Isaura Ibrahim

2015 showed that these programs resulted in higher curative resection rates (60% vs. 25%), longer median survival, and higher 3-year survival rates (35, 36).

Relatively few studies have investigated the cost-effectiveness of surveillance programs for individuals at increased risk of pancreatic cancer. The available studies concluded that pancreatic cancer screening is generally cost-effective in various high-risk groups (37-40). However, no study to date has addressed the cost-effectiveness of screening CDKN2A-p16-Leiden-mutation carriers. In chapter 5, we evaluated the costs of a surveillance program in a large cohort of CDKN2A-p16-Leiden-mutation carriers. The specific aims of this study were (1) to assess the resection rate and related survival, and (2) to assess cost-effectiveness. The study demonstrated that out of the 347 mutation carriers, 31 individuals (8,9 %) developed PDAC and the tumor was resectable in 22 cases (71%). The long-term survival rate for patients with resectable PDAC was estimated at 47,1%. Cost-effectiveness of annual surveillance was estimated at 14,000 euro per QALY.

To date, four studies have addressed the cost-effectiveness of surveillance for individuals at risk for PDAC. Although all reports showed that PDAC surveillance was cost-effective, the populations analyzed (FPC, carriers of various mutations associated with PDAC development), the screening strategies (once in a lifetime, annual or bi-annual screening) and screening methods (EUS or MRI/MRCP) varied widely between the studies.

In the current study, the cost-effectiveness of annual surveillance was estimated at 14,000 euro per QALY, an estimate that is likely to be acceptable in most countries. We observed that several variables in particular influenced our study results. One important factor was the elevated genetic risk of our patient cohort, as CDKN2A-p16-Leiden-mutation carriers show a model-estimated lifetime PDAC risk of 37.6%. We estimated that surveillance could be cost-effective for populations with a lifetime risk of at least 10%. This figure matches earlier studies using hypothetical simulation models which suggested that pancreas screening is ineffective in the general population but effective in patients with a substantial risk (41-43). Screening of low-risk individuals was associated with a reduced life expectancy, an outcome attributed to the increased discovery of insignificant lesions and subsequent unnecessary surgical intervention. As an international consortium of experts currently recommends pancreatic surveillance for HRIs with an estimated lifetime risk of PDAC of >5% (5), more studies are needed to assess the cost-effectiveness of surveillance of individuals with a relatively low risk (i.e., <10%). The other key factor in cost-effectiveness was the ability of the surveillance program to detect PDAC at an earlier stage, which resulted in a considerable increase in patients with resectable PDAC (from 15% to 77.3%). Moreover, a substantial proportion (47,1%, p<0.001) of these patients can be cured. Without this observed cure, it would be difficult to exclude the possibility that improved survival due to surveillance was simply due to lead time bias (whereby improved survival after diagnosis is due to earlier diagnosis rather than longer survival). Under the current surveillance program an estimated 33,5% of diagnosed patients are considered cured, which is enough for the program to be cost-effective. Nevertheless, a few patients developed an advanced cancer within the recommended annual surveillance interval of the current program. Shorter intervals might therefore be considered in individuals with additional risk factors for development of PDAC (e.g., smoking, strong family history for PDAC). The sensitivity analysis indicated that bi-annual surveillance could be cost-effective, if it further improved the probability of cure after surgery. In conclusion, this study demonstrated that screening for PDAC is cost-effective for CDKN2A-p16-Leiden-mutation carriers. In most patients a screen-detected PDAC could be resected and these patients subsequently benefitted from considerably improved survival. Incidental findings detected during surveillance for PDAC in familial PDAC and in PNS-Leiden mutation carriers The widespread use of magnetic resonance imaging (MRI) and computed tomography (CT) has led to a substantial increase in the detection of incidental findings, more commonly referred to as incidentalomas. Currently, an increasing number of centers offer surveillance of the pancreas to individuals at high risk (IARs) of pancreatic ductal adenocarcinoma (PDAC), usually involving MRI and/or endoscopic ultrasonography (EUS)(18, 25, 44, 45). Detection of extrapancreatic incidental lesions in these high-risk groups may offer benefit if the lesion is (pre)malignant. However, if only benign lesions are found, additional imaging and surgical intervention might be a burden, especially in high-risk groups that already undergo surveillance for multiple cancers. In chapter 6, we evaluated the frequency of extrapancreatic incidentalomas in large, long-term, prospective surveillance programs for PDAC at three European expert centers and assessed the benefit of detecting these lesions. The study shows that MRI-based pancreas surveillance programs for PDAC result in the detection of a large number of incidental lesions. The most commonly found lesions were liver cysts, renal cysts and liver hemangioma, which together accounted for 74% of all incidental lesions, followed by adrenal incidentaloma in 6% of patients. Only five (0.9%) patients underwent surgery for a benign lesion: two patients for a liver cyst, one for a renal cyst and two for an adrenal incidentaloma. Extra-pancreatic cancer was detected in 11 patients (1.9%), including seven CDKN2A-p16-Leiden mutation carriers, and metastatic disease was detected in six of the 11 patients. Early detection of tumors was beneficial in at least five of the patients. Our findings for benign lesions are in agreement with studies that have reported frequencies of incidental findings detected during abdominal imaging. However, the rate of incidentally detected cancers in the subgroup of CDKN2A-p16-Leiden mutation carriers was much higher. What was the benefit of the detection of incidental lesions in our study? Although incidental findings were frequent, only 0.9% of the total group of IARs underwent a surgical intervention for a lesion, which was then found to be benign in all cases. A primary cancer, metastases of a previous cancer or a new cancer was detected in 1.9% of the total group. By contrast, in the Leiden cohort of CDKN2A-p16-Leiden mutation carriers, extrapancreatic cancer was detected in a substantial proportion of patients (seven patients out of 217 (3.2%)). The early detection of cancers in seven mutation carriers allowed curative resection of renal cancers in two patients, a gastric stromal tumor in one patient and colonic resection (and early start of chemotherapy) in one patient with CRC. In the German cohort, the detection of a renal cell carcinoma allowed curative resection. In addition, the identification of metastatic breast cancer in two patients allowed the early start of chemotherapy. What are the clinical implications of our findings? First, it is important to inform all participants at the start of the surveillance program about the possibility of detecting usually harmless incidental lesions. However, carriers of a CDKN2A-p16-Leiden mutation should be told that cancer might be detected outside the pancreas in a small proportion of patients. To improve the investigation of the pancreas, there is currently a trend toward restricting MRI scanning to the pancreas only. However, to avoid missing cancers located outside the pancreas in CDKN2A-p16-Leiden mutation carriers, MRI assessment should include at least one scan of all abdominal organs. Dilemma's in the management of carriers of a PNS-Leiden mutation (chapter 7) In chapter 7, we describe surveillance and treatment results for two CDKN2A/p16-Leiden patients with a screen-detected lesion. These two cases clearly illustrate the dilemmas faced in the surveillance of individuals at high-risk for PDAC. The first patient experienced nearly fatal complications due to surgery and was found to have a benign lesion. This is an example of a worst-case scenario that may occur in this type of surveillance program. The second patient, diagnosed shortly after the first case, had very similar imaging findings, an uneventful course after surgery, and was eventually shown to have an early cancer. In chapter 7, we addressed the following questions regarding these two patients: (a) Did the findings, especially in the first patient, justify surgery? (b) Could the benign nature of the lesion in the first patient have been predicted? (c) How can the surveillance programs be improved? (d) How can a devastating course, as seen in the first patient, be prevented? Regarding the first question, the two imaging techniques (MRI and EUS) reportedly show a high sensitivity and specificity (13). In both cases reported here the presence of a solid lesion was shown on MRI and CT, whereas the EUS was unremarkable. The fact that the lesion was palpated in both patients during surgical exploration confirmed the imaging findings and justified surgery in view of the high risk of PDAC. Lesion growth is a strong indicator for malignancy, but both patients showed only slight lesional growth. Due to the reported rapid growth of PDAC, another argument in favour of surgery is the short window of time between the detection of a lesion and development of metastatic disease (25). In relation to the second issue, prediction of the benign nature of a lesion, differentiation of benign and malignant lesions by FNA biopsy might have been considered. In this particular case no abnormalities were found on EUS, ruling out EUS-guided biopsy. In retrospect, even if the lesion had been visible on EUS, performance of an FNA biopsy would not have been useful in decision-making in this case because a negative FNA result does not exclude the presence of PDAC. Regarding the third question—improvement of surveillance methods—this case report underlines the urgent need for modification of screening methods, especially regarding improvements in the sensitivity of MRI imaging of the pancreas. Additional screening tools should also be developed. Another way to improve the surveillance program is the use of circulating tumour markers. The final question concerns how the risks of serious complications due to surgery can be minimized. Recent studies suggest that mortality rates for pancreaticoduodenectomies procedure lie somewhere between 0.5 and 6 %, with a morbidity rate of up to 40 % (46, 47). The only way to achieve the lowest possible mortality and morbidity rates is to restrict prevention programs to expert centres that carry out larges volume of pancreatic surgeries. These case reports illustrate the difficult decisions that have to be made in high-risk individuals with a suspected lesion in the pancreas. It is very important to discuss the advantages and disadvantages with a patient prior to their participation in a surveillance program so that the patient is fully aware of the risks. Advantages of the program in CDKN2A/p16-Leiden mutation carriers are that more tumours are identified at a resectable stage and that the prognosis of patients with screen-detected tumours is better (5-year survival is 24 %) than that of symptomatic patients (5–7 %) (18). Disadvantages include, (1) the surveillance program cannot guarantee that PDAC is always detected at an early and curable stage, (2) the screening protocol is burdensome and may cause anxiety before and shortly after the screening procedure, (3) there may be false positive and false negative cases, and finally, (4) treatment consists of major surgery, a pancreaticoduodenectomy or distal pancreatectomy depending on the site of the tumor, all of which are associated with substantial morbidity and mortality. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. 2. Islami F. WEM, Sung H. 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