A Clinical and Economic Evaluation of Endoscopic Ultrasound for Patients at Risk for Familial Pancreatic Adenocarcinoma

Original Paper Pancreatology 2007;7:514–525 DOI: 10.1159/000108969

Received: January 5, 2007 Accepted after revision: June 6, 2007 Published online: October 1, 2007

A Clinical and Economic Evaluation of Endoscopic Ultrasound for Patients at Risk for Familial Pancreatic Adenocarcinoma Joel H. Rubenstein a, b James M. Scheiman b Michelle A. Anderson b a Ann Arbor Veterans Affairs Medical Center, and b The Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Mich., USA

Key Words Decision support techniques ⴢ Cost-effectiveness ⴢ Endosonography ⴢ Pancreatectomy ⴢ Pancreatic neoplasms ⴢ Precancerous conditions ⴢ Genetic predisposition to disease

Abstract Background and Aims: Approximately 10% of pancreatic adenocarcinoma is familial. Approximately 50% of 1st-degree relatives (FDRs) have endoscopic ultrasound (EUS) findings of chronic pancreatitis. We modeled the natural history of these patients to compare 4 management strategies. Methods: We performed a systematic review, and created a Markov model for 45-year-old male FDRs, with findings of chronic pancreatitis on screening EUS. We compared 4 strategies: doing nothing, prophylactic total pancreatectomy (PTP), annual surveillance by EUS, and annual surveillance with EUS and fine needle aspiration (EUS/FNA). Outcomes incorporated mortality, quality of life, procedural complications, and costs. Results: In the Do Nothing strategy, the lifetime risk of cancer was 20%. Doing nothing provided the greatest remaining years of life, the lowest cost, and the greatest remaining quality-adjusted life years (QALYs). PTP provided the fewest remaining years of life, and the fewest remaining QALYs. Screening with EUS provided nearly identical results to PTP, and screening with EUS/FNA provided intermediate results between PTP and doing nothing. PTP provided the longest life expectancy if the lifetime risk of pancreatic cancer was at least 46%, and provided the most QALYs if the risk was at least 68%. Conclusions: FDRs from

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familial pancreatic cancer kindreds, who have EUS findings of chronic pancreatitis, have increased risk for cancer, but their precise risk is unknown. Without the ability to further quantify that risk, the most effective strategy is to do nothing. Copyright © 2007 S. Karger AG, Basel and IAP

Introduction

Pancreatic cancer (PC) is the 4th most common cause of cancer death in the United States [1]. One risk factor for PC is a history of family members with PC [2–8]. Cancers arising in patients with a family history of PC have been reported to account for 1–8% of PC in retrospective studies [4, 9]. In a prospective cohort of patients with PC who provided detailed family histories, approximately 16% of cancer patients had at least 1 family member (including 1st-, 2nd-, and 3rd-degree relatives) with PC, and 4% had 2 family members with PC, but a germline mutation could not be identified in any of these patients [10]. Based on their experience of endoscopic ultrasound (EUS) and pancreatogram abnormalities in relatives from kindreds with familial pancreatic cancer (FPC), a group has recommended screening followed by prophylactic total pancreatectomy for selected patients [11–14]. Over the last few years, knowledge regarding the epidemiology of FPC kindreds has improved considerably in 3 major avenues. First, there are now estimates of the standardized incidence ratio of PC in people who are

Joel H. Rubenstein, MD, MSc VA Medical Center (111-D) 2215 Fuller Road Ann Arbor, MI 48105 (USA) Tel. +1 734 761 7981, Fax +1 734 761 7549, E-Mail [email protected]

Fig. 1. Simplified schematic of Markov

model health states and transitions. In any given 1-year cycle, hypothetical patients start in one of the three health states (ovals), and have specified rates of transitioning (arrows) to other health states. Each strategy has associated costs and an associated QoL, measured by utility. Some of the transitions also have costs and effects on utility. Patients can undergo TP for resectable cancer, prophylactically, or for a false positive finding suspicious for cancer on EUS or EUS with FNA.

Pancreatic cancer

Chronic pancreatitis (asymptomatic)

Total pancreatectomy and diabetes mellitus

Dead

first-degree relatives (FDRs) of patients with PC and are from FPC kindreds (defined as families with at least 2 members with PC who are FDRs of each other), compared to the expected incidence in the general population [15]. Second, evidence now suggests that the susceptibility to PC in familial kindreds is likely transmitted by a single, dominantly inherited somatic mutation, even though that mutation has not yet been identified [16, 17]. Third, EUS findings have been compared in a large group of asymptomatic patients from FPC kindreds to control subjects [18, 19]. EUS findings of diffuse chronic pancreatitis were found in 60% of high risk subjects, compared to 16% of controls. Recently, the same group has reported that the severity of EUS findings of chronic pancreatitis in these kindreds correlates with the histological density of pancreatic intraepithelial dysplasias in surgically resected specimens [20]. The effectiveness of any screening program for FPC would depend heavily on the subsequent management of the approximately 50% of patients with asymptomatic findings of chronic pancreatitis on EUS, but such management is controversial. Presumably, these patients are at substantial susceptibility for future development of PC, and could benefit from an intervention. Since the entire gland is affected, the only procedure that could exclude the possibility of progression to cancer is total pancreatectomy (TP). TP carries significant operative mortality, and induces insulin-requiring diabetes mellitus which profoundly alters quality and length of life; therefore, selecting the correct patients for TP is paramount. Surveillance with EUS or EUS with fine needle aspiration (EUS/FNA) might detect early stage cancers, but those methods are less accurate in the presence of chronic pancreatitis, which could result in patients undergoing TP unnecessarily. If intervening or performing surveillance

on these patients is more likely to result in harm than benefit, then it may be detrimental to screen family members at all. Management of these patients ought to be made by carefully weighing the risks and benefits of each strategy. Ideally, a randomized controlled trial would be performed to answer this question. In order to account for the long-term morbidity and mortality from diabetes, such a trial would need to last decades. Instead, we sought to utilize the recently published empiric epidemiologic data to model the natural history of these family members with EUS findings of chronic pancreatitis, and compare the outcomes with strategies of prophylactic TP, and surveillance with either EUS or EUS/FNA with the aim of diagnosing cancers at an early stage.

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Methods Subjects The hypothetical cohort consisted of asymptomatic 45-yearold men from FPC kindreds, who had at least one FDR with PC. Subjects had previously undergone screening EUS with findings of chronic pancreatitis. FPC kindreds were defined as families with at least two family members with PC who were FDRs of each other [15, 18]. Subjects were excluded if they were not from FPC kindreds or did not have EUS findings of chronic pancreatitis. The analysis followed the cohort until age 90 or death, whichever occurred first. Model TreeAge Pro 2006 software (TreeAge, Williamstown, Mass., USA) was used to model the decision analysis with a Markov process. A Markov process is a mathematical simulation of hypothetical subjects over time. A simplified schematic of the model is shown in figure 1. The model accounts for the natural history of patients without intervention, the strategy of prophylactic total pancreatectomy (PTP), the two surveillance strategies, procedural and surgical complications, as well as complications of iatrogenic diabetes.

515

Natural History in the Do Nothing Strategy The reference strategy was to do nothing. Patients in this strategy did not undergo surveillance or prophylactic pancreatectomy. The incidence of cancer was derived from the age-specific incidence of PC among men in the general population [21], the agespecific standardized incidence ratio for PC in FDRs of patients with cancer from FPC kindreds overall [15], and the proportion of FDRs from FPC kindreds with EUS findings of chronic pancreatitis (see Appendix for details) [18, 19]. In the Do Nothing strategy, cancer was only diagnosed once symptoms presented. Stage at diagnosis, and stage-specific survival was obtained from Surveillance Epidemiology and End Results (SEER) data [21]. In sensitivity analyses, the mortality from localized cancer was varied to the lowest reported in surgical series [22–29]. Patients could also die from other causes, based on United States life tables [30]. Long-term cancer survivors were assumed to have iatrogenic insulin-requiring diabetes mellitus, which carried increased mortality as described in the next section. The base case values and ranges studied in sensitivity analyses for each variable are detailed in table 1. The model was validated by modifying it to predict the cumulative incidence of cancer in a 45-year-old male from the general population, and comparing the results to data from the SEER database. Using a standardized incidence ratio for cancer of 1.0 compared to the general population resulted in a 1.25% cumulative lifetime incidence of PC; SEER reports the lifetime cumulative incidence for a 45-year-old man from the general population to be 1.31% [1]. Prophylactic Total Pancreatectomy Patients in this strategy underwent TP prophylactically, leaving no residual pancreatic tissue. In the base case of this strategy, PTP was performed at the age of 45 years. Operative mortality from pancreatic surgery has improved substantially over the last few decades, particularly in high-volume centers, such that the mortality has been reported to approach 1% in some centers, and even less for distal pancreatectomy [22, 23, 28, 31–36]. However, these more recent impressive results were primarily for pancreaticoduodenectomy (Whipple procedure) rather than TP, which had largely fallen out of favor by the 1980s. In the base case, we used the 5% operative mortality found in a recent series of 99 total pancreatectomies performed at the Mayo Clinic over 17 years [37]. Operative mortality rates were varied widely in sensitivity analyses. Postoperatively, patients endured life-long iatrogenic, insulinrequiring diabetes mellitus. Long-term excess mortality was assumed to be predominantly due to complications of diabetes, rather than from exocrine deficiencies [37]. Annual mortality rates after PTP were therefore based on age-specific mortality ratios for patients with diabetes compared to the general population. The observation that such ratios tend to be higher in patients with Type 1 diabetes than those with Type 2 [38–46] is likely confounded by the fact that the onset of Type 1 is mostly in childhood, and the mortality rates in the general young adult population is very low [47]. Since mortality ratios for older Type 1 diabetics likely reflect the much longer duration of disease than is present after PTP performed in middle age, we used age-specific mortality ratios obtained primarily from patients with adult-onset Type 2 diabetes [48], but varied those ratios widely in sensitivity analyses [40, 46, 47, 49–52].

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Surveillance by Endoscopic Ultrasound Patients in this strategy underwent annual surveillance for cancer with EUS. Visualization of a discrete mass lesion suspicious for cancer dictated the performance of TP. While there are some studies describing the accuracy of EUS for distinguishing cancer from chronic pancreatitis (typically focal chronic pancreatitis) [53–57], there is little data on the accuracy of EUS for detecting cancer arising within diffuse chronic pancreatitis. Therefore, sensitivity and specificity of EUS in this setting were based on author consensus, which was guided by those studies. The long-term excess mortality of patients with false positive EUS results was due to diabetes, as described in the strategy of PTP. Patients with true positive cancers were assumed to have a higher proportion of locally staged tumors than patients in the Do Nothing strategy. This difference was derived from the one year interval of surveillance, and the published lead-time in survivorship between local and regional cancers [21, 26, 58]. This benefit was varied widely in a sensitivity analysis from no benefit, to the benefit derived if surveillance were performed every 6 months rather than annually. Mortality was stage-specific as described in the Do Nothing strategy. Patients could also suffer mortal complications of EUS or PTP, or die from other causes. Surveillance by Endoscopic Ultrasound with Fine Needle Aspiration This strategy was identical to the EUS strategy, except that FNA was performed on any suspicious mass lesion, and patients only underwent TP for positive or suspicious cytological results. EUS/FNA was more specific, but less sensitive for cancer, and carried a slightly higher risk of complication than EUS alone [59–63]. Previous studies have reported that EUS/FNA is as high as 100% specific for cancer, but those studies were not performed in patients from FPC kindreds [59, 60, 63, 64]. Since high densities of pancreatic dysplasia are found in patients from FPC kindreds [65], and since cytology cannot distinguish dysplasia from invasive cancer, these patients would be expected to have some finite number of false positive FNAs leading to pancreatectomy in the absence of cancer. Therefore, the specificity was assumed to be 99% in the base case, and varied widely in sensitivity analyses. Utilities and Costs We expected that quality of life (QoL) after PTP would greatly impact the choice of strategies. QoL was incorporated in the model by the use of utilities, which are ratios that reflect patient preferences for particular health states, ranging from 0 (death) to 1 (perfect health) [66]. A recent study of long-term survivors after TP found that these patients had generic health-related QoL, and diabetes-specific QoL that is similar to typical patients with insulin-requiring diabetes [37]. We therefore used utilities observed in patients with insulin-requiring or complicated diabetes, varying the range widely in sensitivity analyses [67–74]. Patients without cancer or diabetes, including those undergoing surveillance, were assumed to have perfect QoL (utility = 1) in order to bias the results in favor of surveillance; this value was varied widely in sensitivity analysis. Based on author consensus, patients undergoing PTP suffered an additional short-term decrement in QoL during the year of surgery which was derived by assuming a utility of 0.5 for 3 months during the postoperative recovery. This ‘toll’ on utility was varied widely in sensitivity analysis.

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Table 1. Model assumptions

Variable

Base case value

Range

References

Cancer SIR for cancer in FDRs <65 years old compared to general population SIR for cancer in FDRs ≥65 years old compared to general population Proportion of FDRs who are susceptible to cancer Proportion of cancers that are local without surveillance Proportion of cancers that are local with surveillance Proportion of non-local cancers that have distant metastases Mortality from local cancer Mortality from regional cancer Mortality from distant cancer

15.80 7.40 50% 8.0% 50% 67% 83.9% 93.0% 98.4%

4.31–40.40 2.97–15.20 5–100% 7.5–8.5% 8–71% 65–68% 0–100% 92.8–100% 97.5–100%

[15] [15] [16–18, 98] [21] [21, 26, 58] [21] [21–29] [21] [21]

EUS test characteristics for cancer in setting of chronic pancreatitis Sensitivity of EUS without FNA Specificity of EUS without FNA Sensitivity of EUS with FNA Specificity of EUS with FNA

72% 60% 54% 99%

Complications Mortal complication from EUS without FNA Mortal complication from EUS with FNA Mortal operative complication from PTP

0.0023% 0.0204% 5%

0.0004–0.0129% 0.0036–0.8406% 1–20%

Age at which PTP is performed

45 years

45–75 years

*

Diabetes mellitus Mortality ratio for ages 45–49 years compared to general population Mortality ratio for ages 50–64 years compared to general population Mortality ratio for ages ≥65 years compared to general population

2.7 1.9 1.8

1.2–6.1 1.4–2.5 1.5–2.3

[40, 46–52] [40, 46–52] [40, 46–52]

Costs, USD EUS without FNA EUS with FNA Pancreatectomy Annual care for diabetes mellitus Diagnosis of cancer Treatment of local cancer Treatment of regional cancer Treatment of distant cancer

766 1,065 15,505 11,674 3,270 30,564 23,548 14,415

383–1,531 532–2,129 7,753–31,010 5,837–23,347 1,635–6,540 15,282–61,127 11,774–47,097 7,207–28,830

Utilities Asymptomatic without cancer or pancreatectomy Diabetes mellitus One-time postoperative toll for recuperation

1.0 0.88 0.125

0–1.0 0.43–1.0 0–0.50

Discount rate

3%

50–90% 45–75% 25–81% 82–100%

0–5%

[53–57]* [53–57]* [59, 63] [59, 60, 63]* [61] [61, 62] [22–25, 28, 31–37, 99–107]

CMS CMS CMS [108] [75, 76], CMS [76–78], CMS [76–78], CMS [76–78], CMS * [37, 67–74] * [66]

* Author consensus. CMS = Centers for Medicare and Medicaid Services; EUS = endoscopic ultrasound; FDR = 1st-degree relative; FNA = fine needle aspiration; PTP = prophylactic total pancreatectomy; SIR = standardized incidence ratio.

The perspective was that of a third-party payer; therefore, modeled costs included direct healthcare costs, but not indirect healthcare costs (such as lost productivity costs for patients and their families), or direct non-healthcare costs (such as patient transportation costs) (table 1) [66]. Costs were based on median national

reimbursements from the Centers for Medicare and Medicaid Services for 2005. The cost of diagnosing and staging symptomatic cancer was derived from empiric data of the frequency of tests performed in that process [75, 76]. Costs of cancer care were based on published stage-specific treatment guidelines, and included costs

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Table 2. Outcomes in base case

Strategy

Life years

QALYs

PTP

Cancers

Cancer deaths

PTP surgical deaths Cost, USD

ICER

Do Nothing EUS/FNA EUS PTP

29.16 28.26 24.78 24.65

18.57 17.94 14.54 14.28

0% 24% 98% 100%

20.0% 16.1% 0.5% 0%

19.1% 14.9% 0.4% 0%

0% 1.2% 4.9% 5.0%

– dominated dominated dominated

2,983 42,521 186,089 199,911

QALY = quality-adjusted life year; PTP = total pancreatectomy performed in the absence of cancer; ICER = incremental costeffectiveness ratio; Dominated = the strategy listed is less effective and more expensive than the compared strategy.

We systematically reviewed the published literature by searching MEDLINE from 1966 through September 2005 using the terms pancreatic neoplasms, genetic predisposition to disease, family health, precancerous conditions, pancreatic intraepithelial neoplasia, carcinoma in situ, pancreatitis, risk, pancreatectomy, endosonography, sensitivity and specificity, diabetes mellitus, diabetes complications, mortality, utility, and utilities. Additional articles were identified by searching the references of these articles. Base case values were chosen from the means or medians of the published literature. Except as noted, upper and lower limits were taken from 95% confidence intervals if available; otherwise, inclusive ranges were used.

100 90 80

Survival (%)

70 60 50

Do nothing

40

Pancreatectomy at 45

30

EUS surveillance for cancer EUS/FNA surveillance for cancer

20

General population (for comparison) 10 0 45

55

65

75

85

Age

Fig. 2. Expected survival in base case shows that all strategies are worse than doing nothing. Patients in the Do Nothing strategy (thick line) have shorter survival than the general population (dots). Patients undergoing PTP at age 45 (thin line) are exposed to an initial surgical mortality, and never receive a benefit sufficient to expect a longer survival than patients in Do Nothing. EUS (crosses) provided nearly identical survival as those undergoing pancreatectomy. EUS with FNA (dashes) improved survival compared to either EUS or pancreatectomy, but still had worse survival than Do Nothing.

Outcomes The time horizon of the model was age 90 or death (whichever was earliest). The primary outcome was the life expectancy for each strategy. Secondary outcomes included lifetime cumulative incidence of cancer, quality-adjusted life-years (QALYs), proportion undergoing PTP (patients undergoing TP for false positive findings on EUS or EUS/FNA were considered to have had PTP), operative deaths, costs, and incremental cost-effectiveness ratios (ICERs). ICER is defined as the difference in cost in USD divided by the difference in effectiveness in QALYs between two strategies. Sensitivity Analyses One-way sensitivity analyses were performed over the specified ranges for each variable (table 1), comparing all strategies simultaneously. Two-way sensitivity analyses were performed for selected combinations of variables based on the findings of the one-way sensitivity analyses.

Results of hospice care [76–78]. The cost of pancreatectomy was applied regardless of whether it was performed prophylactically, for true positive diagnosis of cancer, or for a false positive diagnosis. The upper and lower limits of costs were half and twice the base case estimates, respectively. Costs were adjusted to 2005 USD using an inflation rate of 3%. All costs and utilities were discounted at an annual rate of 3%, with sensitivity analysis from 0 to 5%. Systematic Review Unless noted, transition rates between the health states, costs, and utilities were derived from the published literature (table 1).

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Base Case In the cohort of 45-year-old men from FPC kindreds with findings of chronic pancreatitis, the lifetime cumulative incidence of cancer was 20%, while the cumulative incidence by age 65 was 10%. Patients’ median life expectancy was 76 years, with 11% of patients reaching 90 years of age (fig. 2). Patients in the Do Nothing strategy accrued the highest average QALYs and incurred the lowest average lifetime costs (table 2). Patients undergoing PTP at age Rubenstein /Scheiman /Anderson

Sensitivity Analyses In sensitivity analyses, the cumulative lifetime incidence of cancer varied widely depending on the assumptions regarding the magnitude of relative risk of cancer compared to the general population, and regarding the association between findings of chronic pancreatitis and the susceptibility to cancer. Varying these assumptions resulted in a range of lifetime risk of cancer between 4 and 93% (fig. 3). For instance, if the proportion of FDRs

100

80 Worst case

60 50

Best case

40 30 20 10 0

45

50

55

60

65

70 Age

75

80

85

90

3

35 Do nothing PTP 30

Fig. 3. Sensitivity analysis demonstrates wide range of possibili-

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70

Base case

EUS EUS/FNA

25

20

Base case

15

10 0

10

20 30 40 50 60 70 80 90 Cumulative lifetime incidence of cancer (%)

100

4

20

Do nothing PTP EUS EUS/FNA

15 QALYs

ties for lifetime cumulative incidence of cancer. The graph represents the expected natural history of developing cancer under different assumptions. The base case uses the empiric point estimate of the standardized incidence ratio (SIR) of cancer compared to the general population, assumes the susceptibility to cancer is transmitted through a single dominantly inherited gene, and assumes that EUS findings of chronic pancreatitis correlate perfectly with the susceptible genotype. The best case assumes the lower 95% confidence limit of the SIR and that all FDRs are at equal risk for cancer, regardless of EUS findings. The worst case assumes the upper 95% confidence limit of the SIR and is limited to the 5% of FDRs with severe findings of chronic pancreatitis, who are assumed to be the only relatives susceptible to cancer. Fig. 4. Remaining life for each strategy depends on the risk of cancer. In the base case, where the risk of cancer is 20%, Do Nothing provides the longest remaining years of life beyond age 45. With increasing risk of cancer, lifetime is shortened in Do Nothing and the EUS and EUS/FNA strategies. If the risk of cancer is greater than 45%, then PTP provides the longest life. Fig. 5. QALYs for each strategy depends on the risk of cancer. In the base case, where the lifetime risk of cancer is 20%, Do Nothing provides the most QALYs. With increasing risk of cancer, the QALYs decrease for each strategy except PTP. PTP provides the most QALYs when the risk of cancer is greater than 68%.

Cumulative incidence of cancer (%)

90

Remaining years of life

45 had worse outcomes: average remaining lifespan was 4.5 years shorter and they accrued 4.3 fewer QALYs. Patients undergoing EUS surveillance for cancer had slightly better survival and slightly more QALYs than patients undergoing PTP. Patients undergoing surveillance with EUS/FNA had survival, QALYs, and costs that were intermediate between EUS and Do Nothing. EUS prevented 98% of cancers from developing due to repeated chances of false positive surveillance leading to 98% of patients undergoing PTP before cancer developed. EUS/FNA prevented fewer cancers (20%) since the specificity of the procedure was higher than EUS and led to fewer patients undergoing PTP (24%). Neither surveillance technique substantially decreased the mortality from cancer once a cancer developed (95.6% in Do Nothing, 92.7% in EUS/ FNA, 91.8% in EUS) despite the assumption of increased chances of detecting cancer at localized stage.

10 Base case

5 0

10 20 30 40 50 60 70 80 90 Cumulative lifetime incidence of cancer (%)

100

5

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who had EUS findings of chronic pancreatitis was greater than 50% (and hence, the risk of cancer was distributed among a larger number of patients), then the lifetime risk of cancer in an individual FDR was lower. One-way sensitivity analyses were performed on each of the variables in the model to determine if changes in any altered the outcome of which strategy provided the most remaining years of life or the most QALYs. These analyses indicated that if the cumulative lifetime incidence of cancer was greater than 46%, then PTP provided the most average life years (fig. 4). PTP provided the most QALYs if the cumulative incidence of cancer was greater than 68% (fig. 5). If the utility of either doing nothing or undergoing surveillance (without cancer or diabetes) was less than 0.77, then PTP provided the most QALYs, but doing nothing still provided the most absolute life years. No other variable changes allowed for any strategy to provide more life years or more QALYs than Do Nothing. For instance, altering the sensitivity or specificity of either EUS or EUS/FNA did not affect the outcome of which strategy provided the most life years or QALYs. Likewise, regardless of whether the surgical mortality from PTP was as low as 1% or as high as 20%, Do Nothing provided more life years and more QALYs than any other strategy. Exploratory two-way sensitivity analysis found that EUS/FNA provided the most average life years if its specificity for PC was 100% and the mortality from localized cancer was less than 76%. EUS/FNA provided the most QALYs if the specificity was 100% with mortality from localized cancer less than 71%.

Discussion

We modeled the natural history of asymptomatic patients with EUS findings of chronic pancreatitis who come from FPC kindreds and are FDRs of PC patients. We found that in the base case, doing nothing (including avoiding surveillance) provided the most life years and the most QALYs, despite a 20% cumulative lifetime risk of cancer. PTP provided the most life years if the cumulative lifetime risk of cancer was greater than approximately 46%, and provided the most QALYs if that risk was greater than 68%. As figure 2 demonstrates, the lack of a clear understanding of the lifetime risk of cancer is a critical barrier to determining the clinical management of these patients. Our study demonstrates the weaknesses of a strategy of surveillance for early cancer. Because the mortality of 520

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even local PC is so high, efforts aimed at diagnosing cancer early, rather than preventing cancer, can only have minimal impact on life expectancy, even with a test that has 100% accuracy. Repeatedly applying a test with even a small false positive rate, as in annual surveillance, would lead to a substantial proportion of patients eventually undergoing TP. Such a strategy has the unplanned outcome of preventing cancer (table 2), but with risks of diabetes and surgical mortality that may not be balanced to the risk of cancer. While we chose to explicitly detail surveillance with EUS or EUS/FNA, the results of the model are applicable to any imaging technique (such as helical computed tomography or magnetic resonance imaging), as the effectiveness of surveillance depends entirely on the combined sensitivity and specificity of the modality, and the sensitivity analyses cover the range that would be found with other imaging modalities [79, 80]. Our results show that rather than attempting to detect PC earlier, efforts ought to be directed at developing novel strategies of reducing the incidence of cancer among high-risk patients. Clearly, despite the recent advances in knowledge regarding the epidemiology of FPC, better risk stratification is needed than currently exists in order to guide management. If such a method of risk stratification were validated, then the results of this model could be used to select which patients to submit to PTP. Until such a method is developed, we do not recommend that asymptomatic family members undergo screening, unless as part of a research study. The results of screening would not alter management, and could cause unnecessary harm, anxiety, or a false sense of security. The results of screening could also affect the access to affordable life and health insurance. We found that if the QoL of being susceptible to PC is less than 77% of normal, then PTP would provide the most QALYs. Patients who are susceptible to PC and who have witnessed their loved-ones die from the disease almost certainly have decreased QoL, but even major depression only incurs a 3% maximal decrement in QoL [81], so it is very unlikely that the QoL of susceptible patients is severe enough to warrant PTP. There are a number of potential means of stratifying risk further. For instance, EUS criteria for determining the severity of chronic pancreatitis or other specific features might be validated as predictors of risk. Other strategies might include detection of germline somatic mutations [10], histologic or cytologic sampling of the pancreas for pancreatic dysplasia [12, 20, 82–84], or detection of mutated k-ras genes in pancreatic secretions [85–87]. These strategies are potentially compromised by samRubenstein /Scheiman /Anderson

pling error [88], intraobserver agreement [89], and contradictory findings in preliminary studies [90]. Furthermore, we were not able to model these strategies because there is insufficient empiric data regarding the natural history of patients stratified by these means. While histologic sampling of the pancreas for pancreatic dysplasia by distal pancreatectomy is currently feasible and is therefore an attractive strategy, clinicians (and not just modelers) ought to be wary of using such a strategy due to the insufficient data regarding natural history of pancreatic dysplasia. Pancreatic dysplasia may not necessarily progress to cancer in a patient’s lifetime, and do not themselves cause any morbidity or mortality. It is important to note that our results are not applicable to kindreds of Hereditary Pancreatitis (HP). Family members afflicted by that condition develop recurrent acute pancreatitis years before developing PC, and develop PC at much higher rates than found in unselected FPC kindreds (SIR 53 compared to the general population) [91]. Since patients with HP are at substantially high risk for PC, they might benefit from PTP [92]. We restricted our analysis to asymptomatic patients, since they likely account for the majority of FPC kindreds, and the relative benefits of PTP are higher in HP patients suffering from recurrent bouts of painful and life-threatening pancreatitis, and the relative risks of PTP are lower in patients who already endure diabetes mellitus. As with all cost-effectiveness analyses, ours is limited by the available published data. For instance, the risk of mortal complications from TP reported in the published literature is likely biased by selection – patients were almost exclusively undergoing TP for PC or for alcoholic pancreatitis; young, healthy patients in our study would likely have lower surgical complications. Furthermore, iatrogenic diabetes mellitus is physiologically different from both Type 1 and Type 2 diabetes, which is partly explained by the added glucagon deficiency [93–96]. Because of this, iatrogenic diabetes may be associated with more frequent hypoglycemic episodes, and may be less likely to cause vascular disease than typical diabetes [96]. Since generic and diabetes-specific QoL are similar in iatrogenic and typical diabetes, we used utilities from patients with typical diabetes [37]. No long-term studies exist of otherwise healthy patients with iatrogenic diabetes from which we could have modeled the long-term agespecific mortality. Instead, we assumed the mortality was similar to typical diabetics. Additionally, an attractive strategy might be partial pancreatectomy for FDRs with focal findings of chronic pancreatitis, but we were not able to model such a strategy due to the absence of empiric data

regarding the risk of cancer in the remnant pancreas. Finally, we resorted to author consensus to determine the accuracy of EUS for detecting cancer in the setting of chronic pancreatitis, since all previous studies only evaluated the accuracy of EUS for distinguishing cancer from chronic pancreatitis, a subtle but important difference. Despite this, sensitivity analyses demonstrated that the exact value of these variables is irrelevant when the incidence of cancer is at the base case. If the incidence of cancer were higher, then the outcomes would be sensitive to the performance characteristics of EUS and EUS/FNA. Our analysis is based on the finding that chronic pancreatitis on EUS among FPC kindreds correlates with dysplastic epithelium of microscopic ducts [20], and assumes that PC in these kindreds arises from these dysplasias. Intraductal papillary mucinous neoplasms (IPMNs) have been found in a minority of patients from FPC kindreds undergoing screening [19]. IPMNs are precancerous lesions of the main pancreatic duct and side branches. This may represent a pathway to cancer that is distinct from the one via intraepithelial dysplasia of the microscopic ducts; IPMNs produce lesions identifiable by EUS that are distinct from chronic pancreatitis. Further research is required to determine what proportion of patients from FPC kindreds develops cancer via each pathway, and whether resection of these localized lesions will prevent cancer from developing in the remaining pancreas. Incorporating results from such studies may alter the conclusions of the model in its current form. A previous cost-effectiveness analysis [11] of this issue concluded that PTP in selected patients is cost-effective, but did not incorporate QoL, information regarding the likely dominant inheritance found in segregation analyses [16, 17], the SIR of cancer in FPC kindreds [15], the EUS findings in FDRs from a larger number of FPC kindreds [18], or the long-term outcomes after TP [37], which were published subsequently. A different analysis suggested that a screening test would need at least 99.9% specificity for cancer in order to detect more true positives than false positives [97]. In conclusion, we found that FDRs from kindreds of FPC who have EUS findings of chronic pancreatitis are likely at substantial lifetime risk for PC. However, PTP is not warranted unless that risk can be stratified further, and is greater than approximately 46% (for maximizing length of life) or 68% (for maximization of quality-adjusted length of life). When mortality from locally-staged cancer is less than 76%, surveillance with EUS/FNA might be useful. Future research should be directed at methods which characterize and define the risk to allow

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application of our data to individual patients. In the meantime, asymptomatic family members from FPC kindreds should not undergo screening, unless as part of a research program, since the results should not alter management, and could potentially cause substantial harm. Acknowledgements

phenotype of chronic pancreatitis exhibited on EUS corresponds perfectly with the cancer susceptible genotype. We also assumed complete penetrance of the phenotype of EUS findings of chronic pancreatitis by the age of 45 years. The incidence of PC in FPC kindreds as a whole is therefore almost entirely attributable to the fraction of susceptible FDRs (those with endosonographic chronic pancreatitis), and the remainder of FDRs without the phenotype have an incidence of cancer similar to that of the general population. Under these assumptions, it can be shown that: Icp = (SIR + Ps – 1) ! Ipop/Ps

J.H.R. was supported by the GlaxoSmithKline Institute for Digestive Health Clinical Research Award. M.A.A. was supported by a Career Development Award from the American Society for Gastrointestinal Endoscopy. We are grateful to Dr. Brian Billings and Dr. Michael Sarr [37], who generously offered us access to their manuscript while it was in submission, and to Dr. Marcia Canto and Dr. Shyam Varadarajulu, who generously offered us access to their manuscripts while they were in press [19, 63]. Cost data were obtained with the assistance of Mary Caudill, Teresa Baker, Katherine Kastle, and Marc Halman.

Appendix: Derivation of Incidence of PC in Familial Kindreds Based on segregation analyses of FPC kindreds, the susceptibility to PC is likely transmitted by a single, dominantly inherited gene [16, 17]. Therefore, FDRs have a 50% risk of carrying the susceptibility gene, a fraction that could correspond to the empirically observed excess prevalence of 44–58% of FDRs with findings of chronic pancreatitis [19]. We therefore assumed that the

where Icp is the age-specific incidence of pancreatic adenocarcinoma among FDRs with chronic pancreatitis, SIR is the age-specific standardized incidence ratio for FDRs overall compared to the general population, Ps is the proportion of FDRs who carry the susceptibility genotype (which is identical in the base case to the prevalence of EUS findings of chronic pancreatitis in FDRs), and Ipop is the age-specific incidence in the general population. The robustness of the results to changes in these assumptions was evaluated in sensitivity analyses. The cumulative lifetime incidence of cancer was varied by (i) varying the SIR for FDRs overall compared to the general population, and by (ii) varying the proportion of FDRs who carry the susceptible genotype. When varying the proportion of FDRs who carry the susceptible genotype, we assumed that stricter EUS criteria could identify a phenotype that corresponds to the susceptible genotype, and we restricted the analysis to those patients. For instance, at one end of the range, we assumed that the susceptibility for cancer was in fact inherited in an autosomal recessive or multiallelic fashion, and that only FDRs with severe findings on EUS (5% of FDRs in the Johns Hopkins series) carried the susceptibility [19]. At the other end of the range, we assumed that EUS findings did not correlate with susceptibility at all, and all FDRs were at equal risk. Thus we were able to stratify results based on risk for cancer.

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