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Tuesday, April 19, 2011

Colorectal Cancer Screening - New biomarkers (ColoVantage)

Colon Cancer Screening:  To scope or not to scope?

By Yusuf M. Saleeby, MD

Colon cancer screening by fiberoptic colonoscopy is recommended by the vast majority of physicians and the American Cancer Society as a screening test for colorectal cancer.  While colonoscopy is the “gold standard” for colon cancer screening, nearly 50% of Americans over the age of 50-years avoid the procedure and ignore the recommendation. There are some obvious and not so obvious complications and risks associated with the procedure and the notions people have with the bowel prep process and undergoing conscious sedation are not at all appealing.  But many avoid the procedure due to expense, discomfort of procedure, and inability to devote the time for the relatively invasive procedure.  A recent study by a British group of researchers published in the peer-reviewed medical journal Lancet calls into question the validity of conventional fiber-optic colonoscopy as a screening tool.

Colorectal cancer is the third most common cancer and the 2nd leading cause of cancer death in the US, Canada and Europe.  There are about 100,000 new colon cancer cases in the US each year and approximately 40,000 new cases of rectal cancer.  Of these, there are about 50,000 deaths annually attributed to colorectal cancer.  What causes colon cancer is a difficult and elusive question that has not been fully explained.  However, epidemiological studies have revealed that dietary constituents are implicated in colorectal carcinogenesis.  Those constituents are a diet high in fat and red meats, considered causative, and a diet low in calcium and fiber as these would be considered protective.  Additionally, there are genetic factors.   For example, researchers have found that certain biomarkers in both animal and human trials affect the dietary factors.  Colon cancer develops by an adenoma-carcinoma sequence in the pre-cancerous or injured cell.  The appearance of colonic polyps has been an end-point in some research trials, however, normal appearing mucosa can still contain very small foci of aberrant crypts (invisible to colonscopy) referred to as micro-adenomas and these will certainly lead to dysplasia.  Researchers are studying these small foci and discovering what diet and chemopreventive agents work best at suppressing their growth.  Omega-6 fatty acids affect lipid peroxidation of DNA and this exposure provides stimulation for precursor tumor cells.  Diets low in calcium apparently inhibit apoptosis (cancer cell death) leading to higher risk as well.  Calcium has also been shown to reduce the recurrence of adenomas in three recent trials.  However, in one of these studies the use of fiber in the diet actually increased recurrence dramatically, counter to what we currently believed about fiber.  Much study is needed to realize the impact of our diet and environment on ur genes and how that interaction produces cancer.

It has been shown through many trials that colon cancer screening, effective follow-up and treatment can reduce risk of colon cancer death by as much as 35% and risk of getting colon cancer by 20% with early detection of precancerous polyps, this according to Dr. Otis Brawley, chief medical officer of the American Cancer Society.  The much used, most efficient, least expensive and practical screening test is the stool occult blood test (aka FOB or Hemoccult®).  With an abnormal finding (positive for occult blood) the next step can be taken.  Most American physicians would opt for a referral for colonoscopy.  But there are alternatives.  There are less expensive and possibly safer alternatives to the more invasive conventional colonoscopy which has been the predominant method for further screening (and now primary screening) for colon cancer.
A 2004 research study performed in England over a 4-month period reviewed the results of some 9223 colonoscopies performed in the traditional flexible colonoscopy fiber-optic method, the majority of which were conducted in teaching hospitals.  To paraphrase the study, it revealed that IV sedation was used in just over 94%, cecal intubation (the ability to run the scope to the end-point which is the cecum) was only 56.9%.  Reasons for failure were attributed to patient discomfort (35%), looping (30%), and poor bowel prep (19%).  Normal results were reported in 42.1%.  Polyps were reported in 22.5% (a pre-cancerous finding) while evidence of carcinoma was only realized in 3.8% of cases.  Rectal bleeding requiring admission was reported in six patients and the overall perforation rate was one in 769 cases.  Colonoscopy was also considered a factor in six deaths occurring immediately following the procedure.  The conclusion of this study revealed a wide variation of sedation guidelines, the studies were often incomplete and does not achieve the targeted 90% cecal intubation rate.  Serious complications were comparative with previous studies and points out that while thousands are done in America, there are inherent risks and short-comings.

The American Cancer Society is now recommending the use of Virtual Colonoscopy as an alternative to traditional fiber-optic conventional colonoscopy (CC).  Virtual Colonoscopy is the use of a spiral Computed Tomograph (CT) to visualize the colon.  The trade offs are a little radiation exposure in virtual, but the gain is a better study technically, with no failure to “progress to the cecum” issue, the ability to re-visit the study and finer resolution.  The upside continues as it is non-invasive and thus the risk of perforation, post-operative complications, bleeding and risks of anesthesia are eliminated.  Cost is another factor in favor of VC over conventional fiber-optic method.  The most obvious downside is that if a malignant lesion is noticed there is no way to perform an excisional biopsy for further pathological study; one would have to sit for a conventional colonoscopy.

Virtual colonoscopy as it continues to develop, evolve and become more popular will realize a costs drop.  Patients find it more comfortable, there is no need for procedural sedation, and the risk of penetrating iatrogenic complications are almost nil.  Insufflations of colon with air is the only “invasiveness” and can be mildly uncomfortable, though nothing like the introduction of a scope.  Another benefit is that a day off from work and limiting other activities is not necessary.  By insertion of a short rectal tube, carbon dioxide is used to insufflate or expand the colon lumen for better visualization.  No sedation is required, the spiral CT study only lasts 15-minutes at most and the patient can return to normal activities post study.
Specialized software is used to produce 2D and 3D reconstructions of the colon for radiological interpretation.  Using VC permits assessment of colonic segments that are rendered inaccessible to CC as in the case of an obstructing lesion or patient intolerance.   Additionally, the modality of CT in the performance of a VC allows detection of potentially important extra-intestinal findings (e.g. tumor in another solid organ) that would not be found by any of the other screening techniques.

In a recent clinical study involving 6,283 screening subjects, the diagnostic yield and use of resources for screening purposes compared VC to CC. The study found that VC and CC had similar rates for detecting advanced cancer, but CC had considerably greater complication.  The American College of Radiology Imaging Network trial revealed that CC does have the advantage of being both a screening and therapeutic tool, but VC appears to be a good screening alternative due to its good performance in recent studies, less invasive method, and more efficient use of resources.

Colorectal cancer screening with VC has been endorsed by the three major gastrointestinal societies: the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (AGSE), and the American College of Gastroenterology (ACG).
VC is also indicated after incomplete conventional colonoscopy, as up to 13% of incomplete CC were found to have lesions 6mm and larger.  VC is better than a barium-air contrasted study due to reduction in sensitivity of the contrast.  Because of the nature of the CC exam, and the unwillingness of the population at large to undergo this type of exam, this may explain the reason as to why 50% of eligible adults needing the CC do not get it performed. 

The one main concern with using VC is the radiation exposure.  However, the use of very low dose scanning protocols that reduced radiation exposure can still maintaining image quality.  Even with the use of multi-slice spiral scanners, radiation dose is kept to a minimum by reducing the mili-Amp current used.  In one study researchers found that the absolute life time risk for cancer induction from a normal dose virtual colonoscopy was only 0.14% in a 50 year-old person and about 0.07% in a 70 year-old person.  When you compare the 6% mortality risk from colon cancer against the much smaller cancer risk from VC radiation exposure, the benefits far outweigh the risks.  Risk of perforation with current carbon dioxide pumps is about 0.005%, again far less than with standard CC procedures.

When running a cost analysis, this is what I have found to be the case:  A standard doctor’s office visit for consultation, pre-procedure lasting no more than 5-minutes costs $216.  Estimates for the procedure itself for specialist performing it was around $850.  The estimated cost for anesthesia was somewhere between $300 and $400.  Not figured into this cost was the use of the GI suite/operating room.  That would have been billed separately from the hospital used.  So you are going to walk away with a bill at or over $1400.  That is even before any intervention that may be involved.  If a biopsy is taken, then you have that additional procedure billed and then there are the costs of the cyto-pathology report.  So this becomes a very expensive screening process.  Often too expensive for the vast majority of Americans who don’t have the health care coverage or who are uninsured.  VC typically comes in at about $1200 for the procedure and reading, but that cost will certainly drop it becomes more popular.  That being said, you are paying for convenience, comfort and putting yourself at less risk for untoward outcomes.  More people can be screened with the less expensive VC procedure, thus eliminating the risks associated with CC, the expense and time involved.  When positive findings are found on VC they can be referred to a gastroenterologist for CC and biopsy and further workup, thus lightening the screening burden on this sub-specialist group.  Virtual colonoscopy may not be covered by third-party payers for screening purposes at this time; however that is likely to change in the near future.
But for most patients seeking screening exams there are still far less invasive, less costly and less time consuming options.  The keyword here is medical biomarkers.  Not to be overlooked, and worth mentioning again is the most simple and effective screening method on the first tier; the stool occult blood test (FOB, Guaiac® or Hemoccult® test).  This test can be performed by your doctor or at home by yourself with a simple kit.  The test kit is then developed with a chemical solution to detect microscopic blood in your feces that is typically associated with a pre-cancerous or cancerous lesion.  While a positive test may mean other things besides malignancy (hemorrhoids, fissures, infection, recent intake of undercooked red meat) there are other tests used to back this screening modality up.  This occult blood test can be had for a few dollars. 

The advent of biomarkers has made the screening and management of many cancers less invasive in the 21st century.  There are dozens of biomarkers that already exist and many more in development with new tests coming to clinical use each year.  There are biomarkers for the detection of prostate, breast, lung cancers and many more.  For the purpose of this discussion we will limit ourselves to the biomarkers currently available for the potential screening and management of colorectal cancer.  Chief among the markers is Carcinoembryonic Antigen (CEA), it is rather non-specific as it can detect different malignancies that arise under the diaphragm.  Smokers typically have an elevated CEA for starters and this must be realized when using this test as a screening tool.

Another cancer biomarker is CA 19-9.  The CA is shorthand for carbohydrate antigen.  This test is also known as sialylated Lewis (a) antigen and is also a blood test like CEA, but more specific for colon cancer and pancreatic cancer.  The CA 19-9 test was discovered in 1981.  While elevated levels in the blood can be found in non-malignant conditions such as Mirizzi’s syndrome and diseases of the liver and bile ducts it is currently one of the key tests for pancreatic and colon cancer management.  The reluctance of using these tests more widely comes from the guidelines for the American Society of Clinical Oncology and the American Cancer Society which are still discouraging the use of CA 19-9 and other cancer markers as “dedicated screening” tests.  Their reasons are mostly the higher incidence of false positives.  That would be a person with a positive test with no malignancy.  Other reasons may be purely political, as a simple blood tests would “take away” expensive and profitable procedures from those performing flexible sigmoidoscopies and colonoscopies.  The main use of CA 19-9 is with following pancreatic tumors that are being treated with chemo or surgery; by checking for increases in levels that would indicate recurrence or worsening of the disease.  As with any test, there is never a 100% specificity/sensitivity.  In CA 19-9 about 5% of the population does not possess the ability to produce the Lewis antigen because of a deficiency of a fucosyltransferase enzyme and thus no Lewis antigen or CA 19-9 would be produced even with large tumor burden.

There are other markers under investigation that may become more useful in the future.  In 2009 researchers at the University of Cincinnati (UC) published in a genetics journal their findings about a gene called AMACR which regulates cancer development and discovered a polymorphism (mutation) related to colon cancer.  Dr. Xiang Zhang, PhD who was the lead researcher of the UC study explains, "From the colon tissues, we've identified two types of genetic deletions [of the AMACR gene] that may allow us to predict whether people will have a good or bad cancer outcome," Dr. Zhang continued to say, "If a person carries one of the deletions, it may predispose him or her to a more aggressive type of colon cancer."  While not developed as of yet as a screening tool, it will help physicians determine prognosis and treatment protocols for those that have colon cancer.  Yet another cancer biomarker for colon cancer is CA 242.  Elevated levels of CA 242 in colorectal cancer patients had similar rates of being positive as CEA and CA 19-9.  The sensitivities are similar as well, and more so for recurrence and metastatic detection using CA 242.
While there is an increased demand for biomarkers of colorectal cancer (and other cancers for that matter), for early detection, risk assessment, prognosis and follow up post treatment, the perfect, gold-standard test has not yet been realized.  Short comings are: too frequent false positives and false negatives as a stand-alone screening test.  Other biomarkers under the microscope for consideration are APC, p53 and Ki-ras.  These are still in development for use as viable clinical tests.  The detecting of colon cancer in the early stages offers clinical advantages and better outcomes; therefore, the National Cancer Institute has established an Early Detection Research Network to promote more research in this field of study.  The emphasis of the network is on translational research and collaboration among scientists in the field of oncology with the hopeful development of better cancer markers in the near future. 

A rather new and promising colorectal biomarker is the ColoVantage® (methylated DNA from SEPT9 gene marker).  ColoVantage® is the brand name of a test launched in 2010 by Quest Diagnostic Labs and as of March 2011, has gained approval by the New York Health Department as a sanctioned colorectal screening test.  With its reported 70% sensitivity and 89% specificity rating, it is a good first line test for screening large numbers of people less likely to undergo colonoscopy of any type (CC or VC).  The American Cancer Society is also warming up to the idea, but is slower to act as they are advocating more scrutiny.  Quest Diagnostic is offering the ColoVantage at a retail cost of $355.   Direct Access Testing sites such as eStatLabs offer this test direct-to-consumer for $300.

My current recommendations are with what is available to the public today a viable biomarker testing protocol.   It has a two-prong approach:  First, the inexpensive and readily available FOB (Hemoccult®) test.  This is still the mainstay of colorectal screening and probably will be into the foreseeable future.  The second recommendation is not in the realm of CC or even VC, but rather a chemical biomarker.  Cheap by comparison and readily accessible with no risk of untoward affects is the ColoVantage test.  It would be done in combination with the FOB to complete the evaluation.  CA 19-9, CEA or the CA 242 biomarkers would be my second choice in biomarkers for initial testing.  Finally, if both FOB & ColoVantage tests are positive, the algorithm would proceed to a 2nd tier, the virtual colonoscopy or conventional fiber-optic colonoscopy.



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Quest Diagnostic Laboratory web site, Information on ColoVantage.  Acquired 3/25/2011. Acquired 4/12/2011

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