April 25, 2018
17 min read

‘Strategic menu’ of noninvasive options needed to boost colorectal cancer screening rates

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

Only two-thirds of Americans aged 50 to 75 years are up to date with colorectal cancer screening.

Although uptake has increased steadily over time, it remains far below the National Colorectal Cancer Roundtable’s goal of an 80% screening rate for average-risk individuals.

The traditional characterization of colonoscopy as the gold standard screening strategy may be one explanation. Many individuals are unwilling to undergo colonoscopy due to fear, cost concerns, perceived inconvenience or a lack of desire to complete the necessary bowel preparation regimen.

Navkiran Shokar, MD, MPH, MA, and colleagues received a $4.5 million grant to determine the relative effectiveness of four fecal immunochemical tests.
Navkiran Shokar, MD, MPH, MA, and colleagues received a $4.5 million grant to determine the relative effectiveness of four fecal immunochemical tests. “This study will give physicians and patients better information about test sensitivity and test characteristics in the real world,” Shokar said.

Source: Tommie Morelos/Texas Tech University Health Sciences Center El Paso.

“In the United States, physicians tend to prefer recommending colonoscopy because it is a one-time test, and they don’t have to worry about it again for 5 or 10 years. The problem is that patients aren’t necessarily as enthusiastic about colonoscopy as some physicians are,” Navkiran Shokar, MD, MPH, MA, vice chair for research and director for cancer prevention and control at Texas Tech University Health Sciences Center El Paso, told HemOnc Today.

Several noninvasive screening options — such as fecal immunochemical tests (FIT), guaiac-based fecal occult blood tests and stool DNA testing — have emerged in the past decade.

Unlike colonoscopy, CT colonography and flexible sigmoidoscopy, the noninvasive options primarily detect cancer, not polyps.

However, a groundswell of support within the clinical community is based on the belief that increased availability and awareness of noninvasive options, as well as mounting scientific evidence that demonstrates their effectiveness, may encourage adults who refuse to undergo colonoscopy — as well as those who are not eligible because of comorbidities — to seek an alternative.

“The best colorectal cancer screening test is the one that gets done,” Richard Wender, MD, chief cancer control officer at American Cancer Society, said in an interview. “Not only are these less invasive and more affordable screening tests helpful options, they are critical options, and we should view them as one of our greatest tools in our fight against colorectal cancer.”

HemOnc Today spoke with clinicians and cancer prevention advocates about the benefits and disadvantages of noninvasive colorectal cancer screening methods, how availability and awareness of these approaches may contribute to increased screening uptake, the need for more comparative studies, and whether a simple blood test eventually could become a viable screening option.


No more ‘gold standard’

The U.S. Preventive Services Task Force issued updated colorectal cancer screening guidelines in 2016.

The document — given an A grade, which indicates evidence suggests “high certainty” that the net benefit is substantial — recommends colorectal cancer screening from age 50 years to age 75 years.

However, it outlines several screening options, including colonoscopy every 10 years, other direct visualization tests — such as CT colonography every 5 years, flexible sigmoidoscopy every 5 years, and flexible sigmoidoscopy every 10 years plus FIT every year — and noninvasive stool-based tests, such as FIT once a year, guaiac-based fecal occult blood test annually, or FIT-DNA annually or every 3 years.

Cologuard (Exact Sciences) — the only FIT-DNA test available in the United States — looks for certain abnormal sections of DNA from cancer or polyp cells, and also tests for blood in the stool.

“The screening tests are not presented in any preferred or ranked order,” task force members wrote. “Rather, the goal is to maximize the total number of persons who are screened because that will have the largest effect on reducing colorectal cancer deaths.”

The American Cancer Society is updating its colorectal cancer screening guidelines. Scientific evidence has changed considerably since the last update in 2008.

“We now have very good modeling data that demonstrates if people adhere perfectly to any of the recommended screening options — and, of course, that is a big ‘if’ — we can prevent essentially the same number of colorectal cancer deaths over a 10-year period,” Wender said.

Richard Wender, MD
Richard Wender

Consequently, the message to the public and the clinical community must evolve.

“We don’t consider colonoscopy as the gold standard anymore,” Wender said. “When you say something is the gold standard, you communicate the assumption that it is essentially perfect. We know it’s not perfect, and we know the quality of colonoscopy varies widely.

“An important component of the effort to achieve an 80% screening rate by 2018 is emphasizing not just which test you get done, but the test you get done well,” he added. “That’s true for colonoscopy and noninvasive options.”

Evidence also suggests screening adherence is enhanced by offering patients choices, Wender said.

More than 150 individual organizations — including large hospital systems, community health centers and the U.S. Department of Veteran Affairs — have achieved 80% colorectal cancer screening within their eligible populations.

“None of them have achieved this with colonoscopy alone. All of them rely on a variety of screening options,” Wender said. “We are deeply committed to making sure clinicians present these different screening options the right way.


“In too many practices, patients are offered only colonoscopy and, if they are not adherent, they are not offered another choice,” he added. “Other times, clinicians use language that makes noninvasive tests sound like a poor compromise, and that is not the best way to increase screening rates.”

Ranking the options

David A. Johnson, MD, chief of gastroenterology at Eastern Virginia School of Medicine and coauthor of the U.S. Multi-Society Task Force on Colorectal Cancer (MSTF) screening guideline, echoed the sentiment about the benefits of multiple options.

“Because patients seem to respond to opportunities of choice rather than absolute direction, we need a strategic menu that will allow us options beyond ... screening colonoscopy,” Johnson said in an interview.

At the same time, the MSTF guideline — issued last year — did rank colorectal cancer screening options for average-risk individuals.

The ranking — structured in three tiers — accounts for performance features, costs and practical considerations.

Task force members identified two first-tier approaches — colonoscopy every 10 years, and annual FIT — and labeled them “the cornerstones of screening.”

Second-tier options included CT colonography every 5 years, flexible sigmoidoscopy every 5 to 10 years, or use of a FIT-DNA test every 3 years.

The task force designated capsule colonoscopy every 5 years as a third-tier option due to limited evidence and barriers to access.

The panel suggested the Septin9 serum assay (Epi proColon, Epigenomics) — based on detecting aberrantly methylated DNA of the v2 region of the Septin9 gene in blood plasma — not be used due to lack of evidence.

The guideline no longer recommended use of conventional guaiac fecal occult blood testing, given FIT detects colorectal cancer and advanced neoplasia with better sensitivity and comparable specificity.

FIT is noninvasive, offers the convenience of at-home testing with no bowel prep, and carries no medical restrictions. It has a one-time sensitivity of 79% for detecting cancer, a sensitivity of approximately 30% for detecting advanced adenomas and a low one-time cost of about $20.

Consequently, it often is the preferred test for programmatic screening.

The task force’s tier one ranking of the modality reflects the panel’s view of FIT as “an essential element of the colorectal cancer screening armamentarium for all practitioners.”

However, FIT does have limitations, including the need for repeated testing. The MSTF noted this is a major drawback of stool-based tests, as achieving compliance with tests that need to be repeated at short intervals can be difficult in the United States.

FIT also lacks sensitivity for detecting serrated lesions.


“The serrated pathway has become an increasingly apparent pathway, not only for primary colon cancer but also for interval colon cancers after people have had a colonoscopy,” Johnson said.

Cologuard — a stool-based test that received FDA approval in 2014 — can detect these high-risk lesions with better sensitivity. However, specificity is lower and costs are significantly higher, according to Seth A. Gross, MD, FACG, chief of gastroenterology at NYU Langone Health.

“The fecal DNA stool test is becoming more popular because it’s better at identifying advanced adenomas, whereas the primary aim of other noninvasive screening techniques is to diagnose colon cancer,” Gross said in an interview. “The stool DNA test is more sensitive to picking up advanced adenomas and sessile serrated polyps, which are important because — in some situations — they have a shorter pathway to moving onto colon cancer than a traditional precancerous tubular adenoma.”

Cologuard is recommended every 3 years rather than annually. However, Exact Sciences is performing a longitudinal follow-up study to make sure the 3-year interval is optimal.

“For people who prefer a less frequent noninvasive test, stool DNA FIT is the best option, though at a greater cost,” Thomas F. Imperiale, MD, professor at Indiana University School of Medicine and staff physician at Richard L. Roudebush VA Medical Center in Indianapolis, said in an interview.

Thomas F. Imperiale, MD
Thomas F. Imperiale

Cologuard’s website indicates a list price of $649, but it is covered by CMS and several other major payors.

“There are issues with the cost-effectiveness of this test, but the sensitivity of stool DNA is better than FIT alone,” Imperiale said.

In one study, the FIT-fecal DNA test showed a one-time sensitivity for colorectal cancer of 92%. That is the “highest single-time testing sensitivity for cancer of any noninvasive, nonimaging colorectal cancer screening test,” according to the MSTF guideline. The study also showed 40% sensitivity for sessile serrated polyps greater than 1 cm.

“Where it has some drawback is with specificity, which is not as good as FIT, particularly [for] people older than age 65,” Imperiale said.

Comparative studies needed

At least 16 different FIT tests are available in the United States, but their efficacy relative to each other is unclear.

Researchers at three U.S. sites — including Shokar and her team at Texas Tech University Health Sciences Center El Paso — received a $4.5 million grant to determine the relative effectiveness of four FIT tests.

Investigators intend to enroll 3,600 adults aged 50 to 85 years. Study participants will be given four FIT tests, and then they will undergo colonoscopy. The investigators hope to determine which FIT test is most accurate, while also increasing awareness of FIT tests.


“If we want to get population-based screening rates improved, we have got to do a better job recommending FIT. That’s where this study comes in,” Shokar told HemOnc Today. “Although stool-based tests are cleared by the FDA, there still is not good real-world information that will allow us to compare across different tests. This study will give physicians and patients better information about test sensitivity and test characteristics in the real world.”

A study by Shapiro and colleagues, published in American Journal of Gastroenterology, enrolled more than 1,000 patients and compared three fecal occult blood tests. Results showed the InSure FIT (Clinical Genomics) demonstrated greater sensitivity (26.3%) for advanced colorectal neoplasia detection than the OC FIT-CHEK (Somagen Diagnostics; 15.1%) and Hemoccult II SENSA (HemoCue; 7.4%).

Another study by Gies and colleagues, published in Gastroenterology, compared nine quantitative FITs and showed wide variability when using sensitivity and specificity thresholds recommended by the manufacturers. Investigators concluded the heterogeneity in diagnostic performance “can be overcome to a large extent by adjusting thresholds to yield defined levels of specificity or positivity rates.”

Randomized trials designed to compare the outcomes of colorectal cancer screening tests other than FIT also are needed.

Johnson and colleagues on the MSTF noted that, because of a lack of data, they took “practical considerations” into account when designating modalities into their tiers.

Test availability appears to have factored into the tiering criteria, Imperiale said.

“Even though it seems like [we have] a lot of good choices, what really is most readily available and best known in the U.S. at this time is colonoscopy and FIT,” he said. “Flexible sigmoidoscopy has, by far, the strongest and most consistent evidence supporting efficacy than any screening currently available, but no one’s getting screened with it in the United States.

“It’s shown fairly good incidence and mortality reductions but it’s essentially unavailable here, so the tiering criteria goes beyond published evidence about effectiveness,” he added. “Unlike flexible sigmoidoscopy, there are no completed randomized controlled trials involving colonoscopy.”

That is about to change, however.

Four randomized trials are underway worldwide to compare colonoscopy with FIT or other less invasive screening strategies.

Imperiale and colleagues completed enrollment in the CONFIRM study, which will compare the efficacy of screening colonoscopy with FIT for preventing colorectal cancer mortality among 50,000 average-risk patients in the VA system.

“We really don’t know which strategy is better — colonoscopy every 10 years or a FIT test every year,” Imperiale said. “We don’t know which is better in terms of uptake, adherence, and colorectal cancer morbidity and mortality reduction.”


The COLONPREV study, conducted in Spain, was designed to compare colonoscopy with FIT. Colorectal cancer death rate at 10 years served as the primary endpoint, and outcomes data are expected in 2021.

The NordiCC trial included centers in Poland, the Netherlands, Norway, Sweden and Iceland. Researchers compared colonoscopy with no screening — the standard of care in trial regions — to determine its effect on colorectal cancer incidence and mortality. Fifteen-year results are expected in 2026.

Impact on uptake

Patient compliance with different tests is an important consideration in these large studies.

“A screening test can’t be effective if people don’t do it,” Imperiale said. “The most effective it can be is the extent to which it’s taken up.

“If 30% of the colonoscopy group gets colonoscopy, the most it can reduce colon cancer incidence or mortality is by 30%,” Imperiale added. “If 80% of the FIT group gets FIT done regularly, and it detects 75% of all colorectal cancers, FIT will outperform colonoscopy in the long run. But we just don’t know the answers to these basic questions about uptake, adherence and effectiveness.”

Interim results from the COLONPREV study provided some insights, as it showed the participation rate for FIT was 39% higher than for colonoscopy, but both methods resulted in the same colorectal cancer detection rate (0.1%).

However, results of a randomized clinical trial published last year in JAMA showed higher screening completion rates with mailed colonoscopy outreach than mailed FIT outreach over 3 years (38.4% vs. 28%).

The reasons why people do not undergo screening must be better understood — and addressed — before colorectal cancer screening uptake will improve, according to Douglas G. Adler, MD, professor of medicine at University of Utah School of Medicine, as well as investigator and director of therapeutic endoscopy at Huntsman Cancer Institute, said in an interview.

“There are lots of reasons why people don’t get screening colonoscopy,” he said. “Their primary care provider may not think to offer it. They may fear it will be uncomfortable, painful or embarrassing. And bowel prep is inconvenient. ... These are all classic barriers.”

People who live in more remote areas also face access challenges.

“Many small towns have no gastroenterologist,” Adler said. “If people live in rural Wyoming or Montana or Nevada, if the nearest GI doctor is hours away, they’re just not going to prioritize getting a colonoscopy if they have to designate 2 days to drive 4 hours, get a colonoscopy and stay overnight at a hotel.”


Barriers to colonoscopy must be eliminated regardless of a person’s initial colorectal cancer screening strategy, Wender said.

“You either go direct to colonoscopy as your primary screening choice, or you have to get a colonoscopy if any of the other initial screening options are positive,” he said. “The reality is, if someone has no opportunity to undergo a colonoscopy, we actually don’t have an effective screening strategy for them.”

Screening age

Young-onset colorectal cancers are relatively rare in the United States. Individuals aged younger than 50 years account for 11% of colon cancers and 18% of rectal cancers.

However, incidence has increased among this population over time.

A study by Siegel and colleagues, published last year in Journal of the National Cancer institute, showed colorectal cancer incidence among those aged younger than 50 years decreased from the mid-1970s to the mid-1980s.

However, since the mid-1980s, incidence rose 2.4% annually among adults aged 20 to 29 years and 1% annually among adults aged 30 to 39 years. From the mid-1990s, rates increased 1.3% annually among adults aged 40 to 49 years and 0.5% annually among adults aged 50 to 54 years.

The proportion of diagnoses among adults aged younger than 55 years doubled from 14.6% to 29.2% for rectal cancer and increased from 11.6% to 16.6% for colon cancer.

This trend has prompted some in the clinical community to suggest the screening age for average-risk individuals be lowered from age 50 to age 45.

Similarly, because of racial disparities in colorectal cancer risk and screening, the MSTF suggested lowering the screening age among black Americans to 45 years.

“I am definitely concerned about the evidence that colorectal cancer is occurring more frequently in patients under the age of 50, so I don’t think we can ignore that, and the risk appears to be higher in black people, in particular,” Jonathan A. Leighton, MD, chair of the division of gastroenterology at Mayo Clinic in Arizona, said in an interview. “Based on that, we certainly need to consider lowering the screening age in certain subpopulations, but it requires further study.”

A study by Karsenti and colleagues, presented at United European Gastroenterology Week, showed marked increases in the detection of neoplasia, polyps and adenomas among colonoscopy recipients aged 45 to 49 years compared with those aged 40 to 44 years, which led investigators to recommend that screening should begin at age 45 years.

FIT shows the most promise for expanding the screening population in a cost-effective way, Leighton said.


“Lowering the screening age may turn out not to be as cost-effective but, from the standpoint of the individual patient, I think it’s something that we have to strongly consider,” he said. “It at least needs to be further studied so that we can make an educated decision but, in the meantime, I think doing FIT plus or minus flexible sigmoidoscopy ... would be a very reasonable approach to do initially rather than necessarily going straight to colonoscopy.”

Imperiale said he does not believe lowering the screening age is appropriate.

“Lowering the screening age now would be an emotional response to a problem that needs reason and a greater understanding of etiologic factors, risk factors, and the balance of benefits and harms under varying conditions,” he wrote in a recent editorial.

Immediate efforts should focus on patient education and prevention, he added.

Modeling studies show it is best to start screening around age 50, but the number is somewhat arbitrary, and there are inherent inefficiencies in choosing a single age to start screening for everyone, Imperiale said.

“If we could tailor the age at which to begin screening, we would do better as far as efficiency, except it becomes more complicated to start younger in one demographic group and start older in another,” he said. “Men’s risks for advanced adenoma and colon cancer are 1.5 to two times that of women irrespective of age until around 70, where women start to catch up, but we don’t screen men earlier or women later given the challenges to implementing it.

“Even though the risk of colon cancer is rising in young people, it’s rising slowly and the risk is still an order of magnitude less than it is in people who are 50 and older,” Imperiale added. “To say we should start screening earlier could cause a lot of mischief ... and it’s quite possible that the frequency of major complications would outweigh curable-stage cancer detection.”

The American Cancer Society’s updated guideline will include a review of available evidence that can help determine the appropriate age to begin screening, Wender said.

“We will use epidemiologic trends and trial data, but we also have to rely on modeling because, although there have been trials of colorectal cancer screening for people younger than age 50, there are relatively few and they are unlikely to be sufficient to answer this question,” he said.

Liquid biopsy

Although the MSTF recommended against the use of the Septin9 serum assay due to its inferior performance relative to FIT, experts agreed an accurate blood test for colorectal cancer would be valuable.


“Blood testing is kind of the holy grail,” Adler said. “A very high-sensitivity, high-specificity blood test with a good positive predictive value would be very widely adopted. However, it has been extremely difficult to develop such a test, and I suspect one would be used to detect cancer rather than polyps.”

A study presented at this year’s Gastrointestinal Cancers Symposium showed a circulating tumor blood test (CellMax Life) detected precancerous lesions with 84% accuracy and cancerous lesions with 88% accuracy.

Investigators evaluated 620 individuals who were scheduled for routine colonoscopy or had a colorectal cancer diagnosis; of these, 438 had either adenomatous polyps or early- to late-stage colorectal cancers.

The CellMax biomimetic platform identified these lesions with 97.3% specificity. Sensitivity was 76.6% (95% CI, 67.9-83.5) for detection of circulating tumor cells in precancerous lesions, and 86.9% (95% CI, 82.8-90.1) for stage I to stage IV cancers.

The accuracy of the test is superior to stool-based tests such as fecal occult blood test or FIT for detecting stage I to stage IV cancers, study investigators Wen-Sy Tsai, MD, PhD, assistant professor at Linkou Chang Gung Memorial Hospital in Taipei, Taiwan, and Ashish Nimgaonkar, MD, assistant professor of medicine at Johns Hopkins University, told HemOnc Today via email.

“The key difference between this circulating tumor cell blood test and stool-based tests is its higher sensitivity in the detection of precancerous lesions,” they wrote. “Stool-based tests have roughly 40% or lower sensitivity in the detection of precancerous lesions.”

The test could cost less than $100, according to a company press release.

“Surveys conducted to find the cause of low screening rates demonstrated that most people would rather get a routine blood test than a routine colonoscopy or stool-based tests due to its convenience and noninvasive nature,” Tsai and Nimgaonkar wrote. “The ... CTC blood test ... offers individuals a convenient and accurate test option so that they routinely get tested, which is essential.”

The blood test is commercially available in Asia and the company is evaluating commercialization options in the United States, Tsai and Nimgaonkar said.

Wender said use of blood markers — whether through free DNA, free RNA or proteomics — is an exciting area of research for all types of screening, including colorectal cancer.

“However, it really is a double-edged sword,” he said. “The advantage is, more people will want to opt for the blood test because it’s an easy thing to do, and that’s terrific, but you really have to make sure the blood test performs as well as other existing options.”


Until a reliable and cost-effective blood test becomes available, providers must spread awareness and promote use of available noninvasive options to help maximize screening rates, Imperiale said.

“Some providers may not give their patients a choice, perhaps because they don’t believe that these tests are effective,” Imperiale said. “We have to be good stewards of the different options for colon cancer screening and support primary care providers and patients in their choices.”

Adler agreed, but he emphasized patient education is just as important as patient choice.

“Colon cancer, like a lot of malignancies, is asymptomatic until it’s very advanced,” he said. “If people don’t really have a sense of the risk and danger of colon cancer, they are less likely to be screened.”

Campaigns designed to increase awareness among the public “tend to be extremely successful,” Adler added.

“The biggest thing we can do is awareness and education,” Adler said. “The goal was 80% by 2018, and we’re certainly far below that. So, a very large swath of this country who is eligible has still not had any colorectal cancer screening test. We’re in a good time in the sense that we have so many tests now at our disposal. It’s very hard for a patient to say they don’t want to be screened.” – by Adam Leitenberger and Rob Volansky


American Cancer Society. “Colorectal Cancer Facts & Figures 2017-2019.” www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-facts-and-figures-2017-2019.pdf. Accessed on April 4, 2018.

CDC. Colorectal Cancer Statistics. Available at: www.cdc.gov/cancer/colorectal/statistics/index.htm. Accessed on March 28, 2018.

Chen C, et al. Gastrointest Endosc. 2018;doi:10.1016/j.gie.2017.04.005.

Gies A, et al. Gastroenterol. 2018;doi:10.1053/j.gastro.2017.09.018.

Imperiale TF. Gastrointest Endosc. 2017;doi:10.1016/j.gie.2017.05.035.

Jung YS, et al. Gastrointest Endosc. 2017;doi:10.1016/j.gie.2017.03.1531.

Kaminski MF, et al. Endoscopy. 2012;doi:10.1055/s-0032-1306895.

Karsenti D, et al. Abstract OP023. Presented at: UEG Week; Oct. 28-Nov. 1, 2017; Barcelona, Spain.

Quintero E, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1108895.

Rex DK, et al. Am J Gastroenterol. 2017;doi:10.1038/ajg.2017.174.

Robertson L, et al. Am J Gastroenterol. 2017;doi:10.1053/j.gastro.2016.08.053.

Singal AG, et al. JAMA. 2017;doi:10.1001/jama.2017.11389.

Shapiro JA, et. al. Am J Gastroenterol. 2017;doi:10.1038/ajg.2017.285.

Siegel RL, et al. J Natl Cancer Inst. 2017;doi:10.1093/jnci/djw322.

Spada C, et al. Clin Gastroenterol Hepatol. 2016;doi:10.1016/j.cgh.2016.04.038.

Tsai W-S, et al. Abstract 556. Presented at: Gastrointestinal Cancers Symposium; Jan. 18-20, 2018; San Francisco.

U.S. Preventive Services Task Force. Final recommendation statement: Colorectal cancer screening. Available at: www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectal-cancer-screening2#noted. Accessed on April 4, 2018.

For more information:

Douglas G. Adler, MD, can be reached at dougraham2001@gmail.com.

Seth A. Gross, MD, FACG, can be reached at seth.gross@nyumc.org.

Thomas F. Imperiale, MD, can be reached at timperia@iu.edu.

David A. Johnson, MD, can be reached at dajevms@aol.com.

Jonathan A. Leighton, MD, can be reached at leighton.jonathan@mayo.edu.

Navkiran K. Shokar, MD, MPH, MA, can be reached at navkiran.shokar@ttuhsc.edu.

Richard Wender, MD, can be reached at richard.wender@cancer.org.

Disclosures: Imperiale reports grant support through Indiana University from Exact Sciences. Leighton reports consultant and research relationships with Covidien, Given Imaging and Medtronic related to colon capsule technology. Adler, Gross, Johnson, Shokar and Wender report no relevant financial disclosures.