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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: J Natl Compr Canc Netw. 2016 Nov;14(11):1479–1485. doi: 10.6004/jnccn.2016.0154

Use of National Comprehensive Cancer Network and Other Guidelines and Biomarkers for Colorectal Cancer Screening

Christina D Williams 1,2, William M Grady 3,5, Leah L Zullig 5,6
PMCID: PMC5117951  NIHMSID: NIHMS815936  PMID: 27799515

Abstract

Colorectal cancer (CRC) remains a common cancer and significant public health burden. CRC-related mortality is declining, in part due to the early detection of CRC through robust screening. The National Comprehensive Cancer Network (NCCN) has established CRC screening guidelines to aid healthcare providers in making appropriate recommendations for screening according to a patient’s risk of developing CRC. The purpose of this review is to describe the evolution of CRC screening guidelines for average risk individuals, discuss the role of NCCN CRC screening guidelines in cancer prevention, and comment on the current and emerging use of biomarkers for CRC screening.

Keywords: colorectal neoplasms, cancer screening, clinical practice guidelines

1. Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the U.S. and second leading cause of cancer-related death among both men and women. In 2016, an estimated 134,490 new CRC cases and 49,190 CRC-related deaths are expected.1 Despite the considerable public health burden of CRC, incidence and mortality rates have significantly declined in the last few decades. This trend is mainly attributed to treatment innovations and increased CRC screening.1-3 The goals of CRC screening among average-risk individuals are twofold: 1) to identify and remove precancerous polyps, and thereby reduce CRC incidence, and 2) detect CRC at an early stage when curative therapy is most likely possible, and thereby reduce CRC mortality. Currently, 40% of CRC cases are diagnosed with localized disease3 and the 5-year survival rate for localized CRC is 90%.4 The purpose of this review is to describe the evolution of CRC screening guidelines for average risk individuals, identify predictors of adherence to these screening guidelines, discuss the role of the National Comprehensive Cancer Network (NCCN) CRC screening guidelines in cancer prevention, and comment on the current and emerging use of biomarkers for CRC screening.

2. Evolution and comparison of CRC screening guidelines

Over the past 30 years, available CRC screening options and guidelines have evolved. In the 1980s, for average-risk individuals 50 years or older, formal CRC screening guidelines focused on annual guaiac fecal occult blood test (gFOBT). Since then, professional societies have revised the guidelines regarding the use of fecal immunochemical tests (FIT), sigmoidoscopy, barium enema, and colonoscopy and their use as appropriate screening modalities. Most recently, FIT-DNA (i.e. FIT plus stool DNA) and computed tomographic colonography (CTC) have also been included.5

The most sensitive screening tests for reducing CRC mortality have the ability to detect both advanced serrated and adenomatous polyps and cancer. Colonoscopy is one such test and, thus, may be preferred over other screening modalities that can detect cancer, but not polyps (i.e., stool-based tests). Because of its ability to detect and remove pre-cancerous polyps, colonoscopy is a useful and unique tool not only in the early detection of cancer, but also in cancer prevention.6

A number of organizations have established recommendations and clinical practice guidelines for colorectal screening, and these guidelines encompass multiple screening modalities. CRC screening guidelines have been developed by the US Preventive Service Task Force (USPSTF)7, American Cancer Society (ACS)8, American College of Gastroenterology (ACG)9, U.S. Multi-Society Task Force10, and National Comprehensive Cancer Network (NCCN)4, among others. While there is general consistency among the recommendations set forth by these organizations, there are also a few notable differences in guidance. Table 1 illustrates how NCCN CRC screening guidelines compare to that of other professional societies.

Table 1.

Summary of colorectal cancer screening guidelines.

NCCN2 USPSTF11 ACS/USMSTF/ACR6 ACG9
Detect cancer
    guaiac Fecal Occult Blood Test (gFOBT) Annual Annual Annual Annual
    Fecal Immunochemical Test (FIT) Annual Annual Annual Annual
    Stool DNA (FIT-DNA) Every 3 years Every 1 or 3 years Every 3 years Interval uncertain
Detect cancer and polyps
    Flexible Sigmoidoscopy Every 5-10 years +/− gFOBT/FIT every 3 years Every 5 years OR Every 10 years + annual FIT Every 5 years +/− annual gFOBT/FIT Every 5 years
    Colonoscopy Every 10 years Every 10 years Every 10 years Every 10 years
    Computed Tomography Colonography (CTC) --- --- Every 5 years Every 5 years
    Barium enema --- --- Every 5 years Every 5 years
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Abbreviations:

NCCN: National Comprehensive Cancer Network

ACS: American Cancer Society

USMSTF: U.S. Multi-Society Task Force

ACR: American College of Radiology

USPSTF: U.S. Preventive Services Task Force

ACG: American College of Gastroenterology

NCCN CRC screening guidelines were established to assist providers in making appropriate CRC screening recommendations based on patients’ risk of developing CRC.4 Recommended screening methods, age to initiate screening, and frequency of screening vary by a patient's risk level. For high-risk patients (i.e. those with a personal history of adenomatous polyps, sessile serrated polyps, CRC, or inflammatory bowel disease, or a family history of CRC) the only screening method recommended is colonoscopy.4 In contrast, for average-risk patients, NCCN recommends a choice of initial screening methods – colonoscopy, stool-based test, or flexible sigmoidoscopy with or without a stool-based test.4 NCCN does not currently endorse screening with CTC or barium enema.4 Similarly, the USPSTF guidelines do not include barium enema due to the availability of more sensitive tests. In addition, recommendations regarding use of flexible sigmoidoscopy vary in 2 ways: 1) whether gFOBT and/or FIT are included, and 2) the suggested screening interval.

Recently, both USPSTF and NCCN have revised aspects of their recommendations regarding CRC screening based on recently published evidence.2,11 The crux of the updated USPSTF recommendation is the absence of a preferred screening method and added emphasis on evidence that CRC screening, in general, reduces CRC mortality for asymptomatic individuals between ages of 50 and 75 years.12,13 The updated evidence review did not purport that one screening method was superior to others as it relates to the net benefit.7 The current list of screening options now includes: FIT-DNA every 1 or 3 years, CTC every 5 years, and flexible sigmoidoscopy every 5 years or every 10 years with annual FIT. The USPSTF's current guidance further highlights that while this mortality benefit is greatest for patients aged 50-75 years, the benefit among older persons is minimal. Therefore, the decision to screen should factor in patients’ health status and screening history for those 76 to 85 years, with no screening for those over the age of 85. Given that screening rates are suboptimal, with at least one-third of eligible patients having never been screened, the USPSTF asserts that the “best screening test is the one that gets done.” Shared decision making is one approach to choosing the “best” and preferred test for each patient and it has been shown that patients are more likely to adhere to CRC screening when given a choice of screening method.14

A key modification to NCCN guidelines for average-risk individuals is the emphasis that screening not only lowers CRC mortality, but also reduces CRC incidence by identifying and removing polyps.2 Previously, the recommended interval for flexible sigmoidoscopy was every 5 years with or without stool-based testing every 3 years, whereas current recommendations call for flexible sigmoidoscopy every 5-10 years with or without gFOBT/FIT at year 3. NCCN guidelines now recommend the option of stool DNA for CRC detection and the suggested interval is 3 years, although the appropriateness of this interval is uncertain.15 Regarding stool-based screening in general, it is noted that evidence that FIT is more sensitive than gFOBT was based solely on nonrandomized studies, which also indicate lower mortality with FIT. Language referencing colonoscopy as the “primary method” for CRC screening was modified to “most common” method, presumably to remove the suggestion that colonoscopy is preferred to other screening modalities.

3. Rates and predictors of adherence to guidelines for initial CRC screening

Given the National Colorectal Cancer Roundtable's goal to achieve CRC screening rates of 80% by 2018, it is critical to assess current rates and identify predictors of screening adherence.16 Studies have shown that people who are older and, to a lesser extent, those with higher comorbidity burden,17 who are uninsured18, lack a high school education, are of certain race/ethnic groups, and who report certain health beliefs are less likely to undergo CRC screening.19

A recent 10-year longitudinal study evaluated adherence to USPSTF guidelines and determined that only 64% of insured persons in their cohort were screening according to guidelines. Of those screened, on average, screening was initiated 3 years later than recommended.20 A separate study at a Veterans Affairs (VA) medical center evaluated the impact of a national VA CRC screening initiative by comparing screening rates and outcomes before and after the 1998 initiative.21 The screening rate before and after implementation of the initiative were 45% and 50%, respectively. Pre- and post-initiative stage distribution was only suggestive of a trend toward early stage diagnoses. However, when considering anatomic location there was a significant shift towards early stage diagnoses among distal cancers after the initiative, but no change in stage distribution in proximal cancers. Among all patients with screening-detected CRC, the 5-year all cause survival was approximately 89%.

In 2010, the prevalence estimate of screening by either FOBT or endoscopy (i.e. sigmoidoscopy or colonoscopy) was 59%.3 Screening rates vary by a number of demographic and socioeconomic factors, including patients’ age, race, years of education, insurance status, and immigration status.3 In a study by Shapiro et al utilizing National Health Interview Survey data, the prevalence of guideline-concordant, self-reported CRC screening by any means was 58%, with use of colonoscopy being 55%.22 Substantial differences in receipt of screening were noted within categories of income, education, type of insurance and source of health care. Shapiro and colleagues also captured reasons for not undergoing CRC screening. The most commonly reported reason was ‘no reason or never thought about it’ (41%), followed by a lack of provider recommendation (15%) and absence of symptoms (14%).22 A retrospective cohort study of screening-eligible individuals in a safety-net health system reported 22% being screened in the last 5 years, and significant predictors of screening participation were female gender, Hispanic ethnicity, being between the age of 65-75 years, and having access to care.23 Marital status is another important predictor of screening according to a large study of approximately 300,000 participants which noted that, compared to non-partnered people, married and unmarried couples were more likely to get CRC screening.24

4. Current and emerging use of biomarkers for CRC screening

Despite a strong evidence base supporting its efficacy, colonoscopy is limited by its invasiveness, expense and suboptimal patient compliance, and FOBT and FIT have low sensitivities for detecting colon polyps. This has led to efforts to develop more sensitive and specific non-invasive biomarker assays as an additional means of risk stratification and early detection of advanced colon polyps or CRC. As part of the colorectal carcinogenesis process, gene mutations and epigenetic alterations arise in colon polyps and CRCs and are potentially highly specific diagnostic biomarkers for the detection of colonic polyps and cancers. Feces and blood are the analytes used in the best developed biomarkers for CRC screening at this time and are the analytes used in the recently FDA approved colorectal cancer biomarkers.

4.1 Fecal-based biomarkers

Since the discovery of mutant KRAS in fecal specimens from patients with CRC25, numerous studies support using fecal DNA for potential screening assays for early CRC detection. Biomarkers assessed to date include mutant genes, methylated genes, microRNAs, and mRNA. However, the most successful biomarkers at this time are based on methylated DNA.

A large number Phase I and II biomarker studies have identified fecal-based methylation biomarkers for early CRC detection.26 Studies of methylated SFRP2, SFRP5, PGR, CALCA, and IGFBP2, in fecal DNA identified methylated SFRP2 as a diagnostic biomarker for CRC detection with high sensitivity (77-90%) and specificity (77%).27 A second study of stool DNA markers among subjects with colorectal adenomas demonstrated that methylated SFRP2 can also identify patients with precancerous colonic polyps.28 Another well-studied fecal DNA biomarker for CRC detection is methylated VIM, the gene for vimentin. Methylated VIM specifically occurs in adenoma and CRC tissues and is detected in fecal DNA of patients with colon neoplasms with reasonably high sensitivity (46%) and specificity (90%).29 Studies demonstrating the potential for using methylated VIM as a biomarker for the early detection of CRC led to the development of an assay that detects methylated VIM as one of the first commercial fecal-DNA screening tests for CRC (ColoSure™, Lab Corp, Burlington, NC). Other hypermethylated genes (APC, ATM, BMP3, CDKN2A, SFRP2, GATA4, GSTP1, HLTF, MLH1, MGMT, NDRG4, RASSF2A, TFPI2, VIM, and WIF1) have been analyzed in fecal DNA for the early detection of CRC.29-38

Efforts to develop an accurate noninvasive biomarker assay for CRC and colon polyp detection recently culminated in the development of an FDA-approved, clinically available stool-based CRC screening test – Cologuard® (Exact Sciences Corporation, Madison, WI), which combines both the stool DNA test and the OC Auto FIT. This stool DNA based assay, which detects methylated BMP3, methylated NDRG4, and mutant KRAS, was recently compared to FIT and had better sensitivity than FIT for both CRC and advanced adenomas, but lower specificity for both endpoints.39,40 The Cologuard® assay is approved for use by the FDA and in the European Union; however, its appropriate use in clinical care is in evolution. Of note, the Cologuard® assay has been included as an acceptable screening method in the 2016 USPTF screening guidelines and the 2014 American Cancer Society's colorectal cancer prevention and early detection guidelines.

4.2 Blood-based biomarkers

Due to accessibility and high patient acceptance, blood is invariably the most ideal analyte for cancer biomarkers. With the development of highly sensitive detection methods, like massively parallel sequencing, there have been renewed efforts to determine whether blood-based diagnostic assays based on circulating methylated DNA can be used for colon polyp or CRC detection. Okugawa et al recently summarized aberrantly methylated genes discovered in the plasma or serum of CRC patients which, consequently, are candidate biomarkers.36

Following the initial reports of methylated CDKN2A in circulating DNA in patients with a variety of human cancers in 199938,41,42, a growing number of studies have examined the potential of methylated genes to be blood-based biomarkers for CRC patients. Currently, the most established methylated DNA blood biomarker is methylated Septin 9 (SEPT9). Lofton-Day and colleagues identified methylated SEPT9 as a non-invasive diagnostic biomarker for CRC with 69% sensitivity and 86% specificity for distinguishing CRC patients from healthy individuals.43 Upon further refinement and validation of assays that use methylated SEPT9 as a biomarker for CRC screening, it is now commercially-offered as a blood-based screening test in various assays including Epi proColon® 1.0 (Epigenomics, Seattle, WA), ColoVantage® (Quest Diagnostics, Madison, NJ) and RealTime mS9 (Abbott Laboratories, Des Plaines, IL). A recent prospective clinical trial (PRESEPT) demonstrated equivalent sensitivity and specificity of methylated SEPT9 versus FOBT for CRC, confirming its potential usefulness as a blood-based biomarker for CRC.44 This test has been recently approved by the US FDA for use as a CRC screening assay. However, methylated SEPT9 has a limited sensitivity for the detection of advanced adenomas (11%), underscoring the need for further improvement of this test for implementation for population-based screening of colorectal neoplasia. A recent study demonstrated that the methylated SEPT9 assay was superior to FIT at detecting CRC, but both approaches were suboptimal for diagnosing patients with advanced adenomas.45 To date, several other blood-based diagnostic methylation biomarkers have been identified for CRC detection, including ALX446, APC32, CDKN2A37, HLTF47, HPP148, hMLH147, MGMT32, NEUROG149, NGFR, RASSF2A32, SFRP2, VIM50, and WIF1.32 Unfortunately, there are no Phase III biomarker studies of mutant or methylated DNA based biomarker assays for CRC detection in a screening setting at this time.51 Furthermore and importantly, when considered in the context of other CRC and colon polyp screening methods, while a robust biomarker panel of methylated genes may be developed into a clinically accurate CRC screening method in the near future, the currently available blood based biomarker assays are not appropriate as colon polyp detection methods.

5. Future directions

Given the consensus that CRC screening is beneficial yet underused, efforts to continue improve screening rates will expand and likely focus on historically under screened populations. To this end, having a clear, and ideally unified, set of guidelines could aid in this endeavor. These unified guidelines should be accompanied by research documenting screening adherence, improvements in health outcomes, and whether screening capacity is adequate to achieve current benchmarks. Despite their limitations, blood-based tests have the potential to increase screening rates because they are noninvasive. Moreover, blood-based tests are relatively simple to conduct may be more acceptable to patients than more invasive and labor-intensive options. In addition, shared decision making could result in choosing a screening option that is most consistent with patients’ values and preferences; thus, improving adherence for initial and, if necessary, follow up testing. Additional interventions to improve initial CRC screening may include: screening programs targeting screening naïve and historically under-screened populations, improved care coordination, and utilization of patient and provider reminder tools. As CRC screening recommendations continue evolving, and new technologies and biomarkers emerge, there may be heightened interest in measuring adherence to clinical practice guidelines as a quality indicator in clinical practice. Systematic monitoring of screening and associated health outcomes must be developed and implemented.

6. Conclusion

While CRC screening rates have increased dramatically over the last few decades, they remain suboptimal. Reasons for underutilization of CRC screening are multifactorial and accordingly require changes at multiple levels—patient, provider, and health care system. The guidelines developed by numerous professional organizations continue evolving as more evidence becomes available regarding the sensitivity, specificity, benefits, harms, cost, and availability of current and emerging screening options. There is variation between guidelines about which screening methods are endorsed and the associated time intervals for screening. The screening intervals for FIT-DNA and flexible sigmoidoscopy are least consistent across guidelines. The revised guidelines focus less on the specific screening methods provided to patients and instead emphasize the importance of increasing CRC screening rates overall. While unified guidance for CRC screening may not be on the immediate horizon, improving uptake of CRC screening and consequently improving early detection and reducing mortality is something that all societies support.

Acknowledgments

Research support: This work was supported by a Veterans Affairs Health Services Research and Development Career Development Award (CDA 13-025) (LLZ). This work was also funded by the National Institutes of Health (NIH) awards R01CA194663, P30CA15704, U01CA152756 (WMG). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, Duke University, or the University of Washington.

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