1. Routine Screening

   Aetna considers any of the following colorectal cancer screening tests medically necessary preventive services for members aged 50 years and older when these tests are recommended by their physician:

   • Sigmoidoscopy (considered medically necessary every 5 years for persons at average risk); or
   • Double contrast barium enema (DCBE) (considered medically necessary every 5 years for persons at average risk); or
   • Colonoscopy (considered medically necessary every 10 years for persons at average risk).

   In addition, Aetna considers screening with annual immunohistochemical or guaiac-based fecal occult blood testing (FOBT), either alone or in conjunction with sigmoidoscopy, medically necessary preventive services for members beginning at age 50 years. Colorectal cancer screening beginning at age 40 is considered a medically necessary preventive service for persons with a single first-degree relative (sibling, parent, or child) with a history of colorectal cancer or an adenomatous polyp. Colorectal cancer screening beginning at age 45 is considered a medically necessary preventive service for African Americans because of the high incidence of colorectal cancer and a greater prevalence of proximal or right-sided polyps and cancerous lesions in this population.

   Aetna considers screening upper endoscopy experimental and investigational. No current guidelines of leading medical professional organizations or Federal public health agencies recommend routine upper endoscopy screening of asymptomatic persons.
   
   Aetna considers colorectal cancer screening of stool using molecular genetic techniques experimental and investigational.

2. High-Risk Screening:

   Aetna considers colorectal cancer screening with sigmoidoscopy, DCBE, or colonoscopy as frequently as every two years medically necessary for members with any of the following risk factors for colorectal cancer:

   • A first-degree relative (sibling, parent, child) who has had colorectal cancer or an adenomatous polyposis (screening is considered medically necessary beginning at age 40 years); or
   • Family history of familial adenomatous polyposis (screening is considered medically necessary beginning at puberty); or
   • Family history of hereditary non-polyposis colorectal cancer (HNPCC) (screening is considered medically necessary beginning at age 20 years).
   • Family history of MYH-associated polyposis in siblings (screening is considered medically necessary beginning at age 25 years).

   Aetna considers annual FOBT, alone or in conjunction with sigmoidoscopy, medically necessary for screening of colorectal cancer.

3. Surveillance:

   Aetna considers colorectal cancer surveillance with colonoscopy, flexible sigmoidoscopy or DCBE medically necessary as frequently as every two years for members who meet any of the following criteria:

   • Member has inflammatory bowel disease (including ulcerative colitis or Crohn's disease) (colorectal cancer surveillance is considered medically necessary as frequently as every two years); or
   • Personal history of adenomatous polyps (surveillance is considered medically necessary as frequently as every two years); or
   • Personal history of colorectal cancer (surveillance is considered medically necessary as frequently as every two years).

   Aetna considers annual FOBT, alone or in conjunction with sigmoidoscopy medically necessary for surveillance of colorectal cancer.

4. Diagnostic Testing:

   Aetna considers diagnostic testing with FOBT, colonoscopy, sigmoidoscopy and/or DCBE medically necessary for evaluation of members with signs or symptoms of colorectal cancer or other gastrointestinal diseases. Diagnostic upper endoscopy is considered medically necessary for evaluation of persons with signs and symptoms of upper gastrointestinal disease.

5. Anal Pap Smear:
   
   Aetna considers screening for anal cytological abnormalities (anal Pap smear) or for anal HPV infection experimental and investigational because of the lack of evidence that such screening improves clinical outcomes.

See also CPB 140 - Genetic Testing, and CPB 535 - Virtual Colonoscopy.

This policy is based on recommendations from the U.S. Preventive Services Task Force and the American College of Gastroenterology.

Colorectal cancer is the third most commonly diagnosed cancer among persons in the United States. The five-year survival rate of colorectal cancers detected in early states is 90 percent, but the five-year survival rate is only 8 percent for those diagnosed after the cancer has metastasized. Almost 90 percent of colorectal cancer cases are found in persons age 50 and older.

The American Cancer Society (Levin, et al., 2008) recommends the following testing options for the early detection of adenomatous polyps and cancer for asymptomatic adults aged 50 years and older:

Tests that detect adenomatous polyps and cancer:

• Flexible sigmoidoscopy every 5 years; or
• Colonoscopy every 10 years; or
• Double-contrast barium enema every 5 years; or
• Computed tomographic (CT) colonography every 5 years.

Tests that primarily detect cancer:

• Annual guaiac-based fecal occult blood test with high sensitivity for cancer; or
• Annual fecal immunochemical test with high test sensitivity for cancer; or
• Stool DNA test with high sensitivity for cancer, interval uncertain.

More frequent screening has been recommended for persons with a first-degree relative with a history of colorectal cancer. The increased risk of developing cancer at younger ages may justify beginning screening before the age of 50 in persons with a positive family history, especially when affected relatives developed colorectal cancer at younger ages.

Regular colonoscopic screening is part of the routine diagnosis and management of individuals at high risk of developing colorectal cancer, including those with a family history of hereditary syndromes (familial polyposis, hereditary non-polyposis colon cancer (HNPCC)); individuals with long-standing ulcerative colitis or Crohn's disease; or high-risk adenomatous polyps or colon cancer. Referral to specialists is appropriate. It has been recommended that persons with a family history of adenomatous polyposis begin screening at puberty, and persons with a family history of HNPCC begin screening at 20 to 30 years of age.

Randomized controlled trials have proven that the fecal occult blood test can detect colorectal cancer and significantly lowers the rate of death from the disease.

Although there are no randomized clinical trials proving that sigmoidoscopy reduces the mortality rate from colorectal cancer, a number of case-control studies have suggested that sigmoidoscopy is effective in reducing colorectal cancer mortality. The literature indicates that sigmoidoscopy can detect 70 to 80% of colorectal cancers. However, sigmoidoscopy is unable to detect the substantial number of cancers that arise solely in the proximal colon. The literature indicates that some of the additional neoplasms that it misses can be detected by combining sigmoidoscopy with fecal occult blood testing.

Some have advocated whole-bowel screening with colonoscopy or double contrast barium enema because it is able to detect proximal colon lesions. One study found that approximately 30% of cancers detected by colonoscopy would not have been detected by sigmoidoscopy. However, no direct evidence proves that whole-bowel screening, either by colonoscopy or double contrast barium enema, reduces mortality, although clinical trials are now underway to investigate this.

A study comparing the use of colonoscopy to double contrast barium enema for patients with previously identified polyps found that colonoscopy detected more polyps than double contrast barium enema. Double contrast barium enema found only 20% of adenomatous polyps found by colonoscopy.

Although the rate of complications from colonoscopy has been shown to be low, complications from colonoscopy are more common than from other screening procedures. Perforation of the colon and complications from anesthesia have been reported to occur in 0.1 to 0.3% of colonoscopies performed by gastroenterologists, and death occurs in 0.01% of colonoscopies.

The U.S. Preventive Services Task Force (USPSTF) released updated recommendations on colorectal cancer screening.  In contrast to the 2002 USPSTF recommendation, which applied to all adults 50 years of age and older without regard to an age at which to stop screening, USPSTF now recommends routine colorectal cancer screening in adults beginning at age 50 and continuing only until age 75 (USPSTF, 2008).  The USPSTF recommends the following screening modalities: high-sensitivity fecal occult blood testing (FOBT), sigmoidoscopy with interval FOBT, or colonoscopy.  The risks and benefits of these screening methods vary.  The USPSTF does not recommend routine screening for adults 76 to 85 years of age; however, there may be considerations that support colorectal cancer screening in an individual patient.  The USPSTF recommends against screening adults older than 85 years of age.  The USPSTF concluded that there is insufficient evidence to permit a recommendation for CT colonography and fecal DNA.

The USPSTF found good evidence that periodic FOBT reduces mortality from colorectal cancer and fair evidence that sigmoidoscopy alone or in combination with FOBT reduces mortality. The USPSTF did not find direct evidence that screening colonoscopy is effective in reducing colorectal cancer mortality; efficacy of colonoscopy is supported by its integral role in trials of FOBT, extrapolation from sigmoidoscopy studies, limited case-control evidence, and the ability of colonoscopy to inspect the proximal colon. The USPSTF determined that double-contrast barium enema offers an alternative means of whole-bowel examination, but it is less sensitive than colonoscopy, and there is no direct evidence that it is effective in reducing mortality rates. 

The USPSTF noted that it is unclear whether the increased accuracy of colonoscopy compared with alternative screening methods (for example, the identification of lesions that FOBT and flexible sigmoidoscopy would not detect) offsets the procedure's additional complications, inconvenience, and costs.

Since the last recommendation by the USPSTF in 2002, the mortality reduction previously reported in FOBT trials was maintained in longer-term follow-up, and a recent meta-analysis estimated the overall colorectal cancer morality reduction at 15% for biennial FOBT.  Screening with fecal DNA is still an evolving technology, with only 1 fair-quality study in average-risk patients providing data on sensitivity (better than Hemoccult II) and on the proportion of all tests that have positive results (higher than Hemoccult II).  There are no new trials that report on mortality for colonoscopy and sigmoidoscopy or newer screening methods, such as fecal DNA and fecal immunochemical testing.  The decision analytic modeling analysis performed for the USPSTF projected a comparative benefit to screening with colonoscopy, high-sensitivity fecal blood test, or flexible sigmoidoscopy every 5 years in combination with fecal testing every 3 years or mid-interval screening, relative to the other techniques studied.  Despite the lack of direct evidence from clinical trials to ascertain which is the most effective strategy, any of the recommended screening methods is effective compared with no screening.

Guaiac FOBTs have been recognized among various colorectal cancer screening methods as having the highest quality supporting evidence. Immunochemical tests (e.g., Flexsure OBT, InSure FOBT) may be used as an alternative to standard guaiac-based tests of fecal occult blood, and have several potential advantages that make them more convenient than guaiac tests: 1) unlike guaiac tests, a fecal smear is not required for immunochemical tests -- samples may be obtained from a brush sample of toilet bowl water; 2) unlike guaiac tests, immunochemical tests are not affected by diet or medications, so that dietary and medicinal restrictions are not necessary prior to testing.

In an update of the clinical guidelines on colorectal cancer screening and surveillance that were prepared by a panel convened by the U.S. Agency for Health Care Policy and Research and published in 1997 under the sponsorship of a consortium of gastroenterology societies, Winawer, et al. (2003) stated that promising new screening tests (virtual colonoscopy and tests for altered DNA in stool) are in development but are not yet ready for use outside of research studies.

Genetic testing of stool samples is also under study as a possible way to screen asymptomatic high-risk individuals for colorectal cancer. Colorectal cancer cells are shed into the stool, providing a potential means for the early detection of the disease by detecting specific tumor-associated genetic mutations in stool samples. Several genetic targets (e.g., mutations in p53 genes, deletions within the BAT26 locus, and mutations in K-RAS) are currently under investigation. Research conducted thus far has shown that these tests can detect colorectal cancer in people already diagnosed with this disease by other means. However, more studies are needed to determine whether the test can detect colorectal cancer in asymptomatic individuals. The U.S. Preventive Services Task Force notes that tests that incorporate genetic stool markers have not been evaluated with respect to mortality reduction.

A stool DNA test (PreGen-Plus), which looks for signs of mutant genes in stool, is made by Exact Sciences Corp (Marlborough, MA). A multi-center clinical trial (Imperiale, et al., 2004) reported that analysis of fecal DNA detects a greater proportion of colorectal neoplasia than FOBT. However neither of these non-invasive screening tests approaches the accuracy of a colonoscopy, the gold standard for detecting colorectal cancer. In the study, 4,404 average-risk, asymptomatic persons aged 50 years or older provided one stool specimen for DNA testing, underwent standard Hemoccult II FOBT, and then underwent colonoscopy. The fecal DNA panel, which identifies 21 mutations, detected 16 (51.6%) of 31 invasive cancers, whereas Hemoccult II detected 4 (12.9%) of 31 cancers. The DNA panel detected 29 (40.8%) of 71 invasive cancers plus adenomas with high-grade dysplasia compared with 10 (14.1%) of 71 detected by Hemoccult II.  Among 418 subjects with advanced neoplasia, the DNA panel was positive in 76 (18.2%), and Hemoccult II was positive in 45 (10.8%). Specificity in patients with negative findings on colonoscopy was 94.4% for the fecal DNA panel and 95.2% for Hemoccult II.

An accompanying editorial (Woolf, 2004) suggested that it is too early for the fecal DNA panel to replace FOBT as a screening test for colorectal cancer. Remaining questions include generalizability, low sensitivity in this study for both FOBT and the fecal DNA panel, inability to determine whether the health benefits of fecal DNA testing outweigh the harms, availability and cost of the fecal DNA test, and the need for public access to screening to be more systematic and of higher quality. This is in agreement with the observation of Agrawal and Syngal (2005) who stated that preliminary data on fecal DNA tests show better performance characteristics than FOBT. In their current form, however, it is not clear that the added sensitivity merits the additional cost. These tests must be studied in larger cohorts of asymptomatic patients before adequate comparison can be made to established colorectal cancer screening techniques.

A special report by the BlueCross BlueShield Association Technology Evaluation Center (2006) of fecal DNA analysis for colorectal cancer screening concluded that, although the impact of fecal DNA screening on cancer morbidity and mortality has not yet been studied, it seems reasonable to assume that attaining sensitivities equal to or better than that of FOBT would result in similar or improved outcomes. The report identified several questions that remain to be answered before fecal DNA screening can be widely recommended, including: whether sensitivity for large adenoma be significantly increased compared to FOBT; whether false-positive rates be maintained appropriately low for a screening program; what are the published performance characteristics of the testin in an average-risk screening population; what is the optimal screening interval; which patients should not be screened with fecal DNA testing; does the test improve compliance with colorectal cancer screening recommendations; and is the test cost-effective.

A cost-effectiveness analysis of DNA stool testing prepared for the Agency for Healthcare Research and Quality (Zauber, et al., 2007) found that all DNA stool test strategies considered were dominated by (i.e., more costly and less effective) other recommended colorectal cancer screening tests. The investigators concluded: "These results suggest that screening for CRC with the DNA stool test version 1.1 does provide a benefit in terms of life-years gained compared with no screening but the cost, relative to the benefit derived and to the availability and costs of other CRC screening tests, would need to be in the range of $34 - $60 to be a non-dominated option. Only if significant improvements for the DNA stool test characteristics or relative adherence with DNA stool testing compared with other available options can be demonstrated, will stool DNA testing at the current costs of $350 be cost-effective. These estimates are based on a third-party payer analysis on an unscreened 65-year old cohort. Threshold costs are similar for a 50-year old cohort, but can be somewhat higher from a modified societal perspective ($88 to $134 for 5-yearly testing and $73 to $116 for 3-yearly testing)."

In August  2007, the Centers for Medicare & Medicaid Services (CMS) initiated a national coverage determination process for screening DNA stool testing for colorectal cancer. However, in October 2007, the U.S. Food and Drug Administration (FDA) sent a warning letter to EXACT Sciences, maker of the only commercially available stool DNA test, stating that their PreGen-Plus test is a medical device that requires FDA clearance or approval prior to marketing and is currently being marketed in violation of the Federal and Food Drug and Cosmetic Act. Because of the FDA action, CMS subsequently announced its intention not to expand the colorectal cancer screening benefit to include coverage of this test. CMS stated that they will consider a request for reconsideration when a commercially available stool DNA test has been cleared or approved by the FDA.

The American Cancer Society's guidelines on colorectal cancer screening recommend several methods of screening, including virtual colonoscopy, based in part upon the presumption that the availability of multiple methods of screening will improve compliance (Levin, et al., 2008). Colorectal cancer screening guidelines from the American Cancer Society recommend CT colonography (virtual colonoscopy) performed every 5 years as an acceptable alternative to optical colonoscopy performed every 10 years for screening of average-risk persons. However, there are no studies demonstrating that virtual colonoscopy does, in fact, increase compliance. Virtual colonoscopy is similar to optical colonoscoppy in that it requires completion of a pre-procedure cathartic regimen.  If a lesion in found on virtual colonoscopy, the patient must return another day and complete another cathartic regimen for an optical colonoscopy to remove the lesion. By contrast, optical colonoscopy allows for identification and removal of a lesion in one procedure.

An assessment of CT colonography prepared for the Washington State Health Care Authority (Scherer, et al., 2008) found that, in direct comparison to optical colonoscopy, CT colonography every 10 years is substantially more expensive and marginally less effective in preventing cases of cancer (47 versus 52 in a lifetime cohort of 1,000 individuals) and cancer deaths (24 versus 26). The investigators reported that only one CT colonography screening strategy is as effective as optical colonoscopy every 10 years, and that strategy is to perform CT colonography every 5 years with colonoscopy referral for polyps greater than 6mm.  For this strategy, the cost per life-year gained for CT colonography versus optical colonoscopy was $630,700.

The USPSTF explained that CT colonography involves a wider area of examination than just the interior of the colon and that extra-colonic findings of potential clinical significance are common (7% to 16%).  The USPSTF stated that it is not known whether the serendipitous discovery of these lesions results in better outcomes for patients and that it is possible that they result in extra follow-up testing without associated benefit.  Furthermore, no studies directly addressed cancer-causing effects from CT colonography-associated radiation exposure and that it is not yet possible to quantify accurately the potential harms of extra-colonic findings or radiation exposure associated with CT colonography.  The USPSTF stated that more studies are required to determine all the risks and benefits associated with CT colonography (USPSTF, 2008).

The American College of Gastroenterology (Agrawal, et al., 2005) issued recommendations to healthcare providers to begin colorectal cancer screening in African Americans at age 45 rather than 50 years. Colonoscopy is the preferred method of screening for colorectal cancer and data support the recommendation that African-Americans begin screening at a younger age because of the high incidence of colorectal cancer and a greater prevalence of proximal or right-sided polyps and cancerous lesions in this population.

In a meta-analysis of surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer, Johnson, et al. (2006) concluded that the best available evidence supports surveillance with complete colonoscopy to the cecum every 3 years in patients with hereditary nonpolyposis colorectal cancer (B recommendation). There is no evidence to support or refute more frequent screening. Further research is needed to examine the potential harms and benefits of more frequent screening. However, given the potential for rapid progression from adenoma to carcinoma and missing lesions at colonoscopy, there is consensus that screening more frequently than every 3 years is required.

MYH is a DNA repair gene that corrects DNA base pair mismatch errors in the genetic code before replication. Mutation of the MYH gene may result in colon cancer. In this regard, the MYH gene has been found to be significantly involved in colon cancer, both in cases where there is a clear family history of the disease, as well as in cases without any sign of a hereditary cause.

The National Comprehensive Cancer Network (NCCN, 2006) practice guidelines on colorectal cancer screening (2006) recommends colonoscopy surveillance of asymptomatic individuals with known MYH mutations and colonoscopy screening of siblings of affected patients. Surveillance and screening is recommended beginning at age 25 to 30 years of age at 3 to 5 year intervals (the shorter intervals with advancing age). The NCCN guidelines recommend that patients with MYH-associated colorectal adenomas be managed similarly to patients with attenuated FAP. Those with small adenoma burden are surveilled with colonoscopy and complete polypectomies of all polyps. Those with dense polyposis not manageable by polypectomy are recommended surgery.

No current guidelines of leading medical professional organizations or Federal public health agencies recommend routine upper endoscopy screening of asymptomatic persons. Although screening upper endoscopy has been performed in conjunction with screening colonoscopy, there is no evidence-based support for this practice.

Currently, no leading medical professional organizations or Federal public health agencies recommend anal dysplasia screening. Recommendations from the Centers for Disease Control and Prevention state (Workowski & Berman, 2006): "Routine testing for anal cytological abnormalities or anal HPV infection is not recommended until more data are available on the reliability of screening methods, the safety of and response to treatment, and programmatic considerations." The Ontario Health Technology Advisory Committee (OHTAC, 2007) recently systematically reviewed the evidence for anal dysplasia screening. OHTAC "does not recommend screening of high risk individuals at this time based on the low specificity for cytological screening, inadequate evidence of effectiveness for current treatment of precancerous lesions, high recurrence rates, and no evidence that cytological screening reduces the risk of developing anal cancer."