Colorectal Cancer Screening Update


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  • The reasons for these racial and ethnic differences in disease incidence are unclear. Some of the excess mortality in African Americans appears to be related to lower use of colorectal cancer screening and to differences in treatment.
  • In 2008 update of the colorectal cancer screening guidelines the consensus panel focused on screening in average risk adults and did not review recent literature or make new recommendations regarding colorectal cancer screening or surveillance for individuals at increased and high risk. An appendix to the 2008 guidelines manuscript contains tables summarizing previously published recommendations on screening and surveillance for increased and high risk groups. The remainder of this talk will focus on screening recommendations for those at average risk of developing colorectal cancer.
  • While family history and other conditions can lead to an increased risk for developing CRC, this chart from the Centers for Disease Control and Prevention website illustrates that a significant majority of cases (65 – 85%) are diagnosed in individuals who have no identified risk factor other than being over the age of 50.
  • The transition from normal mucosa to polyp to invasive cancer is usually a lengthy process (7 – 12 years in many cases). This prolonged dwell time provides a unique opportunity for cancer prevention through polyp detection and removal.
  • Ries et al;,2007
  • Data from the CDC’s Behavioral Risk Factor Surveillance System (BRFSS) indicates that in 2006 approximately 60% of adults age 50 and older reported having either an FOBT in the past 1year or an endoscopy within the past 10 years. On the other hand, respondents to the NCI’s 2005 National Health Interview Survey (NHIS) reported an overall compliance rate of 46.8% for FOBT in the past 1year, flexible sigmoidoscopy in the past 5 years, or colonoscopy within the past 10 years. These differences are thought to be in large part due to differences in the survey questions (i.e. NHIS attempts to distinguish between flexible sigmoidoscopy and colonoscopy), and the manner in which these data are collected (BRFSS is a telephone survey, and NHIS data is collected in face to face interviews)
  • Screening rates vary considerably depending on a number of factors, including education, income, insurance status and race/ethnicity.
  • While there has been a downward trend during recent years in the use of FOBT, the prevalence of flexible sigmoidoscopy (FSIG) or colonoscopy increased from 1999 to 2004. Adults with less than a high school education were less likely to report FSIG or colonoscopy than all adults. Even more striking is that the prevalence for adults with no health insurance is approximately 26 percentage points lower than the prevalence for all adults. Continuing efforts are needed to address health system barriers to colon cancer screening, to encourage health care practitioners to promote screening to their patients, and to raise awareness among eligible adults about the importance of getting screened for CRC.
  • The above are reasons for not being screened for colorectal cancer as stated by patients in a number of different studies. The reasons are not arranged by frequency of this response, nor are all of these reasons stated in all studies, however the lack of a recommendation by the primary physician is cited as the most important, or one of the most important reasons for not being screened across nearly all studies examining this issue
  • Most or all of these have been recommended as CRC screening methods since at least 2003 by major health care organizations including: -American Cancer Society -U.S. Preventive Services Task Force -U.S. Multisociety Taskforce on Colorectal Cancer Screening
  • In recognition of the fact that the screening guidelines issued by each organization had, over the past decade, grown increasingly similar, and that the advent of new technologies called for greater multi-disciplinary engagement around colorectal cancer screening, beginning 2006 the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology agreed to collaborate on an update of each organization’s guidelines. It was agreed that the guidelines would be developed through a process of collective deliberation between experts from the three organizations and that the completed guideline would then be reviewed and approved by each organization. It was intended that such consensus recommendations would have a strengthened impact and enhance utilization by primary care providers, specialists and the general public in making decisions around colorectal cancer screening.
  • Individuals and health care professionals should understand that screening tests for colorectal cancer broadly fall into two categories. In one category are the partial or full structural exams (endoscopic and radiographic) which directly or indirectly examine the colon lumen and wall, and are effective at detecting both cancer and premalignant adenomatous polyps. In the other category are the fecal tests, i.e., gFOBT, FIT, and sDNA, which are tests that primarily are effective at identifying colorectal cancer. Some premalignant adenomatous polyps may be detected, providing an opportunity for polypectomy and the prevention of colorectal cancer, but the opportunity for prevention is both limited and incidental and is not the primary goal of colorectal cancer screening with these tests.
  • The updated guidelines establish a sensitivity threshold for recommended tests - all screening tests should have evidence in the medical literature documenting their ability to detect the majority of cancers present at the time of testing. Tests which do not meet this standard should not be used. This criterion is based on expert opinion, and the following considerations: First, recent evidence has revealed an unacceptably wide range of sensitivity among some gFOBT strategies, with some practices and tests performing so poorly that the large majority of cancers are missed at the time of screening. Second, a test like gFOBT that demonstrates poor test sensitivity, but good program sensitivity, depends on high rates of adherence with regular screening. However, many patients have only one test and do not return for annual programmatic testing, and there is a lack of systems to ensure or facilitate adherence with recommended regular screening intervals. For these reasons, the panel concluded that physicians and institutions should select stool blood tests that have been shown in the scientific literature to detect the majority of prevalent colorectal cancers in an asymptomatic population. If there is not evidence that an available test has met that benchmark, it should not be offered to patients for colorectal cancer screening.
  • A study of over 2600 patients showed the extremely low sensitivity (4.9%) of the in-office FOBT done at the time of rectal exam. In other words, this approach missed 95% of significant abnormalities. This is in marked contrast to the much higher detection rates seen for the recommended 3-card, take home FOBT. Although the sensitivities (44% for cancers, 24% for all abnormalities) may still appear somewhat low, it is important to keep in mind that fecal occult blood testing on a one-time basis has never been purported to be of great value. The test derives it's benefit from a program of screening over a number of years - which is why our guidelines explicitly state that if FOBT is the method chosen for screening it must be done annually .
  • In a study published in the same journal, investigators found that nearly one-third of primary care physicians use the in-office FOBT as their primary method of screening. This was common among all types of primary care physicians (Family Medicine, Internal Medicine and Ob/Gyn). In addition, although the recommendations for follow up of a positive FOBT are clear and unequivocal (colonoscopy), a third of patients who reported having a positive fecal occult blood test stated that their doctor followed this positive with another FOBT, or they had no diagnostic work-up for this finding! Getting the best results from any test requires that the test be used as directed. Clearly, based on the findings from these nationwide surveys, many physicians are not following recommendations when it comes to FOBT.
  • Knowledge of molecular genomics provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis. Adenoma and carcinoma cells that contain altered DNA are continuously shed into the large bowel lumen and passed in the feces. Because DNA is stable in stool, it can be differentiated and isolated from bacterial DNA found in the feces
  • Colorectal cancer is a disease in which many DNA mutations associated with the process of carcinogenesis have been characterized. DNA is stable in the stool, it is shed continuously, and, through the use of amplification tests, such as polymerase chain reaction, can be detected in minute amounts. No single mutation has been found that is expressed in all colorectal cancers, but advances in technology have made it possible to examine the stool for an array of mutations. Mutational “hot spots” have been identified on K- ras , APC , and p53 genes, mutations on Bat-26 (a microsatellite instability marker) and long DNA. Methylated Vimentin has also surfaced as an important marker.
  • Beginning in 2003, LabCorp marketed a multicomponent stool DNA test which targets multiple point mutations and which was developed by EXACT Sciences Corporation. From the date of launch through December 31, 2007, LabCorp processed approximately 14,300 sDNA test samples. Their collection kit is pictured here, and the collection process is depicted on the next slide.
  • In order to maximize the volume of colon cells (and their associated DNA content) patients are asked to collect and send an entire bowel movement for analysis.
  • The prototype assay of the commercially marketed sDNA test (version 1.0) for which most of the published evidence is available, consisted of a multiple marker panel that included 21 separate point mutations in the K -ras oncogene, a probe forBAT-26 (a marker of microsatellite instability), and DNA Integrity Analysis (DIA). The sDNA test that was commercially available during the time of the guidelines evidence review and manuscript preparation is version 1.1, which includes this same marker panel, but incorporates several technical advances related to processing and specimen preservation. Version 2.0 may soon be introduced to the market by EXACT Sciences, as well as a similar testing method under development by LabCorp
  • A number of studies have documented the ability of sDNA testing to detect the majority of cancers present at the time of testing. Cancer detection in most published studies ranges between 51.6 to 88% (varies based on which version of test used, screening vs. high risk population sample,…). Reported sensitivity for adenomas has been significantly lower (< 30% in most published reports). Potential advantages of sDNA testing include (1) acceptable sensitivity for colorectal cancer, (2) it is not dependent on the detection of occult blood, which is intermittent, and (3) sDNA requires only a single episode of stool collection. sDNA also is noninvasive, and lacks physical harm. Based on studies performed by the test manufacturer, patient and provider acceptance of this technique appears to be high.
  • Cancer detection 51.6 to 88%; adenoma detection < 30% in most published reports At least four new iterations of molecular stool testing (some using novel technologies) are currently under evaluation, and may soon be on the market The most recently marketed version of the sDNA test was reported to cost $300 - $400 per test; sensitive gFOBT tests costs < $25 in most settings, and available FIT versions are generally priced slightly higher than gFOBT
  • There is no currently published work on rescreening with sDNA tests, therefore no direct evidence on which to base recommendations for screening intervals. In the only large population study completed to date, the sDNA test showed better performance than the comparison gFOBT for the detection of cancer and advanced adenomas, but the detection rate still was not dissimilar to that of a high sensitivity gFOBT or FIT, for which current recommendations are for annual screening There is also scant evidence on which to judge the extent to which a positive test with no evidence of advanced lesions upon completion of colonoscopy is truly negative or whether it may be: positive for a colon or rectal lesion that is not yet clinically evident, or; Indicative of cancer outside of the colon or rectum. Researchers have highlighted the fact that many cancers exfoliate dysplastic cells and that these cells can survive the digestive process and ultimately be excreted in stool. Thus it is possible that high prevalence supracolonic aerodigestive cancers (i.e. those of the lung, head and neck, upper GI track) may also be detected by sDNA. Limited research investigating this phenomenon has been carried out thus far, so at this time the optimal management of a positive sDNA test result followed by negative colonoscopy is uncertain. In October 2007 the FDA contacted Exact Sciences and notified them that the company should submit an application for clearance or approval to the FDA. There were no questions or concerns raised by the FDA regarding test performance at that time, nor have such questions surfaced in any of the company or FDA documents that have been made public to this point. At the time of the colorectal screening evidence review and guidelines manuscript preparation, sDNA testing was available to the public. The issue of FDA categorization came to the attention of the consensus guidelines development panel during the late stages of manuscript editing, well after the screening recommendations had been approved. After lengthy deliberation the expert group decided that the recommendation for inclusion of sDNA in the final guideline should stand. The initial decision to recommend sDNA testing was not dependent on one particular test or manufacturer, but instead was based on scientific evidence that a panel of markers met the rule of evidence established for the guidelines update. (similar to the categorical inclusion of various forms of fecal immunochemical testing). The FDA concerns were not related to the documented performance characteristics or the scientific validity of this form of testing, only that the licensing of the technology to LabCorp and the provision of certain materials had placed it into a category that required EXACT to seek premarket approval. Therefore the evidence for inclusion of this technology in the colorectal cancer screening guidelines remained unaltered. According to an EXACT Sciences spokesperson, LabCorp did not receive any correspondence from the FDA in 2007 or the first quarter of 2008, and version 1.1 of the sDNA test remained available to the public until June 6, 2008, at which time LabCorp announced that they would no longer offer the test. According to an EXACT Sciences news release, LabCorp plans to launch their own in-house molecular stool test at some point in the future. EXACT Sciences has also developed a new version of its test utilizing a simplified set of markers and is working toward FDA clearance or approval for it. At least three other approaches to molecular stool testing are under investigation and may at some point lead to commercial products.
  • CT colonography is an imaging procedure that uses computer programming to combine multiple helical CT scans in order to create two or three-dimensional images of the interior of the patients’ colon. These images can be rotated for different views and even combined for a complete view of the colon that can be “flown through.” The term “virtual colonoscopy” was coined in 1994 by researchers at Wake Forest University who described this procedure as simulating conventional colonoscopy. “CT colonography” has become the accepted medical terminology to describe the procedure, with “virtual colonoscopy” being used as the popular lay term.
  • Adequate bowel preparation and gaseous distention of the colon are essential to insure a successful examination. Patients typically undergo full cathartic preparation along with a clear liquid diet the day before the study, similar to the requirements for colonoscopy. Tagging of residual solid stool and fluid with barium and/or iodine oral contrast agents is being increasingly used and validated in large trials. At CT, a small-caliber rectal catheter is inserted into the rectum, followed by automated or manual insufflation of room air or carbon dioxide. Intravenous contrast generally is not given to patients undergoing screening, but can be helpful in some patients with more advanced symptoms. Typically the entire procedure on the CT table takes approximately ten minutes, with no sedation or recovery time needed.
  • Computer imaging graphics allow for visualization of 3D endoscopic flight paths through the inside of the colon, which can be simultaneously viewed with interactive 2D images. The integrated use of the 3D and 2D techniques allows for ease of polyp detection, as well as characterization of lesion density and location. The 2D images also allow for limited evaluation of the extracolonic structures.
  • Click on image to play movie. Note: Movie will play only if movie clip is saved on your computer in same folder as this ppt file. Movie will only play in “slideshow” mode.
  • In 2005, two meta-analyses reviewed the cumulative published CTC performance data, including both high risk and screening cohorts, with one analysis representing 33 studies on 6393 patients.{Halligan, 2005 #60; Mulhall, 2005 #61} On a per-patient basis, pooled CTC sensitivity and specificity for large (≥ 10 mm) polyps was found to be 85-93% and 97%, respectively. Pooled sensitivity and specificity for detection of small polyps (6-9 mm) was 70-86% and 86-93%, respectively. Of note, the pooled CTC sensitivity for invasive colorectal cancer was 96%,
  • The first large, multi-institutional screening trial using more advanced CTC techniques demonstrated very favorable performance. Pickhardt et al. studied 1233 asymptomatic adults and introduced the techniques of stool tagging and primary 3D polyp detection. This trial reported a 92.2% sensitivity for large adenomas, with a per-patient sensitivity for adenomas ≥ 6 mm of 85.7%.
  • Initial results from smaller screening trials {Cash, 2006, Graser 2006} have shown CTC performance characteristics similar to that of Pickhardt et al, providing at least a measure of independent validation for this screening technique. The recently completed American College of Radiology Imaging Network (ACRIN) Study 6664: National CT Colonography Trial, was sponsored and funded by the National Cancer Institute. The primary aim of this trial was to assess CTC performance for large adenomas and advanced neoplasia in a large screening cohort of more than 2,500 patients across 15 institutions. State-of-the-art technique includes oral contrast tagging, colonic distention with automated carbon dioxide delivery, multi-detector row CT (≥ 16 slice) with thin collimation, and both 2D and 3D polyp detection on dedicated CTC software systems. Nearly all patients had colonoscopy.
  • Although the findings of this trial have not yet been published in the peer-reviewed literature, preliminary findings were announced at the 2007 annual meeting of ACRIN on September 28, 2007 Like the earlier Pickhardt study, these results demonstrated similar performance between CTC and OC, with per-patient sensitivity of 90% for advanced lesions 9 mm or larger, and 84% for 6-9 mm polyps. .
  • Research into non-cathartic approaches to minimize the bowel preparation is underway, but this technique has not yet been validated in a multi-center screening trial. Under conditions where same-day or next-day referral for colonoscopy is possible, one drawback of non-cathartic CTC is that a cathartic bowel preparation would still be required prior to removal of polyps.
  • Inappropriate management of incidental extracolonic findings could potentially compromise clinical care and cost effectiveness. The incidence of clinically significant extracolonic findings at CTC has ranged from 4.5-11% in various patient cohorts. In an asymptomatic screening population, the incidence of unsuspected but potentially important extracolonic findings is approximately 4.5 %, but findings of minimal or moderate potential clinical significance, such as cholelithiasis (6%) and nephrolithiasis (8%) are more common. Detection of major abnormalities (abdominal aortic aneurysm, renal cancer,…) is uncommon, but potentially lifesaving. Concerns have been raised about radiation dose, and potential harms from dose effects from CTC continue to be debated. Published CTC protocols employ radiation doses that are similar to the double-contrast barium enema. In a recent position statement issued by the Health Physics Society, the health effects of low-dose radiation exposure (defined as below 50-100 mSv - a threshold many times higher than typical CTC levels) were considered to be “either to small to be observed or are nonexistent”. Current ACR guidelines for CTC stress the use of low dose techniques for CT colonography will be essential to minimize radiation dose in screening and surveillance patients. There is consensus that all patients with one or more polyps ≥ 10mm or 3 or more polyps ≥ 6 mm should be referred for colonoscopy. Patients with one or two 6-9 mm polyps identified on CTC should be offered therapeutic colonoscopy. Patients who decline referral to colonoscopy or who are not good candidates for colonoscopy should be offered surveillance with CTC. In studies that have been limited to screening cohorts, among individuals whose largest polyp is 6-9 mm in size the prevalence of advanced features tends to be low (3.4 – 6.6%).{Kim, 2007; Moravec, 2007}. Optimal management of patients whose largest polyp is <6mm detected on CTC is controversial. Experts from AGA, ACG and ACR have reported a range of policies on how to handle these lesions.{American College of Radiology, 2006; Rex, 2006; Rockey, 2007}. In general, radiologist would prefer not to report lesions smaller than 5 mm seen at CTC, while gastroenterologist would prefer that all detected polyps be reported and patients referred for diagnostic/therapeutic colonoscopy. There is general agreement that the risk of advanced features in patients whose largest polyp is ≤ 5 mm is very low.
  • Overall, these guidelines are more similar than different, and given the complexity of CRC guidelines, i.e., the number of tests, age-groups, and intervals, it is important to not place too much emphasis on the differences. -Both guidelines recommend screening beginning at age 50 at the same intervals with high sensitivity FOBTs, sigmoidoscopy, or colonoscopy. -The USPSTF gave sDNA and CT colonography a “C” recommendation, which means that they felt there were insufficient data to assess the benefits and harms — they do not state that the tests should not be used .
  • In the JAMA study and elsewhere, flat lesions are defined as those growths that are wider than they are tall. In reality, most of these lesions are not totally flat; they may be elevated above the colon wall or depressed below the colon wall (appearing like a small crater). Obvious, detection may vary significantly depending on which of these forms a lesion takes.
  • The focus of the JAMA study described in the preceding section was the detection of flat lesions by colonoscopy, and the shortcomings of colonoscopy as traditionally performed in the U.S. To date only a few studies have attempted to assess the ability of CTC to detect flat lesions. Results have varied widely, ranging from sensitivities of 13%-65% in early CTC studies {Fidler, 2002} to 80% sensitivity in the hands of experienced radiologists using advanced technologies (MDCT) and protocols (combined 3D-2D polyp detection) that are recommended today {Pickhardt, 2004}.
  • Until the publication of the JAMA paper, many believed that flat lesions were not important in U.S. populations. Consequently, most radiologists and colonoscopists have devoted little time or energy to the detection of these lesions. The JAMA study highlighted the need to re-examine how we practice colonoscopy (and possibly CTC) in this country, particularly among populations with risk factors or symptoms. These findings are likely to stimulate new research in both gastroenterology and radiology on ways to identify those who are most likely to have flat lesions, and identify technologies or procedures that enhance the detection of these lesions. The study also reinforces the fact that if new symptoms (i.e. blood in the stool) develop in individuals who have had a recent colonoscopy, consideration should be given to the possibility of a missed lesion (flat or protruding); new symptoms should never be ignored
  • Colorectal Cancer Screening Update

    1. 1. Colorectal Cancer Prevention & Early Detection : Update 2008 Nadim G. Haddad,M.D. Associate Professor Director of GI Fellowship
    2. 2. Colorectal Cancer <ul><li>The third most common cancer in U.S. </li></ul><ul><li>148,810 new cases expected in 2008 </li></ul><ul><li>The second deadliest cancer </li></ul><ul><li>49,960 deaths nationwide </li></ul><ul><li>More than 1 million Americans living with colorectal cancer </li></ul>
    3. 3. Colorectal Cancer Risk Factors <ul><li>Age </li></ul><ul><ul><li>90% of cases occur in people 50 and older </li></ul></ul><ul><li>Gender </li></ul><ul><ul><li>slight male predominance, but common in both men and women </li></ul></ul><ul><li>Race/Ethnicity </li></ul><ul><ul><li>African Americans have highest incidence and mortality rate of all groups in U.S., Hispanics the lowest (with considerable variation depending on country of origin) </li></ul></ul><ul><ul><li>Increased rates also documented in Alaska Natives, some American Indian tribes, Ashkenazi Jews </li></ul></ul>
    4. 4. Risk Factors (continued) <ul><li>Increased risk with: </li></ul><ul><li>Personal history of inflammatory bowel disease, adenomatous polyps or colon ca </li></ul><ul><li>Family history of adenomatous polyps, colon cancer, other conditions </li></ul>*Individuals with these risk factors may require earlier and more intensive screening
    5. 5. Colorectal Cancer Sporadic (average risk) (65%–85%) Family history (10%–30%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Rare syndromes (<0.1%) CENTERS FOR DISEASE CONTROL AND PREVENTION
    6. 6. Risk Factor - Polyps <ul><li>Different types: </li></ul><ul><li>Hyperplastic </li></ul><ul><ul><li>minimal cancer potential </li></ul></ul><ul><li>Adenomatous </li></ul><ul><ul><li>approximately 90% of colon and rectal cancers arise from adenomas </li></ul></ul>
    7. 7. Normal to Adenoma to Carcinoma Human colon carcinogenesis progresses by the dysplasia/adenoma to carcinoma pathway
    8. 8. Benefits of Screening <ul><li>Cancer Prevention </li></ul><ul><ul><li>Removal of pre-cancerous polyps prevent cancer (unique aspect of colon cancer screening) </li></ul></ul><ul><li>Improved survival </li></ul><ul><ul><li>Early detection markedly improves chances of long term survival </li></ul></ul>
    9. 9. Benefits of Screening *1996 - 2003
    10. 10. Colorectal Screening Rates <ul><li>Just 40% of colorectal cancers are detected at the earliest stage. </li></ul><ul><li>A little more than half * of Americans over age 50 report having had a recent colorectal cancer screening test </li></ul><ul><li>Slow but steady improvement in these numbers over the past decade (but all are not benefiting to the same degree) </li></ul>*varies based on data source
    11. 11. Colorectal Screening Rates Source: MMWR March 2008
    12. 12. Trends in Recent* Endoscopy Prevalence (%), by Educational Attainment and Health Insurance Status, Adults 50 Years and Older, US, 1997-2004 *A flexible sigmoidoscopy or colonoscopy within the past five years. Note: Data from participating states and the District of Columbia were aggregated to represent the United States. Source: Behavioral Risk Factor Surveillance System CD-ROM (1996-1997, 1999) and Public Use Data Tape (2001, 2002, 2004), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention and Prevention, 1999, 2000, 2002, 2003, 2005.
    13. 13. Colorectal Screening Rates Low: Reasons (according to Patients) <ul><li>Low awareness of CRC as a personal health threat </li></ul><ul><li>Lack of knowledge of screening benefits </li></ul><ul><li>Fear, embarrassment, discomfort </li></ul><ul><li>Time </li></ul><ul><li>Cost </li></ul><ul><li>Access </li></ul><ul><li>“ My doctor never talked to me about it!” </li></ul>
    14. 14. Colorectal Cancer Screening 2008
    15. 15. ACS 2003 CRC Prevention and Early Detection Recommendations <ul><li>Fecal Occult Blood Testing (FOBT) </li></ul><ul><ul><li>Guaiac </li></ul></ul><ul><ul><li>Immunochemical </li></ul></ul><ul><li>Flexible Sigmoidoscopy (FSIG) </li></ul><ul><li>FSIG + FOBT </li></ul><ul><li>Colonoscopy </li></ul><ul><li>Double Contrast Barium Enema (DCBE) </li></ul>
    16. 16. The 2008 CRC Guidelines Update was a Joint Effort of 5 Organizations <ul><li>American Cancer Society </li></ul><ul><li>U. S. Multi-Society Task Force on Colorectal Cancer </li></ul><ul><ul><li>American Gastroenterological Association </li></ul></ul><ul><ul><li>American College of Gastroenterology </li></ul></ul><ul><ul><li>American Society of Gastrointestinal Endoscopists </li></ul></ul><ul><li>American College of Radiology </li></ul>
    17. 17. 2008 CRC Screening Guidelines: Process <ul><li>Expert panel reviewed and deliberated on available evidence during two face-to-face meetings and a series of conference calls </li></ul><ul><li>Literature published between January 2002 and January 2008, as well as unpublished abstracts and manuscripts, were reviewed by panel </li></ul>
    18. 18. 2008 CRC Guidelines Update: Evidence Criteria and Limitations <ul><li>Current evidence has a number of limitations: </li></ul><ul><ul><li>Prospective studies are uncommon </li></ul></ul><ul><ul><li>Sample sizes tend to be small </li></ul></ul><ul><ul><li>Study participants often include higher risk, symptomatic patients and/or screening populations (magnitude of bias uncertain) </li></ul></ul><ul><li>Priority placed on prospective studies of asymptomatic adults, with all subjects undergoing colonoscopy </li></ul><ul><li>Because adherence to regular screening is low, we are considering setting a test sensitivity threshold for test acceptance </li></ul>
    19. 19. CRC Screening Guidelines: What’s New? <ul><li>CRC screening tests are grouped into two categories: </li></ul><ul><li>Tests that detect cancer and precancerous polyps* </li></ul><ul><li>Tests that primarily detect cancer </li></ul><ul><li>* It is the strong opinion of the consensus guidelines group that colon cancer prevention should be the primary goal of CRC screening. </li></ul><ul><ul><li>Exams that are designed to detect both early cancer and precancerous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test </li></ul></ul><ul><ul><li>If the full range of screening tests are not available, physicians should make every effort to offer at least one test from each category </li></ul></ul>
    20. 20. CRC Screening Guidelines: What Else is New? <ul><li>Two new tests recommended: </li></ul><ul><ul><li>stool DNA (sDNA) and </li></ul></ul><ul><ul><li>computerized tomographic colonography (CTC) – sometimes referred to as virtual colonoscopy </li></ul></ul><ul><li>The guidelines establish a sensitivity threshold for recommended tests </li></ul><ul><li>The guidelines delineate important quality-related factors for each form of testing </li></ul>The full article can be accessed at:
    21. 21. 2008 CRC Screening Guidelines Beginning at age 50, both men and women at average risk for developing colorectal cancer should use one of the screening tests below: * Colonoscopy should be done if test results are positive. ** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used. gFOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening. Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,** or Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity for cancer *, ** or Tests That Primarily Detect Cancer CT colonography (CTC) every 5 years* Double contrast barium enema (DCBE) every 5 years*, or Colonoscopy every 10 years, or Flexible sigmoidoscopy (FSIG) every 5 years*, or Tests That Detect Adenomatous Polyps and Cancer
    22. 22. 2008 CRC Guidelines Continue to Emphasize Options Because: <ul><li>Evidence does not yet support any single test as “best” </li></ul><ul><li>Uptake of screening remains disappointingly low </li></ul><ul><li>Individuals differ in their preferences for one test or another </li></ul><ul><li>Primary care physicians differ in their ability to offer, explain, or refer patients to all options equally </li></ul><ul><li>Access is uneven geographically, and in terms of test charges and insurance coverage </li></ul><ul><li>Uncertainty exists about performance of different screening methods with regard to benefits, harms, and costs (especially on programmatic basis) </li></ul>
    23. 23. FOBT Sensitivity: Take Home vs. In-Office <ul><li>Sensitivity of Take Home vs. In-Office FOBT </li></ul>Collins et al, Annals of Int Med Jan 2005 Sensitivity Cancer All Advanced Lesions FOBT method (Hemoccult II) 9.5 % 4.9 % Single sample, in-office 43.9 % 23.9 % 3 card, take-home
    24. 24. In-Office FOBT should be abandoned <ul><li>Conclusion </li></ul><ul><li>In-office FOBT is essentially worthless as a screening tool for CRC and must be strongly discouraged </li></ul><ul><li>However; </li></ul><ul><li>In a recent national survey, nearly 30% of physicians reported using single-sample, in-office FOBT as their primary method of screening for colorectal cancer . </li></ul>Nadel et al, Annals of Int Med Jan 2005
    25. 25. 2008 CRC Screening Guidelines New Tests
    26. 26. Stool DNA
    27. 27. Stool DNA Test (sDNA) <ul><li>Rationale </li></ul><ul><li>Fecal occult blood tests detect blood in the stool – which is intermittent and non-specific </li></ul><ul><li>Colon cells are shed continuously </li></ul><ul><li>Polyps and cancer cells contain abnormal DNA </li></ul><ul><li>Stool DNA tests look for abnormal DNA from cells that are passed in the stool* </li></ul>*All positive tests should be followed with colonoscopy
    28. 28. Genetic Model of Colorectal Cancer Bat-26 (Sporadic) p53 Optimum phase for early detection Many decades APC K-ras Mutation Bat-26 (HNPCC) Courtesy of Barry M. Berger. MD, FCAP EXACT Sciences Dwell Time: 2-5 years 2-5 years Late Adenoma Late Cancer Early Cancer Adenoma Normal Epithelium
    29. 29. sDNA - Sample Collection
    30. 30. sDNA - Sample Collection Collection bucket inserted into bracket and installed under toilet seat Patient supplies whole stool sample; no diet or medication restrictions Patient seals sample in outer container and freezer pack Patient seals container and ships back to designated lab (all packing materials and labels supplied)
    31. 31. Performance Characteristics of Stool DNA in the Detection of CRC <ul><li>Three versions of the previously marketed sDNA test have been evaluated </li></ul><ul><ul><li>Version 1 (K-ras, APC, p53,BAT-26, DIA) was evaluated in the Imperiale trial </li></ul></ul><ul><ul><li>Version 1.1 (K-ras, APC, P53), PreGen-Plus is the currently marketed test </li></ul></ul><ul><ul><li>Version 2 (Vimentin only, or Vimentin + DIA) is currently under evaluation and is expected to enter the market in Fall 2008 </li></ul></ul><ul><li>Earlier and more recent tests were evaluated in smaller, mixed populations </li></ul>
    32. 32. Performance Characteristics of Stool DNA in the Detection of CRC <ul><li>Testing evaluates stool for the presence of altered DNA in the adenoma-carcinoma sequence </li></ul><ul><li>No dietary restrictions </li></ul><ul><li>No stool sampling (utilizes the entire stool) </li></ul><ul><li>Several studies suggesting strong patient acceptance </li></ul><ul><li>Testing interval uncertain </li></ul><ul><li>Uncertainty about the meaning of false positives </li></ul>46% Chen, et al JNCI, 2005 (2) 63% Syngal, et. al Cancer, 2006 (1) 70% Whitney, et al J Mol Diagn, 2004 (1.1) 88% Itzkowitz, et al DDW-AB, 2006 (2) 51.6% Imperiale, et al NEJM, 2004 (1) 91% Ahlquist, et al Gastro, 2000 (1) Sensitivity for Cancer Study with One-Time Testing (v)
    33. 33. Stool DNA <ul><li>Limitations </li></ul><ul><li>Misses some cancers </li></ul><ul><li>Sensitivity for adenomas with current commercial version of test is low </li></ul><ul><li>Technology (and test versions) are in transition </li></ul><ul><li>Costs much more than other forms of stool testing (approximately $300 - $400 per test) </li></ul><ul><li>Not covered by most insurers </li></ul>
    34. 34. Stool DNA <ul><li>Limitations (cont.) </li></ul><ul><li>Appropriate re-screening interval is not known </li></ul><ul><li>Not clear how to manage positive stool DNA test if colonoscopy is negative </li></ul><ul><li>FDA issues </li></ul><ul><li>Test availability </li></ul>
    35. 35. CT Colonography (CTC) Courtesy of Beth McFarland, MD CTC Image Optical Colonoscopy
    36. 36. CT Colonography <ul><li>Rationale </li></ul><ul><li>Allows detailed evaluation of the entire colon </li></ul><ul><li>A number of studies have demonstrated a high level of sensitivity for cancer and large polyps </li></ul><ul><li>Minimally invasive (rectal tube for air insufflation) </li></ul><ul><li>No sedation required </li></ul>
    37. 37. CT Colonography Courtesy of Beth McFarland, MD Polyp 3-D view 2-D view Polyp
    38. 38. CTC Virtual “Fly Through” Courtesy of Beth McFarland, MD
    39. 39. CTC vs. Optical Colonoscopy: Meta-Analyses Halligan 2005, Mulhall 2005 ---- 86-93% 97% Pooled Specificity 85.7% 70-86% 85-93% Pooled Sensitivity Cancer 6-9 mm >10mm CTC performance Polyp Size
    40. 40. CTC vs. Optical Colonoscopy: Sensitivities for All Polyps Pickhardt et al, NEJM 2003 90.0% 89.5% 88.2% Colonoscopy 85.7% 92.6% 92.2% CTC >6mm >8mm >10mm Polyp Size
    41. 41. The ACRIN CT Study <ul><li>The ACRIN study is a multi-center study with each site using state-of-the-art technology </li></ul><ul><li>15 participating sites </li></ul><ul><li>Patients underwent both CTC and colonoscopy </li></ul><ul><li>2,531 asymptomatic patients studied </li></ul><ul><li>Findings published Sept 2008 in New England Journal </li></ul>
    42. 42. ACRIN Results Johnson et al, NEJM 2008 86-89% 84% Polyps 6-9 mm 86% 90% Adenomas > 1 cm Specificity Sensitivity
    43. 43. CTC - Extra-Colonic Findings <ul><li>Most have limited clinical impact, but some are important: </li></ul><ul><ul><li>Asymptomatic cancers outside of colon and rectum </li></ul></ul><ul><ul><li>Aortic aneurysms </li></ul></ul><ul><ul><li>Renal and gall bladder calculi </li></ul></ul>
    44. 44. CT Colonography <ul><li>Limitations </li></ul><ul><li>Requires full bowel prep (which most patients find to be the most distressing element of colonoscopy) </li></ul><ul><li>Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep </li></ul><ul><li>Steep learning curve for radiologists </li></ul><ul><li>Limited availability to high quality exams in many parts of the country </li></ul><ul><li>Most insurers do not currently cover CTC as a screening modality </li></ul>
    45. 45. CT Colonography <ul><li>Limitations </li></ul><ul><li>Extra-colonic findings can lead to additional testing (may have both positive and negative connotations) </li></ul><ul><li>Questions regarding: </li></ul><ul><ul><li>Significance of radiation exposure </li></ul></ul><ul><ul><li>Management of small polyps </li></ul></ul>
    46. 46. 2008 USPSTF Guidelines <ul><li>U.S. Preventive Services Task Force, Ann Intern Med 2008 </li></ul>
    47. 47. Flat Lesions <ul><li>Background </li></ul><ul><li>Described in Japanese patients since 1980’s. Thought to be uncommon in the U.S. </li></ul><ul><li>Study published in March 2008 detected flat lesions at much higher rate than any previous U.S. reports </li></ul><ul><li>Colonoscopies in over 1800 veterans found: </li></ul><ul><ul><li>Polyps in 37% </li></ul></ul><ul><ul><li>“ Flat lesions” in 9.35% </li></ul></ul><ul><ul><li>0.8% of flat lesions cancerous or pre-cancerous </li></ul></ul>Soetikno, JAMA 2008
    48. 48. Flat Lesions <ul><li>Caveats </li></ul><ul><li>Most lesions not truly flat </li></ul>Soetikno, JAMA 2008 <ul><li>New Sources of Risk </li></ul><ul><li>Colorectal cancer prevention largely focuses on finding polyps, but flatter, less visible lesions that are not polyps are also cancer risks. </li></ul>Polyp Elevated lesion Flat lesion Depressed lesion The New York Times: Illustrations by JAMA
    49. 49. Flat Lesions <ul><li>Caveats (cont.) </li></ul><ul><li>Only about 1/3 of patients in Soetikno study were average risk screening population </li></ul><ul><ul><li>1/3 were high risk based on personal or family history </li></ul></ul><ul><ul><li>1/3 were symptomatic </li></ul></ul><ul><li>Flat lesions findings were different among average risk patients </li></ul><ul><ul><li>Flat lesions found in only 6% </li></ul></ul><ul><ul><li>Cancer or pre-cancerous findings in only 0.3% </li></ul></ul>Soetikno, JAMA 2008
    50. 50. Flat Lesions <ul><li>Implications for screening </li></ul><ul><li>JAMA study led some to question the ability of CTC to detect flat lesions (although CTC was not utilized in the study) </li></ul><ul><li>Results from early CTC/flat lesion studies were extremely variable (sensitivity 13% - 65%) </li></ul><ul><li>Recent study of experienced radiologist using advanced technology and protocols found 80% sensitivity for flat lesions </li></ul>
    51. 51. Flat Lesions: Conclusions <ul><li>Flat Lesions: </li></ul><ul><li>May be more common in the U.S. than previously believed </li></ul><ul><li>Occur less frequently than protuberant polyps, but are more likely to harbor cancer or pre-cancerous cells </li></ul><ul><li>Appear to occur more frequently in symptomatic patients and in patients with identified CRC risk factors </li></ul><ul><li>New symptoms should not be ignored because patient has history of “normal” colonoscopy </li></ul><ul><li>More research needed on ways to enhance detection of flat lesions by colonoscopy, CTC and other methods </li></ul>
    52. 52. Thank You!