent ileal population) developed biliary complications such as biliary resection have an increased risk of stone disease because colic, acute cholecystitis, cholangitis, biliary pancreatitis, or of reduced ileal bile acid absorption [23, 24]. obstructive jaundice. Twenty-five patients required surgery, Several ileal diseases, such as Crohn’s disease or radiation whereas 11 received pharmacological treatment. Among enteritis, mayleadtoa “broken” enterohepatic circulation, 129 patients who developed biliary stone disease during playing a pivotal role in the pathogenesis of gallstone forma- treatment, 27.9% presented a biliary complication. Median tion. These conditions may lead to bile acid malabsorption and BcDFS was 102 months (95% CI: 61.9–142.0 months). pool depletion, resulting in cholesterol-supersaturated bile At univariate analysis, none of the tested factors (gender, [24–26]. Another possible explanation involves an altered MEN 1 syndrome, site and functionality of primary tumor, microbiota, often coexisting in intestinal diseases, that could surgery of primary tumor or liver metastases, SSAs type and enhance the deconjugation of bilirubin and bile acids with an dose, UDCA prophylaxis) were related to the development of upregulation of enterohepatic cycle of bile pigment and www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 264 Biliary Stone Disease in SSA-Treated NET Patients formation of pigment stones [27]. Finally, no study dealt with in patients with small-bowel NETs who are candidates for the hypothetical role in this setting of the release of active long-term SSAs; cholecystectomy is not suggested in asymp- substances at a local level (e.g., serotonin, FGF19) that could tomatic patients [13]. Moreover, no recommendation is avail- alter GI motility. able in North American guidelines on the role of prophylactic UDCA prophylaxis is indicated in high-risk patients (i.e., cholecystectomy in primary tumor other than intestinal. rapid weight loss in obese patients) to reduce the incidence of biliary stone disease [12]. ENETS guidelines do not express any recommendation about the use of UDCA in patients with CONCLUSION NENs receiving SSAs [1]. On the contrary, EASL guidelines Our data suggest that prophylactic cholecystectomy is rec- recommend consideration of its use during SSA-treatment ommended in all patients undergoing surgery for primary GI- [12]. Interestingly, we did not observe any effect of UDCA on NETs. In all other patients undergoing abdominal surgery for the development of gallstones when used as prophylactic any indication other than GI-NET resection, prophylactic chole- treatment or when used to reduce the risk of biliary compli- cystectomy is suggested. On the other hand, patients with GI- cations in patients with gallstones. NETs with long-life expectancy and who are candidates for Moreover, no patient had to permanently discontinue long-term SSA-treatment where resection of primary is not SSA-treatment because of biliary stone disease or any of its indicated should be considered for prophylactic cholecystec- complications. After medical or surgical treatment, at reso- tomy on a case-by-case evaluation because of the cumulative lution of symptoms if present, all patients could resume high risk of biliary stone disease and related complications. SSA-therapy. With the available data, no conclusion could be drawn on the The main limit of the study is the retrospective design indication of prophylactic cholecystectomy in patients with pri- that could lead to an inhomogeneous diagnostic and thera- mary pancreatic or thoracic NETs for whom abdominal surgery peutic management. In particular, no standardization on is not planned. Further prospective studies should be con- planned exams or treatment schedule has been conceived; ducted to investigate these matters. however, only NEN-dedicated centers have been included, in order to have a better adherence to available guidelines and reduce discrepancies. The study population underwent ACKNOWLEDGMENTS scheduled US or computed tomography scan as suggested The present work was conducted with the support of by most recent guidelines for the oncological follow-up [16, Associazione Italiana Tumori Neuroendocrini (Italian Associ- 17]. Because of the retrospective nature of this study, a spe- ation for Neuroendocrine Tumours). cific workup for the diagnosis or follow-up of biliary stone disease was not preplanned. Similarly, owing to conflicting recommendations, the management of UDCA prophylaxis AUTHOR CONTRIBUTIONS Conception/design: Nicole Brighi, Giuseppe Lamberti, Davide Campana and the treatment of biliary stone disease was not planned, Provision of study material or patients: Nicole Brighi, Francesco Panzuto, but it was conducted at physician’s choice following local Roberta Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, clinical practice. Therefore, our observation of the ineffec- Sara Massironi, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, Diego Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna tive role of UDCA cannot be considered conclusive and Maria Colao, Davide Campana should be addressed in a dedicated trial. Collection and/or assembly of data: Nicole Brighi, Francesco Panzuto, Roberta Our study has for the first time clearly identified which Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, Sara Massironi, Giuseppe Lamberti, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, subgroups of SSA-treated patients with NETs have a higher Diego Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna Maria risk of biliary stone disease. We also observed that these Colao, Davide Campana patients presented a high rate of biliary-related complications Data analysis and interpretation: Nicole Brighi, Francesco Panzuto, Giuseppe Lamberti, Davide Campana (up to 30%) and that a significant amount of them (up to Manuscript writing: Nicole Brighi, Francesco Panzuto, Davide Campana 70%) required cholecystectomy, despite underlying advanced Final approval of manuscript: Nicole Brighi, Francesco Panzuto, Roberta Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, Sara Massironi, Giuseppe oncological disease. Lamberti, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, Diego Current ENETS guidelines weakly suggest considering Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna Maria Colao, prophylactic cholecystectomy in patients who are candi- Davide Campana dates for abdominal surgery; indications are even weaker when surgery is not planned [1]. NANETS guidelines recommend prophylactic cholecystec- DISCLOSURES tomy only if performed at the time of primary tumor resection The authors indicated no financial relationships. REFERENCES 1. Pavel M, Valle JW, Eriksson B et al. ENETS 3. Attanasio R, Mainolfi A, Grimaldi F et al. 5. Mazziotti G, Floriani I, Bonadonna S et al. Consensus Guidelines for the standards of care Somatostatin analogues and gallstones: A retro- Effects of somatostatin analogues on glucose in neuroendocrine neoplasms: Systemic therapy spective survey on a large series of acromegalic homeostasis: A meta-analysis of acromegaly - biotherapy and novel targeted agents. Neuro- patients. J Endocrinol Invest 2008;31:704–710. studies. J Clin Endocrinol Metab 2009;94: endocrinology 2017;105:266–280. 1500–1508. 4. Grasso LF, Auriemma RS, Pivonello R et al. 2. Burt MG, Ho KK. Comparison of efficacy and tol- Adverse events associated with somatostatin ana- 6. Paisley AN, Roberts ME, Trainer PJ. 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Stinton LM, Shaffer EA. Epidemiology of gall- 13. Howe JR, Cardona K, Fraker DL et al. The surgi- 19. Everhart JE, Ruhl CE. Burden of digestive bladder disease: Cholelithiasis and cancer. Gut cal management of small bowel neuroendocrine diseases in the United States Part III: Liver, biliary Liver 2012;6:172–187. www.TheOncologist.com © AlphaMed Press 2019 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

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Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Hepatobiliary Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study a,b c d e f g h NICOLE BRIGHI, FRANCESCO PANZUTO, ROBERTA MODICA, FABIO GELSOMINO, MANUELA ALBERTELLI, SARA PUSCEDDU, SARA MASSIRONI, a,i c k e f g GIUSEPPE LAMBERTI, MARIA RINZIVILLO, ANTONGIULIO FAGGIANO, ANDREA SPALLANZANI, DIEGO FERONE, NATALIE PRINZI, h c d a,j ROBERTA ELISA ROSSI, BRUNO ANNIBALE, ANNA MARIA COLAO, DAVIDE CAMPANA NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy; Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, c d Meldola, Italy; Digestive Disease Unit, Sant’Andrea University Hospital, ENETS Center of Excellence, Rome, Italy; Clinical Medicine and Surgery Department - Federico II University, Naples, Italy; Department of Oncology and Hematology, University Hospital of Modena, f g Modena, Italy; Endocrinology Department (DiMi), San Martino University Hospital, Genova, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy; Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; Departments of Experimental, Diagnostic and Specialty j k Medicine and Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Neuroendocrine neoplasms � Gallstones � Adverse events � Prophylactic cholecystectomy � Ursodeoxycholic acid ABSTRACT Background. Somatostatin analogs (SSAs) are the mainstay biliary stone disease were excluded; 478 patients were of neuroendocrine tumor (NET) treatment. Biliary stone dis- included. Among them, 118 patients (24.7%) received pro- ease is reported as a common side effect of SSAs, with a phylactic ursodeoxycholic acid (UDCA). During the study frequency ranging from 10% to 63%. Studies on SSA-treated period, 129 patients (27.0%) developed biliary stone dis- patients for acromegaly report an increased incidence of ease; of them, 36 (27.9%) developed biliary complications. biliary stone disease compared with the general population, On multivariate analysis, primary gastrointestinal (GI)-NET whereas data on patients with NETs are few. Guidelines are (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were based on weak evidence, thus resulting in conflicting rec- independent risk factors for biliary stone disease. ommendations. The aim of the study is to evaluate biliary Conclusion. We report a high incidence of biliary stone dis- stone disease incidence, complications, and risk factors in a ease particularly in GI-NET or GI surgery. UDCA prophylaxis large population of SSA-treated patients with NETs. does not seem to have a protective role. Our data suggest Materials and Methods. A retrospective analysis of a pro- that all patients with primary GI-NET or undergoing abdom- spectively collected database was performed. Patients with inal surgery should be considered for prophylactic cholecys- a diagnosis of NET in seven dedicated centers from 1995 to tectomy; no conclusion could be drawn on the indication of 2017 were included at the time of SSA start. prophylactic cholecystectomy in patients with primary pan- Results. A total of 754 SSA-treated patients were evaluated. creatic or thoracic NET for whom abdominal surgery is not Patients with history of cholecystectomy or with known planned. The Oncologist 2020;25:259–265 Implications for Practice: The results of this study confirm an increased rate of gallstones development and related compli- cations in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointesti- nal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease. Correspondence: Davide Campana, M.D., Ph.D., Department of Medical and Surgical Sciences – University of Bologna, S. Orsola-Malpighi University Hospital, Via Massarenti 9, Bologna 40138, Italy. Telephone: 390516363067; e-mail: [email protected] Received May 27, 2019; accepted for publication October 3, 2019; published Online First on November 6, 2019. http://dx.doi.org/10.1634/ theoncologist.2019-0403 The Oncologist 2020;25:259–265 www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 260 Biliary Stone Disease in SSA-Treated NET Patients INTRODUCTION Somatostatin analogs (SSAs) represent the backbone of neu- development of biliary complications, death, or SSAs with- roendocrine tumor (NET) treatment. SSAs (octreotide long- drawal; the database was closed in September 2018. acting release [LAR] and lanreotide Autogel) act by binding to The histological specimens were examined by a NEN- somatostatin receptors, variously expressed on neuroendo- dedicated pathologist at each center. When required, an crine cells, resulting in both antisecretive and antip- additional centralized revision of the tumor specimen was roliferative activity [1]. Thus, SSAs are used in patients with performed. Tumors were classified according to the 2010 advanced gastro-entero-pancreatic or thoracic NETs to con- World Health Organization (WHO) classification (gastro- trol not only hormones hypersecretion in functionally active entero-pancreatic neuroendocrine tumors) [14] or 2004 NETs but also tumor growth. WHO classification (thoracic neuroendocrine tumors) [15] SSAs are usually well tolerated and side effects are mostly and the ENETS grading system [1]. Ki-67 proliferation index mild [2, 3]. One of the most severe side effects of SSA is bili- was expressed as a percentage based on the count of Ki- ary stone disease; its occurrence is clinically relevant because 67-positive cells in 2,000 tumor cells in the areas of the it may lead to treatment discontinuation or to medical or sur- highest immunostaining. gical procedures to treat complications [2]. SSA treatment and clinical follow-up have been conducted Several studies reported an increased gallstone inci- according to the most recent ENETS guidelines [1, 16, 17]. dence in patients receiving SSAs if compared with the gen- Due to the few and conflicting recommendations, UDCA eral population, although with very variable data; however, prophylaxis was prescribed on a case-by-case evaluation most of these studies have been conducted among patients according to physicians’ discretion [1, 12]. with acromegaly [2–6]. In fact, only few studies are specifi- The following data were collected: gender, age at the time cally focused in patients with NETs, and all are retrospective of SSAs start, primary NEN site, WHO classification, grade, in nature; the observed incidence of biliary stone disease in functionality, presence of multiple endocrine neoplasia type 1 this specific population ranges from 36% to 63% [7–11]. (MEN 1) syndrome, surgery of primary tumor or hepatic The European Association for the Study of the Liver metastases, type, dose and duration of treatment with SSAs, (EASL) guidelines identify SSA-treated patients as a high-risk and prophylactic treatment with UDCA. Unconventional SSAs group for developing gallstone disease; thus, the use of pro- dose was defined as an increased frequency of drug adminis- phylactic ursodeoxycholic acid (UDCA) is weakly suggested, tration (lanreotide Autogel 120 mg or octreotide LAR 30 mg despite low-quality evidence [12]. On the other hand, both every 21 days) [18]. European Neuroendocrine Tumor Society (ENETS) and North American Neuroendocrine Tumor Society (NANETS) guide- Definitions lines result in weak clinical recommendations only on pro- Incidence of biliary stone disease was defined as the identi- phylactic cholecystectomy, and UDCA prophylaxis is not fication, on ultrasound (US) or cross-sectional imaging, of taken into consideration [1, 13]. suspected findings and subsequent confirmation of gall- The aim of our study was to evaluate the incidence of stones with a dedicated US evaluation. The occurrence of biliary stone disease in a large population of patients with any condition related to biliary stone disease, such as biliary NETs treated with SSAs; we also assessed risk factors for colic, acute cholecystitis, cholangitis, biliary pancreatitis, or stone incidence and for biliary complications, with a partic- obstructive jaundice, was classified as a biliary complication. ular focus on debated issues such as the role of UDCA Biliary stone disease-free survival (BsDFS) was defined as prophylaxis. the interval between the start of SSAs and the time of bili- ary stone disease occurrence. Biliary complications disease- free survival (BcDFS) was defined as the interval between the start of SSAs and the time of biliary complications occurrence (only in patients with biliary stone disease). MATERIALS AND METHODS All patients or their legal representatives provided writ- ten informed consent for anonymous review of their data for Study Design research purpose. The study protocol was approved by a A retrospective analysis of a multicenter prospectively col- local institutional review board (Comitato Etico Indipendente, lected database was performed. All consecutive patients S. Orsola-Malpighi University Hospital, Bologna, Italy) and with NETs starting SSA treatment at seven Italian dedicated was conducted in accordance with the principles of the Dec- centers from 1995 to 2017 were analyzed. All data were laration of Helsinki (6th revision, 2008). prospectively retrieved at the center where the patient had been enrolled and then collected in a single computerized data sheet. Statistical Analysis Study inclusion criteria were as follows: histological diagno- The distribution of the continuous variables was reported as sis of neuroendocrine neoplasms (NENs) of any grade and site, median (range); categorical variables were described as num- and treatment start with SSAs for metastatic or nonresectable ber (percentage). Risk factors for biliary stone disease and disease at conventional or unconventional dose between related complications were evaluated by univariate and mul- January 1995 and December 2017. Patients with a history of tivariate analysis using the Cox proportional hazards method cholecystectomy or biliary stone disease at the time of SSA and expressed as hazard ratio (HR) and 95% confidence inter- start were excluded. Included patients were followed up until val (CI). The multivariate model was designed using the © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Brighi, Panzuto, Modica et al. 261 forward stepwise method after including all variables. Analy- Table 1. Baseline characteristics of the study population sis A included also the variable SSA type (lanreotide Autogel Patients vs. octreotide LAR); thus, patients sequentially treated with Characteristic (n = 478) both octreotide and lanreotide Autogel have been censored. Demographic Analysis B was conducted in order to include all patients in Gender (male), n (%) 263 (55.0) the multivariate model; therefore, the limiting variable Median age (range) at SSA start, years 61 (18–87) (SSA type, lanreotide Autogel vs. octreotide LAR) has been Primary tumor site excluded. BsDFS and BcDFS were measured using the Kaplan- Gastrointestinal tract, n (%) 211 (44.1) Meier method, and the results were compared using the Pancreas, n (%) 184 (38.5) log-rank test. Lung, n (%) 47 (9.8) The p value was considered significant when inferior to Unknown, n (%) 36 (7.5) .05. Statistical analysis was performed using a dedicated soft- WHO classification ware (IBM – SPSS Statistics v. 22.0; IBM Corp., Armonk, NY). G1 or typical carcinoid, n (%) 280 (58.6) G2 or atypical carcinoid, n (%) 156 (32.6) RESULTS Missing data, n (%) 42 (8.8) MEN 1 syndrome, n (%) 38 (7.9) Study Population Functioning tumors, n (%) 87 (18.2) Seven hundred fifty-four patients treated with SSAs for advanced disease were included. Among them, 225 patients Carcinoid syndrome, n 59 with a history of cholecystectomy and 51 with known biliary Zollinger-Ellison syndrome, n 10 stone disease were excluded from the analysis. Finally, 478 Insulinoma syndrome, n 8 patients were evaluated; baseline characteristics are described PTH-rP hypercalcemia, n 5 in Table 1. Cushing syndrome, n 2 Two hundred sixty-three patients (55.0%) were male. Glucagonoma syndrome, n 2 Median age at SSA start was 61 years (range 18–87). Primary tumor site was gastrointestinal (GI) tract in 211 patients VIPoma syndrome, n 1 (44.1%), pancreas in 184 (38.5%), lung in 47 (9.8%), and Surgery unknown in 36 (7.5%). As for WHO classification, 280 Primary tumor surgery, n (%) 218 (45.6) patients (58.6%) had a NET G1 or typical lung carcinoid and Pancreatic surgery, n 48 156 (32.6%) a NET G2 or atypical lung carcinoid; data were Gastrointestinal surgery, n 133 missing in 42 cases (8.8%). Thoracic surgery, n 37 MEN 1 syndrome was present in 38 patients (7.9%). Eighty-seven patients (18.2%) had a functioning tumor. Liver metastases surgery, n (%) 51 (10.7) Among them, 59 presented with carcinoid syndrome, 10 Medical treatment Zollinger-Ellison syndrome, 8 insulinoma syndrome, 5 parathy- SSAs treatment characteristics roid hormone-related peptide hypercalcemia, 2 glucagonoma Octreotide LAR, n (%) 276 (57.7) syndrome, 2 Cushing syndrome, and 1 VIPoma syndrome. Lanreotide Autogel, n (%) 144 (30.1) Primary tumor surgery was performed in 218 (45.6%) patients: of them, 133 underwent resection of GI tract (gas- Both, n (%) 58 (12.1) tric or ileal resection or partial or total colectomy), 48 pan- Conventional doses, n (%) 438 (91.6) creatic surgery, and 37 thoracic surgery. Fifty-one patients Unconventional doses, n (%) 40 (8.4) (10.7%) underwent hepatic surgery for liver metastases. UDCA prophylaxis 118 (24.7) As for SSA treatment, 276 patients (57.7%) received Abbreviations: LAR, long-acting release; MEN 1, multiple endocrine octreotide LAR 30 mg every 28 days, 144 (30.1%) lanreotide neoplasia type 1; PTH-rP, parathyroid hormone-related peptide; SSA, Autogel 120 mg every 28 days, and 58 (12.1%) both, sequen- somatostatin analogs; UDCA, ursodeoxycholic acid; WHO, World Health Organization. tially. Forty patients (8.4%) received SSAs at unconventional doses (lanreotide Autogel 120 mg or octreotide LAR 30 mg every 21 days). Median duration of SSAs was 31.5 months (range 1–263 months). One hundred eighteen patients GI primary tumor (HR 2.36, p < .001) and related surgery (24.7%) received prophylactic UDCA (with variable dosing (HR 2.33, p < .001). Gender, age, MEN 1 syndrome, func- schedules based on local clinical practice). tionality of primary tumor, hepatic metastases surgery, SSA type, and dose were not related to biliary stone disease Biliary Stone Disease Frequency and Risk Factors development. Patients were followed up for a median of 31.5 (1–263) Multivariate Analysis A (performed after exclusion of 58 months. During the study period, 129 patients (27.0%) devel- patients sequentially treated with both lanreotide Autogel oped gallstones. and octreotide LAR, 420 patients) identified only GI primary Risk factors for biliary stone disease are reported in tumor (HR 1.89, p = .012) as an independent risk factor for Table 2. At univariate analysis, significant risk factors were biliary stone disease development. Multivariate Analysis B www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 262 Biliary Stone Disease in SSA-Treated NET Patients Table 2. Risk factors for biliary stone disease a b Univariate analysis Multivariate analysis A Multivariate analysis B Characteristic HR 95% CI p value HR 95% CI p value HR 95% CI p value Male (gender) 1.00 0.70–1.42 .998 —— — — — — Age 1.01 0.99–1.02 .182 —— — — — — MEN 1 syndrome 0.82 0.43–1.57 .549 —— — — — — Gastrointestinal 2.36 1.64–3.39 <.001 1.89 1.15–3.09 .012 1.76 1.10–2.82 .018 primary tumor Functioning tumor 1.14 0.75–1.72 .547 —— — — — — Gastrointestinal surgery 2.33 1.64–3.30 <.001 1.59 0.98–2.58 .058 1.58 1.003–2.49 .049 Liver metastases surgery 1.26 0.77–2.05 .357 —— — — — — UDCA prophylaxis 0.99 0.67–1.47 .952 —— — — — — c c c Lanreotide vs. octreotide LAR 1.44 0.95–2.17 .082 1.49 0.99–2.25 .059 — — — Unconventional dose SSA 1.32 0.79–2–21 .281 —— — — — — Analysis A: Analysis performed on 420 patients (excluding 58 patients sequentially treated with both lanreotide Autogel and octreotide LAR). Analysis B: Analysis performed on the entire population of 478 patients. Parameter not included in analysis. Significant risk factors at multivariate analysis are marked in bold. Abbreviations: CI, confidence interval; HR, hazard ratio; LAR, long-acting release; MEN 1, multiple endocrine neoplasia type 1; SSA, somatostatin analogs; UDCA, ursodeoxycholic acid. Figure 2. Kaplan-Meier estimates of biliary stone disease-free survival according to the site of primary tumor: gastrointestinal Figure 1. Kaplan-Meier estimates of biliary stone disease-free tract (dotted line) versus other sites (continuous line); p < .001. survival in patients with neuroendocrine tumors treated with somatostatin analogs. (performed on the entire population of 478 patients) identi- Figure 3 shows Kaplan-Meier curves for BsDFS comparing fied both GI primary (HR 1.76, p = .018) and related GI sur- patients who underwent GI primary tumor surgery versus all gery (HR 1.58, p = .049) as independent risk factors for other patients (median 65 months, 95% CI: 51.3–78.7 months biliary stone disease development. vs. 165 months, 95% CI: 106.6–223.4 months; p <.001). No difference was observed when correlating BsDFS to gender (median in male: 120 months, female: 102 months; Biliary Stone Disease-Free Survival p = .998), MEN 1 syndrome (median with MEN 1 syndrome: Figure 1 shows Kaplan-Meier curve for BsDFS; median BsDFS 93 months, without MEN 1 syndrome: 120 months; p =.547), was 120 months (95% CI: 87.7–152.3 months). Significant dif- hormone secretion syndrome (median in patients with ferences in BsDFS were observed according to primary tumor syndrome: 120 months, without syndrome: 136 months; site; in particular, Figure 2 shows Kaplan-Meier curves for p = .545), hepatic metastases surgery (median yes: 124 BsDFS according to primary GI tumor versus other primary months, no: 120 months; p = .355), UDCA prophylaxis tumor sites (median 73 months, 95% CI: 62.7–83.3 months (median with prophylaxis: 120 months, without prophylaxis: vs. 214 months, 95% CI: 101.3–326.6 months; p <.001). 124 months; p = .952), SSA type (median octreotide LAR: 136 © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 Brighi, Panzuto, Modica et al. 263 biliary complications (Table 3). Kaplan-Meier curves analysis did not identify any correlation with BcDFS. DISCUSSION To the best of our knowledge, we conducted the largest study specifically dealing with biliary stone disease in patients with NENs treated with SSAs and observed a high frequency (27%) of biliary stone disease occurrence. As stated by EASL guidelines, we agree that SSA-treated patients with NENs should be considered a high-risk popula- tion for biliary stone disease [12]. Based on our results, this population has a higher frequency of biliary stone disease compared with the general population, where the preva- lence is 10%–20%. As for complications, in the general popu- lation, 0.7%–2.5% of patients with asymptomatic gallstones develop gallstone-related symptoms yearly; the annual inci- dence of complications is 0.1%–0.3% [12, 19–21]. Thus, our study population can be considered at high risk not only for Figure 3. Kaplan-Meier estimates of biliary stone disease-free gallstone developments but also for related complications. survival according to surgery of gastrointestinal primary tumor Data from CLARINET and PROMID trials showed a sensi- (dotted line) versus other patients (continuous line); p < .001. bly lower frequency (10%–14%), probably due to a shorter period of exposure to SSAs (with a median of 14 months in PROMID and 24 months in the CLARINET study vs. 31.5 in our analysis) and a shorter follow-up [10, 11]. Table 3. Risk factors for biliary complications A previous single-center analysis from our institute Univariate analysis reported a comparably high frequency of biliary stone dis- Characteristic HR 95% CI p value ease (36.6%) [7]. Other retrospective studies based on Male (gender) 0.78 0.39–1.53 .467 patients with NENs reported a prevalence of 52%–63%, but studies on this specific population are few [8, 9]. On the con- MEN 1 syndrome 0.70 0.21–2.35 .563 trary, many studies on patients receiving SSAs to treat acro- Gastrointestinal primary tumor 2.06 0.97–4.36 .060 megaly are available, reporting a very variable biliary stone Functioning tumor 0.61 0.27–1.38 .239 frequency (3%–56% in the first 2 years of treatment) [2, 4, Gastrointestinal surgery 1.11 0.57–2.16 .764 6]. However, patients with acromegaly are not comparable to Liver metastases surgery 0.31 0.07–1.29 .108 those with NETs, because acromegaly has already been iden- UDCA prophylaxis 0.58 0.25–1.34 .206 tified as a risk factor for gallstones occurrence per se [3]. The role of SSAs in the pathogenesis of gallstone disease Lanreotide vs. octreotide LAR 0.78 0.33–1.83 .570 is related to several factors. First, SSAs tend to inhibit meal- Unconventional dose SSAs 0.47 0.14–1.55 .217 stimulated cholecystokinin release, resulting in reduced Abbreviations: CI, confidence interval; HR, hazard ratio; LAR, gallbladder motility [4, 6]. In addition, SSAs slow intestinal long-acting release; MEN 1, multiple endocrine neoplasia type 1; SSAs, somatostatin analogs; UDCA, ursodeoxycholic acid. transit, allowing intestinal bacteria to increase the amounts of deoxycholate, which favors the aggregation of cholesterol crystals into stones. Finally, SSAs inhibit postprandial Oddi’s months, median lanreotide Autogel: 76 months; p =.079), sphincter relaxation, further increasing bile stasis [22, 23]. and SSA dose (median conventional dose: 136 months, We identified GI-NET and surgery for primary GI-NET as unconventional dose: 71 months; p =.278). independent risk factors for biliary stone disease develop- ment. Despite the fact that studies on cholesterol and bile Biliary Stone Disease Complications and Risk Factors acids metabolism in patients with GI-NET are lacking, it has During the study period, 36 patients (7.5% of the entire been previously reported that patients who underwent ileal population) developed biliary complications such as biliary resection have an increased risk of stone disease because colic, acute cholecystitis, cholangitis, biliary pancreatitis, or of reduced ileal bile acid absorption [23, 24]. obstructive jaundice. Twenty-five patients required surgery, Several ileal diseases, such as Crohn’s disease or radiation whereas 11 received pharmacological treatment. Among enteritis, mayleadtoa “broken” enterohepatic circulation, 129 patients who developed biliary stone disease during playing a pivotal role in the pathogenesis of gallstone forma- treatment, 27.9% presented a biliary complication. Median tion. These conditions may lead to bile acid malabsorption and BcDFS was 102 months (95% CI: 61.9–142.0 months). pool depletion, resulting in cholesterol-supersaturated bile At univariate analysis, none of the tested factors (gender, [24–26]. Another possible explanation involves an altered MEN 1 syndrome, site and functionality of primary tumor, microbiota, often coexisting in intestinal diseases, that could surgery of primary tumor or liver metastases, SSAs type and enhance the deconjugation of bilirubin and bile acids with an dose, UDCA prophylaxis) were related to the development of upregulation of enterohepatic cycle of bile pigment and www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/25/3/259/6443343 by DeepDyve user on 01 February 2022 264 Biliary Stone Disease in SSA-Treated NET Patients formation of pigment stones [27]. Finally, no study dealt with in patients with small-bowel NETs who are candidates for the hypothetical role in this setting of the release of active long-term SSAs; cholecystectomy is not suggested in asymp- substances at a local level (e.g., serotonin, FGF19) that could tomatic patients [13]. Moreover, no recommendation is avail- alter GI motility. able in North American guidelines on the role of prophylactic UDCA prophylaxis is indicated in high-risk patients (i.e., cholecystectomy in primary tumor other than intestinal. rapid weight loss in obese patients) to reduce the incidence of biliary stone disease [12]. ENETS guidelines do not express any recommendation about the use of UDCA in patients with CONCLUSION NENs receiving SSAs [1]. On the contrary, EASL guidelines Our data suggest that prophylactic cholecystectomy is rec- recommend consideration of its use during SSA-treatment ommended in all patients undergoing surgery for primary GI- [12]. Interestingly, we did not observe any effect of UDCA on NETs. In all other patients undergoing abdominal surgery for the development of gallstones when used as prophylactic any indication other than GI-NET resection, prophylactic chole- treatment or when used to reduce the risk of biliary compli- cystectomy is suggested. On the other hand, patients with GI- cations in patients with gallstones. NETs with long-life expectancy and who are candidates for Moreover, no patient had to permanently discontinue long-term SSA-treatment where resection of primary is not SSA-treatment because of biliary stone disease or any of its indicated should be considered for prophylactic cholecystec- complications. After medical or surgical treatment, at reso- tomy on a case-by-case evaluation because of the cumulative lution of symptoms if present, all patients could resume high risk of biliary stone disease and related complications. SSA-therapy. With the available data, no conclusion could be drawn on the The main limit of the study is the retrospective design indication of prophylactic cholecystectomy in patients with pri- that could lead to an inhomogeneous diagnostic and thera- mary pancreatic or thoracic NETs for whom abdominal surgery peutic management. In particular, no standardization on is not planned. Further prospective studies should be con- planned exams or treatment schedule has been conceived; ducted to investigate these matters. however, only NEN-dedicated centers have been included, in order to have a better adherence to available guidelines and reduce discrepancies. The study population underwent ACKNOWLEDGMENTS scheduled US or computed tomography scan as suggested The present work was conducted with the support of by most recent guidelines for the oncological follow-up [16, Associazione Italiana Tumori Neuroendocrini (Italian Associ- 17]. Because of the retrospective nature of this study, a spe- ation for Neuroendocrine Tumours). cific workup for the diagnosis or follow-up of biliary stone disease was not preplanned. Similarly, owing to conflicting recommendations, the management of UDCA prophylaxis AUTHOR CONTRIBUTIONS Conception/design: Nicole Brighi, Giuseppe Lamberti, Davide Campana and the treatment of biliary stone disease was not planned, Provision of study material or patients: Nicole Brighi, Francesco Panzuto, but it was conducted at physician’s choice following local Roberta Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, clinical practice. Therefore, our observation of the ineffec- Sara Massironi, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, Diego Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna tive role of UDCA cannot be considered conclusive and Maria Colao, Davide Campana should be addressed in a dedicated trial. Collection and/or assembly of data: Nicole Brighi, Francesco Panzuto, Roberta Our study has for the first time clearly identified which Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, Sara Massironi, Giuseppe Lamberti, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, subgroups of SSA-treated patients with NETs have a higher Diego Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna Maria risk of biliary stone disease. We also observed that these Colao, Davide Campana patients presented a high rate of biliary-related complications Data analysis and interpretation: Nicole Brighi, Francesco Panzuto, Giuseppe Lamberti, Davide Campana (up to 30%) and that a significant amount of them (up to Manuscript writing: Nicole Brighi, Francesco Panzuto, Davide Campana 70%) required cholecystectomy, despite underlying advanced Final approval of manuscript: Nicole Brighi, Francesco Panzuto, Roberta Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, Sara Massironi, Giuseppe oncological disease. Lamberti, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, Diego Current ENETS guidelines weakly suggest considering Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno Annibale, Anna Maria Colao, prophylactic cholecystectomy in patients who are candi- Davide Campana dates for abdominal surgery; indications are even weaker when surgery is not planned [1]. 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