Objective: To explore the performance of a protocol combining fecal immunochemical test (FIT) and a high-risk factor questionnaire (HRFQ) for selecting patients requiring colonoscopy as part of a population-based colorectal cancer (CRC) screening program in China. Methods: From 2015 to 2016, we conducted a CRC screening program for all residents aged 45 years or older in Tianhe District, Guangzhou City, China. Participants underwent an FIT and received an HRFQ as part of primary screening. Those with positive FIT and/or HRFQ results were considered to be at high risk and were recommended to undergo colonoscopy. Results: A total of 10 074 subjects were recruited and enrolled in the screening program. In the enrolled population, 17.5% had positive FIT results and 19.4% had positive HRFQ results. Of those recommended to undergo diagnostic colonoscopy, 773 did so. The screening method’s overall positive predictive value (PPV) was 4.9% for non-adenomatous polyps, 11.4% for low-risk adenomas (LRAs), 15.9% for high-risk adenomas (HRAs) and 1.6% for CRC. The PPVs of positive FIT results for non- adenomatous polyps, LRAs, HRAs and CRC were 5.2%, 15.9%, 22.5% and 2.5%, respectively. The PPVs of positive HRFQ results for non-adenomatous polyps, LRA, HRA and CRC were 4.1%, 10.2%, 14.3% and 1.4%, respectively. The PPVs associated with combined positive FIT and HRFQ results for non-adenomatous polyps, LRAs, HRAs and CRC were 4.5%, 16.4%, 23.7% and 2.8%, respectively. Conclusion: Our results suggest that this two-step CRC screening strategy, involving a combination of FIT and HRFQ followed by colonoscopy, is useful to identify early-stage CRC. The high detection rates and PPVs for CRC and adenomas encourage this strategy’s use in ongoing screening programs. Key words: colorectal cancer, screening, fecal immunochemical test, high-risk factors, colonoscopy, positive predictive value Submitted: 4 May 2017; Revised: 16 July 2017; Accepted: 20 July 2017 V C The Author(s) 2017. Published by Oxford University Press and Sixth Afﬁliated Hospital of Sun Yat-Sen University This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/gastro/article-abstract/6/2/132/4104492 by Ed 'DeepDyve' Gillespie user on 20 June 2018 CRC screening in Tianhe, Guangzhou | 133 FOBT Introduction All participants provided written informed consent to undergo According to the global 2012 cancer statistics, colorectal cancer FOBT. After providing instructions on stool sampling, each par- (CRC) continues to be the third most frequently diagnosed can- ticipant was asked to collect samples from six areas of a stool cer in men and the second most frequent in women, with an es- specimen, place the samples in a small container filled with buf- timated 1.4 million cases and 693 900 associated deaths fer fluid (provided by the CDC) and immediately send the sam- worldwide. The highest incidence is in more developed counties ples to a community hospital laboratory. Laboratory assistants and regions, such as Australia/New Zealand, Europe and North tested each stool sample for occult blood using a qualitative fecal America . However, during the past two decades, there has immunochemical test (FIT) kit (Wanhua-Puman Biol. Tech Ltd been a remarkable increase in the incidence of CRC and associ- Company, China), with a detection threshold of 100 ng/mL. If the ated deaths in Asian countries . In China, CRC is the fourth first FIT result was negative, participants underwent a second most common carcinoma and the fifth most common cause of FIT screening. There were no dietary restrictions during the test. mortality, with an estimated 331 300 new cases and 159 300 as- sociated deaths annually . HRFQ It is increasingly acknowledged that most CRCs originate from adenomas, which develop slowly and sometimes undergo Information regarding risk factors was collected using a ques- malignant transformation through a series of genetic and epige- tionnaire. A positive HRFQ indicated that the participant had netic alterations . A period of at least 10 years may be required one of the following: a family history of CRC in a first-degree rel- for the transition from detectable adenoma to cancer. During ative, a history of polyps, chronic constipation, chronic diar- this period, CRC screening can identify and allow the removal of rhea, a history of appendicitis or appendectomy, chronic adenomas that may be cancer precursors. In addition, the time cholecystitis or cholecystectomy, a history of cancer or a history from early to invasive cancer may span several years. This win- of psychiatric trauma within the past 20 years. HRFQs were dow provides an opportunity for screening to detect early-stage completed by well-trained physicians who met the participant cancer, when treatment is more effective. This is the rationale at a convenient time that did not interfere with the participant’s for a screening program aimed at reducing the incidence of CRC work. The questionnaires were checked for completeness and and associated mortality. Several randomized controlled trials entered into a database by CDC staff. conducted in developed countries showed the effective early de- tection of cancer and increased long-term survival rates follow- Colonoscopy ing the use of population-based CRC screening [5–7]. Following a positive FIT or HRFQ result, participants were offered In China, CRC screening began in the 1970s. A randomized, con- a free colonoscopy. Colonoscopy examinations were performed trolled, population-based trial in Jiashan revealed that mass by expert gastroenterologists at the endoscopy center of the screening effectively reduced rectal cancer mortality by 31.7% . Sixth Affiliated Hospital of Sun Yat-sen University or at other Beginning in 2015, CRC screening was established as a major public hospitals in Guangzhou. The day before the colonoscopy, partici- health project in Guangzhou; we were responsible for the screen- pants were provided with instructions for bowel preparation ing program in Tianhe District. According to the recommendation over the phone, which involved a low-fiber diet and the con- by the China National Committee of Cancer Early Detection and sumption of hypertonic polyethylene glycol solution (2 L). If a co- Treatment, we conducted a two-step screening strategy that in- lonoscopy failed due to incomplete bowel preparation or other volved fecal occult blood test (FOBT) combined with a high-risk fac- reasons, a second diagnostic colonoscopy would be performed. tor questionnaire (HRFQ) as the primary screening method. The The number, size, location and morphology of any detected screening program included follow-up colonoscopies aimed at polyps were recorded. If the polyp diameter was <2 cm, the polyp identifying more premalignant lesions and early CRC cases. was removed endoscopically and sent for histopathologic exami- nation after the patient provided written consent. Surgery was recommended for patients with lesions suspected to be cancer- Methods ous or that were too large or too complicated for endoscopic re- Patient population moval. The major complications were also documented. From 2015 to 2016, a CRC screening program was conducted for all residents aged 45 years or older in Tianhe District, Histological classification Guangzhou City, China. The program was directed by the Low-risk adenomas (LRAs) were defined as adenomas showing Chronic Disease Center (CDC) and the Sixth Affiliated Hospital the following features: one or two lesions, size <10 mm, tubular of Sun Yat-sen University. Patients with current or prior CRC histology and low-grade dysplasia. High-risk adenomas (HRAs) were not included in the study. Those who had recently under- were defined as either adenomatous polyps measuring 10 mm gone a colon examination (colonoscopy or sigmoidoscopy) were in size, more than two adenomas, any adenoma with tubulovil- provided with the option to reject the screening invitation. lous or villous histology or high-grade dysplasia; carcinoma in situ was also classified as HRA. The non-adenomatous polyps included serrated polyps, juvenile polyps, inflammatory polyps Study participant recruitment and hyperplastic polyps. To promote participation in CRC screening, information was provided to citizens through the media, including television, ra- Statistical analysis dio and newspaper advertisements, posters in public places, and distributed pamphlets and brochures. Study participants SPSS 16.0 (IBM, Armonk, NY, USA) and Excel (Microsoft, were recruited at the CDC, with the cooperation of community Redmond, WA, USA) were employed for data analyses. doctors. The CDC staff explained the screening purpose and Differences in rates and proportions were calculated using process to all participants. Chi-square tests. Percentages and corresponding 95% Downloaded from https://academic.oup.com/gastro/article-abstract/6/2/132/4104492 by Ed 'DeepDyve' Gillespie user on 20 June 2018 134 | Y. Liao et al. Table 1. Characteristics of recruited participants confidence intervals (CIs) were used to assess differences. Statistical significance was defined as p < 0.05. Characteristics No. (%) Sex Results Male 4080 (40.5%) A total of 10 074 subjects were recruited and enrolled in the Female 5994 (59.5%) screening program, including 4080 men and 5994 women. The Age, years mean age of the participants was 67.4 years. Each participant Male completed both an HRFQ and at least one FIT. Table 1 shows the Range 45–82 characteristics of the recruited population. Mean6SD 67.6611.2 Female Range 45–78 Primary screening results Mean6SD 67.2610.8 Overall, 27.4% of the participants had positive results in the first Positive items stage of screening; 17.5% had positive FIT and 19.4% had posi- Fecal immunochemical test 1763 (17.5%) tive HRFQ results. When stratified by sex, the overall positive Family history of colorectal cancer 440 (4.4%) Chronic constipation 1035 (10.3%) rate was higher among men (29.9%) than among women Chronic diarrhea 472 (4.7%) (25.8%). The rates of positive HRFQ results were similar between History of appendicitis or appendectomy 712 (7.1%) men and women; however, the FIT-positive rates were higher History of cancer 256 (2.5%) among men than among women. When stratified by age, the History of psychiatric trauma 1213 (12.0%) overall positive rates (FIT and HRFQ) were higher for individuals 60 years old than for those <60 years old (Table 2). There were 2763 participants with positive FIT and/or HRFQ re- were 4.5%, 16.4%, 23.7% and 2.8%, respectively. The FIT PPVs for sults who were referred for colonoscopy. The average age was LRAs and HRAs were higher than those for HRFQ (Table 4). 64.4 6 9.4 and 1219 were males. Among them, 617 (76.3%) with pos- However, using HRFQ, we found that 30.6% of non-adenoma- itive FIT, 706 (70.6%) with positive HRFQ and 667 (69.9%) with both tous polyps (11/36), 13.6% of LRAs (12/88) and 12.2% (15/123) of positive FIT and HRFQ results refused to undergo colonoscopy ex- HRAs were missed by the FIT method. aminations. Therefore, 773 participants underwent diagnostic colo- Except for non-adenomatous polyps, the PPVs for each noscopy, including 192 FIT-positive individuals, 294 HRFQ-positive method, individually or combined, were higher for men than for individuals and 287 who were both FIT- and HRFQ-positive. women. PPVs were also higher for all lesion types in partici- pants 60 years than in those <60 years. Colonoscopy findings Of the 773 patients undergoing colonoscopy, the colonoscopy procedures were completed to the cecum in 753 patients (cecal Discussion intubation rate, 97.4%). Colonoscopy was not completed due to Our results suggest that a CRC screening program, involving FIT incomplete bowel preparation, neoplastic stenosis, discomfort and HRFQ combined with follow-up colonoscopy, allows early or technical issues. No serious colonoscopy complications oc- detection of CRC. The high detection rates and PPVs for CRCs curred, except for a minor perforation that occurred during en- and adenomas encourage the use of this strategy in ongoing doscopic polyp removal in one participant; surgery was not screening programs. required in this patient and there was no serious outcome. The FOBT, recommended in both the European Union and During colonoscopy screening, neoplasms were found in 259 the USA [8,9], is the most widely used CRC screening test. The (33.5%) individuals and included adenomas, non-adenomatous test is inexpensive, non-invasive and easy to use at home. polyps and CRC. When stratified by sex, the detection rates for Currently, two major approaches are available: the guaiac- LRAs and HRAs were 14.3% and 20.2%, respectively, among based FOBT (gFOBT) and FIT. Compared to the gFBOT, FIT has a men; the detection rates were lower for women (LRAs, 8.9%; higher sensitivity and better specificity for both CRC and ad- HRAs, 12.2%). There were no differences in the detection rates vanced adenoma detection [10,11]. However, FIT misses disease of non-adenomatous polyps and CRC between men and associated with non-bleeding or intermittent bleeding lesions. women. When stratified by age, the detection rates for non-ade- Thus, the HRFQ may be a complement to that test. Our results nomatous polyps, LRAs and HRAs were higher for individuals showed that the PPV of combined positive FIT and HRFQ results 60 years old than for those <60 years old. However, we did not was higher for HRAs than that of a positive FIT alone; the differ- observe a higher CRC detection rate for individuals 60 years ence did not reach statistical significance. This may due to the old than for younger individuals (Table 3). small number of individuals participating in the colonoscopy screening. A limitation of our study is the low response rate for Positive predictive values for the primary screening patients undergoing follow-up colonoscopies. Participation methods rates in primary colonoscopy screenings are generally subopti- In this study, the overall positive predictive values (PPVs) were mal . Because <70% of the eligible patients participated in 4.9% for non-adenomatous polyps, 11.4% for LRAs, 15.9% for the colonoscopy screening, our results may have been biased. HRAs and 1.6% for CRCs. The FIT PPVs for non-adenomatous The HRFQ investigation aims to identify participants with an polyps, LRAs, HRAs and CRCs were5.2%, 15.9%, 22.5% and 2.5%, increased risk of CRC owing to a family history or a predisposing respectively. The HRFQ PPVs for non-adenomatous polyps, condition. In our screening program, the FIT PPVs for LRAs and LRAs, HRAs and CRCs were 4.1%, 10.2%, 14.3% and 1.4%, respec- HRAs were higher than the HRFQ PPVs for the same lesions. tively. For individuals with both positive FIT and HRFQ results, However, using the HRFQ, we found that 30.6% of non-adeno- the PPVs for non-adenomatous polyps, LRAs, HRAs and CRCs matous polyps, 13.6% of LRAs and 12.2% of HRA were missed by Downloaded from https://academic.oup.com/gastro/article-abstract/6/2/132/4104492 by Ed 'DeepDyve' Gillespie user on 20 June 2018 CRC screening in Tianhe, Guangzhou | 135 Table 2. Sex- and age-speciﬁc rates of positive fecal immunochemical tests (FITs) and high-risk factor questionnaires (HRFQs) Screening test Male (n¼4080) Female (n¼5994) P-value <60 years (n¼3716) 60 years (n¼6358) P-value FIT, n (%) 765 (18.8) 998 (16.6) 0.006 592 (15.9) 1171 (18.4) 0.002 HRFQ, n (%) 811 (19.9) 1143 (19.1) 0.314 676 (17.2) 1278 (20.7) 0.019 FIT/HRFQ, n (%) 1219 (29.9) 1544 (25.8) <0.001 924 (24.9) 1839 (28.9) <0.001 Table 3. Sex- and age-speciﬁc colonoscopy results Screening test Male (n¼356) Female (n¼417) P-value <60 years (n¼269) 60 years (n¼504) P-value Non-adenomatous polyp, n (%) 19 (5.3) 17 (4.1) 0.41 6 (2.2) 30 (6.0) 0.019 Low-risk adenoma, n (%) 51 (14.3) 37 (8.9) 0.017 19 (7.1) 69 (13.7) 0.006 High-risk adenoma, n (%) 72 (20.2) 51 (12.2) 0.002 24 (8.9) 99 (19.6) <0.001 Colorectal cancer, n (%) 7 (2.0) 5 (1.2) 0.39 3 (1.1) 9 (1.8) 0.47 Table 4. Positive predictive values for the different screening tests used in colorectal cancer screening Screening test No. Positive predictive value, n (%) Non-adenomatous polyps Low-risk adenomas High-risk adenomas Colorectal cancer FIT only 479 25 (5.2) 76 (15.9) 108 (22.5) 12 (2.5) HRFQ only 581 24 (4.1) 59 (10.2) 83 (14.3) 8 (1.4) FIT and HRFQ 287 13 (4.5) 47 (16.4) 68 (23.7) 8 (2.8) FIT or HRFQ 773 36 (4.9) 88 (11.4) 123 (15.9) 12 (1.6) FIT, fecal immunochemical test; HRFQ, high-risk factor questionnaire. the FIT method. Thus, HRFQ is a supplemental method for CRC intubation rate, a measure of the endoscopists’ ability to reach screening. the cecum, was 97.4% in our screening program; no serious Colonoscopy allows direct observation of the total colonic complications were observed. These two parameters indicate and rectal mucosa. Moreover, tissue biopsy and polyp removal that high-quality colonoscopies were being performed. from the colorectum can be completed during the same proce- In our study, male sex and older age contributed to the high dure. These features may enable colonoscopy to be a reliable rate of positive colonoscopy screenings. These observations cor- tool for the early detection of CRC and also allow prevention of respond to the fact that colorectal neoplasms occur more often the progression of other lesions to CRC. Many Western coun- in men and in older individuals. However, some authors have tries include colonoscopy in their CRC screening programs reported that younger age is also associated with higher rates of [13,14]. Although the program was widely advertised before the positive CRC screenings [17,18]. start of screening, our reported colonoscopy compliance rate In this study, the overall PPVs were 1.6% for CRCs, 15.9% for was unsatisfactory. Colonoscopy is invasive, is associated with HRAs and 33.5% for total colorectal neoplasms. These results potential complications and procedural discomfort, and re- mean that patients with positive results on primary screening quires prior bowel preparation. A small proportion of popula- would have a 1.6% possibility of having CRC, 15.9% possibility of tion was aware that colonoscopy is a useful method for having an HRA and a 33.5% possibility of any type of colorectal detecting CRC. Together, these factors may have contributed to neoplasm. The PPV results in our study were consistent with the low percentage of our study population choosing to undergo those from the Tianjin CRC screening program , but were colonoscopies. Therefore, much more needs to be done to im- relatively high compared to the results from rural Zhejiang . prove colonoscopy participation rates in the target population. Lifestyle and dietary habit changes between urban and rural To achieve successful colonoscopy screening outcomes, the areas in China may contribute to the high PPVs that have been quality of the colonoscopy procedure is a key factor. Several observed. Additionally, physician experience, bowel preparation studies have shown that the most important cause of interval quality, sedation and instrument quality may also contribute to CRC is related to colonoscopy quality. Approximately half of in- the different detection rates. However, 66.5% (false-positive terval CRCs seem to result from lesions that were missed during rate) of participants without colorectal neoplasms underwent colonoscopy . Some studies have indicated that variations colonoscopies. If this false-positive rate can be reduced, the among endoscopists and endoscopy centers lead to changes in screening efficiency would be greatly improved. A new, more ef- the quality of colonoscopy procedures. Corley et al. reported ficient method is still needed for CRC screening. that the adenoma detection rate (ADR) ranges from 7.4% to Patients prefer non-invasive options such as FOBT instead of 52.5%, based on a review of over 300 000 colonoscopies per- colonoscopy for CRC screening. Nevertheless, the sensitivity of formed by 136 different gastroenterologists . In our screen- FIT for detecting colorectal neoplasms is unsatisfactory, leading ing program, the ADR was 32.6% in men and 20.4% in women, to the active exploration of other non-invasive screening mo- corresponding to the target ADR recommended by the 2014 dalities. Fecal DNA testing is based on the identification of spe- American Society for Gastrointestinal Endoscopy for popula- cific genetic alterations in the adenoma cancer sequence. A tions undergoing screening colonoscopies. Moreover, the cecal study by Imperiale et al. reported that the sDNA panel Downloaded from https://academic.oup.com/gastro/article-abstract/6/2/132/4104492 by Ed 'DeepDyve' Gillespie user on 20 June 2018 136 | Y. Liao et al. Luxembourg: Ofﬁce for Ofﬁcial Publications of the European demonstrated a 92.3% sensitivity for detecting cancer in com- parison to a 73.8% sensitivity for FIT. Similarly, the sDNA panel Communities, 2010. had a 42.4% sensitivity for detecting HRAs, compared with 9. Smith RA, Mettlin CJ, Davis KJ et al. American Cancer Society 23.8% for FIT . Other non-invasive screening tests, such as guidelines for the early detection of cancer. CA Cancer J Clin microRNA, plasma-based DNA and stool protein tests, are being 2000;50:34–49. investigated for their potential use . The unremitting explo- 10. Whitlock EP, Lin JS, Liles E et al. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive ration of non-invasive tests will probably greatly improve the efficiency of CRC screening. Services Task Force. Ann Intern Med 2008;149:638–58. 11. Ouyang DL, Chen JJ, Getzenberg RH et al. Noninvasive testing for colorectal cancer: a review. Am J Gastroenterol 2005;100: 1393–1403. Acknowledgements 12. Scott RG, Edwards JT, Fritschi L et al. Community-based We thank the CDC staff for recording data. 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Gastroenterology Report – Oxford University Press
Published: Sep 5, 2017
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