By Gray, Stephen H Hawn, Mary T; Kilgore, Meredith L; Yun, Huifeng; Christein, John D
Early diagnosis and curative resection are significant predictors of survival in patients with pancreatic cancer. We hypothesize that cholecystectomy within 12 months of pancreatic cancer affects 1- year survival. The Surveillance Epidemiology and End Result (SEER) database linked to Medicare data was used to identify patients diagnosed with pancreatic cancer who underwent cholecystectomy 1 to 12 months prior to cancer diagnosis. The SEER database identified 32,569 patients from 1995 to 2002; 415 (1.3%) underwent cholecystectomy prior to cancer diagnosis. Patients who underwent cholecystectomy had a higher proportion of diabetes (40.2% vs 20.5%; P
Cholecystectomy is recommended for those who experience biliary colic, acute cholecystitis, cholangitis, or gallstone pancreatitis.8 The introduction of laparoscopic cholecystectomy has led to increased cholecystectomy rates and a decreased threshold for surgical intervention.9-13 Biliary-type symptoms have shown improvement after cholecystectomy, although the definition of these symptoms has varied and are often vague.14, 15 Unfortunately, actual symptoms caused by gallstones are incompletely understood, making it difficult to define symptoms that will be cured by cholecystectomy.16 As a result of the lack of specificity of pancreatic cancer symptoms while still at an early stage of disease, patients are often treated for more common disorders such as gallstones prior to more extensive evaluation.
Furthermore, prior studies have demonstrated that early stage at diagnosis and curative resection are the key factors determining outcome in patients with pancreatic cancer.6, 17 We hypothesize that cholecystectomy within 12 months prior to the diagnosis of pancreatic cancer affects outcomes. The aim of this study is to describe a cohort who underwent cholecystectomy within 12 months prior to the diagnosis of pancreatic cancer and its effect on survival.
Methods
The Surveillance, Epidemiology and End Results (SEER)-Medicare Database, a linkage of the SEER Program of the National Cancer Institute and the Medicare claims data for covered health services for individuals from the point of eligibility to death, was used to obtain the patient population for this study.18 The SEER allows epidemiologic surveillance of population-based tumor registries tracking cancer incidence and survival. Data collected include demographics (age, sex, and ethnicity), cancer specifics (date of diagnosis, type of cancer), follow-up vital status, and cause of death. The Medicare database includes claims data and International Classification of Diseases, 9th Revision, Healthcare Common Procedure Coding System, or Diagnostic-Related Group codes to identify diagnoses and procedures.
The SEER data cover a service area that includes approximately 14 per cent of the U.S. population, represented by Connecticut, Hawaii, Iowa, and New Mexico and the metropolitan areas of Detroit, San Francisco-Oakland, Atlanta, Seattle-Puget Sound, Los Angeles County, and San Jose-Monterey. The SEER data are highly valid, and the program’s standard for completeness is 98 per cent.18 Medicare provides health insurance for approximately 96 per cent of the population aged 65 and older. Only persons covered by traditional Medicare Parts A and B and not enrolled in managed care are included in this analysis. The SEER-Medicare population is similar to the entire U.S. population aged 65 and older in terms of age and sex distribution but is less likely to be white (79.8% vs 86.7%), impoverished (9.5% vs 12.8%), or to experience cancer mortality (1,039 per 100,000 persons aged 65 and older vs 1,128) and more likely to be living in an urban area (86.9% vs 73.0%) and participating in a health maintenance organization (approximately 26.0% vs 17.0%).
Medicare data were used to identify patients who underwent a cholecystectomy within 12 months prior to the diagnosis of pancreatic cancer. Patient comorbid conditions and demographics were obtained from 12 months prior to diagnosis of pancreatic cancer or at the time of cholecystectomy.
This research received approval from the University of Alabama at Birmingham Institutional Review Board.
Analysis
Statistical analyses were performed using Stata v9.0 (StataCorp., LP, College Station, TX). Comorbidities specifically related to pancreatitis or pancreatic cancer were identified using International Classification of Diseases, 9th Revision diagnosis codes (Table 1). Descriptive statistics were calculated and chi^sup 2^ tests were used to test the significance of differences between patients with cancer undergoing a previous cholecystectomy with those who did not. Multivariable logistic regressions were used to identify significant predictors of receiving a prediagnosis cholecystectomy more than 1 month but within 12 months of the cancer diagnosis and to test the significance of any association between prediagnosis cholecystectomy and 1-year survival.
Results
Of the 32,569 patients available for analysis, 54.0 per cent were men and median age was 74.4 years old. Overall, there was documentation of cholecystectomy in 415 (1.3%) patients within the 12 months prior to diagnosis of pancreatic cancer. There were significant differences in patient comorbidities among patients who underwent cholecystectomy. There was a higher proportion of diabetes, obesity, jaundice, presence of gallstones, weight loss, abdominal pain, steatorrhea, and cholecystitis among patients who underwent a cholecystectomy prior to the diagnosis of pancreatic cancer (Table 2).
Patients who underwent cholecystectomy had a lower proportion of distant stage (Stage IV) disease at the time of diagnosis (40.2% vs 45.6%; P = 0.05). However, patients who underwent cholecystectomy prior to diagnosis had similar 1-year survival (25.0% vs 27.6%; P = nonsignificant) in univariate analysis.
Logistic regression analysis of patient factors associated with cholecystectomy prior to the diagnosis of pancreatic cancer found a significant association in patients who presented with cholelithiasis, jaundice, weight loss, cholecystitis, abdominal pain, steatorrhea, and distant stage disease (Table 3). Models were adjusted for age at diagnosis, sex, marital status, race, and patient comorbidities. Regression analysis of 1-year survival demonstrates the occurrence of a previous cholecystectomy is associated with a significantly decreased likelihood of survival (Table 4). Models were adjusted for age at diagnosis, sex, marital status, race, and patient comorbidities.
TABLE 1. International Classification of Disease, 9th Revision (ICD-9) Codes Used to Identify Comorbidities
TABLE 2. Patient Comorbidities Identified at Time of Cholecystectomy or 12 Months Before Cancer Diagnosis
TABLE 3. Regression Model for Cholecystectomy Defined as Greater Than 1 Month and No More Than 12 Months Before Pancreatic Cancer Diagnosis
Discussion
Our study found that cholecystectomy prior to the diagnosis of pancreatic cancer is associated with decreased 1-year survival. Of the cohort analyzed, 1.3 per cent underwent cholecystectomy within the 12 months prior to the diagnosis of pancreatic cancer. The occurrence of cholecystectomy was significantly associated with cholelithiasis, jaundice, weight loss, cholecystitis, abdominal pain, and steatorrhea prior to the diagnosis of cancer.
Over 70 per cent of the patients who underwent cholecystectomy had cholelithiasis; however, a significant proportion of patients was jaundiced and had experienced weight loss at the time of cholecystectomy. These symptoms attributed to gallstones are not specific to biliary pathology, and the presence of cholelithiasis does not confirm a biliary source. Our regression models demonstrate a greater than threefold increase in the rate of cholecystectomy among patients with pancreatic cancer with jaundice or steatorrhea. Jaundice, weight loss, and steatorrhea are commonly associated with malignancy and, in this age group, should prompt a workup to exclude malignancy. TABLE 4. Regression Model for 1-Year Survival After a Diagnosis of Pancreatic Cancer
A previously published study demonstrated that 9 per cent of patients with pancreatic cancer had undergone cholecystectomy within 2 years before the diagnosis of pancreatic cancer. Additionally, prior cholecystectomy was associated with a decreased rate of curative resection.19 Pancreatectomy is underused for early-stage pancreatic cancer; 38.2 per cent of patients without identifiable contraindication failed to undergo surgery.20 We hypothesize that the symptoms leading to cholecystectomy were likely the result of pancreatic cancer in the setting of incidental cholelithiasis. Factors most associated with survival are stage of disease at presentation and the margin of resection at operation.6, 17, 21 Both stage and resection margin are adversely affected by delay in diagnosis.
The threshold for cholecystectomy has decreased since the introduction of laparoscopic cholecystectomy.9-13 The diagnosis of malignant disease, including colon and pancreatic cancer, is often missed at the time of laparoscopic cholecystectomy.1, 22, 23 The lack of tactile sensation, limited visualization of the lesser sac, and patient body habitus can make the diagnosis of malignancy during laparoscopy difficult. This emphasizes the necessity of recognizing symptoms suspicious for pancreatic cancer prior to cholecystectomy, including weight loss, jaundice, and steatorrhea. Although benign biliary pathology is much more frequent than pancreatic cancer, these warning signs warrant more extensive evaluation.
The primary limitation of this study is that it uses retrospective analysis of observational data. Additionally, the limitations of the data set do not allow complete analysis of all patient variables of interest. However, our data do illustrate the need for increased screening and diagnostic workup prior to cholecystectomy with the potential for earlier diagnosis and cure for a subset of patients with pancreatic cancer. A prospectively collected observational study of patients undergoing cholecystectomy may help to define which patients would benefit from increased diagnostic workup prior to cholecystectomy.
Early diagnosis allowing the potential for curative resection is currently the most significant predictor of survival in patients with pancreatic cancer. Our regression model demonstrates a significant association between the occurrence of a cholecystectomy prior to pancreatic cancer diagnosis and decreased odds of survival at 1 year. The occurrence of a cholecystectomy is likely a marker of attributing vague biliary symptoms and incidental cholelithiasis to benign biliary pathology. Unfortunately, cholecystectomy leads to a delay in the diagnosis of pancreatic cancer and may allow for disease progression. For patients older than 65 years of age, further evaluation prior to cholecystectomy may be necessary to exclude pancreatic cancer, especially in patients with weight loss, jaundice, and steatorrhea.
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STEPHEN H. GRAY, M.D., M.S.P.H.,* MARY T. HAWN, M.D., M.P.H.,* MEREDITH L. KILGORE, Ph.D.,[dagger] HUIFENG YUN, M.S.,[dagger] JOHN D. CHRISTEIN, M.D.*
From the * Department of Surgery and the [dagger] School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Birmingham, AL, February 9-12, 2008.
Address correspondence and reprint requests to John D. Christein, M.D., University of Alabama, 1530 3rd Avenue South, KB 417, Birmingham, AL 35294. E-mail: [email protected].
DISCUSSION
DIMITRIOS STEFANIDIS, M.D. (Charlotte, TN; Opening Discussion): Pancreatic cancer is the fourth leading cause of cancer-associated mortality in the United States with a dismal 5-year survival rate. Stage for stage, pancreatic cancer is associated with the lowest survival rate of any cancer site. Advanced stage at presentation is the result of the lack of early specific symptoms. The aggressive nature of such cancers and the limited effectiveness of adjuvant treatments are thought to be the main reasons for the poor outcomes. Thus, the imperative clearly exists to determine modifiable risk factors to develop methods to detect pancreatic cancer at earlier stages in the general population and to identify individuals at high risk who would benefit from more intensive screening. Such risk factors have been found to include cigarette smoking, family history of pancreatic cancer, diabetes mellitus, and even history of cholelithiasis and cholecystectomy.
The authors of this article identified patients with pancreatic cancer who had undergone cholecystectomy the year before their cancer diagnosis by reviewing the SEER database and linking to Medicare data. They conclude that recent cholecystectomy is associated with decreased 1-year survival among patients with pancreatic cancer and recommend that patients older than 65 years of age are worked up for pancreatic cancer before cholecystectomy, especially if they are jaundiced.
How do the authors explain their findings that patients who had undergone prior cholecystectomy had a lower proportion of Stage IV disease at diagnosis but also a lower 1-year survival rate? Do these statements not contradict each other?
In your discussion, I did not see an explanation as to why cholecystectomy leads to worse pancreatic cancer outcomes. What is your hypothesis? What makes cholecystectomy harmful? If it is delay in diagnosis, as you imply, then why did those patients have a lower incidence of Stage IV disease at presentation? Could it be related to the higher incidence of comorbid conditions that you demonstrated for the cholecystectomy group? Does postsurgical immunosuppression play a role?
Some authors have suggested that cholelithiasis and the need for cholecystectomy are a consequence of the presence of pancreatic cancer rather than representing true risk factors for its development. Could this also be true for your findings as well? Finally, based on your study, how do you recommend we change our practice when we see an elderly patient who is a candidate for cholecystectomy?
STEPHEN H. GRAY, M.D. (Birmingham, AL; Closing Discussion): Based on our study, we would suggest that these patients who present with atypical benign pathology should have further workup before their cholecystectomy to exclude the cholecystectomy being performed for incidental cholelithiasis. These symptoms are actually symptoms of pancreatic disease that are being misinterpreted.
Regarding the lower proportion of Stage IV disease, if these patients at the time of the cholecystectomy had postperitoneal spread, this would be seen at that time of cholecystectomy. A decreased 1-year survival rate is likely the result of a delay in their diagnosis. These were patients who may have progressed from having a resectable disease when they initially presented for the cholecystectomy to unresectable disease at the time the pancreatic cancer is actually diagnosed.
MURRAY F. BRENNAN (New York, NY): Cholecystectomy does not affect the outcome of pancreatic cancer. Cholecystectomy is associated with it as you so nicely said. I think it is what is called the “black swan syndrome.” We look for information that supports our biases, when we should be looking for information that proves our biases wrong. One way you might have done that was to take the survival from the date of cholecystectomy.
WILLIAM C. WOOD, M.D. (Atlanta, GA): I fear that this is the tip of the iceberg. If we look carefully at a variety of operations that are done before another operation, we will find that these are cases in which we are missing something. I think specifically of a series of chondrosarcomas of the pelvis I resected. Over 50 per cent of them had a lumbar laminectomy in the preceding 12 months because their symptoms were assumed to be the more common disease herniated disk than the more rare. This is an alert to all of us.
STEPHEN H. GRAY, M.D. (Birmingham, AL; Closing Discussion): This points out the difference between association and causation and demonstrates that it may be impossible to tell the difference between a patient with symptoms of pancreatic cancer and gallbladder disease. Imaging studies may not show evidence of pancreatic cancer. If those patients do not get well after cholecystectomy and remain symptomatic, a red flag should go up, and you should evaluate those patients promptly for the possibility of other pathology.
KENNETH LIPSHY, M.D. (Hampton, VA): A retrospective review from our institution 10 years ago studied patients before and after the laparoscopic era. We assessed patients who were subsequently admitted within a 2- to 6-month time period after cholecystectomy to determine if there was an association of potentially missed lesions resulting from our rapid intervention in the laparoscopic cholecystectomy era versus the prior era when we tended to do a few more studies before an open operation. Often there appeared to be a rush to proceed with laparoscopic cholecystectomy, and occasionally another lesion was missed.
KAUSHIK MUKHERJEE, M.D. (Nashville, TN): Any thought of doing a preoperative endoscopic retrograde cholangiopancreatography, particularly in patients who were jaundiced?
STEPHEN H. GRAY, M.D. (Birmingham, AL; Closing Discussion): Our study was a retrospective study of the SEER database. An interesting question would be to prospectively collect this data so we could ascertain which patients undergoing cholecystectomy would benefit from an increased diagnostic workup.
Copyright Southeastern Surgical Congress Jul 2008
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