Analysis of Current Pancreatic Cancer Screening Methods & Future Recommendations

ABSTRACT PAGE
Objective
Background
Results
Conclusion
(1) what the objectives of the study were; :)
(2) how the study was done; ---
(3) what results were obtained;
(4) and the significance of the results.

Treatment for pancreatic cancer is often no longer viable (practical) by the time the condition can be diagnosed. This is due to the lack of effective screening methods to detect the tumor or cyst in its earliest curable stages. The ability to successfully detect pancreatic cancer is highly dependent on an effective screening method with high sensitivity and specificity that can detect the tumor or cyst early in its development. In the United States, many of the current methods are too costly, too invasive, unavailable for widespread use, and lack high sensitivity and specificity. There is a strong need to find a more promising screening method that is inexpensive, noninvasive, available for widespread use, and maintains high sensitivity and specificity. The immediate objective of this research project was to evaluate the current screening methods and make a recommendation for a future screening strategy with strong potential to detect the cancer in its earliest stages while improving the sensitivity and maintaining high specificity. The first step in the investigation process was to identify a high-risk population for pancreatic cancer. Then, current screening methods were evaluated based on their ability to detect pancreatic cancer among the defined high-risk population and their cost, invasiveness, availability, sensitivity and specificity. After determining the Magnetic Resonance Imaging (MRI) as the best current screening method, further research indicated that plasma microRNA in combination with the biomarker CA 19-9 has potential to detect pancreatic cancer in its early stages while improving the sensitivity, specificity, availability, cost, and invasiveness. The microRNA and CA 19-9 assay demonstrated a sensitivity of 92.0% and a specificity of 95.6% in differentiating pancreatic cancer from a population of otherwise healthy controls. In the future, microRNA and CA 19-9 assay should be implemented and advocated as a novel screening method for pancreatic cancer.

A. The Problem
Pancreatic cancer ranks fourth among cancer-related death in the United States and has one of the worst survival rates of all cancers (American Cancer Society 1).The American Cancer Society’s estimates that in 2013, 45,220 people will be diagnosed with pancreatic cancer and approximately 38,460 Americans will die of pancreatic cancer (D. Hariharan, A. Saied,). Diagnosing and determining the size and extent of the pancreatic tumor or cyst is one of the first steps in finding the most effective treatment. However, most current screening methods for pancreatic cancer can only detect the pancreatic tumor or cyst in advanced stages, when treatment may no longer be viable. The purpose of this investigation is to analyze and compare current screening methods for pancreatic cancer and make a recommendation for a future screening strategy with strong potential to detect the cancer in its earliest stages while improving the sensitivity and maintaining high specificity.
This investigation began by identifying and defining a high-risk population of pancreatic cancer to focus on. The current screening methods selected for evaluation included the Magnetic Resonance Imaging (MRI), the biomarker CA19-9, the Endoscopic Retrograde Cholangiopancreatography (ERCP), the Fine Needle Biopsy, the Endoscopic Ultrasound, the Positron Emission tomography (PET), and the Computed Tomography (CT). Each of these methods were analyzed and rated on a scale of 1 to 5 based on their costs, risks and invasiveness,` convenience, sensitivity, and specificity. After each method received an average score, comparisons between the various methods were facilitated. However, further research indicated that biomarkers in combination with CA 19-9 exhibited greater potential for detecting pancreatic cancer in its earliest stages. In particular, biomarker CA19-9 combined with microRNA (miRNA) has the ability to compensate for each other’s limitations and detect pancreatic cyst and tumors earlier than the other current screening methods evaluated.

B. Analysis of Current Screening Methods
A list of current screening methods were narrowed down from a pool of many current screening methods for pancreatic cancer. These methods were selected because they were commonly examined in journal articles to screen for pancreatic cancer. Furthermore, it was necessary to determine the feasibility of each diagnostic measure as a screening method. An efficient screening method must be useful on a widespread basis and on an asymptomatic population. The PET scan, CT scan, Endoscopic Ultrasound, CA 19-9, Fine Needle Biopsy/Fine Needle Aspiration, ERCP, and MRI were assessed according to several important criteria--costs, risks and invasiveness, convenience, sensitivity, and specificity.

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These categories were ranked on a scale of one to five, five being the best and one being the worst. Most of these rankings were on a relative basis. For risks and invasiveness, a score of five indicated no risk or side-effects except to a select population, and a score of one indicated some risk of fatality. A score of five for cost was $200 and below, and a score of one for cost was upwards of $5000. Convenience a combination of two categories, which included time it took to get results and availability of the technique (what hospitals or clinics had the screening method and how difficult it was to operate the apparatus or read the results). Time to receive results was distinguished between a five for a day or less and a one for more than a week. A score of five for availability described a screening method present in major hospitals and small clinics. A score of one was designated to a screening method only available in a few places and high skill needed to conduct the screen or examine the results. The rankings for specificity and sensitivity were five – 90-100%, four – 71-90%, and a three – 51-70%. The rating scale was not weighted because each patient has individual needs and preferences. The information for each current screening method is included in Figure 2. Then the respective point values were attributed to each screening method based on the categories illustrated in Figure 3. These points were averaged in Figure 4 to compare with the other screening methods.
Ankit charts

C. Evaluating Best Screening Method
Out of all the various screening methods listed, the MRI was determined to be the most favorable and efficient choice because of its overall rating in terms of cost, time, risks, invasiveness, side effects, labor, sensitivity, and specificity.
The average MRI cost for pancreatic screening within the United States ranges anywhere from $400 to $3500 depending on where the patient is tested (citation).The cost is broken down into two parts, the technical fees and the professional fees. Insurance was not taken into account because of the large variance in coverage. Below is a table of average costs for MRIs across the country. Testing Facility Location | Test Type | Average Cost | Orlando, FL | MRI | $2,229 | Dallas, TX - MRI Testing Facility A | MRI | $3,624 | Dallas, TX - MRI Testing Facility B | MRI | $2,172 | San Diego, CA | MRI | $2,826 | Salt Lake City, UT | MRI | $1,694 | Detroit, MI | MRI | $3,461 | New York, NY - MRI Testing Facility A | MRI | $1,785 | New York, NY - MRI Testing Facility B | MRI | $2,199 | Raleigh, NC | MRI | $3,001 | Omaha, NE | MRI | $2,502 |

Figure 5:
Compared to the other scans like the CT scan that costs between $1200-$3200 or the PET scan that cost $3000-$6000, the MRI procedure will generally cost less. For this reason, the MRI was given a score of three.
In terms of time, the MRI procedure takes longer than most scans, but the test results come back faster than the other available scans. On average, the MRI scan ranges from 30 minutes up to 2 hours. If a radiologist is present, results can be immediately interpreted after the procedure is completed The average time it takes for MRI results to get back range from 1 to 2 days. The PET scan takes much longer to perform (2-4 hours) and the CT scan only takes 5 minutes but the time it takes for the results to come back are longer. The MRI received a score of four in this category.
MRIs have very few risks and most of them are minimal. There are no known harmful effects from the strong magnets but pacemakers, artificial limbs, and metal medical devices that contain iron may be affected. Metal foreign bodies in the eye can damage the retina. Iron pigments in the skin from tattoos can cause skin or eye irritation? (citation). The MRI can cause a burn in medication patches and there may be a slight risk of an allergic reaction to the contrast material (IV) used along with a chance of infection at the IV site (citation). Most of these risks are preventable if the harmful parts are removed before the test. If the risk cannot be avoided, and it puts the person at high risk, he or she will be recommended to undergo another test such as a PET scan. Due to its low risk factor and minimal invasiveness, the MRI was given a score of five for this category.
After an MRI is completed, there are no side effects from the magnetic field or radio waves. The patient may feel tired or sore from lying in one position for such a long period of time. If one has fillings, a tingling feeling in the mouth will be experienced. Additionally, the area examined with the MRI will feel warm. These side effects are not harmful but are just important things people should be informed of before the procedure just to be sure the patient is up to date and agrees to move on with the procedure. The fact that the MRI has no harmful side effects or delivers no pain makes it more favorable unlike some other scans which involved a fatality risk.
This scanning method is not labor intensive; in fact it has minimal labor involved. Only two people are really needed for this test: a technician and a radiologist. The technician is in charge of handling the whole procedure which includes placing the patient within the machine and observing the patient so nothing goes wrong. The radiologist merely just reads the end scan and provides feedback and results. Having little labor involvement is an advantage to the MRI scanning method.
In comparison to other evaluated screening methods, the sensitivity and specificity of the MRI were higher. It has a sensitivity of 96.2% and a specificity of 98.6% (Ichikawa, 2007). The MRI was the only method to receive a five in both rating categories for sensitivity and specificity. When taking into account all the advantages that an MRI has to offer, it became evident that the MRI was the established and dominant current scanning method.
Based off the averaged rating score, the MRI was the best current scanning method. However, it is not the best recommendation for the future primarily because the MRI scanning method is not viable for large scale implementation. It would cost too much and take too long to screen a large population using the MRI. Although the MRI received the highest mean score, several methods were less expensive and more convenient, especially CA19-9. Therefore, further research was complbiomarkers were evaluated for future use.

D. Defining High Risk Population
Evaluation began by narrowing the asymptomatic population for screening. A high risk population was defined using four parameters: familial history of pancreatic cancer, age, smoking and diabetic status. Only those at high risk were to be tested for pancreatic cancer with a multiplex assay. Figure 1: A decision tree describing the recommended algorithm for determining if an individual is at high risk.
Age is the primary factor in this algorithm because the age of the individual is almost always known compared to that of familial history. The majority of people who develop pancreatic cancer are above age 45. An individual who is of 45 years of age and has familial history of pancreatic cancer should be screened. It was observed that individuals with two first degree relatives develop pancreatic cancer at an average of ten years sooner (at age 57.6) than those with no familial history. They also have a chance of developing pancreatic cancer that is two times that of an individual without familial history before the age of 50 years (James, Ted A., 2004). If individuals do not have a familial history, they should still be tested if they are either above 60 years of age and diabetic, or diabetic smokers. Smokers tend to develop pancreatic cancer an average of 20 years prior to that of non-smokers (Klein, A. P. (2013).
A recent meta-analysis of 35 cohort studies concluded that those with DM (Diabetes Mellitus) had an increased relative risk (RR) of developing pancreatic cancer of 1.94 (Cui, Y.Andersen, D. K.). A clear positive association of diabetes and pancreatic cancer has been observed, but a mechanism explaining this association has not been fully discerned yet. Insulin resistance and induced compensatory hyperinsulinemia are believed to be likely mechanisms to explain the association between DM and pancreatic cancer. These conditions could lead to the stimulation of proliferative and anti-apoptotic pathways potentially inducing cancer development(Cui, Y.Andersen, D. K.). Therefore, diabetics are more likely to develop pancreatic cancer and are considered as high risk. If an individual is of age 45 and has a familial history of pancreatic cancer but does not possess any of the other high risk characterizes then they should be tested on an annual basis for pancreatic cancer. The appropriate frequency was decided to be a year because as stated earlier: the purpose of this study is to detect the cancer in its earliest stages. This is an appropriate frequency because after the initiating mutation, it is estimated that it takes 15 years for pancreatic cancer to develop to a metastatic stage of cancer. Therefore, the frequency with which we test must be significantly shorter than 15 years and could coincide with annual doctor visits (Klein, A. P. (2013)). By narrowing the general population to a high risk population the probability of producing a false negative from the biomarker assay is lessened and therefore increases the specificity of the assays.

E. Analysis of Biomarkers A biomarker is a biological indicator of a physiological occurrences. There are specific biomarkers that can be used to detect pancreatic cancer. In order to decrease the death rate of pancreatic cancer, biomarkers that can identify malignant tissue during earlier stages are preferred. In addition, the biomarkers with the highest sensitivities and specificities should be implemented in the screening of pancreatic cancer. While CA 19-9 is not used to screen asymptomatic populations, it is the only biomarker currently used in clinical practice for pancreatic cancer screening (Eguia, Gonda, & Saif, 2012). “Newer markers are currently under investigation and preliminary data suggests that some of these could be utilized on their own, or in combination with current screening and diagnostic modalities, in an effort to improve our early tumor detection rate” (Eguia et al., 2012). Since CA 19-9 is the singly implemented biomarker for pancreatic cancer screening, the most feasible and effective method would be a combination biomarker assay including CA 19-9 and other biomarkers.
At first, sensitivity and specificity were the most important criteria in choosing the best biomarker(s). The PAM4-based serum enzyme immunoassay (EIA) had a sensitivity and specificity of 77% and 95%, respectively, for late stage pancreatic cancer; the sensitivity for stage 1 was 62% and 86% for stage 2 (Gold et al., 2010). MUC4 proved to be an accurate diagnostic biomarker, but required a Surface-Enhanced Raman Scattering (SERS) assay, which is an unconventional test (Wang et al., 2011). Metabolomic profiling for biomarkers involves the extraction of cancerous tissue for analysis (Kaur et al., 2010). Tissue based indicators such as TROP2 should be disregarded for asymptomatic screening, as this would involve invasive procedures. Therefore, viable early screening methods should consist of serum-based assays, or any other minimally invasive methods. Combining ULBP2 with CA 19-9 increases sensitivity to early stage pancreatic adenocarcinoma; however, the high-throughput localized surface plasmon coupled harmonic biosensor is employed instead of the conventional enzyme-linked immunosorbent assay (ELISA) for detection (Chang et al., 2013). Although certain biomarkers exhibited high accuracy detection, the practicality of the screening methods has to be taken into account. Several combinatorial biomarker panels were found that included CA 19-9 using conventional screening methods for detection while also demonstrating high sensitivities and specificities. Buenger explains that MCSF with CA 19-9, CEA with CA 19-9, SAA, Haptoglobin and CA 19-9, TSGF, CA 242 and CA 19-9, and HSP27 with CA 19-9 are potential panels (Buenger, Laubert, Roblick, & Habermann, 2011). The screening methods for these various panels are conventional, including ELISA, MEIA, and RIA (Buenger et al., 2011). Using the values for the sensitivity and specificity of CA 19-9 as a benchmark, every panel demonstrated improved diagnostic performance, with the lowest sensitivity of the aforementioned combinations being 77% and the lowest specificity at 87% (Buenger et al., 2011). However, the miRNA + CA 19-9 panel outperformed all of the listed multiplex assays.
F. Evaluation of Biomarkers
The biomarkers were narrowed down by the way they were tested in patients. Tissue-based testing for biomarkers was completely eliminated because the invasiveness was high. The biomarkers that were serum based and blood tested were used because the invasiveness was low. Some testing forms were the ELISA test, MEIA, Plasma Samples with PCR, Affymetrix Human Genome U133 plus 2.0 Array, RIA test, and the immune-magnetic separation. After the testing methods were evaluated, the biomarkers were narrowed down by their sensitivity and specificity values. The biomarkers chosen had increased sensitivity without sacrificing specificity. After finding similar values of poor performance in the early stage of pancreatic cancer, combinations of biomarkers were considered. (mostly redundant to E.)
Figure 3: Evaluation of Combined Biomarkers
The performances of these assays were compared to CA19-9’s. Even though there are many combinations, the miRNA + CA19-9 combination was selected because CA19-9 is currently used. Figure 3 organizes the combinations assessed, adding the stage of detection as a new criterion for evaluation. This criterion was only added to narrow down the last few combinations because the investigation incorporates the detection stages. It would be practical and more beneficial if an early stage detection method was found. Using this, the top combinations showed an increased sensitivity without sacrificing specificity. In Figure 3, different colors marked the narrowing down of biomarker combinations even further. These biomarkers were distributed in 3 categories according to specificity and sensitivity compared with numbers close to CA19-9. The green selections were categorized with combinations that had close to or equal to 100% specificity but sacrificed sensitivity. The orange section was categorized with combinations that illustrated increased specificity and sensitivity or similar percentages to CA19-9. The yellow selection was categorized with combinations that showed increased specificity without sacrificing sensitivity compared to CA19-9. One of the panels evaluated targeted CA19-9 and plasma microRNA. Recent cancer research has pointed to miRNA as a viable target for cancer screening. MicroRNAs are short, non-encoding RNA sequences that silence their corresponding mRNAs by binding to a complementary sequence (Sassen, Miska, & Caldas, 2008). This downregulates whatever protein that the mRNA codes for (Sassen et al., 2008). Since miRNAs perform key regulatory functions, some suspected that they might be aberrantly expressed in cancer, and studies have indicated that this is the case (Sassen et al., 2008). Based on the available literature, it was decided to recommend the multiplex assay targeting miRNA and CA19-9. Research performed by Liu et al. (2012) indicates that this panel will detect stage one pancreatic tumors. It demonstrated a sensitivity and specificity of 92.0% and 95.6% (respectively) in differentiating pancreatic cancer patients from healthy individuals (Liu et al., 2012). In distinguishing pancreatic cancer from chronic pancreatitis, the authors found a sensitivity of 87.7% and a specificity of 96.3% (Liu et al., 2012). This high performance is crucial, because the two conditions present with similar symptoms and require different therapeutic approaches (Freedman, 2012). The panel was also effective in distinguishing pancreatic cancer in a combined population of healthy and chronic pancreatitis patients; it demonstrated a sensitivity of 87.7% and a specificity of 97.7% (Liu et al., 2012). This method should be fairly cost effective to implement. The necessary blood sample can be collected using standard lab procedures, which are easy and inexpensive to perform. In conducting their research, Liu et al. (2012) used a TaqMan MicroRNA Reverse Transcription Kit (which costs $306.00 and can be used for 200 reactions), a TaqMan Universal Master Mix real-time PCR kit (which costs $448.00 and can be used for 200 reactions), and a 7500 HT quantitative PCR machine, all from Applied Biosystems ("Life Technologies: Applied Biosystems," 2012). Considering that their research only identified two microRNAs that were effective as screening targets, this method should only be a little more expensive than CA19-9 screening alone. Even with strong performance in pancreatic cancer detection, clinical implementation of miRNA screening would be questionable if the method lacked wider applicability. Fortunately, miRNA can be used to screen for other cancers. In one study, researchers were able to identify 12 out of 17 poorly differentiated tumors based on their microRNA profiles (Sassen et al., 2008). Unique microRNA profiles have been discovered for “cancers of epithelial and hematopoietic origin” and “a subgroup of gastrointestinal tumors” (Sassen et al., 2008). The relevance of microRNA is likely to expand as more literature is published.

G. Future Recommendation
A methodology for the application of the microRNA/CA 19-9 multiplex assay was a vital part of the final recommendation. Before screening an individual with the microRNA/CA 19-9 immunoassay, their risk for pancreatic cancer would be determined using the aforementioned criteria and flow chart (SPECIFY CHART). A high-risk patient would ideally be screened during their annual checkups for pancreatic cancer with the microRNA and CA 19-9 assay.
The final results of the assay would influence the recommendation for future diagnostic and prognostic testing. If both the microRNA and the CA 19-9 levels indicate a positive result for pancreatic cancer, an endoscopic ultrasound in conjunction with fine needle aspiration (EUS/FNA) would be recommended. The increase in invasiveness of EUS/FNA is countered by its increase in sensitivity and specificity to almost 100%. (GET REFERENCE). The probability of a false positive (92% sensitivity) with combined testing for microRNA and CA 19-9 allows for an increased sense of urgency. if the result is two positives, which warrants the more invasive testing to be completed earlier in the diagnostic process. (WHAT?)
*If the microRNA and the CA 19-9 levels indicate one positive result and one negative result, an MRI scan would be recommended. The uncertainty within one positive result and one negative result merits further testing. However, this additional testing would not be as extreme as testing required when the multiplex assay results in two positives. There would likely be less of a time constraint on the patient to get treatment since the cancer may be in its earlier stages or not present at all. Therefore, the MRI would be the most feasible and useful method to proceed screening because of its low risk, convenience, and relatively high sensitivity and high specificity.
If negative results were observed in both microRNA and the CA 19-9, no further diagnostic testing would be recommended. However, annual screening would be continued. The high risk patient would still need to be screened according to the methodology proposed. Annual screening would allow for physicians to watch the levels of each biomarker over time. If physician observe steadily rising levels of microRNA and/or CA 19-9, even if it is below the standard levels for a positive result on the assay, they would recommend further testing to check for pancreatic cancer. (or ascertain the reason for the increasing levels.)

H. Conclusion:
Current pancreatic cancer screening is plainly inadequate. Before selecting a novel pancreatic cancer screening method, current detection methods were analyzed, evaluated, and rated. Only then were possible screening methods for the future evaluated and recommended. Overall, MRI was found to be the most advantageous of the current screening methods because of its high availability, sensitivity, and specificity, as well as its low risk and relatively low cost. Unfortunately, this high score does not qualify MRI as a viable screening method. It is too expensive and too inefficient to ever be considered for large scale implementation. Therefore, it was determined that only a serum or saliva based biomarker assay could be utilized as a screening method. Consequently, a multiplex assay of CA 19-9 and microRNA was recommended based on its practicality (the screening can be conducted using a blood sample), its effectiveness in detecting early pancreatic cancer, and its high specificity and sensitivity. A broad plan of action was recommended so that physicians could implement it. This methodology should detect pancreatic cancer at an early stage and subsequently increase the survival rate for the condition.

Works Cited

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Christina

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Joshua
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