Stool DNA testing for colorectal cancer (CRC) screening

Research area: Prevention and screening

Duration: April 2021 – July 2021
Language: English (with German summary)

Publication: Policy Brief No 011: https://eprints.aihta.at/1335

Background: Colorectal Carcinoma (CRC) is the third most frequent cancer type, with an incidence and prevalence of approximately 4,800 and 40,000 cases respectively each year [1]. In Austria, the option of Guaiac (based) fecal occult blood test (gFOBT) screening to detect CRC exists each year for individuals aged 50 and above since 2005. Additionally, a colonoscopy is offered in a 10 years interval for asymptomatic individuals within this age group [2].

DNA stool testing is a novel non-invasive screening test that may be able to supplement or replace established stool tests such as gFOBT to detect CRC by analysing (stool-based) tumour DNA. A recent EUnetHTA report 2019 evaluated the evidence regarding an additional benefit of adopting this test into diverse screening pathways. In this assessment, no direct evidence derived from randomised controlled trials were identified, although three diagnostic accuracy studies and five patient surveys were included. Based on indirect evidence, stool DNA testing showed a promising benefit–harm balance when different screening strategies were compared, although these results are only applicable to one of two currently available DNA stool tests (Cologuard®) [3].  

In the absence of direct evidence regarding a clinical benefit of DNA stool tests, it is still uncertain whether this screening test (as add-on of the existing screening pathway or potential replacement of gFOBT) yields additional population-based benefits in terms of a reduced disease burden of CRC.

Aims of the project and research questions: The project aims at providing an update on the latest evidence on whether the implementation of stool-based DNA testing (add-on or replacement of existing screening tests) results in a better detection of CRC (in healthy individuals aged 50 or older) and is associated with patient-relevant benefits. The following research questions are to be answered:

RQ1:What is the latest evidence on the test accuracy of DNA stool testing as an add-on or replacement of existing screening tests in different screening pathways in healthy individuals aged 50 or older?

RQ2: Is a screening pathway with DNA stool testing more effective than, and at least as safe as, a conventional screening pathway in terms of reducing CRC related mortality and potential harms?

Inclusion criteria (PICO):

Population	Asymptomatic, predominantly healthy persons aged 45 years or older, who do not belong to a high-risk group for the development of CRC (e.g., individuals with a family history of CRC, carriers for hereditary CRC, people found to have five colorectal adenomas, and patients with inflammatory bowel disease)
Intervention	Standard screening pathway with a stool test for the detection of altered DNA from cancerous and precancerous lesions of the colonic mucosa (also in addition to occult blood testing). Product names: ColoAlert® (PharmGenomics), Cologuard® DNA test (Exact Sciences)
Control	Conventional screening pathway that may or may not include one of the following: Colonoscopy (which also is the reference standard for test accuracy studies) (Flexible) Sigmoidoscopy gFOBT FIT M2-PK test SEPTIN9 test CT colonography
Endpunkte
Outcomes	Effectiveness sensitivity for CRC sensitivity for precancerous lesions specificity for CRC specificity for precancerous lesions positive predictive value negative predictive value CRC incidence CRC mortality overall mortality number needed to screen (NNS) to detect CRC NNS to detect advanced adenoma Safety false negative rate for CRC and/or precancerous lesions false positive rate for CRC and/or precancerous lesions psychological harms from false negative and false positive test results number needed to harm (NNH) Other outcomes test performance: test failure rate test performance: uncertain results rate handling problems carrying out the test and/or taking the specimen patient adherence (patient preference) cost of test (intervention)
Study design
Effectiveness	diagnostic accuracy studies, randomized controlled trials, prospective controlled studies,
Safety	randomized controlled trials, prospective studies with or without a control group, qualitative studies for the psychological harm outcome
Other outcomes	qualitative studies, such as patient surveys

Notes: slightly adapted from [3]

Abbreviations: CRC=colorectal cancer; CT=computed tomography; DNA=deoxyribonucleic acid; FIT=fecal immunochemical test; gFOBT=guaiac (based) fecal occult blood test.

Methods: This policy brief represents an evidence synthesis based on a recent EUnetHTA report 2019 and an update of the evidence of the screening test under investigation:

•          Critical appraisal and synthesis of the evidence (relevant for Austria) from the EUnetHTA report 2019 with a focus on Austria using the AMSTAR-II checklist [4]

•          An update systematic literature search (8/2018-5/2021) will be conducted in four databases (Cochrane (CENTRAL), Centre for Research and Dissemination (CRD), Embase, Ovid MEDLINE) using the search strategy deployed in the EUnetHTA report 2019 [3]

The PRISMA statement [5, 6]and the EUnetHTA Core Model ® [7]will be used as reporting standards: Study selection (Screening of abstracts, and full-texts) and critical appraisal (=risk of bias assessment) will be performed by one researcher (GG). For the risk of bias assessment, adequate instruments will be utilised: e.g., Cochrane Risk of Bias tool v.1 [8]for randomised trials, ROBINS-I for non-randomised controlled trials [9]and QUADAS-II for diagnostic studies [10]. Relevant data from eligible studies will be systematically extracted into piloted data-extraction tables. A qualitative evidence synthesis will be conducted.

If direct evidence (RCTs or NRCTs of acceptable quality) is available, only this evidence will be considered in the course of the update systematic review. In this case, the evidence synthesis on diagnostic accuracy will be based on the EUnetHTA report [3]only.

Timeplan/ milestones:

Periode	Leistungen
May 2021	Systematic search, AMSTAR-II appraisal of EUnetHTA report, study selection
June 2021	Critical appraisal (=risk of bias assessment), data extraction, writing the report
July 2021	Internal Review, publication

References:

[1]        Statitstics Austria. Krebserkrankungen in Österreich 2020. 2020 [cited 21.04.2021]. Available from: http://www.statistik.at/web_de/services/publikationen/4/index.html?includePage=detailedView&sectionName=Gesundheit&pubId=679.

[2]        Fröschl B, Antony K and Ivansits S. Übersicht nationaler Kolonkrebs-Screening-Programme. Vienna: GÖG: 2017 [cited 21.04.2021]. Available from: https://jasmin.goeg.at/57/1/%C3%9Cbersicht%20nationaler%20Kolonkrebs-Screening-Programme%C2%A0.pdf.

[3]        Stürzlinger H, Conrads-Frank A, Eisenmann A, Ivansits S, Jahn B, Janzic A, et al. Stool DNA testing for early detection of colorectal cancer. Joint Assessment. . Vienna: EUnetHTA: 2019 [cited 21.04.2021]. Available from: https://eunethta.eu/wp-content/uploads/2019/07/Assessment-WP4_OTJA-10.pdf.

[4]        Shea B. J., Reeves B. C., Wells G., Thuku M., Hamel C., Moran J., et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. Epub 2017/09/25. DOI: 10.1136/bmj.j4008.

[5]        Liberati A., Altman D. G., Tetzlaff J., Mulrow C., Gøtzsche P. C., Ioannidis J. P. A., et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology. 2009;62(10):e1-e34. DOI: https://doi.org/10.1016/j.jclinepi.2009.06.006.

[6]        Moher D., Liberati A., Tetzlaff J. and Altman D. G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. International Journal of Surgery. 2010;8(5):336-341. DOI: https://doi.org/10.1016/j.ijsu.2010.02.007.

[7]        EUnetHTA. Methodology Guidelines. 2015 [cited 01.02.2019]. Available from: https://www.eunethta.eu/methodology-guidelines/.

[8]        Higgins J. P. T., Altman D. G., Gøtzsche P. C., Jüni P., Moher D., Oxman A. D., et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. DOI: 10.1136/bmj.d5928.

[9]        Sterne J. A. C., Hernán M. A., Reeves B. C., Savovi? J., Berkman N. D., Viswanathan M., et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. DOI: 10.1136/bmj.i4919.

[10]      Whiting P. F., Rutjes A. W., Westwood M. E., Mallett S., Deeks J. J., Reitsma J. B., et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):529-536. Epub 2011/10/19. DOI: 10.7326/0003-4819-155-8-201110180-00009.