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Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e9
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Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms Kevin P. Shah, MD, Katherine A. Baugh, MD, Lisa S. Brubaker, MD, George Van Buren II, MD, Nicole Villafane-Ferriol, MD, Amy L. McElhany, MPH, Sadde Mohamed, Eric J. Silberfein, MD, Cary Hsu, MD, Nader N. Massarweh, MD, Hop S. Tran Cao, MD, Jose E. Mendez-Reyes, MD, and William E. Fisher, MD* Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
article info
abstract
Article history:
Background: With advances in cross-sectional imaging, pancreatic cysts are more
Received 24 May 2019
frequently diagnosed and have become a common indication for pancreatectomy. The
Received in revised form
impact of pancreatectomy in these patients is important. The purpose of this study was to
20 August 2019
assess short-term outcomes, long-term nutritional status, quality of life (QOL), and
Accepted 19 September 2019
pancreas function after pancreatectomy for cystic neoplasms.
Available online xxx
Materials and methods: At a single institution, patients at least 3 y post-pancreatectomy for benign cystic neoplasms were identified. Using a validated questionnaire, short-term
Keywords:
outcomes, long-term outcomes including endocrine and exocrine insufficiency, long-
Pancreatic resection
term nutritional status, and preoperative and postoperative QOL were compared based
Long-term functional outcomes
on operation and indication for resection.
Exocrine and endocrine
Results: Among 102 eligible patients, 70 had valid contact information and 51 (72.9%) agreed
insufficiency Quality of life Benign pancreatic cystic lesions
to participate. Median follow-up was 6 (4-8) y. Patients undergoing pancreatoduodenectomy for benign cysts had higher morbidity than a similar cohort resected for pancreatic adenocarcinoma (patients with at least 1 grade 2 complication [49.0% versus 31.6%, P ¼ 0.038]). After long-term follow-up, pancreatectomy did not significantly affect perceived QOL. Half of patients had mild-moderate or severe malnourishment, but pancreatic enzyme replacement was reported by only 4 (7.8%) patients. New-onset diabetes was present in 15 (29.4%) patients with median time-to-diagnosis of 6 (1-12) mo after resection. Conclusions: Pancreatectomy for benign cysts did not negatively impact patients’ perceived QOL. However, after long-term follow-up, malnutrition and pancreatic insufficiency occurred in a significant percentage and may be greater than previously estimated. Consideration of short- and long-term outcomes should factor into preoperative counseling, especially in cysts with minimal risk of progression to malignancy. ª 2019 Published by Elsevier Inc.
Presentation: Presented at the 2017 Clinical Congress in San Diego, California. * Corresponding author. Division of General Surgery, Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, 6620 Main Street, Suite 1425, Houston, TX 77030. Tel.: þ1 713 798 4321; fax: þ1 713 610 2489. E-mail address: [email protected] (W.E. Fisher). 0022-4804/$ e see front matter ª 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.jss.2019.09.045
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Introduction Pancreatic cysts are increasingly becoming a common imaging finding with a prevalence of 2% in the general population.1 This estimate is likely conservative because of the widespread use and advancement of cross-sectional imaging. The majority of incidentally found cystic lesions are benign and require no further medical intervention.2,3 However, preoperative characterization and prediction of the behavior of these lesions remain challenging as cystic lesions can vary widely in their risk of malignant transformation. Owing to the aggressive nature of pancreatic ductal adenocarcinoma (PDAC) even at an early stage, pancreas surgeons are highly motivated to avoid allowing a pancreas cyst to progress to invasive cancer while undergoing surveillance. Pancreatectomy remains the cornerstone of treatment for cystic lesions with multiple high-risk features including solid component, dilated main pancreatic duct, and concerning features on endoscopic ultrasound with fine needle aspiration.4,5 Patient-centered outcomes, such as quality of life (QOL), are an important factor to consider after pancreatectomy. Prior studies examining long-term outcomes such as overall survival and QOL in pancreatectomy patients had been conducted but focused largely on PDAC survivors.6-11 Historically, pancreatectomy was reserved for malignant pathology, but lesions are now identified much earlier in the spectrum of disease. Patients, benefitting from detection of premalignant pathology, are now living longer after surgery, and the understanding of long-term outcomes including QOL, malnutrition, exocrine, and endocrine insufficiency are becoming increasingly relevant. Only a few studies have examined longterm outcomes in patients undergoing resection for benign cystic lesions, but all have been centered on European populations.12,13 The generalizability of these studies to the United States is consequently limited because of the inherent differences in patient populations and access to nationalized health care. Examination of patient outcomes after resection for benign disease in the United States is needed to direct preoperative decision-making and patient counseling. Therefore, the objectives of this study were to evaluate the short-term morbidity of pancreatectomy for cystic neoplasms in comparison with pancreatectomy for pancreatic adenocarcinoma (PDAC) and to determine long-term pancreatic function after pancreatoduodenectomy and distal pancreatectomy for pancreatic cysts. We hypothesized that shortterm morbidity would be higher in patients with lesions undergoing resection for cystic neoplasms due to the presence of a soft gland and a nondilated duct and that long-term pancreatic function, nutrition, and QOL would be affected.
Materials and methods Data source We analyzed data from a prospectively maintained Pancreas Surgery Registry in a high-volume academic pancreas center to identify patients undergoing pancreatectomy for cystic neoplasms. The database stores information including
baseline demographics, comorbidities, perioperative characteristics, and graded complications within 60 d of surgery using the Accordion Severity Grading for Surgical Complications14 and the International Study Group of Pancreatic Fistula and International Study Group of Pancreatic Surgery definitions15,16 for pancreatic fistula and delayed gastric emptying. A detailed definition of complications has been previously reported.17
Study cohort We identified patients undergoing pancreatoduodenectomy and distal pancreatectomy at a single institution between January 2005 and January 2014. All patients with benign cystic neoplasms on final pathology were included, and cystic neoplasms with malignant features were excluded, including pancreatic adenocarcinoma, cholangiocarcinoma, ampullary carcinoma, duodenal adenomas, and tumors metastatic to the pancreas. Cystic lesions in the setting of neuroendocrine tumors and chronic pancreatitis were also excluded. Patients meeting inclusion criteria were contacted and consented via telephone. Permission for this study was obtained from an institutional review board (H-35341). Surgeons in this study followed the consensus set forth by the International Association of Pancreatology, including the Sendai and Fukuoka guidelines for management of cystic neoplasms of the pancreas.18-20
Short-term outcomes All patients who underwent pancreatectomy for benign cysts were compared with a cohort of all patients who underwent pancreatectomy for PDAC within the same time period. Shortterm outcomes were identified using the database and a comprehensive chart review when applicable. Outcomes included all complications within 60 d, length of stay, and overall mortality within 90 d.21 Short-term complications were graded using the Accordion Severity Grading for Surgical Complications.14 The Pancreatic Fistula Risk Score was calculated using an online medical calculator.22,23
Long-term outcomes and survey Long-term outcomes were examined in patients who were resected for benign cysts. Patients who underwent resection for PDAC were excluded because of concerns regarding longterm survival and confounding variables such as adjuvant therapy affecting QOL. Data on long-term outcomes were obtained through a telephone survey evaluating four sections of interest: (1) QOL, (2) nutritional status, (3) pancreatic endocrine, and (4) exocrine function. The survey comprised validated questions from the Subjective Global Assessment (SGA)24 and the Functional Assessment of Cancer Therapy (FACT-Hep)25 questionnaires. Questions about body mass index (BMI), gastrointestinal symptoms (nausea, vomiting, diarrhea, pain on eating), dietary intake, weight loss (recent or long term), and day-to-day functional capacity (ability to perform activities of daily living) were derived from the SGA questionnaire.24 The FACT-Hep questionnaire provided
shah et al long-term outcomes after pancreatectomy
3
validated questions concerning the following subcategories to assess QOL: physical well-being, social well-being, emotional well-being, functional well-being, and hepatobiliary-specific subscale. The remaining variables including alcohol and tobacco intake, hospitalizations, and symptoms of exocrine and endocrine insufficiency were developed by the authors for this study. The Centers for Disease Control and Prevention and National Institute of Health’s definition of heavy drinking (15 drinks weekly or 5 or more on occasion for men and 8 drinks weekly or 4 or more on occasion for women) was used to report clinically significant alcohol intake.26,27 Data from the questionnaire, including long-term nutritional status and incidence of pancreatic endocrine and exocrine insufficiency, was compared between pancreatoduodenectomy and distal pancreatectomy patients. Fig. 1 e Flow diagram of patient selection.
Statistical analysis Chi-square, Fisher’s exact, or McNemar’s test, when appropriate, was used to analyze categorical variables. The Student’s t-test or Mann-Whitney test was used to evaluate continuous variables. All statistical analyses were performed using SPSS v25 (IBM Corp., Armonk, NY). Median values are reported with interquartile range in the following format: median (interquartile range).
Results Cohort characteristics We identified 115 total patients who underwent pancreatectomy (either pancreatoduodenectomy or distal pancreatectomy) for benign cystic neoplasms. Thirteen patients were excluded only from long-term analysis because of death before contact date (10), advanced Alzheimer’s disease (1), severe hearing loss (1), or completion of total pancreatectomy after initial pancreatoduodenectomy (1). This cohort was compared with a cohort of 131 patients who underwent pancreatectomy for PDAC (for short-term outcomes). Age was lower in the cohort of patients undergoing surgery for a cyst (61.45 versus 66.23, P ¼ 0.00199). Gender distribution was also significant (cyst: male 30.4%; PDAC: male 50.8%; P ¼ 0.00125). The Charlson-Deyo comorbidity score was not significantly different between the cohorts (0.62 versus 0.64, P ¼ 0.823). Only 8% of the cohort of patients undergoing pancreatectomy for PDAC received neoadjuvant radiation therapy. The median pancreatic duct size of patients who underwent pancreatoduodenectomy for cystic lesions was 3.0 (2.0-5.0) mm. The median pancreatic duct size for patients who underwent pancreatoduodenectomy for PDAC was 5.0 (4.0-6.0) mm. Of the 102 eligible participants, 70 had valid contact information and 51 completed the survey for a response rate of 72.9% (Fig. 1). Median age at the time of survey was 68 (63-77) y. General nutritional findings and medical history of participants are summarized in Table 1. Median follow-up was 6 (4-8) y after pancreatectomy. The most common diagnoses for distal pancreatectomy patients were intraductal papillary mucinous neoplasm (IPMN) (20%), mucinous cystic neoplasm (33%), and serous cystadenomas (20%). The most common
pathology for pancreatoduodenectomy patients was IPMN (71%) followed by serous cystadenoma (24%). Only 3 of 51 (5.8%) patients, each with IPMN, had high-grade dysplasia on final pathology.
Short-term outcomes Short-term 60-d outcomes between the 115 patients who underwent pancreatectomy for benign cystic were compared with the 131 patients who underwent pancreatectomy for an indication of PDAC during the same time period (shown in Table 2 stratified by pancreatoduodenectomy and distal pancreatectomy). Complications (grade 2) for patients undergoing pancreatoduodenectomy for cystic lesions were significantly greater than those undergoing pancreaticoduodenectomy for cancer [49.0% versus 31.6%, P ¼ 0.038]). There was an increased frequency of all and clinically relevant pancreatic fistulas (P < 0.001; P < 0.001) and intra-abdominal abscesses (P ¼ 0.027). As expected, the Fistula Risk Score was significantly higher in the cohort undergoing pancreatoduodenectomy for cystic lesions than that for PDAC (4.64 versus 1.67, P < 0.001).22,23 The increase in complications did not translate to significant differences in length of stay or 90-d mortality (P ¼ 0.079; P ¼ 1). Complications, such as pancreatic fistula, wound infections, and intra-abdominal abscesses, in those undergoing distal pancreatectomy were not significant between patients undergoing resection for cystic neoplasms or cancer.
Long-term patient-reported outcomes Preoperatively, the majority of patients (58.8%) perceived a “high risk” of malignant transformation of their lesion with 43.1% identifying malignant potential as the primary reason for deciding to undergo resection (versus symptomatic relief, or both symptomatic relief and malignant potential of lesion). Postoperatively, the majority of patients (62.7%) perceived “low risk” of pancreatic malignancy in the future. At followup, 19 patients (37.3%) reported regular continued surveillance imaging. Ninety percentage of patients believed they had no nutritional problems, with the remaining 10%
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Table 1 e Nutritional and medical history of survey participants. n ¼ 51 Age at follow-up survey
n (%) or median (interquartile range) 68 (63-77)
Body mass index at surgery
27.8 (25.0-31.8)
Body mass index at follow-up
26.7 (23.3-29.6)
Weight loss in last 6 mo
15 (29%)
Long-term QOL
Time from operation until follow-up 3-4 y
18 (35%)
5-6 y
11 (22%)
7-8 y
13 (25%)
9-10 y
7 (14%)
11-12 y
2 (4%)
Dietary intake Normal intake
37 (73%)
Reduced intake
12 (24%)
Semisolid or liquid diet Very poor intake or starvation
0 1 (2%)
Gastrointestinal symptoms last 2 wk Pain on eating
10 (20%)
Nausea
11 (22%)
Vomiting
1 (2%)
Diarrhea
13 (26%)
Functional capacity Normal Reduced capacity Unable to work Ambulatory Alcohol abuse Current tobacco use
41 (80%) 6 (12%) 0 3 (6%) 15 (29%) 2 (4%)
At least 150 min exercise per week
30 (59%)
Hospitalized in last 2 y
21 (41%)
Enzyme replacement
4 (8%)
Proton pump inhibitor
18 (35%)
Nutritional supplement
3 (6%)
New-onset diabetes since surgery
15 (29%)
Do you see yourself having nutritional problems? Major malnutrition Moderate malnutrition No nutritional problems
0 5 (10%) 46 (90%)
Health status compared with others of same age? Not as good Don’t know
whereas 8 patients (15.7%) considered their health status to be worse than other people of the same age. Among the cohort, 43 (84.3%) patients cited the risk of malignancy as the reason they chose to undergo surgery with the remainder citing symptom management. Thirty-nine patients (76.5%) reported a moderate-to-high risk of cancer before surgery, whereas 32 (62.7%) perceived a negligible-tolow risk of malignancy after cyst resection (P 0.001).
8 (16%) 3 (6%)
As good
12 (24%)
Better
28 (55%)
believing they had a moderate level of malnutrition. No patient believed they had a severe level of malnutrition. In terms of perceived health status, 40 patients (78.4%) considered it to be as good as or better than other people of the same age,
Thirteen patients had both preoperative and postoperative QOL data available. Mean FACT-Hep QOL scores in these patients increased by 9.81 points after pancreatectomy (95% CI 9.45 to 29.07, P ¼ 0.29). A complete FACT-Hep was obtained from all patients after pancreatectomy. The overall median score for these patients was 160 (138-167.42) of 180 total points. Table 3 shows a comparison between preoperative and postoperative QOL. There was no difference in the QOL scores between subjects who had distal pancreatectomy (158.42 [139.75-164]) or pancreatoduodenectomy (162.67 [137-172]). Table 4 shows an in-depth analysis of the FACT-Hep QOL scores comparing patients who underwent pancreatoduodenectomy and distal pancreatectomy.
Long-term nutritional status When assessing long-term nutritional status with the SGA questionnaire, twenty-seven (52.9%) patients were well nourished (SGA A Rating) and 23 (45.1%) had mild-moderate malnourishment (SGA B rating). Only one (2.0%) patient was severely malnourished (SGA C rating). Fifteen (29.4%) patients reported an average of 7.5 pounds of weight loss in the 6 mo before follow-up. However, average weight loss at follow-up was found to be 9.7 pounds and was significantly decreased from the time of surgery (P < 0.001).
Long-term exocrine and endocrine pancreatic function Both exocrine and endocrine pancreatic functional outcomes after pancreatectomy for benign cystic neoplasms were assessed (Table 5). Four patients (7.8%) reported no evidence of subjective decline in exocrine pancreas function. However, 28 patients (55.0%) reported steatorrhea and 25 patients experienced early satiety. One-fourth of patients had abnormal stool color, bloating after meals, a decrease in number of daily meals postoperatively, or loss of appetite. Despite at least half of patients being symptomatic, only 4 patients were taking pancreatic enzyme replacement (7.8%); 3 of which underwent a pancreatoduodenectomy. Additional patient-reported outcomes are reported in Figure 2. At long-term follow-up, 21 (41.2%) patients reported a diagnosis of diabetes, fifteen of which had new-onset diabetes mellitus (NODM) postoperatively (29.4%). There was no significant difference in NODM between pancreaticoduodenectomy and distal pancreatectomy patients (28.6% versus 30.0%, P ¼ 0.91). Median time at diagnosis of diabetes was 6 (1.25-12) mo after resection. Of those with NODM, 13 patients (86.67%) developed diabetes within 1 y of pancreatectomy. Insulin was required for glycemic control by 9 patients
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Table 2 e Comparison of short-term (60-d) complications. All procedures Cyst (n ¼ 115)
PDAC (n ¼ 131)
Any grade 2 complication
43 (37%)
38 (29 %)
Postoperative pancreatic fistula
40 (35%)
18 (14%)
Clinically relevant postoperative pancreatic fistula
17 (15%)
Intra-abdominal abscess
Pancreatoduodenectomy P-value
Cyst (n ¼ 51)
PDAC (n ¼ 98)
P-value
Cyst (n ¼ 64)
PDAC (n ¼ 33)
P-value
0.163
25 (49%)
31 (32%)
0.038
18 (28%)
7 (21%)
0.461
<0.001
24 (47%)
11 (11%)
<0.001
16 (25%)
7 (21%)
0.678
6 (5%)
0.006
11 (22%)
2 (2%)
<0.001
6 (9%)
4 (12%)
0.731
4 (6%)
1 (3%)
0.659
13 (11%)
7 (5%)
0.088
9 (18%)
6 (6%)
0.027
Abdominal fluid collection
9 (8%)
14 (11%)
0.431
2 (4%)
12 (12%)
0.140
Wound infection
8 (7%)
6 (5%)
0.422
2 (4%)
6 (6%)
0.716
Delayed gastric emptying
Distal pancreatectomy
7(11%)
2 (6%)
0.713
6 (9%)
0
0.092 0.369
19 (17%)
26 (20%)
0.501
10 (20%)
19 (19%)
0.974
9 (14%)
7 (21%)
Gastrointestinal hemorrhage
2 (1.7%)
1 (0.8%)
0.600
2 (4%)
1 (1%)
0.270
0 (0%)
0 (0%)
Length of stay, median (IQR)
7 (6-8)
7 (6-8)
0.345
7 (7-8.5)
7 (6-9)
0.1078
6 (5-8)
6(5-8)
0.518
90-d mortality
1 (0.9%)
3 (2.3%)
0.625
1 (2%)
3 (3%)
1.000
0 (0%)
0 (0%)
1.0
1.0
Bold ¼ P < 0.05 Chi-square, Fisher’s exact, or McNemar’s test for categorical variables, Student’s t-test or Mann-Whitney test for continuous variables.
(60%), but no significant difference in incidence occurred between distal pancreatectomy and pancreatoduodenectomy (P ¼ 0.136).
Discussion An understanding of the true short- and long-term morbidity of pancreatectomy is necessary to determine the risk-benefit ratio that is vital to preoperative counseling.28,29 Of great importance to patient counseling is an understanding of patient-centered outcomes. However, studies examining patient outcomes after resection for cystic neoplasms centered on European populations.12,13 Therefore, we sought to assess the short- and long-term risks of pancreatectomy for benign cystic neoplasms of the pancreas and patient perceived QOL in the American population. With regard to short-term outcomes, our study revealed that compared with patients undergoing resection for cancer, perioperative complications are
greater in patients undergoing pancreaticoduodenectomy for cystic lesions. After long-term (6 y) follow-up, our study, which is the only study to analyze long-term outcomes after distal pancreatectomy or pancreatoduodenectomy for benign cystic lesions in a US population, revealed that half of patients exhibited symptoms of malnourishment and a third of patients developed diabetes postoperatively. We intentionally excluded patients with PDAC and chronic pancreatitis from our long-term outcome survey as the physiology of these diseases confounds our analysis of the effect of pancreatectomy on long-term nutritional status, QOL, and pancreas function. Compared with patients undergoing pancreatectomy for cystic neoplasms, patients undergoing pancreatectomy for PDAC have a higher preoperative incidence of recent weight loss and new-onset diabetes.30 The presence of these conditions preoperatively impacts the prevalence of these conditions in the immediate and long-term postoperative periods.31 Preoperative exocrine pancreatic insufficiency is also more common in patients with malignancy and chronic
Table 3 e Comparison of preoperative and postoperative QOL scores. FACT scale/Subscale
Preoperative median (IQR) QOL score (n ¼ 13)
Postoperative median (IQR) QOL score (n ¼ 13)
P-value
Physical well-being (0-28)
27 (26-28)
26 (24-27)
0.30
Social well-being (0-28)
24 (22-28)
26 (25-28)
0.49
Emotional well-being (0-28)
20 (18-22)
23 (22-24)
0.21
27 (24-28)
0.63
Functional well-being (0-28)
27 (22-28)
Hepatobiliary cancer subscale (0-72)
57 (48-64)
60.5 (56.75-67.25)
0.29
FACT-general (0-108)
96 (88-99)
102 (90-105)
0.59
112 (100-121)
0.34
163 (154.5-172.25)
0.29
Trial outcome index (0-128) FACT-Hep total (0-180)
104 (96-119.25) 148.63 (137.5-162.75)
FACT ¼ functional assessment of cancer therapy, IQR ¼ interquartile range, QOL ¼ quality of life.
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Table 4 e Comparison of pancreatoduodenectomy and distal pancreatectomy QOL scores. FACT scale/Subscale (n ¼ 50)
Overall median (IQR) QOL score
Physical well-being (0-28) Social well-being (0-28)
Pancreatoduodenectomy median (IQR) QOL score
26 (19.5-27.5) 25.67 (22-28)
26 (19-28) 25.67 (24-28)
Distal pancreatectomy median (IQR) QOL score 25.5 (22-27)
P-value 0.57
25.83 (20.13-28)
0.90
Emotional well-being (0-28)
22 (17.5-24)
22 (16-24)
22 (18-24)
0.77
Functional well-being (0-28)
26 (21-28)
26 (24-28)
26 (18.5-27)
0.30
Hepatobiliary cancer subscale (0-72)
61 (56-66)
62 (57-68)
59.5 (56-64.5)
0.37
FACT-general (0-108)
97.83 (80-103.83)
97.92 (81-102.75)
0.80
Trial outcome index (0-128)
111 (98-118)
FACT-Hep total (0-180)
160 (138-167.42)
97.67 (80-104) 113 (98-124) 162.67 (137-172)
pancreatitisda population excluded from our analysisdsecondary to the fibrosis of the pancreatic ducts and the fibrotic replacement of the parenchyma, respectively.32 In addition to the physiologic differences between patients undergoing pancreatectomy for cystic neoplasms and those undergoing pancreatectomy for cancer, another variable that significantly affects the long-term QOL in PDAC patients is the receipt of adjuvant therapy. Short-term morbidity of pancreatic resection, especially pancreatoduodenectomy, is greater for patients undergoing resection of pancreatic cysts than it is for patients undergoing resection for cancer. Van der Gaag et al.13 assessed long-term outcomes in patients resected for cystic neoplasms (n ¼ 65)
110 (98.5-116.92)
0.56
158.42 (139.75-164)
0.61
with a reported complication rate of 20%; however, the classification system and time frame after surgery were not provided. In contrast, Falconi et al.12 demonstrated a 52% complication rate using the Dindo-Clavien classification in their cross-sectional study of patients resected for benign tumors. Heerkens et al.33 similarly reported a 39% incidence of severe complications in their study examining QOL after resection for malignancy. In the present study, the complication rate of 49% in patients who underwent pancreatoduodenectomy for benign disease is consistent with the literature. Although there is significant variability in complication occurrence, this likely represents the variation in indication for surgery with an increased risk of complications
Table 5 e Comparison between pancreatoduodenectomy and distal pancreatectomy patients. Pancreatoduodenectomy (n ¼ 21)
Distal pancreatectomy (n ¼ 30)
P-value
13 (62%)
23 (77%)
0.255
68 (62-77)
68.5 (64.25-73.75)
Gender Female Age* Pathology IPMNy
15 (71%)
6 (20%)
MCN
1 (5%)
10 (33%)
Serous cystadenoma
5 (24%)
6 (20%)
Cystadenoma NOS
0
2 (8%)
Lymphoepithelial cyst
0
2 (7%)
Pseudocyst
0
4 (13%)
1 (5%)
0
Well-nourished (SGA A)
12 (57%)
15 (50%)
Mild-moderately malnourished (SGA B)
9 (43%)
14 (46.7%)
Pseudopapillary tumor
0.4 0.005
SGA
0.0651
Severely malnourished (SGA C)
0 (0%)
1 (3%)
Pancreatic enzyme replacementz
3 (14%)
1 (4%)
0.08
New-onset diabetes
6 (29%)
9 (30%)
0.3
*
Mann-Whitney U test. y 1 patient had moderate to severe dysplasia, and 2 patients had focal high grade dysplasia. The remainder of patients had no, low, or moderate dysplasia. z Fisher’s exact test.
shah et al long-term outcomes after pancreatectomy
Fig. 2 e Pancreatic functional outcomes (exocrine). (Color version of figure is available online.)
in benign resections due to the well-established risk factors for postoperative pancreatic fistula of small duct and soft pancreas relative to resection for PDAC in which a more firm pancreas with a larger duct would be less prone to short-term morbidities. These risk factors are a major component of the Pancreatic Fistula Risk Score; a prospectively validated score that accurately predicts clinically relevant postoperative pancreatic fistula based on intraoperative findings.22,23 Of note, short-term morbidity was greater in patients undergoing pancreaticoduodenectomy but decision to resect should be based on current consensus guidelines as well as a careful and detailed discussion with the patient about risks and benefits of an operation. Although it is generally known that misuse of alcohol can put patients at risk for surgical complications, the 29% incidence of alcohol abuse in the cohort of patients who underwent pancreas resection for benign cystic lesions corresponds to the statistic put forth by the Substance Abuse and Mental Health Services Administration in which 26.9% of adults nationally had engaged in binge drinking in 2015.34-36 This consistency between our own study’s investigation and national agency estimates suggest that the short-term morbidities highlighted in our results are not primarily or in great part due to alcohol abuse. Our findings expand upon the existing literature in terms of QOL after pancreas resection. In a recent cross-sectional study by Massachusetts General Hospital, Fong et al.7 examined QOL of 305 patients who underwent pancreatoduodenectomy for benign or malignant lesions. Median follow-up was 9.1 y with a higher QOL noted when compared with sex- and age-adjusted healthy individuals. No difference was noted when accounting for resection due to benign versus malignant pathology. However, the study only encompasses patients who underwent pancreatoduodenectomy and does not include preoperative baseline testing. Huang et al.37 also compared QOL in post-pancreatoduodenectomy patients (n ¼ 192) to a cohort of healthy laparoscopic cholecystectomy patients (n ¼ 31) and discovered no difference. In a comparative study, Van der Gaag et al.13 examined QOL after resection for benign cystic neoplasms (n ¼ 65) and found no difference
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in physical or mental QOL scores when compared with healthy references. However, this study encompasses patients cared for under nationalized health care and is, therefore, limited in terms of generalizability to the US due to the fundamental differences between the health care systems and patient populations. The present study provides the only focused examination of perceived QOL in a US population undergoing distal pancreatectomy or pancreaticoduodenectomy for benign disease. An important long-term concern in patients after pancreatic resection is nutritional status. Frequently, postoperative nutritional status returns to preoperative levels with dietary counseling. However, long-term information on nutritional status is less well characterized as the majority of studies examine preoperative nutritional status.31 Postoperative nutritional assessments usually center on weight loss, changes in BMI, and exocrine insufficiency. However, weight loss and BMI do not provide an accurate assessment. BMI does not account for tissue types (fat and muscle) and the change in composition that occurs over time (i.e., muscle wasting).38 Patients may therefore benefit from routine screenings with a knowledgeable provider or a multidisciplinary team postresection may improve identification of nutritional and vitamin deficiencies and raise patient awareness. Despite the lack of nutritional testing preoperatively, the present study provides unique insight into patient perceptions and the prevalence of malnutrition after resection. Other symptoms that patients may experience after pancreaticoduodenectomy for benign or malignant lesions are gastroesophageal reflux disease and peptic ulcer disease. These processes are related to functional changes in the duodenum and pancreas.39 To minimize symptoms and complications related to these processes, it is our practice to discharge all pancreaticoduodenectomy patients on proton-pump inhibitors postoperatively. In addition to examining QOL, our study assessed longterm pancreatic exocrine and endocrine insufficiency in the only US study to focus solely on pancreatectomy for cystic lesions. Fong et al.7 previously assessed 119 patients postpancreatoduodenectomy (for cystic or malignant lesions) for exocrine and endocrine insufficiency and found an incidence rate of 50% and 11% at a median follow-up of 9.1 y, respectively. Falconi et al.12 similarly assessed exocrine and endocrine insufficiency among Italian patients undergoing resection for benign disease with a 33% and 18% incidence at 5 y. Insufficiency in this study was determined by abnormal 72-h fecal chymotrypsin and oral glucose tolerance tests. Fujii et al.40 reported that 47% and 9% of Japanese patients developed exocrine insufficiency or NODM following pylorus preserving pancreatoduodenectomy in 55 patients after a median follow-up of 42.5 mo.40 In a more recent study, Roeyen et al.10 examined 78 patients undergoing pancreatoduodenectomy for oncologic indication and reported an incidence of 20% and 40%, respectively. Although each study has merits, the conflicting incidences likely arise from variable diagnostic testing and indications for surgery. Discordant from the previous studies, we report only 8% of patients were taking enzymes, which likely reflects the prohibitive cost. Although a minority reported requiring supplementation, more than half of patients described symptoms indicating exocrine insufficiency.
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The 29% incidence of new-onset diabetes within our study remains consistent with the literature; however, owing to limited sample size, we were not able to demonstrate a difference in the incidence of diabetes after pancreatoduodenectomy compared with distal pancreatectomy. This rate of new-onset diabetes should be an important consideration for surgeons before resection of benign cystic lesions who are weighing risk of malignant potential of lesions versus complications from pancreatectomy. Despite the strengths, this study must be interpreted in the context of several limitations. It is retrospective in nature and can be subject to recall bias. Sample size was small and was limited by patient participation and validity of contact information. The study yielded a lower than expected overall response rate. However, the impact of this is unclear as 32 patients were lost to follow-up because of invalid or outdated contact information. Over 70% (51/70) of patients with valid contact information were successfully contacted and consented to participate in the study. In addition, long-term outcomes data were obtained through telephone interviews to increase participation but may limit patient disclosure of sensitive subject matter. Data support the possibility of patients underreporting symptom severity when contacted for follow-up directly by a provider as opposed to automated or anonymous Web-based survey administration.41,42 Preoperative questionnaires were not performed, which limited the ability to draw conclusions about changes in patient perceptions over time. Although this study provides valuable data on patients’ perceived long-term QOL and functional outcomes specifically for the resection of benign cystic lesions, this study does not have a control group to compare QOL and pancreas function between patients with cystic lesions who undergo resection compared with those who pursue surveillance. A limitation of our database is that only patients who undergo resection are considered. This limitation highlights an area where further research is required as the natural history of cystic neoplasms with regard to their effect on QOL/pancreas function has not been evaluated. The study was strengthened by the utilization of multiple validated assessment tools including the SGA and FACT-Hep. Acknowledging these limitations, this study provides a comprehensive and patient-centered evaluation of short- and long-term outcomes after pancreatectomy specifically for pancreatic cysts and provides important data to clinicians in preoperative counseling as well as postoperative monitoring.
Conclusion Short-term morbidity of pancreatic resection, especially pancreatoduodenectomy, is greater for patients undergoing resection of pancreatic cysts than it is for patients undergoing resection for cancer. In addition, a significant portion of these patients will experience long-term complications including diabetes, exocrine insufficiency, and malnutrition. Regular long-term follow-up and screening for pancreas insufficiency after pancreatectomy is required to ensure appropriate diagnosis and treatment. In addition to the assessment of malignant transformation, these data should be an integral part of
the preoperative discussion and analysis of the risk-benefit ratio of pancreas resection versus continued observation of cystic neoplasms.
Acknowledgment No funding received. LSB was supported by NIH/NHLBI T32 HL139425. The funding body played no part in the design and/ or conduct of this study, had no access to the data or a role in data collection, management, analysis, or interpretation, and had no role in preparation, review, or approval of the manuscript. This study (protocol H-35341) was approved by the Institutional Review Board at the Baylor College of Medicine. Informed consent was obtained from patients who served as subjects of investigation. All investigators involved in this study ensured HIPPA compliance. Authors’ contributions: All authors substantially contributed to the conception and design of the study. K.P.S., G.V.B., N.V.F., A.M., J.E.M., and W.E.F. acquired, analyzed, and interpreted the data. L.S.B. and S.M. analyzed and interpreted the data. K.P.S., K.A.B., and N.V.F. drafted the initial manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version of the manuscript for submission.
Disclosure No conflicts of interest. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
references
1. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. Am J Roentgenol. 2008;191:802e807. 2. Winter JM, Cameron JL, Lillemoe KD, et al. Periampullary and pancreatic incidentaloma. Ann Surg. 2006;243:673e683. 3. Lahat G, Lubezky N, Haim MB, et al. Cystic tumors of the pancreas: high malignant potential. Isr Med Assoc J. 2011;13:284e289. 4. Hoffman RL, Gates JL, Kochman ML, et al. Analysis of cyst size and tumor markers in the management of pancreatic cysts: support for the original sendai criteria. J Am Coll Surg. 2015;220:1087e1095. 5. Sighinolfi M, Quan SY, Lee Y, et al. Fukuoka and AGA criteria have superior diagnostic accuracy for advanced cystic neoplasms than sendai criteria. Dig Dis Sci. 2017;62:626e632. 6. Cloyd JM, Tran Cao HS, Petzel MQB, et al. Impact of pancreatectomy on long-term patient-reported symptoms and quality of life in recurrence-free survivors of pancreatic and periampullary neoplasms. J Surg Oncol. 2017;115:144e150. 7. Fong ZV, Alvino DM, Castillo CFD, et al. Health-related quality of life and functional outcomes in 5-year survivors after pancreaticoduodenectomy. Ann Surg. 2017;266:685e692. 8. Witkowski ER, Smith JK, Tseng JF. Outcomes following resection of pancreatic cancer. J Surg Oncol. 2013;107:97e103. 9. Murakawa M, Aoyama T, Asari M, et al. The short- and longterm outcomes of radical antegrade modular
shah et al long-term outcomes after pancreatectomy
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas. BMC Surg. 2015;15:120. Roeyen G, Jansen M, Hartman V, et al. The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: a prospective cohort study based on preand postoperative function tests. Pancreatology. 2017;17:974e982. Beger HG, Poch B, Mayer B, Siech M. New onset of diabetes and pancreatic exocrine insufficiency after pancreaticoduodenectomy for benign and malignant tumors: a systematic review and meta-analysis of long-term results. Ann Surg. 2018;267:259e270. Falconi M, Mantovani W, Crippa S, Mascetta G, Salvia R, Pederzoli P. Pancreatic insufficiency after different resections for benign tumours. Br J Surg. 2008;95:85e91. Van Der Gaag NA, Berkhemer OA, Sprangers MA, et al. Quality of life and functional outcome after resection of pancreatic cystic neoplasm. Pancreas. 2014;43:755e761. Strasberg SM, Linehan DC, Hawkins WG. The accordion severity grading system of surgical complications. Ann Surg. 2009;250:177e186. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138:8e13. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2007;142:761e768. Moskovic DJ, Hodges SE, Wu MF, Brunicardi FC, Hilsenbeck SG, Fisher WE. Drain data to predict clinically relevant pancreatic fistula. HPB. 2010;12:472e481. Tanaka M, Ferna´ndez-Del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183e197. Tanaka M, Ferna´ndez-del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17:738e753. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17e32. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery. 2017;161:584e591. Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer CM. A prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreatoduodenectomy. J Am Coll Surg. 2013;216:1e14. Miller BC, Christein JD, Behrman SW, et al. A multiinstitutional external validation of the fistula risk score for pancreatoduodenectomy. J Gastrointest Surg. 2014;18:172e179. Makhija S, Baker J. The subjective global assessment: a review of its use in clinical practice. Nutr Clin Pract. 2008;23:405e409. Heffernan N, Cella D, Webster K, et al. Measuring healthrelated quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol. 2002;20:2229e2239. National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. Available at: https://www.niaaa.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
9
nih.gov/publications/brochures-and-fact-sheets/alcoholfacts-and-statistics. Accessed August 1, 2019. Centers for Disease Control and Prevention. Alcohol and Public Health. https://www.cdc.gov/alcohol/fact-sheets.htm. Accessed August 1, 2019. Park JW, Jang JY, Kang MJ, Kwon W, Chang YR, Kim SW. Mucinous cystic neoplasm of the pancreas: is surgical resection recommended for all surgically fit patients? Pancreatology. 2014;14:131e136. de Castro SMM, Houwert JT, van der Gaag NA, Busch ORC, van Gulik TM, Gouma DJ. Evaluation of a selective management strategy of patients with primary cystic neoplasms of the pancreas. Int J Surg. 2011;9:655e658. Olson SH, Xu Y, Herzog K, et al. Weight loss, diabetes, fatigue, and depression preceding pancreatic cancer. Pancreas. 2016;45:986e991. Gilliland TM, Villafane-Ferriol N, Shah KP, et al. Nutritional and metabolic derangements in pancreatic cancer and pancreatic resection. Nutrients. 2017;9. Aleassa EM, Morris-Stiff G. Perioperative exocrine pancreatic insufficiency and pancreatic enzyme replacement therapy. J Pancreas. 2018;19:91e95. Heerkens HD, Tseng DSJ, Lips IM, et al. Health-related quality of life after pancreatic resection for malignancy. Br J Surg. 2016;103:257e266. Shabanzadeh DM, Sørensen LT. Alcohol consumption increases post-operative infection but not mortality: a systematic review and meta-analysis. Surg Infect (Larchmt). 2015;16:657e668. Eliasen M, Grønkjær M, Skov-Ettrup LS, et al. Preoperative alcohol consumption and postoperative complications: a systematic review and meta-analysis. Ann Surg. 2013;258:930e942. Center for Behavioral Health Statistics and Quality. 2015 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental. Rockville, MD: Health Services Administration; 2016. Huang JJ, Yeo CJ, Sohn TA, et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann Surg. 2000;231:890e898. Gianotti L, Besselink MG, Sandini M, et al. Nutritional support and therapy in pancreatic surgery: a position paper of the International Study Group on Pancreatic Surgery (ISGPS). Surgery. 2018;164:1035e1048. Tran TC, van Lanschot JJ, Bruno MJ, van Ejick CH. Functional changes after pancreatoduodenectomy: diagnosis and treatment. Pancreatology. 2009;9:729e737. Fujii T, Kanda M, Kodera Y, et al. Comparison of pancreatic head resection with segmental duodenectomy and pyloruspreserving pancreatoduodenectomy for benign and lowgrade malignant neoplasms of the pancreatic head. Pancreas. 2011;40:1258e1263. Milton AC, Ellis LA, Davenport TA, Burns JM, Hickie IB. Comparison of self-reported telephone interviewing and web-based survey responses: findings from the second Australian young and well national survey. JMIR Ment Heal. 2017;4:e37. Sikorskii A, Given CW, Given B, Jeon S, You M. Differential symptom reporting by mode of administration of the assessment: automated voice response system versus a live telephone interview. Med Care. 2009;47:866e874.
Available online at www.sciencedirect.com
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Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms Kevin P. Shah, MD, Katherine A. Baugh, MD, Lisa S. Brubaker, MD, George Van Buren II, MD, Nicole Villafane-Ferriol, MD, Amy L. McElhany, MPH, Sadde Mohamed, Eric J. Silberfein, MD, Cary Hsu, MD, Nader N. Massarweh, MD, Hop S. Tran Cao, MD, Jose E. Mendez-Reyes, MD, and William E. Fisher, MD* Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
article info
abstract
Article history:
Background: With advances in cross-sectional imaging, pancreatic cysts are more
Received 24 May 2019
frequently diagnosed and have become a common indication for pancreatectomy. The
Received in revised form
impact of pancreatectomy in these patients is important. The purpose of this study was to
20 August 2019
assess short-term outcomes, long-term nutritional status, quality of life (QOL), and
Accepted 19 September 2019
pancreas function after pancreatectomy for cystic neoplasms.
Available online xxx
Materials and methods: At a single institution, patients at least 3 y post-pancreatectomy for benign cystic neoplasms were identified. Using a validated questionnaire, short-term
Keywords:
outcomes, long-term outcomes including endocrine and exocrine insufficiency, long-
Pancreatic resection
term nutritional status, and preoperative and postoperative QOL were compared based
Long-term functional outcomes
on operation and indication for resection.
Exocrine and endocrine
Results: Among 102 eligible patients, 70 had valid contact information and 51 (72.9%) agreed
insufficiency Quality of life Benign pancreatic cystic lesions
to participate. Median follow-up was 6 (4-8) y. Patients undergoing pancreatoduodenectomy for benign cysts had higher morbidity than a similar cohort resected for pancreatic adenocarcinoma (patients with at least 1 grade 2 complication [49.0% versus 31.6%, P ¼ 0.038]). After long-term follow-up, pancreatectomy did not significantly affect perceived QOL. Half of patients had mild-moderate or severe malnourishment, but pancreatic enzyme replacement was reported by only 4 (7.8%) patients. New-onset diabetes was present in 15 (29.4%) patients with median time-to-diagnosis of 6 (1-12) mo after resection. Conclusions: Pancreatectomy for benign cysts did not negatively impact patients’ perceived QOL. However, after long-term follow-up, malnutrition and pancreatic insufficiency occurred in a significant percentage and may be greater than previously estimated. Consideration of short- and long-term outcomes should factor into preoperative counseling, especially in cysts with minimal risk of progression to malignancy. ª 2019 Published by Elsevier Inc.
Presentation: Presented at the 2017 Clinical Congress in San Diego, California. * Corresponding author. Division of General Surgery, Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, 6620 Main Street, Suite 1425, Houston, TX 77030. Tel.: þ1 713 798 4321; fax: þ1 713 610 2489. E-mail address: [email protected] (W.E. Fisher). 0022-4804/$ e see front matter ª 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.jss.2019.09.045
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Introduction Pancreatic cysts are increasingly becoming a common imaging finding with a prevalence of 2% in the general population.1 This estimate is likely conservative because of the widespread use and advancement of cross-sectional imaging. The majority of incidentally found cystic lesions are benign and require no further medical intervention.2,3 However, preoperative characterization and prediction of the behavior of these lesions remain challenging as cystic lesions can vary widely in their risk of malignant transformation. Owing to the aggressive nature of pancreatic ductal adenocarcinoma (PDAC) even at an early stage, pancreas surgeons are highly motivated to avoid allowing a pancreas cyst to progress to invasive cancer while undergoing surveillance. Pancreatectomy remains the cornerstone of treatment for cystic lesions with multiple high-risk features including solid component, dilated main pancreatic duct, and concerning features on endoscopic ultrasound with fine needle aspiration.4,5 Patient-centered outcomes, such as quality of life (QOL), are an important factor to consider after pancreatectomy. Prior studies examining long-term outcomes such as overall survival and QOL in pancreatectomy patients had been conducted but focused largely on PDAC survivors.6-11 Historically, pancreatectomy was reserved for malignant pathology, but lesions are now identified much earlier in the spectrum of disease. Patients, benefitting from detection of premalignant pathology, are now living longer after surgery, and the understanding of long-term outcomes including QOL, malnutrition, exocrine, and endocrine insufficiency are becoming increasingly relevant. Only a few studies have examined longterm outcomes in patients undergoing resection for benign cystic lesions, but all have been centered on European populations.12,13 The generalizability of these studies to the United States is consequently limited because of the inherent differences in patient populations and access to nationalized health care. Examination of patient outcomes after resection for benign disease in the United States is needed to direct preoperative decision-making and patient counseling. Therefore, the objectives of this study were to evaluate the short-term morbidity of pancreatectomy for cystic neoplasms in comparison with pancreatectomy for pancreatic adenocarcinoma (PDAC) and to determine long-term pancreatic function after pancreatoduodenectomy and distal pancreatectomy for pancreatic cysts. We hypothesized that shortterm morbidity would be higher in patients with lesions undergoing resection for cystic neoplasms due to the presence of a soft gland and a nondilated duct and that long-term pancreatic function, nutrition, and QOL would be affected.
Materials and methods Data source We analyzed data from a prospectively maintained Pancreas Surgery Registry in a high-volume academic pancreas center to identify patients undergoing pancreatectomy for cystic neoplasms. The database stores information including
baseline demographics, comorbidities, perioperative characteristics, and graded complications within 60 d of surgery using the Accordion Severity Grading for Surgical Complications14 and the International Study Group of Pancreatic Fistula and International Study Group of Pancreatic Surgery definitions15,16 for pancreatic fistula and delayed gastric emptying. A detailed definition of complications has been previously reported.17
Study cohort We identified patients undergoing pancreatoduodenectomy and distal pancreatectomy at a single institution between January 2005 and January 2014. All patients with benign cystic neoplasms on final pathology were included, and cystic neoplasms with malignant features were excluded, including pancreatic adenocarcinoma, cholangiocarcinoma, ampullary carcinoma, duodenal adenomas, and tumors metastatic to the pancreas. Cystic lesions in the setting of neuroendocrine tumors and chronic pancreatitis were also excluded. Patients meeting inclusion criteria were contacted and consented via telephone. Permission for this study was obtained from an institutional review board (H-35341). Surgeons in this study followed the consensus set forth by the International Association of Pancreatology, including the Sendai and Fukuoka guidelines for management of cystic neoplasms of the pancreas.18-20
Short-term outcomes All patients who underwent pancreatectomy for benign cysts were compared with a cohort of all patients who underwent pancreatectomy for PDAC within the same time period. Shortterm outcomes were identified using the database and a comprehensive chart review when applicable. Outcomes included all complications within 60 d, length of stay, and overall mortality within 90 d.21 Short-term complications were graded using the Accordion Severity Grading for Surgical Complications.14 The Pancreatic Fistula Risk Score was calculated using an online medical calculator.22,23
Long-term outcomes and survey Long-term outcomes were examined in patients who were resected for benign cysts. Patients who underwent resection for PDAC were excluded because of concerns regarding longterm survival and confounding variables such as adjuvant therapy affecting QOL. Data on long-term outcomes were obtained through a telephone survey evaluating four sections of interest: (1) QOL, (2) nutritional status, (3) pancreatic endocrine, and (4) exocrine function. The survey comprised validated questions from the Subjective Global Assessment (SGA)24 and the Functional Assessment of Cancer Therapy (FACT-Hep)25 questionnaires. Questions about body mass index (BMI), gastrointestinal symptoms (nausea, vomiting, diarrhea, pain on eating), dietary intake, weight loss (recent or long term), and day-to-day functional capacity (ability to perform activities of daily living) were derived from the SGA questionnaire.24 The FACT-Hep questionnaire provided
shah et al long-term outcomes after pancreatectomy
3
validated questions concerning the following subcategories to assess QOL: physical well-being, social well-being, emotional well-being, functional well-being, and hepatobiliary-specific subscale. The remaining variables including alcohol and tobacco intake, hospitalizations, and symptoms of exocrine and endocrine insufficiency were developed by the authors for this study. The Centers for Disease Control and Prevention and National Institute of Health’s definition of heavy drinking (15 drinks weekly or 5 or more on occasion for men and 8 drinks weekly or 4 or more on occasion for women) was used to report clinically significant alcohol intake.26,27 Data from the questionnaire, including long-term nutritional status and incidence of pancreatic endocrine and exocrine insufficiency, was compared between pancreatoduodenectomy and distal pancreatectomy patients. Fig. 1 e Flow diagram of patient selection.
Statistical analysis Chi-square, Fisher’s exact, or McNemar’s test, when appropriate, was used to analyze categorical variables. The Student’s t-test or Mann-Whitney test was used to evaluate continuous variables. All statistical analyses were performed using SPSS v25 (IBM Corp., Armonk, NY). Median values are reported with interquartile range in the following format: median (interquartile range).
Results Cohort characteristics We identified 115 total patients who underwent pancreatectomy (either pancreatoduodenectomy or distal pancreatectomy) for benign cystic neoplasms. Thirteen patients were excluded only from long-term analysis because of death before contact date (10), advanced Alzheimer’s disease (1), severe hearing loss (1), or completion of total pancreatectomy after initial pancreatoduodenectomy (1). This cohort was compared with a cohort of 131 patients who underwent pancreatectomy for PDAC (for short-term outcomes). Age was lower in the cohort of patients undergoing surgery for a cyst (61.45 versus 66.23, P ¼ 0.00199). Gender distribution was also significant (cyst: male 30.4%; PDAC: male 50.8%; P ¼ 0.00125). The Charlson-Deyo comorbidity score was not significantly different between the cohorts (0.62 versus 0.64, P ¼ 0.823). Only 8% of the cohort of patients undergoing pancreatectomy for PDAC received neoadjuvant radiation therapy. The median pancreatic duct size of patients who underwent pancreatoduodenectomy for cystic lesions was 3.0 (2.0-5.0) mm. The median pancreatic duct size for patients who underwent pancreatoduodenectomy for PDAC was 5.0 (4.0-6.0) mm. Of the 102 eligible participants, 70 had valid contact information and 51 completed the survey for a response rate of 72.9% (Fig. 1). Median age at the time of survey was 68 (63-77) y. General nutritional findings and medical history of participants are summarized in Table 1. Median follow-up was 6 (4-8) y after pancreatectomy. The most common diagnoses for distal pancreatectomy patients were intraductal papillary mucinous neoplasm (IPMN) (20%), mucinous cystic neoplasm (33%), and serous cystadenomas (20%). The most common
pathology for pancreatoduodenectomy patients was IPMN (71%) followed by serous cystadenoma (24%). Only 3 of 51 (5.8%) patients, each with IPMN, had high-grade dysplasia on final pathology.
Short-term outcomes Short-term 60-d outcomes between the 115 patients who underwent pancreatectomy for benign cystic were compared with the 131 patients who underwent pancreatectomy for an indication of PDAC during the same time period (shown in Table 2 stratified by pancreatoduodenectomy and distal pancreatectomy). Complications (grade 2) for patients undergoing pancreatoduodenectomy for cystic lesions were significantly greater than those undergoing pancreaticoduodenectomy for cancer [49.0% versus 31.6%, P ¼ 0.038]). There was an increased frequency of all and clinically relevant pancreatic fistulas (P < 0.001; P < 0.001) and intra-abdominal abscesses (P ¼ 0.027). As expected, the Fistula Risk Score was significantly higher in the cohort undergoing pancreatoduodenectomy for cystic lesions than that for PDAC (4.64 versus 1.67, P < 0.001).22,23 The increase in complications did not translate to significant differences in length of stay or 90-d mortality (P ¼ 0.079; P ¼ 1). Complications, such as pancreatic fistula, wound infections, and intra-abdominal abscesses, in those undergoing distal pancreatectomy were not significant between patients undergoing resection for cystic neoplasms or cancer.
Long-term patient-reported outcomes Preoperatively, the majority of patients (58.8%) perceived a “high risk” of malignant transformation of their lesion with 43.1% identifying malignant potential as the primary reason for deciding to undergo resection (versus symptomatic relief, or both symptomatic relief and malignant potential of lesion). Postoperatively, the majority of patients (62.7%) perceived “low risk” of pancreatic malignancy in the future. At followup, 19 patients (37.3%) reported regular continued surveillance imaging. Ninety percentage of patients believed they had no nutritional problems, with the remaining 10%
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Table 1 e Nutritional and medical history of survey participants. n ¼ 51 Age at follow-up survey
n (%) or median (interquartile range) 68 (63-77)
Body mass index at surgery
27.8 (25.0-31.8)
Body mass index at follow-up
26.7 (23.3-29.6)
Weight loss in last 6 mo
15 (29%)
Long-term QOL
Time from operation until follow-up 3-4 y
18 (35%)
5-6 y
11 (22%)
7-8 y
13 (25%)
9-10 y
7 (14%)
11-12 y
2 (4%)
Dietary intake Normal intake
37 (73%)
Reduced intake
12 (24%)
Semisolid or liquid diet Very poor intake or starvation
0 1 (2%)
Gastrointestinal symptoms last 2 wk Pain on eating
10 (20%)
Nausea
11 (22%)
Vomiting
1 (2%)
Diarrhea
13 (26%)
Functional capacity Normal Reduced capacity Unable to work Ambulatory Alcohol abuse Current tobacco use
41 (80%) 6 (12%) 0 3 (6%) 15 (29%) 2 (4%)
At least 150 min exercise per week
30 (59%)
Hospitalized in last 2 y
21 (41%)
Enzyme replacement
4 (8%)
Proton pump inhibitor
18 (35%)
Nutritional supplement
3 (6%)
New-onset diabetes since surgery
15 (29%)
Do you see yourself having nutritional problems? Major malnutrition Moderate malnutrition No nutritional problems
0 5 (10%) 46 (90%)
Health status compared with others of same age? Not as good Don’t know
whereas 8 patients (15.7%) considered their health status to be worse than other people of the same age. Among the cohort, 43 (84.3%) patients cited the risk of malignancy as the reason they chose to undergo surgery with the remainder citing symptom management. Thirty-nine patients (76.5%) reported a moderate-to-high risk of cancer before surgery, whereas 32 (62.7%) perceived a negligible-tolow risk of malignancy after cyst resection (P 0.001).
8 (16%) 3 (6%)
As good
12 (24%)
Better
28 (55%)
believing they had a moderate level of malnutrition. No patient believed they had a severe level of malnutrition. In terms of perceived health status, 40 patients (78.4%) considered it to be as good as or better than other people of the same age,
Thirteen patients had both preoperative and postoperative QOL data available. Mean FACT-Hep QOL scores in these patients increased by 9.81 points after pancreatectomy (95% CI 9.45 to 29.07, P ¼ 0.29). A complete FACT-Hep was obtained from all patients after pancreatectomy. The overall median score for these patients was 160 (138-167.42) of 180 total points. Table 3 shows a comparison between preoperative and postoperative QOL. There was no difference in the QOL scores between subjects who had distal pancreatectomy (158.42 [139.75-164]) or pancreatoduodenectomy (162.67 [137-172]). Table 4 shows an in-depth analysis of the FACT-Hep QOL scores comparing patients who underwent pancreatoduodenectomy and distal pancreatectomy.
Long-term nutritional status When assessing long-term nutritional status with the SGA questionnaire, twenty-seven (52.9%) patients were well nourished (SGA A Rating) and 23 (45.1%) had mild-moderate malnourishment (SGA B rating). Only one (2.0%) patient was severely malnourished (SGA C rating). Fifteen (29.4%) patients reported an average of 7.5 pounds of weight loss in the 6 mo before follow-up. However, average weight loss at follow-up was found to be 9.7 pounds and was significantly decreased from the time of surgery (P < 0.001).
Long-term exocrine and endocrine pancreatic function Both exocrine and endocrine pancreatic functional outcomes after pancreatectomy for benign cystic neoplasms were assessed (Table 5). Four patients (7.8%) reported no evidence of subjective decline in exocrine pancreas function. However, 28 patients (55.0%) reported steatorrhea and 25 patients experienced early satiety. One-fourth of patients had abnormal stool color, bloating after meals, a decrease in number of daily meals postoperatively, or loss of appetite. Despite at least half of patients being symptomatic, only 4 patients were taking pancreatic enzyme replacement (7.8%); 3 of which underwent a pancreatoduodenectomy. Additional patient-reported outcomes are reported in Figure 2. At long-term follow-up, 21 (41.2%) patients reported a diagnosis of diabetes, fifteen of which had new-onset diabetes mellitus (NODM) postoperatively (29.4%). There was no significant difference in NODM between pancreaticoduodenectomy and distal pancreatectomy patients (28.6% versus 30.0%, P ¼ 0.91). Median time at diagnosis of diabetes was 6 (1.25-12) mo after resection. Of those with NODM, 13 patients (86.67%) developed diabetes within 1 y of pancreatectomy. Insulin was required for glycemic control by 9 patients
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Table 2 e Comparison of short-term (60-d) complications. All procedures Cyst (n ¼ 115)
PDAC (n ¼ 131)
Any grade 2 complication
43 (37%)
38 (29 %)
Postoperative pancreatic fistula
40 (35%)
18 (14%)
Clinically relevant postoperative pancreatic fistula
17 (15%)
Intra-abdominal abscess
Pancreatoduodenectomy P-value
Cyst (n ¼ 51)
PDAC (n ¼ 98)
P-value
Cyst (n ¼ 64)
PDAC (n ¼ 33)
P-value
0.163
25 (49%)
31 (32%)
0.038
18 (28%)
7 (21%)
0.461
<0.001
24 (47%)
11 (11%)
<0.001
16 (25%)
7 (21%)
0.678
6 (5%)
0.006
11 (22%)
2 (2%)
<0.001
6 (9%)
4 (12%)
0.731
4 (6%)
1 (3%)
0.659
13 (11%)
7 (5%)
0.088
9 (18%)
6 (6%)
0.027
Abdominal fluid collection
9 (8%)
14 (11%)
0.431
2 (4%)
12 (12%)
0.140
Wound infection
8 (7%)
6 (5%)
0.422
2 (4%)
6 (6%)
0.716
Delayed gastric emptying
Distal pancreatectomy
7(11%)
2 (6%)
0.713
6 (9%)
0
0.092 0.369
19 (17%)
26 (20%)
0.501
10 (20%)
19 (19%)
0.974
9 (14%)
7 (21%)
Gastrointestinal hemorrhage
2 (1.7%)
1 (0.8%)
0.600
2 (4%)
1 (1%)
0.270
0 (0%)
0 (0%)
Length of stay, median (IQR)
7 (6-8)
7 (6-8)
0.345
7 (7-8.5)
7 (6-9)
0.1078
6 (5-8)
6(5-8)
0.518
90-d mortality
1 (0.9%)
3 (2.3%)
0.625
1 (2%)
3 (3%)
1.000
0 (0%)
0 (0%)
1.0
1.0
Bold ¼ P < 0.05 Chi-square, Fisher’s exact, or McNemar’s test for categorical variables, Student’s t-test or Mann-Whitney test for continuous variables.
(60%), but no significant difference in incidence occurred between distal pancreatectomy and pancreatoduodenectomy (P ¼ 0.136).
Discussion An understanding of the true short- and long-term morbidity of pancreatectomy is necessary to determine the risk-benefit ratio that is vital to preoperative counseling.28,29 Of great importance to patient counseling is an understanding of patient-centered outcomes. However, studies examining patient outcomes after resection for cystic neoplasms centered on European populations.12,13 Therefore, we sought to assess the short- and long-term risks of pancreatectomy for benign cystic neoplasms of the pancreas and patient perceived QOL in the American population. With regard to short-term outcomes, our study revealed that compared with patients undergoing resection for cancer, perioperative complications are
greater in patients undergoing pancreaticoduodenectomy for cystic lesions. After long-term (6 y) follow-up, our study, which is the only study to analyze long-term outcomes after distal pancreatectomy or pancreatoduodenectomy for benign cystic lesions in a US population, revealed that half of patients exhibited symptoms of malnourishment and a third of patients developed diabetes postoperatively. We intentionally excluded patients with PDAC and chronic pancreatitis from our long-term outcome survey as the physiology of these diseases confounds our analysis of the effect of pancreatectomy on long-term nutritional status, QOL, and pancreas function. Compared with patients undergoing pancreatectomy for cystic neoplasms, patients undergoing pancreatectomy for PDAC have a higher preoperative incidence of recent weight loss and new-onset diabetes.30 The presence of these conditions preoperatively impacts the prevalence of these conditions in the immediate and long-term postoperative periods.31 Preoperative exocrine pancreatic insufficiency is also more common in patients with malignancy and chronic
Table 3 e Comparison of preoperative and postoperative QOL scores. FACT scale/Subscale
Preoperative median (IQR) QOL score (n ¼ 13)
Postoperative median (IQR) QOL score (n ¼ 13)
P-value
Physical well-being (0-28)
27 (26-28)
26 (24-27)
0.30
Social well-being (0-28)
24 (22-28)
26 (25-28)
0.49
Emotional well-being (0-28)
20 (18-22)
23 (22-24)
0.21
27 (24-28)
0.63
Functional well-being (0-28)
27 (22-28)
Hepatobiliary cancer subscale (0-72)
57 (48-64)
60.5 (56.75-67.25)
0.29
FACT-general (0-108)
96 (88-99)
102 (90-105)
0.59
112 (100-121)
0.34
163 (154.5-172.25)
0.29
Trial outcome index (0-128) FACT-Hep total (0-180)
104 (96-119.25) 148.63 (137.5-162.75)
FACT ¼ functional assessment of cancer therapy, IQR ¼ interquartile range, QOL ¼ quality of life.
6
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e9
Table 4 e Comparison of pancreatoduodenectomy and distal pancreatectomy QOL scores. FACT scale/Subscale (n ¼ 50)
Overall median (IQR) QOL score
Physical well-being (0-28) Social well-being (0-28)
Pancreatoduodenectomy median (IQR) QOL score
26 (19.5-27.5) 25.67 (22-28)
26 (19-28) 25.67 (24-28)
Distal pancreatectomy median (IQR) QOL score 25.5 (22-27)
P-value 0.57
25.83 (20.13-28)
0.90
Emotional well-being (0-28)
22 (17.5-24)
22 (16-24)
22 (18-24)
0.77
Functional well-being (0-28)
26 (21-28)
26 (24-28)
26 (18.5-27)
0.30
Hepatobiliary cancer subscale (0-72)
61 (56-66)
62 (57-68)
59.5 (56-64.5)
0.37
FACT-general (0-108)
97.83 (80-103.83)
97.92 (81-102.75)
0.80
Trial outcome index (0-128)
111 (98-118)
FACT-Hep total (0-180)
160 (138-167.42)
97.67 (80-104) 113 (98-124) 162.67 (137-172)
pancreatitisda population excluded from our analysisdsecondary to the fibrosis of the pancreatic ducts and the fibrotic replacement of the parenchyma, respectively.32 In addition to the physiologic differences between patients undergoing pancreatectomy for cystic neoplasms and those undergoing pancreatectomy for cancer, another variable that significantly affects the long-term QOL in PDAC patients is the receipt of adjuvant therapy. Short-term morbidity of pancreatic resection, especially pancreatoduodenectomy, is greater for patients undergoing resection of pancreatic cysts than it is for patients undergoing resection for cancer. Van der Gaag et al.13 assessed long-term outcomes in patients resected for cystic neoplasms (n ¼ 65)
110 (98.5-116.92)
0.56
158.42 (139.75-164)
0.61
with a reported complication rate of 20%; however, the classification system and time frame after surgery were not provided. In contrast, Falconi et al.12 demonstrated a 52% complication rate using the Dindo-Clavien classification in their cross-sectional study of patients resected for benign tumors. Heerkens et al.33 similarly reported a 39% incidence of severe complications in their study examining QOL after resection for malignancy. In the present study, the complication rate of 49% in patients who underwent pancreatoduodenectomy for benign disease is consistent with the literature. Although there is significant variability in complication occurrence, this likely represents the variation in indication for surgery with an increased risk of complications
Table 5 e Comparison between pancreatoduodenectomy and distal pancreatectomy patients. Pancreatoduodenectomy (n ¼ 21)
Distal pancreatectomy (n ¼ 30)
P-value
13 (62%)
23 (77%)
0.255
68 (62-77)
68.5 (64.25-73.75)
Gender Female Age* Pathology IPMNy
15 (71%)
6 (20%)
MCN
1 (5%)
10 (33%)
Serous cystadenoma
5 (24%)
6 (20%)
Cystadenoma NOS
0
2 (8%)
Lymphoepithelial cyst
0
2 (7%)
Pseudocyst
0
4 (13%)
1 (5%)
0
Well-nourished (SGA A)
12 (57%)
15 (50%)
Mild-moderately malnourished (SGA B)
9 (43%)
14 (46.7%)
Pseudopapillary tumor
0.4 0.005
SGA
0.0651
Severely malnourished (SGA C)
0 (0%)
1 (3%)
Pancreatic enzyme replacementz
3 (14%)
1 (4%)
0.08
New-onset diabetes
6 (29%)
9 (30%)
0.3
*
Mann-Whitney U test. y 1 patient had moderate to severe dysplasia, and 2 patients had focal high grade dysplasia. The remainder of patients had no, low, or moderate dysplasia. z Fisher’s exact test.
shah et al long-term outcomes after pancreatectomy
Fig. 2 e Pancreatic functional outcomes (exocrine). (Color version of figure is available online.)
in benign resections due to the well-established risk factors for postoperative pancreatic fistula of small duct and soft pancreas relative to resection for PDAC in which a more firm pancreas with a larger duct would be less prone to short-term morbidities. These risk factors are a major component of the Pancreatic Fistula Risk Score; a prospectively validated score that accurately predicts clinically relevant postoperative pancreatic fistula based on intraoperative findings.22,23 Of note, short-term morbidity was greater in patients undergoing pancreaticoduodenectomy but decision to resect should be based on current consensus guidelines as well as a careful and detailed discussion with the patient about risks and benefits of an operation. Although it is generally known that misuse of alcohol can put patients at risk for surgical complications, the 29% incidence of alcohol abuse in the cohort of patients who underwent pancreas resection for benign cystic lesions corresponds to the statistic put forth by the Substance Abuse and Mental Health Services Administration in which 26.9% of adults nationally had engaged in binge drinking in 2015.34-36 This consistency between our own study’s investigation and national agency estimates suggest that the short-term morbidities highlighted in our results are not primarily or in great part due to alcohol abuse. Our findings expand upon the existing literature in terms of QOL after pancreas resection. In a recent cross-sectional study by Massachusetts General Hospital, Fong et al.7 examined QOL of 305 patients who underwent pancreatoduodenectomy for benign or malignant lesions. Median follow-up was 9.1 y with a higher QOL noted when compared with sex- and age-adjusted healthy individuals. No difference was noted when accounting for resection due to benign versus malignant pathology. However, the study only encompasses patients who underwent pancreatoduodenectomy and does not include preoperative baseline testing. Huang et al.37 also compared QOL in post-pancreatoduodenectomy patients (n ¼ 192) to a cohort of healthy laparoscopic cholecystectomy patients (n ¼ 31) and discovered no difference. In a comparative study, Van der Gaag et al.13 examined QOL after resection for benign cystic neoplasms (n ¼ 65) and found no difference
7
in physical or mental QOL scores when compared with healthy references. However, this study encompasses patients cared for under nationalized health care and is, therefore, limited in terms of generalizability to the US due to the fundamental differences between the health care systems and patient populations. The present study provides the only focused examination of perceived QOL in a US population undergoing distal pancreatectomy or pancreaticoduodenectomy for benign disease. An important long-term concern in patients after pancreatic resection is nutritional status. Frequently, postoperative nutritional status returns to preoperative levels with dietary counseling. However, long-term information on nutritional status is less well characterized as the majority of studies examine preoperative nutritional status.31 Postoperative nutritional assessments usually center on weight loss, changes in BMI, and exocrine insufficiency. However, weight loss and BMI do not provide an accurate assessment. BMI does not account for tissue types (fat and muscle) and the change in composition that occurs over time (i.e., muscle wasting).38 Patients may therefore benefit from routine screenings with a knowledgeable provider or a multidisciplinary team postresection may improve identification of nutritional and vitamin deficiencies and raise patient awareness. Despite the lack of nutritional testing preoperatively, the present study provides unique insight into patient perceptions and the prevalence of malnutrition after resection. Other symptoms that patients may experience after pancreaticoduodenectomy for benign or malignant lesions are gastroesophageal reflux disease and peptic ulcer disease. These processes are related to functional changes in the duodenum and pancreas.39 To minimize symptoms and complications related to these processes, it is our practice to discharge all pancreaticoduodenectomy patients on proton-pump inhibitors postoperatively. In addition to examining QOL, our study assessed longterm pancreatic exocrine and endocrine insufficiency in the only US study to focus solely on pancreatectomy for cystic lesions. Fong et al.7 previously assessed 119 patients postpancreatoduodenectomy (for cystic or malignant lesions) for exocrine and endocrine insufficiency and found an incidence rate of 50% and 11% at a median follow-up of 9.1 y, respectively. Falconi et al.12 similarly assessed exocrine and endocrine insufficiency among Italian patients undergoing resection for benign disease with a 33% and 18% incidence at 5 y. Insufficiency in this study was determined by abnormal 72-h fecal chymotrypsin and oral glucose tolerance tests. Fujii et al.40 reported that 47% and 9% of Japanese patients developed exocrine insufficiency or NODM following pylorus preserving pancreatoduodenectomy in 55 patients after a median follow-up of 42.5 mo.40 In a more recent study, Roeyen et al.10 examined 78 patients undergoing pancreatoduodenectomy for oncologic indication and reported an incidence of 20% and 40%, respectively. Although each study has merits, the conflicting incidences likely arise from variable diagnostic testing and indications for surgery. Discordant from the previous studies, we report only 8% of patients were taking enzymes, which likely reflects the prohibitive cost. Although a minority reported requiring supplementation, more than half of patients described symptoms indicating exocrine insufficiency.
8
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e9
The 29% incidence of new-onset diabetes within our study remains consistent with the literature; however, owing to limited sample size, we were not able to demonstrate a difference in the incidence of diabetes after pancreatoduodenectomy compared with distal pancreatectomy. This rate of new-onset diabetes should be an important consideration for surgeons before resection of benign cystic lesions who are weighing risk of malignant potential of lesions versus complications from pancreatectomy. Despite the strengths, this study must be interpreted in the context of several limitations. It is retrospective in nature and can be subject to recall bias. Sample size was small and was limited by patient participation and validity of contact information. The study yielded a lower than expected overall response rate. However, the impact of this is unclear as 32 patients were lost to follow-up because of invalid or outdated contact information. Over 70% (51/70) of patients with valid contact information were successfully contacted and consented to participate in the study. In addition, long-term outcomes data were obtained through telephone interviews to increase participation but may limit patient disclosure of sensitive subject matter. Data support the possibility of patients underreporting symptom severity when contacted for follow-up directly by a provider as opposed to automated or anonymous Web-based survey administration.41,42 Preoperative questionnaires were not performed, which limited the ability to draw conclusions about changes in patient perceptions over time. Although this study provides valuable data on patients’ perceived long-term QOL and functional outcomes specifically for the resection of benign cystic lesions, this study does not have a control group to compare QOL and pancreas function between patients with cystic lesions who undergo resection compared with those who pursue surveillance. A limitation of our database is that only patients who undergo resection are considered. This limitation highlights an area where further research is required as the natural history of cystic neoplasms with regard to their effect on QOL/pancreas function has not been evaluated. The study was strengthened by the utilization of multiple validated assessment tools including the SGA and FACT-Hep. Acknowledging these limitations, this study provides a comprehensive and patient-centered evaluation of short- and long-term outcomes after pancreatectomy specifically for pancreatic cysts and provides important data to clinicians in preoperative counseling as well as postoperative monitoring.
Conclusion Short-term morbidity of pancreatic resection, especially pancreatoduodenectomy, is greater for patients undergoing resection of pancreatic cysts than it is for patients undergoing resection for cancer. In addition, a significant portion of these patients will experience long-term complications including diabetes, exocrine insufficiency, and malnutrition. Regular long-term follow-up and screening for pancreas insufficiency after pancreatectomy is required to ensure appropriate diagnosis and treatment. In addition to the assessment of malignant transformation, these data should be an integral part of
the preoperative discussion and analysis of the risk-benefit ratio of pancreas resection versus continued observation of cystic neoplasms.
Acknowledgment No funding received. LSB was supported by NIH/NHLBI T32 HL139425. The funding body played no part in the design and/ or conduct of this study, had no access to the data or a role in data collection, management, analysis, or interpretation, and had no role in preparation, review, or approval of the manuscript. This study (protocol H-35341) was approved by the Institutional Review Board at the Baylor College of Medicine. Informed consent was obtained from patients who served as subjects of investigation. All investigators involved in this study ensured HIPPA compliance. Authors’ contributions: All authors substantially contributed to the conception and design of the study. K.P.S., G.V.B., N.V.F., A.M., J.E.M., and W.E.F. acquired, analyzed, and interpreted the data. L.S.B. and S.M. analyzed and interpreted the data. K.P.S., K.A.B., and N.V.F. drafted the initial manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version of the manuscript for submission.
Disclosure No conflicts of interest. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
references
1. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. Am J Roentgenol. 2008;191:802e807. 2. Winter JM, Cameron JL, Lillemoe KD, et al. Periampullary and pancreatic incidentaloma. Ann Surg. 2006;243:673e683. 3. Lahat G, Lubezky N, Haim MB, et al. Cystic tumors of the pancreas: high malignant potential. Isr Med Assoc J. 2011;13:284e289. 4. Hoffman RL, Gates JL, Kochman ML, et al. Analysis of cyst size and tumor markers in the management of pancreatic cysts: support for the original sendai criteria. J Am Coll Surg. 2015;220:1087e1095. 5. Sighinolfi M, Quan SY, Lee Y, et al. Fukuoka and AGA criteria have superior diagnostic accuracy for advanced cystic neoplasms than sendai criteria. Dig Dis Sci. 2017;62:626e632. 6. Cloyd JM, Tran Cao HS, Petzel MQB, et al. Impact of pancreatectomy on long-term patient-reported symptoms and quality of life in recurrence-free survivors of pancreatic and periampullary neoplasms. J Surg Oncol. 2017;115:144e150. 7. Fong ZV, Alvino DM, Castillo CFD, et al. Health-related quality of life and functional outcomes in 5-year survivors after pancreaticoduodenectomy. Ann Surg. 2017;266:685e692. 8. Witkowski ER, Smith JK, Tseng JF. Outcomes following resection of pancreatic cancer. J Surg Oncol. 2013;107:97e103. 9. Murakawa M, Aoyama T, Asari M, et al. The short- and longterm outcomes of radical antegrade modular
shah et al long-term outcomes after pancreatectomy
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas. BMC Surg. 2015;15:120. Roeyen G, Jansen M, Hartman V, et al. The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: a prospective cohort study based on preand postoperative function tests. Pancreatology. 2017;17:974e982. Beger HG, Poch B, Mayer B, Siech M. New onset of diabetes and pancreatic exocrine insufficiency after pancreaticoduodenectomy for benign and malignant tumors: a systematic review and meta-analysis of long-term results. Ann Surg. 2018;267:259e270. Falconi M, Mantovani W, Crippa S, Mascetta G, Salvia R, Pederzoli P. Pancreatic insufficiency after different resections for benign tumours. Br J Surg. 2008;95:85e91. Van Der Gaag NA, Berkhemer OA, Sprangers MA, et al. Quality of life and functional outcome after resection of pancreatic cystic neoplasm. Pancreas. 2014;43:755e761. Strasberg SM, Linehan DC, Hawkins WG. The accordion severity grading system of surgical complications. Ann Surg. 2009;250:177e186. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138:8e13. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2007;142:761e768. Moskovic DJ, Hodges SE, Wu MF, Brunicardi FC, Hilsenbeck SG, Fisher WE. Drain data to predict clinically relevant pancreatic fistula. HPB. 2010;12:472e481. Tanaka M, Ferna´ndez-Del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183e197. Tanaka M, Ferna´ndez-del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17:738e753. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17e32. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery. 2017;161:584e591. Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer CM. A prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreatoduodenectomy. J Am Coll Surg. 2013;216:1e14. Miller BC, Christein JD, Behrman SW, et al. A multiinstitutional external validation of the fistula risk score for pancreatoduodenectomy. J Gastrointest Surg. 2014;18:172e179. Makhija S, Baker J. The subjective global assessment: a review of its use in clinical practice. Nutr Clin Pract. 2008;23:405e409. Heffernan N, Cella D, Webster K, et al. Measuring healthrelated quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol. 2002;20:2229e2239. National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. Available at: https://www.niaaa.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
9
nih.gov/publications/brochures-and-fact-sheets/alcoholfacts-and-statistics. Accessed August 1, 2019. Centers for Disease Control and Prevention. Alcohol and Public Health. https://www.cdc.gov/alcohol/fact-sheets.htm. Accessed August 1, 2019. Park JW, Jang JY, Kang MJ, Kwon W, Chang YR, Kim SW. Mucinous cystic neoplasm of the pancreas: is surgical resection recommended for all surgically fit patients? Pancreatology. 2014;14:131e136. de Castro SMM, Houwert JT, van der Gaag NA, Busch ORC, van Gulik TM, Gouma DJ. Evaluation of a selective management strategy of patients with primary cystic neoplasms of the pancreas. Int J Surg. 2011;9:655e658. Olson SH, Xu Y, Herzog K, et al. Weight loss, diabetes, fatigue, and depression preceding pancreatic cancer. Pancreas. 2016;45:986e991. Gilliland TM, Villafane-Ferriol N, Shah KP, et al. Nutritional and metabolic derangements in pancreatic cancer and pancreatic resection. Nutrients. 2017;9. Aleassa EM, Morris-Stiff G. Perioperative exocrine pancreatic insufficiency and pancreatic enzyme replacement therapy. J Pancreas. 2018;19:91e95. Heerkens HD, Tseng DSJ, Lips IM, et al. Health-related quality of life after pancreatic resection for malignancy. Br J Surg. 2016;103:257e266. Shabanzadeh DM, Sørensen LT. Alcohol consumption increases post-operative infection but not mortality: a systematic review and meta-analysis. Surg Infect (Larchmt). 2015;16:657e668. Eliasen M, Grønkjær M, Skov-Ettrup LS, et al. Preoperative alcohol consumption and postoperative complications: a systematic review and meta-analysis. Ann Surg. 2013;258:930e942. Center for Behavioral Health Statistics and Quality. 2015 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental. Rockville, MD: Health Services Administration; 2016. Huang JJ, Yeo CJ, Sohn TA, et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann Surg. 2000;231:890e898. Gianotti L, Besselink MG, Sandini M, et al. Nutritional support and therapy in pancreatic surgery: a position paper of the International Study Group on Pancreatic Surgery (ISGPS). Surgery. 2018;164:1035e1048. Tran TC, van Lanschot JJ, Bruno MJ, van Ejick CH. Functional changes after pancreatoduodenectomy: diagnosis and treatment. Pancreatology. 2009;9:729e737. Fujii T, Kanda M, Kodera Y, et al. Comparison of pancreatic head resection with segmental duodenectomy and pyloruspreserving pancreatoduodenectomy for benign and lowgrade malignant neoplasms of the pancreatic head. Pancreas. 2011;40:1258e1263. Milton AC, Ellis LA, Davenport TA, Burns JM, Hickie IB. Comparison of self-reported telephone interviewing and web-based survey responses: findings from the second Australian young and well national survey. JMIR Ment Heal. 2017;4:e37. Sikorskii A, Given CW, Given B, Jeon S, You M. Differential symptom reporting by mode of administration of the assessment: automated voice response system versus a live telephone interview. Med Care. 2009;47:866e874.