Thursday, January 12, 2012

Screening Challenges for Pancreatic Cancer in High-Risk Population

The simple fact that the U.S. Preventive Services Task Force (USPSTF) recommended against routine screening for pancreatic cancer in asymptomatic adults (we discussed in the previous post), and just recently adjusted its position, shows clearly that the screening effectiveness for pancreatic cancer is still more than questionable, and more research is needed to develop the cost-effective, safe, and efficient ways of the early tumor detection. However, shift in the general attitude of the professionals’ approach allows allocating more significant amount of funds for the investigation and trials.

Screening Tests Accuracy

Adenocarcinoma is the principal form of pancreatic neoplasm for which screening has been considered. So far, there are no reliable screening tests for detecting pancreatic cancer in asymptomatic persons, which will allow catching the problem on the early stages, when the disease is still curable. The deep anatomic location of the pancreas makes detection of small localized tumors extremely challenging during the routine abdominal examination. Even in patients with confirmed pancreatic cancer, an abdominal mass is palpable in only 15–25% of all cases.

Imaging procedures such as magnetic resonance imaging and computed tomography are too costly to use as routine screening tests, while more accurate tests such as endoscopic retrograde cholangiopancreatography and endoscopic ultrasound are inappropriate for screening asymptomatic patients due to their invasiveness. Abdominal ultrasonography is a noninvasive screening test, but there is little information on the usefulness of abdominal ultrasound as a screening test for pancreatic cancer in asymptomatic persons. In symptomatic patients with suspected disease it has a reported sensitivity of 40–98% and specificity as high as 90–94%. Conventional ultrasonography is limited by visualization difficulties in the presence of bowel gas or obesity and by its range of resolution (2–3 cm). Even tumors <2 cm in diameter are frequently associated with metastatic disease, thus limiting the ability of ultrasound to detect early disease.

Most persons with pancreatic malignancy have elevated levels of certain serologic markers such as CA19-9, peanut agglutinin, pancreatic oncofetal antigen, DU-PAN-2, carcinoembryonic antigen, α-fetoprotein, CA-50, SPan-1, and tissue polypeptide antigen. None of these markers is, however, tumor specific or organ specific; elevations of various serologic markers also occur in significant proportions of persons with benign gastrointestinal diseases or malignancies other than pancreatic cancer.

Most of these markers have been studied exclusively in high-risk populations, such as symptomatic patients with suspected pancreatic cancer. CA19-9 has probably achieved the widest acceptance as a serodiagnostic test for pancreatic carcinoma in symptomatic patients, with an overall sensitivity of approximately 80% (68–93%) and specificity of 90% (73–100%); while the overall sensitivity was highest in patients with more advanced disease stages.

Among healthy subjects, CA19-9 has good specificity (94–99%) but nevertheless generates a large proportion of false-positive results due to the very low prevalence of pancreatic cancer in the general population.

A study of a mass screening of more than 10,000 asymptomatic persons for pancreatic cancer in Japan, using either ultrasonography alone or CA19-9 plus elastase-1, found the likelihood of pancreatic cancer given a positive screening test to be 0.5%; only one of the four cancers discovered could be curably. The predictive value of a positive test could be improved if a population at substantially higher risk could be identified. Diabetes mellitus in older adult patients might be useful as a marker for a population at high risk of having pancreatic cancer. Cohort studies have reported incidences of pancreatic cancer among diabetic patients ranging from 51 to 166/100,000 person-years.

We will review several studies which are give hope for the possibility of development for the efficient screening procedure for pancreatic cancer early detection in asymptomatic population.

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Northwestern University Study, 2007

Optical technology developed by a Northwestern University with proven efficiency dealing with the early detection of colon cancer has been successfully used in research for early detection of pancreatic cancer as well. Vadim Backman and Yang Liu teamed up with physicians at Evanston Northwestern Healthcare (ENH) to confirm they could detect both early- and advanced-stage pancreatic cancer without touching or imaging the pancreas.

The extraordinarily sensitive technique, which is minimally invasive and takes advantage of certain light-scattering effects, can detect abnormal changes in cells lining the duodenum even though the cells appear normal when examined with a conventional microscope, detecting the changes which could accurately predict the presence of cancer.

More than 30,000 people in the United States die each year from pancreatic cancer. The overall five-year survival rate is less than 5 percent; most patients die within the first two years. If detected early, when the tumor can be successfully removed, however, the survival rate is 100 percent if a precancerous lesion is found and 50 percent for a stage 1 cancer.

“Using endoscopy and taking biopsies of the pancreas are extremely risky procedures that are not used on asymptomatic patients,” said Backman. “When a patient becomes symptomatic, it is too late. This creates a vicious cycle that we want to break.

“We have found that we can take measurements safely in the duodenum and use a biological phenomenon called the 'field effect' to our advantage,” he said. “If you have a precancerous or cancerous lesion in the pancreas, even tissue that looks normal and is away from the lesion -- including in the duodenum, a different organ than the pancreas -- will have molecular and other kinds of abnormal changes. No one can detect these changes earlier than we can.”

 “We also found that the diagnostic performance of the technique is not compromised by risk factors in the patients,” said Liu. “The markers don't depend on age -- the cells know if they are old or if they are cancerous. The markers do not change if the patient is a smoker. And the markers do not change with the location, stage or size of the tumor in the pancreas.”

Most cancers in the pancreas originate from the main pancreatic duct, a 10-centimeter-long duct located in the pancreas that perforates the duodenum, the first and shortest part of the small intestine. The pancreatic duct is difficult to reach and if attempted, it is a risky procedure with a 20 percent chance of significant complications, including acute pancreatitis.

In the study, biopsies of normal-looking tissue were taken from the duodenum near the opening of the pancreatic duct for analysis. For each sample, light is shined on the tissue. The light scatters and some of it bounces back to sensors in the fiber-optic probe. A computer analyzes the pattern of light scattering, looking for the “fingerprint” of carcinogenesis in the nanoarchitecture of the cells.

The researchers found the technique identified with 100 percent accuracy each person who had a resectable (the tumor can be removed surgically) cancerous tumor in the pancreas. Some people were identified who did not have a tumor; it is uncertain whether this is a false finding or if it means those people could be at risk for developing pancreatic cancer and need to be watched closely.

The method combines two complementary technologies developed by Backman and colleagues in his lab: four-dimensional elastic light-scattering fingerprinting (4D-ELF) and low-coherence enhanced backscattering spectroscopy (LEBS). The researchers found that the two combined work better than one alone in pancreatic cancer screening.

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University of Michigan Comprehensive Cancer Center Study, 2011

Researchers at the University of Michigan Comprehensive Cancer Center have identified a protein that shows distinct changes in structure between pancreatic cancer, non-cancerous diseases and normal blood serum. The protein also changes from early stage pancreatic cancer to advanced disease. The finding suggests a blood test could serve as a potential screening tool to detect pancreatic cancer -- which has the worst prognosis of any cancer type -- at an earlier, more treatable stage.

In this study, senior study author David M. Lubman and colleagues looked at proteins in the blood, and identified one, haptoglobin, that is in fairly high abundance. Haptoglobin is a type of glycoprotein, a category of proteins that has complex chains of sugar groups attached to it. These sugar groups are highly regulated in normal cells but develop a different structure in cancer cells.

Because haptoglobin appears in abundance in serum, it is easy to pull out and isolate from the blood serum with an antibody. The researchers could then look at the structure of the sugar groups from the haptoglobin in the serum using a mass spectrometer, which is a device that separates and identifies molecules based on their molecular weight. They found it was easy to see the changes in the structure of the sugar groups from serum samples of pancreatic cancer versus non-cancerous disease, with distinct changes in structure or the amount of each structure present for each stage of pancreatic cancer versus pancreatitis, diabetes or normal samples.

Researchers are looking to develop a method that would allow them to evaluate hundreds of samples at once. Eventually, they hope this would lead to a test in which patients submit blood samples through their local doctors' offices, which are then sent to centralized laboratories for processing.

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University of Vermont Study, 2011

A screening modality that combines serum carbohydrate antigen (CA) 19-9 and endoscopic ultrasound (EUS), applied to persons at high risk for pancreatic cancer appears to be effective, based on the results of a feasibility study conducted by researchers from the University of Vermont.

“Our hypothesis was that a high-risk population identified by age and at least one first-degree relative with pancreatic cancer can be successfully screened,” said lead author Richard Zubarik, MD. “Our objective was to determine whether early pancreatic neoplasia can be detected in a high-risk population by using tumor marker CA 19-9 followed by targeted EUS. We also sought to determine whether this protocol was more likely to detect early-stage pancreatic cancer than standard means of detection,” he said.

“As a sole screening test, it would not be appropriate, but it is a way of enriching the population of patients,” Dr. Zubarik added. Elevated levels of CA 19-9 indicate screening with EUS with fine-needle aspiration (FNA) biopsy, “which improves the specificity dramatically.”

Traditionally, CA 19-9 has performed poorly as a screening modality for pancreatic cancer in studies of the general population, but those studies have included patients younger than age 50 years or have employed insensitive imaging modalities. More recent screening protocols have focused on populations at high risk for pancreatic cancer, as this study did.

Regarding the decision to use CA 19-9, Dr. Zubarik noted that it is inexpensive and is relatively sensitive (85%) and specific (90%-95%). The study suggests that potentially curative pancreatic cancer can be identified with CA 19-9 testing combined with targeted EUS, and that stage I pancreatic cancer is more likely to be found using this screening protocol than with standard means of detection, Dr. Zubarik concluded. The potential advantages of this strategy include acceptable rates of disease diagnosis and exclusion, as well as acceptable costs, he added. The cost of detecting one pancreatic neoplasia as part of the protocol was $8,430.75, while detecting one adenocarcinoma cost $41,133.

In spite of the noticeable positive development, However, Dr. Ma, involved in the study, suggested that this screening protocol is still cannot be recommended for clinical applications due to the several obstacles. Only 70% to 80% of pancreatic cancer patients express CA 19-9, so this approach will not pick up the other 30% who have pancreatic cancer but do not express this biomarker, he pointed out. "We need a better, more specific serum biomarker for pancreatic cancer screening than CA 19-9." In addition, EUS fine-needle aspiration (FNA) is highly complex, operator-dependent, and requires specialized expertise. "The centers that can do good, safe EUS FNA of the pancreas are often confined to tertiary centers, posing a limitation to large-scale screening," he said.

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