
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01445-5
10.1016/j.esmoop.2024.103676
103676
Original Research
Combining FITs and HRFQ with colonoscopy improve the cost-effectiveness of a 9-year mass colorectal cancer screening program
Cai S.-R. 12†
Huang Y.-Q. 12†
Li Q.-R. 3†
Zhu H.-H. zhuhh2297@126.com
4∗
Zhang S.-Z. 12
Song Y.-M. 5
Yang J.-H. 3
Zheng S. 12
1 Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, the China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang, The Zhejiang University School of Medicine Affiliated Second Hospital, Zhejiang
2 Zhejiang Provincial Clinical Research Center for Cancer and Cancer Center of Zhejiang University, Hangzhou, Zhejiang
3 Cancer Prevention Institute of Jiashan County, Jiashan, Zhejiang
4 Center for Medical Research, Zhejiang Chinese Medical University Affiliated Four-Province-Bordering Hospital of Traditional Chinese Medicine (Quzhou Hospital of Traditional Chinese Medicine), Quzhou, Zhejiang
5 Department of Colorectal Surgery, The Zhejiang University School of Medicine Affiliated Second Hospital, Hangzhou, Zhejiang, P.R. China
∗ Correspondence to: Dr Hong-Hong Zhu, Researcher and Head of the Center for Medical Research, Quzhou Hospital of Traditional Chinese Medicine (Zhejiang Chinese Medical University Affiliated Four-Province-Bordering Hospital of Traditional Chinese Medicine), 117 Quhua Road, Quzhou, Zhejiang, 324000, P.R. China. Tel: +86-152-57029247/+86-186-57005699 zhuhh2297@126.com
† Contributed equally to this work.

20 8 2024
9 2024
20 8 2024
9 9 103676© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Colorectal cancer (CRC) incidence has been increasing. Colonoscopy is still a gold standard method for its early diagnosis but using colonoscopy alone as a mass screening method is unrealistic. This study is to investigate whether combining fecal immunochemical test (FIT) and high-risk-factors questionnaire (HRFQ) with colonoscopy improve the cost-effectiveness of a mass CRC screening.

Patients and methods

CRC screening protocol combining FITs and HRFQ in the first stage and colonoscopy in the second stage was used in 50 villages/towns in 2007-2015. Residents aged 40-74 years were eligible for this free screening. A total of 160 210 (76.12%) participants completed first-stage screening, and 28 679 (17.90%) participants were defined as positive, among which 21 715 (75.72%) participants completed colonoscopy and were included in the final analysis. Outcomes were followed up until 2020.

Results

The compliance was 76.12% and 75.72% in the first and second screening stage, respectively. A total of 252 CRC, 4033 adenoma, 1234 advanced neoplasm, and 5534 total neoplasm cases were detected in the screening. The positive predictive values of CRC, adenoma, advanced neoplasm, and total neoplasm were higher in FITs+ than those in the HRFQ+ population, respectively. A total of 64.60% and 43.42% total neoplasm cases were found in FITs+ and HRFQ+ (8.02% for both), respectively. The total colorectal neoplasm and CRC cases detected by combining HRFQ and FITs increased by 55.08% and 40.00%, respectively, and their increases were higher compared to HRFQ. The detection cost per any neoplasm by combining HRFQ and FITs was <$5331, while that by FITs and HRFQ alone was <$4570 and $5380, respectively.

Conclusions

Combining FITs and HRFQ with colonoscopy improve the cost-effectiveness of a mass CRC screening program. This protocol can be recommended for most populations, especially those in the countries and areas with high population density and low physician/population ratio.

Highlights

• Combining FIT and HRFQ in the first screening stage helped increase the compliance rate of colonoscopy in the second stage.

• Combining FIT and HRFQ helped detect an additional 55% of the total colorectal neoplasm and 40% of the CRC cases.

• Considering the pros and cons of colonoscopy, FITs, and HRFQ, detection cost by combining FIT and HRFQ was acceptable.

• This screening protocol should be recommended for most populations in the world.

Key words

colorectal cancer
mass screening
colonoscopy
FIT
HRFQ
cost-effectiveness
==== Body
pmcIntroduction

Colorectal cancer (CRC) is one of the leading causes of cancer death1, 2, 3, 4, 5, 6 which has become a global burden of disease. In the United States, CRC remains the third leading cause of cancer deaths.1 In recent years, CRC incidence has been increasing rapidly in some developing countries, such as China, Philippines, and Brazil.4,6, 7, 8 In China, CRC incidence and mortality have been incessantly increasing for >30 years,9 with standardized incidence increasing by 48.3% from 12.15/100 000 in 1990 to 18.02/100 000 in 2015 and its death number increasing by 140.1% (77 900 in 1990 versus 187 000 in 2015).10,11 Newly diagnosed CRC cases and deaths in China accounted for 28.8% of all 36 cancer cases and 30.6% of all 36 cancer deaths worldwide in 2020, respectively, where age standardized incidence was 23.9/100 000, higher than that worldwide (19.5/100 000).4 Therefore, it is very urgent to reduce CRC incidence and mortality in China.

Early diagnosis and mass screening have been verified effectively to reduce CRC incidence and mortality.6,12, 13, 14 In the United States, CRC mortality was decreased by 26% during 1975-2000; 53% of this decline was estimated due to increase in the removal of precancerous polyps and detection of early-stage CRC15,16 in mass screening. The selection of the screening method usually determines the effectiveness of a screening program. To date, there are various screening methods reported and applied in some countries.6,13,14,17,18

An effective mass CRC screening test should be sensitive, specific, safe, and acceptable to people.19, 20, 21 Colonoscopy has high sensitivity and specificity but it is invasive, costly, and less acceptable to patients than noninvasive fecal screening.22, 23, 24 In China, a two-stage mass CRC screening protocol combining the high-risk-factors questionnaire (HRFQ) and fecal immunochemical test (FIT) as the first-stage screening method, and then using colonoscopy as the secondary-stage screening method has been used to find colorectal neoplasm in more than 50 districts25,26 in China. This study was to evaluate the cost-effectiveness of these screening methods in our two-stage mass CRC screening program in China.

Patients and methods

Study design and participants

All residents aged 40-74 years old in Jiashan county were our target population. The population in Jiashan county during 2007-2015 was averagely 385 628 (195 206 men and 190 422 women). A total of 210 478 participants (104 314 men and 106 164 women) aged 40-74 years old were eligible for this mass CRC screening program which covered the cost for all participants to complete the screening. A total of 160 210 participants signed the written consent form before screening and completed the first-stage screening; of them, 28 679 participants were either HRFQ+ which definition was described in our published articles24,25 or FITs+ in the first stage, which were eligible for a free colonoscopy; and finally, a total of 21 715 participants completed colonoscopy. A flow chart of CRC screening is presented in Figure 1. This study has been reviewed and approved by the ethics committees at the Zhejiang University Affiliated Second Hospital and the Zhejiang Chinese Medical University Affiliated Four-Province-Bordering Hospital of Traditional Chinese Medicine (Quzhou Hospital of Traditional Chinese Medicine) (Approval NO: 2023-08-202).Figure 1 Flow chart of study participant recruitment in a mass CRC screening program in the whole population aged 40-74 years in Jiashan County, China, 2007-2015. CRC, colorectal cancer; FIT, fecal immunochemical test; HRFQ, high-risk-factors questionnaire.

We used our two-stage design of CRC screening strategy13,25,26 to complete this free mass screening in all 50 villages/towns in Gan Yao, Da Yun, Yao Zhang, Tao Zhang, Luo Xing, Hui Min, Hong Xi, Tian Ni, Wei Tang, Xi Tang, Yang Miao, and Ding Shan, one by one, across the entire Jiashan county, in Zhejiang province during 2007-2015. HRFQ and FIT were used as primary screening methods in the first stage. HRFQ data were collected through face-to-face inquiry by local hospital doctors who had completed systematic trainings. FIT was repeated twice with an interval of 1 week. If either HRFQ or FITs was positive, a colonoscopy was recommended in the second stage except those who finished colonoscopy within the past year. If any FIT was positive, then we defined FITs-positive (FITs+). The screening participants were followed up through the Jiashan Cancer Registration System until 2020.

Data collection

Collection of fecal samples, preparation and conduction of colonoscopy, histopathologic diagnosis, and the cost of HRFQ, FIT, and colonoscopy for the mass screening was already described in a previous publication.24, 25, 26 Advanced adenoma was defined as adenoma of 10 mm or more, or with a history showing either a 20% or more villous component, or with high-grade dysplasia. All cancer cases were enrolled into the Jiashan Cancer Registration System.

Statistical analysis

SPSS 21.0 software was used for data analysis. Differences in proportions of results between primary screening methods and colonoscopy were expressed in number and percentage and compared using the χ2 test. The positive predictive value (PPV) was defined as the proportion of patients who had true-positive findings divided by any positive population in the first screening stage. Advanced neoplasm included advanced adenoma and CRC. There were 54 participants who had positive results at the first-stage screening and refused to complete colonoscopy but were diagnosed with CRC within 1 year after the completion of the first-phase screening. These 54 cases were regarded as being found by the screening, and classified into the CRC group in the final analysis. These 54 cases cost ¥14 580 (RMB) for colonoscopy which was supposed to be free during the screening period, so this cost was not included in the cost analysis due to the cost accounting for about 0.017% (14 580/8 539 8561 Yuan) of total costs in the screening and will not influence the cost-analysis results.

Results

A total of 160 210 participants including 78 231 men and 81 979 women, whose average age was 54.6 years [standard deviation (SD): 9.25], completed HRFQ and FITs in the first stage, and a total of 21 715 participants whose average age was 56.3 years (SD: 8.74) completed colonoscopy in the second stage in this mass CRC screening program.

The compliance rate of HRFQ, FITs, and colonoscopy

The compliance rate in the first and second stage was 76.12% (160 210/210 478) and 75.72% (21 715/28 679), respectively. The compliance rate of FITs was 64.87% (136 539/210 478), which was significantly lower (P < 0.01) than that of HRFQ (160 210/210 478 = 76.12% shown in Figure 1 and Table 1). In men, the compliance rate of either HRFQ or FITs in the first stage was 75.05% (78 231/104 284), which was significantly lower than that in women (81 979/106 164 = 77.22%) with a P < 0.01 (Supplementary Tables S1.1 and S1.2, available at https://doi.org/10.1016/j.esmoop.2024.103676).Table 1 Participants and results by age group, screening method, and stage in a mass colorectal cancer (CRC) screening in the whole population aged 40-74 years in Jiashan County, China, 2007-2015

Screening stage	Age 40-54 years (n = 82 217)	
FITs	HRFQ	HRFQ with FITs	HRFQ without FITs		
First stage:
Either FITs or HRFQ	Participant	67 646	82 217		67 646		14 571		
Result	FITs+	HRFQ+	FITs+/HRFQ−	FITs−/HRFQ+	FITs+/HRFQ+	HRFQ+	Any+	
n (%a)	6655 (9.84)	5750 (7.00)	6073 (8.98)	4511 (6.67)	582 (8.60)	657 (4.51)	11 823 (14.38)	
Second stage:
Colonoscopy	Participant (%b)	5267 (79.14)	4369 (75.98)	4817 (79.32)	3663 (81.20)	450 (77.32)	256 (38.96)	9186 (77.70)	
Result	CRC	34	20	31	15	3	2	51	
Adenoma (nc)	823 (192)	505 (81)	743 (172)	400 (58)	80 (20)	25 (3)	1248 (253)	
Non-adenomatous polyps	229	208	222	190	7	11	430	
Advanced neoplasm	226	101	203	73	23	5	304	
Total neoplasm	1086	733	996	605	90	38	192	
Screening stage	Age 40-54 years (n = 77 993)	
FITs	HRFQ	HRFQ with FITs	HRFQ without FITs		
First stage:
Either FITs or HRFQ	Participant	68 893	77 993		68 893		9100		
Result	FITs+	HRFQ+	FITs+/HRFQ−	FITs−/HRFQ+	FITs+/HRFQ+	HRFQ+	Any+	
n (%a)	9502 (13.79)	8709 (11.17)	8147 (11.83)	6589 (9.56)	1355 (1.97)	765 (8.41)	16 856 (21.61)	
Second stage:
Colonoscopy	Participant (%b)	7154 (75.29)	6358 (73.00)	6171 (75.75)	5086 (77.19)	983 (72.55)	292 (38.17)	12 529 (74.33)	
Result	CRC	146	88	113	50	33	5	201	
Adenoma (nc)	1878 (544)	1191 (261)	1594 (468)	856 (175)	284 (76)	51 (10)	2785 (729)	
Non-adenomatous polyps	465	391	428	337	37	17	819	
Advanced neoplasm	690	349	581	225	109	15	930	
Total neoplasm	2489	1670	2135	1243	354	73	3805	
Screening stage	Age 40-74 years (n = 160 210)	
FITs	HRFQ	HRFQ with FITs	HRFQ without FITs		
First stage:
Either FITs or HRFQ	Participant	136 539	160 210		136 539		23 671		
Result	FITs+	HRFQ+	FITs+/HRFQ−	FITs−/HRFQ+	FITs+/HRFQ+	HRFQ+	Any+	
n (%a)	16 157 (11.83)	14 459 (9.03)	14 220 (10.41)	11 100 (8.13)	1937 (1.42)	1422 (6.01)	28 679 (17.90)	
Second stage:
Colonoscopy	Participant (%b)	12 421 (76.88)	10 727 (74.19)	10 989 (77.28)	8746 (78.79)	1433 (73.98)	548 (38.54)	21 715 (75.72)	
Result	CRC	180	108	144	65	36	7	252	
Adenoma (nc)	2701 (736)	1696 (342)	2337 (640)	1256 (233)	364 (96)	76 (13)	4033 (982)	
Non-adenomatous polyps	694	599	650	527	44	28	1249	
Advanced neoplasm	916	450	784	298	132	20	1234	
Total neoplasm	3575	2403	3131	1848	444	111	5534	
FIT, fecal immunochemical test; HRFQ, high-risk-factors questionnaire.

a Positive rate in participants in the first screening stage and using the χ2 test to compare positive rates among FITs and HRFQ subgroups with a P < 0.01 for all comparisons.

b Compliance rate of participants completing colonoscopy in those positive in the first screening stage and using the χ2 test to compare compliance rates among FITs and HRFQ subgroups with a P < 0.01 for all comparisons.

c The number of advanced adenoma and using the χ2 test to compare PPVs of CRC, adenoma, advanced neoplasm, and total neoplasm among FITs and HRFQ subgroups with a P < 0.01 for all comparisons.

The positive rate of HRFQ, FITs, and colonoscopy

In the total population, the positive rate of either HRFQ+ or FITs+ in the first stage was 17.90% (28 679/160 210). The positive rate of FITs was significantly higher than that of HRFQ (10.41% versus 8.13%) with a P < 0.01 (Table 1 and Figure 2). The positive rates obtained by HFRQ, FITs, and their combinations in the first stage were shown in the same pattern between men and women (Supplementary Tables S1.1 and S1.2, and Supplementary Figures S1.A and S1.B, available at https://doi.org/10.1016/j.esmoop.2024.103676). In men, the positive rate obtained by colonoscopy in the second stage was 16.98% (13 282/78 231) which was significantly lower than that in women (15 397/81 979 = 18.78%) with a P < 0.01.Figure 2 Positive rate by screening method in the first screening stage (left) and PPVs of various kinds of neoplasm in participants completing colonoscopy (right) in a mass CRC screening program in the whole population aged 40-74 years in Jiashan County, 2007-2015. CRC, colorectal cancer; FIT, fecal immunochemical test; HRFQ, high-risk-factors questionnaire; PPV, positive predictive value.

The PPV of HRFQ, FITs, and colonoscopy

There were 5534 colorectal neoplasm cases found in this screening program. Among them, there were 252 CRC (4.56%), 4033 adenoma (72.88%), 1249 non-adenomatous polyps (22.57%), and 1234 advanced neoplasm (252 CRC + 982 advanced adenoma, 22.30%). In the total population, the PPV of total neoplasm was 25.48% (5534/21 715), adenoma was 18.57% (4033/21 715), non-adenomatous polyps was 5.75% (1249/21 715), advanced adenoma was 4.52% (982/21 715), advanced neoplasm was 5.68% (1234/21 715), and CRC was 1.16% (252/21 715) (Table 1 and Figure 2).

By screening method, the PPVs of CRC, adenoma, CRC + adenoma, advanced neoplasm, and total neoplasm were the highest in both the FITs+ and HRFQ+ subgroups, followed by the FITs+ and HRFQ− subgroups, and the lowest in the HRFQ+ only population (Table 1 and Figure 2), and the same order of PPVs of any type of tumor was seen in both men and women (Supplementary Tables S1.1 and S1.2, and Supplementary Figures S2.A and S2.B, available at https://doi.org/10.1016/j.esmoop.2024.103676). Regardless of any screening method, the PPVs of adenoma, CRC + adenoma, and total neoplasm cases were higher than 10% (Figure 2).

FITs+ and HRFQ+ cases accounted 64.60% (3575/5534) and 43.42% (2403/5534) of the total neoplasm, respectively, with 8.02% (444/5534) being positive for both. The combination of HRFQ and FITs detected 40.00% (72/180) more cases of CRC, 48.73% (1404/2881) more cases of CRC + adenoma, 79.97% (555/694) more cases of non-adenomatous polyps, 33.42% (246/736) more cases of advanced neoplasm, and 55.08% (1959/3575) more cases of total neoplasm cases compared to FITs alone (Table 1 and Figure 2).

The detection cost estimates by HRFQ, FITs, and colonoscopy

The detection cost estimates by screening method in the mass screening program are shown in Table 2 and Supplementary Figure S3.A, available at https://doi.org/10.1016/j.esmoop.2024.103676. The cost for HRFQ was significantly lower than that of FIT (their cost ratios ranged from 0.71 to 1.00), and the cost for combining FITs and HRFQ was increased to 163% compared to that of FIT only.Table 2 Estimated costs by age group and screening method in a mass colorectal cancer screening program in the whole population aged 40-74 years in Jiashan County, China, 2007-2015

Age in years old	Method	Participant	Cost 1	Cost 2	Cost 3	
¥/$	%	Ratio	Colonoscopy (n)	¥/$	Ratio	¥/$	Ratio	
40-54	FITs	67 646	920 858/144 857	69.14	1.00	5267	1 422 090/223 705	1.00	2 342 948/368 562	1.00	
	HRFQ	82 217	411 085/64 667	30.86	0.45	4369	1 179 630/185 564	0.83	1 590 715/250 230	0.68	
	Subtotal	82 217	1 331 943/209 524	100.00	1.45	9186	2 480 220/390 156	1.74	3 812 163/599 680	1.63	
55-74	FITs	68 893	954 898/150 212	71.00	1.00	7154	1 931 580/303 851	1.00	2 886 478/454 063	1.00	
	HRFQ	77 993	389 965/61 344	29.00	0.41	6358	1 716 660/270 042	0.89	2 106 625/331 387	0.73	
	Subtotal	77 993	1 344 863/211 556	100.00	1.41	12 529	3 382 830/532 143	1.75	4 727 693/743 699	1.64	
40-74	FITs	136 539	1 875 756/295 069	70.07	1.00	12 412	3 353 670/527 555	1.00	5 229 426/822 625	1.00	
	HRFQ	160 210	801 050/126 011	29.93	0.43	10 727	2 896 290/455 606	0.86	3 697 340/581 617	0.71	
	Total	160 210	2 676 806/421 080	100.00	1.43	21 715	5 863 050/922 298	1.75	8 539 856/1 343 378	1.63	
Notes: ¥ is Chinese money Yuan (Renminbi); $ is US dollar; the currency exchange rate was 1.000 USD = 6.357 CNY at the time when the screening program was carried out; cost 1 refers to the cost for completing FITs or HRFQ; cost 2 = colonoscopy participants∗ ¥270 per person, referring to the cost for completing the colonoscopy; cost 3 = cost 1 + cost 2, referring to the total screening cost covering the first and second stages; when estimating cost 2 and cost 3 relevant to colonoscopy, % should not be estimated because some overlapping participants in the FITs- and HRFQ-positive subgroups only need one colonoscopy; FITs refer to those who completed either of FIT1 and FIT2.

FIT, fecal immunochemical test; HRFQ, high-risk-factors questionnaire.

In any gender and age group, the detection cost for each adenoma, CRC + adenoma, and total neoplasm case was not significantly different between FITs and HRFQ (Supplementary Tables S2.1 and S2.2, and Supplementary Figures S2.A and S2.B, S3.A S3.B and S3.C, available at https://doi.org/10.1016/j.esmoop.2024.103676). Using FITs as the reference, the cost ratios of the combination of FIT and HRFQ for detecting adenoma, CRC + adenoma, and total neoplasm cases were ranging from 1.01 to 1.10, while those for detecting CRC cases were from 1.14 to 1.19 and advanced neoplasm cases were from 1.18 to 1.22 (Table 3, Supplementary Tables S2.1 and S2.2, and Supplementary Figures S3.A and S3.C, available at https://doi.org/10.1016/j.esmoop.2024.103676). Compared to FITs, the cost of the combination of FIT and HRFQ for detecting CRC and advanced neoplasm cases was increased by about 20%, and for adenoma, total neoplasm, and CRC + adenoma, it was increased by <10%. However, by combining HRFQ and FITs for CRC screening, the detection cost for each CRC, adenoma, CRC + adenoma, advanced neoplasm, and total neoplasm case was $5331, $333, $314, $1089, and $243, respectively.Table 3 Estimated detection costs for each clinical outcome by age group and screening method in a mass colorectal cancer (CRC) screening program in the whole population aged 40-74 years in Jiashan County, China, 2007-2015

Outcome		Aged 40-54 years old	Aged 55-74 years old	Aged 40-74 years old	
FITs	HRFQ	Total	FITs	HRFQ	Total	FITs	HRFQ	Total	
CRC	Number	34	20	51	146	88	201	180	108	252	
	Cost	¥/$	68 910/10 840	79 536/12 512	74 747/11 758	19 770/3110	23 939/3766	23 521/3700	29 052/4570	34 235/5385	33 888/5331	
	Ratio	1.00	1.15	1.08	1.00	1.21	1.19	1.00	1.18	1.17	
Adenoma	Number	823	505	1248	1878	1191	2785	2701	1696	4033	
	Cost	¥/$	2847/448	3150/496	3055/481	1537/242	1769/278	1698/267	1936/305	2180/343	2117/333	
	Ratio	1.00	1.11	1.07	1.00	1.15	1.10	1.00	1.12	1.09	
Advanced	Number	226	101	304	690	349	930	916	450	1234	
	Cost	¥/$	10 367/1631	15 750/2478	12 540/1973	4183/658	6036/950	5084/800	5709/898	8216/1292	6920/1089	
	Ratio	1.00	1.52	1.21	1.00	1.44	1.22	1.00	1.44	1.21	
Total	Number	1086	733	1729	2489	1670	3805	3575	2403	5534	
	Cost	¥/$	2157/339	2170/341	2205/347	1160/182	1261/198	1242/195	1463/230	1539/242	1543/243	
	Ratio	1.00	1.01	1.02	1.00	1.09	1.07	1.00	1.05	1.06	
CRC + adenoma	Number	857	525	1299	2024	1279	2986	2881	1804	4285	
	Cost	¥/$	2734/430	3030/477	2935/462	1426/224	1647/259	1583/249	1815/286	2050/322	1993/314	
	Ratio	1.00	1.11	1.07	1.00	1.16	1.11	1.00	1.13	1.10	
Note: ¥ is Chinese money Yuan (Renminbi); $ is US dollar; the currency exchange rate was 1.000 USD = 6.357 CNY at the time when the screening program was carried out; FITs refer to those who completed either of FIT1 and FIT2; if colonoscopy was used as primary screening, the total cost would be 160210 ∗ 270 = ¥43 256 700 ($1 018 455); even if the detected number of CRC and total neoplasm doubled, their detection cost would be ¥85 827 ($13 501) and ¥3908 ($615), respectively.

FIT, fecal immunochemical test; HRFQ, high-risk-factors questionnaire.

If colonoscopy was used as a primary screening method, the total cost would be ¥160 210∗270 = ¥43 256 700 ($1 018 455). Even if the detected number of CRC and total neoplasm doubled, the detection costs for CRC and total neoplasm would reach ¥85 827 ($13 501) and ¥3908 ($615), respectively, which are 253% of the detection cost by combining HRFQ and FITs (Table 3).

Discussion

Mass screening has been proven to be the most powerful tool to reduce CRC mortality.13,25, 26, 27, 28, 29, 30 Its effectiveness depends not only on the characteristics of the screening method but also on adherence.25,26 Differential adherence to screening will influence the benefits and costs of the mass screening program and may deeply affect the selection of a preferred CRC screening strategy.31, 32, 33

The compliance in mass CRC screening varies greatly in some countries.34,35 The compliance rate in the United State ranges from 13% to 55%,36 and the adherence rates to screening are no better than those Asia-Pacific countries where they range from 21% in South Korea to 62.9% in Thailand.37 The compliance rate in the Netherlands is relatively high (68.2%), while that in Canada is relatively low (16%).37 In this mass CRC screening program, the compliance rates in the first and second screening stages were 76.12% and 75.72%, respectively, which are higher than those in most countries in the world.

Sensitivity and specificity are the most commonly used index to evaluate how good screening methods are. PPV not only depends on sensitivity and specificity, but also depends on disease prevalence. If the prevalence of colorectal tumors is the same, PPV is a reliable comprehensive indicator to compare screening methods used in the same population which should have a similar sensitivity and specificity.38, 39, 40

In the first screening stage, the compliance rate for FITs was 64.87%, significantly lower (P < 0.01) than that of HRFQ (76.12%), which indicates that HRFQ was more acceptable than FITs by participants in the mass screening. The positive rates of FITs were slightly higher than those of HRFQ (10.41% versus 8.13%), and the positive rate of both FITs+ and HRFQ+ (1.42%) was significantly lower than that of FITs+ or HRFQ+ alone (Table 1 and Figure 2). Intuitively, the higher the positive rate of the first-stage screening, the more people will need to complete colonoscopy in the second phase, and the number of detected colorectal neoplasm and the total screening cost would inevitably increase. Therefore, analyzing the PPV and the detection cost per each tumor by screening method is particularly important. The removal of precancerous polyps has been proven to help reduce the CRC incidence.41, 42, 43 In this screening program, adenoma and advanced neoplasm cases (including advanced adenoma) accounted for 72.88% and 22.30% of total neoplasm cases, respectively.

Since both CRC incidence and prevalence are significantly lower than those of the adenoma and non-adenomatous polyps,44,45 the PPV of CRC is naturally lower than that of polyps. The PPV of CRC in this screening program, however, reached a high level which is >30 times higher than the average CRC incidence in China (743/100 000 above versus 23.9/100 000, Figure 2).4

FITs had higher PPVs for CRC and precancerous lesions than HRFQ. In the FITs+ and HRFQ− population, compared to the FITs− and HRFQ+ population, the PPVs of CRC and CRC + adenoma increased by 76.31% and 49.48%, respectively, and the PPV of advanced neoplasm was doubled, while the PPV of non-adenomatous polyps decreased by 0.02%. These results reflect that compared to HRFQ, FIT can detect more adenoma and advanced neoplasm, possibly because adenoma and CRC may be more prone to bleed than non-adenomatous polyps.45,46

In the evaluation of gastrointestinal tract cancer including CRC screening methods, the detection cost was also crucial.47,48 Compared to the total cost, the cost spending on HRFQ was 29% lower than that on FITs (0.71 versus 1.00, Table 2), and the cost ratios of detecting CRC, adenoma, CRC + adenoma, and total neoplasm were <1.18 among HRFQ+ and either HRFQ+ or FITs+ participants, compared to FITs+ participants. Therefore, HRFQ, of course, can be used as an acceptable low-cost CRC screening method, just like FITs used in the mass CRC screening program in China. To date, there is still insufficient evidence to identify which screening method is definitively superior, and no mass CRC screening strategy can be defined as universally ideal. The best strategy would be the one that can be economically viable and in which the participants are willing to adhere to the screening program over time.19,49, 50, 51

In this screening program, >65% of CRC, advanced adenoma, CRC + adenoma, advanced neoplasm, and total neoplasm cases were FITs+; HRFQ+ cases accounted for only >42% of total colorectal neoplasm case; and the screening cost of combining HRFQ and FITs methods was 63% higher than that of using FITs only. But the combination of HRFQ and FITs detected 55.08% more cases of total neoplasm cases (including 40.00% more cases of CRC and 33.42% more cases of advanced neoplasm, respectively), compared to FITs alone. For combining HRFQ and FITs, the detection cost per case of CRC, adenoma, CRC + adenoma, advanced neoplasm, and total neoplasm was $5331, $333, $314, $1089, and $243, respectively, whereas the detection cost by FITs and HRFQ for any colorectal neoplasm was <$4570 and $5380, respectively.

If colonoscopy was used as screening, and even if the detected number of CRC and total neoplasm doubled, the detection cost of CRC and total neoplasm will reach ¥85 827 ($13 501) and ¥3908 ($615), respectively, which are 253% of the detection cost by combining HRFQ and FITs as primary screening. If using colonoscopy as a mass screening method, its acceptability is much lower than FITs22, 23, 24,42 for its cumbersome bowel preparation and terrifying complication, such as intestinal perforation and bleeding, and low cost-effectiveness in China.

The detection costs of all methods except colonoscopy as primary screening were not high, and were acceptable by people in China. Therefore, on the basis of comparable balance between benefits and screening burden, using the combination of FITs and HRFQ as the primary screening method, and colonoscopy as secondary screening for CRC is effective and feasible in the mass CRC screening program in China.

Conclusions

Using colonoscopy alone as the primary mass screening method is unrealistic due to its characteristics of low compliance, being costly and invasive, and especially because of the high population density and low physician/population ratio in China. Although FITs were more cost-effective than HRFQ in mass CRC screening, combining FITs and HRFQ can detect more CRC and precancer lesion cases with a relatively low and acceptable cost. Considering the pros and cons of colonoscopy, FITs and HRFQ, our two-stage CRC screening protocol combining FITs and HRFQ as the primary screening method and colonoscopy as the secondary is cost-effective. This protocol should be recommended for most populations, especially those in the countries and areas with high population density and low physician/population ratio.

Supplementary data

Supplementary Material

Acknowledgements

The authors thank all endoscopists, histopathologists, endoscopy nurses, and administrative staff who participated in the mass CRC screening program in Jiashan county, Zhejiang province, P. R. China. The authors also thank for their editorial review of an early draft of this article.

Funding

This work was supported by the Research on Prevention and Control of Major Chronic Non-communicable Diseases of the China National Key R&D Program [grant number 2016YFC1302803], the Fundamental Research Funds for the Central Universities in China [grant number 226-2023-00088], a Special Fund to the Local Public Health by the China National Fiscal Supplement—National Cancer Early Detection and Treatment Program (2006-2017, Ministry of Health, Ministry of Finance, China, [no grant number]), the Medical Science and Technology Project of Zhejiang Province (CN) [grant number 2013KYA091], the Key Project of the Zhejiang Chinese Medical University Affiliated Hospital Specific Scientific Research Fund [grant number 2021FSYYZZ11], and the Key Project of the Quzhou City Bureau of Science and Technology Grant [grant number 2023K154]. These funding sources covered the cost for all participants to complete the colorectal cancer screening but they are independent of the study design, data collection and interpretation, and manuscript preparation.

Disclosure

The authors have declared no conflicts of interest.

Data sharing

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
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