Commercial

Medical Policy

Title:

Colorectal Cancer Screening

Policy #:

11.03.12t

Policy

State mandates do not automatically apply to self-funded groups; therefore, individual group benefits must be verified.

AVERAGE-RISK INDIVIDUALS

The Company recognizes recommendations from the American Cancer Society (ACS) and the United States Preventive Services Task Force (USPSTF) for colorectal cancer screening for average-risk individuals, as well as federal and state mandates for colorectal cancer screening.

Individuals at average risk are those without a history of adenomatous polyps or colorectal cancer (CRC) and not at increased risk for CRC due to a family history of CRC, a confirmed or suspected hereditary CRC syndrome (such as familial adenomatous polyposis or Lynch syndrome), a personal history of abdominal or pelvic irradiation for a previous cancer, or a personal history of inflammatory bowel disease. In accordance with ACS, beginning at age 45, the following screening tests are covered:

Tests that find polyps and cancer:

Colonoscopy every 10 years
Computed tomographic colonography (virtual colonoscopy) every 5 years*
Double contrast barium enema every 5 years*
Flexible sigmoidoscopy every 5 years*

Tests that mainly find cancer*:

Fecal immunochemical test (FIT) every year*,**
Fecal occult blood test (FOBT) every year*,**
Stool DNA test (sDNA) alone or combined with FIT, (e.g., Cologuard™), every three years*

* Colonoscopy is recommended if test results are positive.

** For FOBT or FIT used as a screening test, the take-home multiple method is recommended. An FOBT or FIT done during a digital rectal exam in the professional provider's office is not adequate for screening.

INCREASED-RISK OR HIGH-RISK INDIVIDUALS

The Company recognizes recommendations from the American Cancer Society and state mandates for CRC screening for increased- or high-risk individuals.

Coverage is provided for CRC screening for individuals at increased-risk or high-risk of developing CRC. Coverage will be provided for individuals at increased-risk or high-risk of developing CRC at any age and at a frequency recommended by the treating professional provider. The following conditions place the individual at increased- or high-risk:

A personal history of CRC or adenomatous polyps
A personal history of inflammatory bowel disease (ulcerative colitis or Crohn's disease)
A strong family history of CRC or polyps (see Risk Factors for Colorectal Cancer at https://www.cancer.org/cancer/types/colon-rectal-cancer/causes-risks-prevention/risk-factors.html)
A known family history of a hereditary CRC syndrome such as familial adenomatous polyposis or hereditary nonpolyposis colon cancer
A personal history of irradiation to the abdomen or pelvic area to treat a prior cancer.

EXPERIMENTAL/INVESTIGATIONAL

The Epi proColon™, a test to detect methylated Septin 9 (SEPT9) gene, and the PolypDx™ test are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to, records from the physician's office, hospital, nursing home, home health agencies, therapies, other healthcare professionals, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, colorectal cancer screening is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in the medical policy are met.

Subject to the terms of the member's benefit contract, $0 cost share will be applied when colorectal cancer screening is performed as a preventive service at a participating provider, and there is direction from regulatory laws, such as the Affordable Care Act, to adjudicate the preventive service claim at $0 cost share.

STATE MANDATES

This policy is consistent with applicable state mandates. The laws of the state where the group benefit contract is issued determine the mandated coverage.

US FOOD AND DRUG ADMINISTRATION STATUS

The US Food and Drug Administration (FDA) has approved several noninvasive colorectal screening tests (e.g., Cologuard™, Epi proColon™, fecal occult blood tests, and fecal immunochemical tests) for colorectal cancer screening.

Description

Colorectal cancer (CRC) is a disease in which abnormal cell growth leads to tumor formation in the colon and/or rectum. It is the second leading cause of cancer-related death in the United States. CRC primarily affects men and women 50 years of age and older, and risks increase with age. If detected early, CRC may be treated and cured.

Depending on the CRC screening methodologies, they may detect cancer, precancerous polyps, and other abnormalities in the colon and/or rectum. CRC usually starts as a polyp (a growth of tissue in the inner wall of the colon and/or rectum) with no symptoms. Polyps are thought to develop into cancer over a period of several years. Polyps identified through CRC screening can be removed before they develop into cancer. Therefore, in addition to identifying existing CRC, screening also helps prevent the disease. If diagnosed in its early stages, CRC is highly curable, with a survival rate of approximately 90%.

In 2018, the American Cancer Society (ACS) recommended initiating screening at 45 years of age for men and women at average risk for CRC, based on the incidence of cancer above this age in the general population. Aggressive screening strategies contribute significantly to the early detection and subsequent treatment of CRC. Various methods are used to screen for CRC. The choice of method depends on the individual's risk, personal preference, and access, and should be discussed with the professional provider. For high-risk individuals, and those with a personal or family history, more frequent screening may be required, based on the recommendations of their professional provider.

In 2016, the US Preventive Services Task Force (USPSTF) revised their recommendation for CRC screening to be performed beginning at 50 years of age and continuing until 75 years of age. The decision to screen for CRC in adults aged 76 to 85 years should be an individual one, taking into account the individual’s overall health and prior screening history. The USPSTF concludes with moderate certainty that the net benefit of screening for CRC in adults aged 76 to 85 years who have been previously screened is small. Adults who have never been screened for CRC are more likely to benefit. In addition, after 85 years of age, the USPSTF feels there is moderate or high certainty that CRC screening has no net benefit, or that the harms outweigh the benefits. USPSTF continues to recommend screening with either one of the stool-based tests (e.g., annual fecal immunochemical test [FIT], annual high-sensitivity fecal occult blood test [FOBT], or stool DNA test [sDNA] every 3 years); or one of the direct visualization tests (e.g., colonoscopy every 10 years, or flexible sigmoidoscopy every 5 years combined with high-sensitivity FOBT every 3 years). Additionally, in the current recommendation, the USPSTF highlights that there is convincing evidence that CRC screening substantially reduces deaths from the disease among adults aged 50 to 75 years and that not enough adults in the United States are using this effective preventive intervention. The reasons for this gap between evidence and practice are multifaceted and will require sustained effort among clinicians, policy makers, advocates, and individuals to overcome.

To update its 2016 recommendation, in 2021 the USPSTF commissioned a systematic review to evaluate the benefits and harms of screening for CRC in adults 40 years or older. The population consisted of asymptomatic adults 45 years or older at average risk of CRC. The USPSTF recommends screening for CRC in all adults aged 45 to 75 years. The USPSTF recommends that clinicians selectively offer screening for CRC in adults aged 76 to 85 years. Evidence indicates that the net benefit of screening all persons in this age group is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the patient's overall health, prior screening history, and preferences. Because of limited available evidence, the USPSTF recommendation does not include serum tests, urine tests, or capsule endoscopy for CRC screening. The USPSTF continues to recommend screening with either one of the stool-based tests (e.g., annual FIT, annual high-sensitivity FOBT, or sDNA test every 1 to 3 years); or one of the direct visualization tests (e.g., colonoscopy every 10 years, computed tomography colonography every 5 years, flexible sigmoidoscopy every 5 years, or flexible sigmoidoscopy every 10 years combined with FIT every year).

The USPSTF highlights that CRC is the third leading cause of cancer death for both men and women, with an estimated 52,980 persons in the US projected to die of CRC in 2021. The USPSTF concludes with high certainty that screening for CRC in adults aged 50 to 75 years has substantial net benefit. The USPSTF concludes with moderate certainty that screening for CRC in adults aged 45 to 49 years has moderate net benefit. The USPSTF concludes with moderate certainty that screening for CRC in adults aged 76 to 85 years who have been previously screened has small net benefit. Adults who have never been screened for CRC are more likely to benefit.

The 2018 American Cancer Society Guidelines Update for CRC Screening focused on CRC screening in average-risk adults and did not address screening or surveillance in individuals at increased or high risk for developing CRC. Individuals at increased or high-risk for CRC include individuals with history of adenomatous polyps, a personal history of CRC, a family history of CRC or adenomatous polyps diagnosed in a relative before age 60 years, a personal history of inflammatory bowel disease, a confirmed or suspected hereditary CRC syndrome, or a history of abdominal or pelvic radiation for a previous cancer. Updated screening and surveillance recommendations for these groups have been developed by other organizations:

American College of Gastroenterology (ACG) clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes (2015)
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on Colorectal Cancer (2014)
Colonoscopy surveillance after CRC resection: recommendations of the US Multi-Society Task Force on Colorectal Cancer (2016)
Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer (2012)

Identification of candidates for differential screening requires adequate collection and updating of family history information and appropriate referral for genetic counseling and testing of individuals at increased risk for hereditary syndromes.

NONINVASIVE COLORECTAL CANCER SCREENING TESTS

COLOGUARD™
Cologuard uses sDNA samples to test multiple biomarkers known to be associated with CRC and premalignant colorectal adenomas. The assay utilizes a novel polymerase chain reaction (PCR)–based method known as Quantitative Allele-specific Real-time Target and Signal (QuARTS) amplification to analyze the levels of methylated bone morphogenetic protein 3 (BMP3) and NDRG4 and to test for seven specific variants in the KRAS gene. In addition, an analysis of the beta-actin gene (ACTB) is performed to control for variability in sDNA concentration. Finally, FIT is used to measure the hemoglobin (Hb) concentration in each stool sample. A positive Cologuard test result indicates that abnormal gene methylation, sequence variants, and/or elevated Hb were detected; a negative result indicates that none of these were identified in the individual’s stool. Based on the available evidence, Cologuard may be considered in individuals who are at least 50 years of age and have an average risk of CRC, based on personal and family histories. Based on the available evidence, Cologuard is not appropriate for individuals with a history of CRC or colorectal adenomas, individuals with a hereditary cancer predisposition syndrome associated with CRC, or individuals with other chronic colorectal disorders (e.g., inflammatory bowel disease or Crohn’s disease), because these individuals do not present with average-risk for CRC.

Early studies relating to the analytical validity of the Cologuard assay included analyses of two additional markers that are not used in the test’s current commercially available form (i.e., methylated tissue factor pathway inhibitor 2 [TFPI2] and vimentin [VIM]). However, each of these studies used the same methods for testing, and each reports data relevant for an assessment of biomarkers included in the Cologuard assay. This preliminary data revealed that methylated NDRG4 and BMP3 were two of the most discriminative markers and that, while levels of all four methylated genes evaluated were affected by individual age, methylated TFPI2 was more significantly affected than the other three markers. In addition, when examining the contribution of the individual markers to test accuracy, test performance was not significantly affected when the two methylated TFPI2 and VIM were excluded from the panel. Specifically, the sensitivity of the multimarker sDNA test (with the two additional methylated genes) ranged from 78% to 89% for CRC and from 62% to 64% for advanced adenomas (AAs), compared with 82% for CRC and 62% for AAs when TFPI2 and VIM were omitted.

Based on the data from these preliminary studies, TFPI2 and VIM were removed from the multimarker sDNA test, and the performance of the final assay was examined using two different testing algorithms. This analysis showed that a logistic regression-based testing algorithm had a higher sensitivity than a single-marker cutoff algorithm. Consequently, the logistic regression-based testing algorithm was used in all subsequent studies and is used in the commercially available Cologuard assay. In the initial studies using this logistic regression-based algorithm, the test sensitivity was 98% for CRC, 56% for AAs, and 55% for sessile serrated adenomas (SSAs, a type of AA), at a specificity of ≥90%. Among individuals with any AA, test sensitivity increased with the size of the colorectal lesion and was higher in those with high-grade dysplasia (abnormal cell growth with a high risk of becoming malignant). In the largest and most recent study of analytical validity, the sensitivity and specificity of the Cologuard assay were 92.3% for CRC and 42.4% for AAs, with a specificity of 86.6%. The detection rate was 93.3% for curable-stage CRC (i.e., stages I to III) and 69.2% for AAs exhibiting high-grade dysplasia. In addition, when compared with FIT, the Cologuard assay was superior in all measures except test specificity (86.6% for Cologuard and 94.9% for FIT).

Finally, additional evidence supporting the analytical validity of Cologuard testing was reported in an FDA Summary of Safety and Effectiveness. A variety of evaluations examining the technical aspects of the Cologuard assay (including the limit of detection [LoD], the limit of quantification [LoQ], and lot-to-lot reproducibility) yielded results that met or exceeded FDA requirements. In addition, studies of cross-reactivity showed minimal cross-reactivity in the presence of partially methylated BMP3 or NDRG4, normal KRAS sequences, and other types of colorectal diseases or noncolorectal malignancies. Furthermore, an analysis of the FIT portion of the Cologuard test demonstrated that the assay would detect less common forms of Hb but would not detect animal Hb or myoglobin. A variety of potentially interfering substances (such as lotions and medications) were also evaluated and none significantly affected the results of Cologuard testing. Based on these data and the findings reported in the previously described studies, Cologuard received FDA premarket approval in August 2014.

Studies evaluating the clinical validity of Cologuard testing are currently limited. However, because the most recent studies of analytical validity compare the results of the Cologuard assay with the current reference standard for the diagnosis of CRC (i.e., colonoscopy followed by histology), their results may also support the clinical validity of Cologuard testing. In addition, the largest of these studies calculated positive and negative predictive values (PPV and NPV, respectively), which are important measures of clinical validity. For the detection of CRC, the PPV and NPV for the Cologuard test were 3.7% and 99.9% for CRC and 23.6% and 94.7% for AAs, respectively, which were comparable to the PPV and NPV for FIT. Overall, a negative Cologuard result would reduce an individual’s chance of CRC from 1 in 154 (0.7%) to 1 in 1675 (0.06%), with a false-negative rate of 5.3%. However, according to the FDA’s documentation, an analysis of data stratified by sex revealed that the clinical sensitivity of the Cologuard assay may be higher in men than in women, and could potentially be affected by an individual's ethnicity.

Additional data regarding the clinical validity of Cologuard testing demonstrated that methylated BMP3 and NDRG4 levels normalized in 13 of 14 (93%) individuals with CRC after removal of the colorectal tumor, and that one Cologuard-negative individual with a sharp increase in methylated NDRG4 after surgery was subsequently found to have recurrent CRC. These findings confirmed that methylated BMP3 and NDRG4 levels are associated with CRC and suggest that it may be used for continued surveillance.

With regard to the clinical utility of Cologuard testing, it has been suggested that use of this noninvasive screening tool will increase the rate of compliance in individuals, leading to an increase in the detection of precancerous lesions and early-stage CRC, resulting in improved overall survival. Consistent with the hypothesis of increased compliance, a survey of individuals who used a different, first-generation sDNA-based assay suggested a relatively high individual acceptance rate for this form of CRC screening.

EPI PROCOLON™
Epi proColon is an in vitro diagnostic (IVD) test to detect methylated Septin 9 (SEPT9) gene in ethylenediaminetetraacetic acid (EDTA) plasma derived from an individual's whole-blood specimens. This test involves DNA extraction from individual's plasma, bisulfite conversion of DNA, and real-time PCR amplification of bisulfite-treated DNA for quantitation. The test comprises the Epi proColon Plasma Quick kit, Sensitive PCR kit, and Control kit.

No studies were identified that specifically stated that the FDA-approved version of the Epi proColon was evaluated. However, three studies included both analytical validity and clinical validity, and one clinical utility study provided evidence for the Epi proColon 2.0 test, which uses the same kits as the FDA-approved version. Only studies that assessed the Epi proColon 2.0 test and defined methylation-positive result as ≥1 of 3 replicates positive were included in support of the accuracy and performance of this test. Significant changes to the assay or data interpretation impact the test’s validity. The analytical validity of Epi proColon has been evaluated by several studies that support the test’s reproducibility, its ability to detect low levels of methylated SEPT9, and the fact that potential interfering substances do not affect test results. In addition, there is a defined assay process and the test has received FDA approval. In three case-control studies with mixed populations, the sensitivity for detecting CRC ranged from 68% to 95.6%, and specificity ranged from 78.8% to 84.8%. However, for high-risk or advanced adenomas, the sensitivity was very low, ranging from 14% to 22%. One additional study reported that the majority of individuals who decline colonoscopy elected to undergo the Epi proColon test for CRC rather than a stool-based test. However, there was no evidence demonstrating improved health outcomes from this test.

Epi proColon has a defined assay process approved by the FDA. However, there are discrepancies regarding the criteria for methylation-positive result as outlined in the FDA summary and presented on the manufacturer’s website. There is some evidence of clinical validity to support its use in the approved population; however, no studies have directly shown that the test results have a positive impact on health outcomes.

POLYPDX TEST™
PolypDx is purportedly the first and only urine-based test (which detects three metabolites) for CRC prevention. There is no publicly available information regarding the makeup (including any information regarding the biomarkers that may be part of this test) of PolypDx Test.There are no peer-reviewed published data nor pertinent directions from professional/clinical guidelines for this test.

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Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

0091U, 74263, 81528, 82270

EXPERIMENTAL/INVESTIGATIONAL

0163U

THE FOLLOWING CODES ARE USED TO REPRESENT EPI PROCOLON / METHYLATION ANALYSIS OF SEPT9

81327, 81479

THE FOLLOWING CODE IS USED TO REPRESENT POLYPDX

0002U

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medical necessity as listed in the policy.

HCPCS Level II Code Number(s)

G0104 Colorectal cancer screening; flexible sigmoidoscopy

G0105 Colorectal cancer screening; colonoscopy on individual at high risk

G0106 Colorectal cancer screening; alternative to G0104, screening sigmoidoscopy, barium enema

G0120 Colorectal cancer screening; alternative to G0105, screening colonoscopy, barium enema

G0121 Colorectal cancer screening; colonoscopy on individual not meeting criteria for high risk

G0122 Colorectal cancer screening; barium enema

G0328 Colorectal cancer screening; fecal occult blood test, immunoassay, 1-3 simultaneous determinations

EXPERIMENTAL/INVESTIGATIONAL

G0327 Colorectal cancer screening; blood-based biomarker

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 11.03.12t:

04/17/2024	This policy has been reissued in accordance with the Company's annual review process.
06/14/2023	This policy has been reissued in accordance with the Company's annual review process.The policy has been reviewed and reissued to communicate the Company's continuing position on Colorectal Cancer Screening.

11/16/2022	This policy has been reissued in accordance with the Company's annual review process.
11/17/2021	This policy has been reissued in accordance with the Company's annual review process.
07/01/2021	This version of the policy went through a code update process effective 07/01/2021 and procedure code G0327 was added to this policy on that date.

Revisions From 11.03.12s:

11/18/2020	This policy has been reissued in accordance with the Company's annual review process.
04/01/2020	This version of the policy went through a code update process effective 04/01/2020 and 0163U was added to this policy on that date.

Revisions From 11.03.12r:

07/01/2019

This version of the policy went through a code update process effective 07/01/2019 and 0091U was added to this policy on that date.

Revisions From 11.03.12q:

01/01/2019

Effective 01/01/2019, the following procedure code's narrative was revised in this policy due to coding updates:

81327

Revisions From 11.03.12p:

10/01/2018

This version of the policy is effective as of 10/01/2018.

The following procedure code has been deleted from this policy: G0464

Revisions From 11.03.12o:

07/01/2018

This version of the policy is effective as of 07/01/2018.

The policy has been reviewed to communicate the Company’s updated positions for the following (in accordance with American Cancer Society’s 2018 updates to the Colorectal Cancer Screening Guidelines):

For average-risk individuals, colorectal cancer screening is covered starting at age 45 instead of age 50.
A personal history of radiation to the abdomen or pelvic area to treat a prior cancer qualifies an individual as at increased- or high-risk indication.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

7/1/2021

Version Issued Date: