The effect on colorectal cancer incidence and stage with population-based FOBT-screening in Sweden

The effect on colorectal cancer incidence and stage with population-based FOBT-screening in Sweden | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effect on colorectal cancer incidence and stage with population-based FOBT-screening in Sweden Hanna Ribbing Wilén, Håkan Jonsson, Johannes Blom This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4575023/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Apr, 2025 Read the published version in BMC Public Health → Version 1 posted 14 You are reading this latest preprint version Abstract Aim To investigate colorectal cancer (CRC) incidence and stage of disease in the population invited vs not invited to the guaiac-based Fecal Occult Blood (gFOBT) and Fecal Immunochemical Test (FIT) colorectal cancer screening program in Stockholm-Gotland, Sweden, 2008–2021 and to estimate the incidence rate by gender and localization in the colorectum. Methods The study cohort consisted of all 60-69-years-old residents of the Stockholm-Gotland region 2008–2012 according to the population register. Screening with biennial gFOBT was introduced in randomized birth cohorts from 2008 and replaced by FIT with cut-off level 40µg/g in women and 80µg/g in men for a positive test in 2015. Record linkage was made to the National Cancer Register and to the Swedish Colorectal Cancer Register (SCRCR). The age-standardized CRC incidence ratio was compared in invited and non-invited during screening and in 70-75-year-olds and assessed overall and by gender, CRC stage and localization. Results In total, 320 989 and 151 533 individuals were invited to a first gFOBT and FIT round, and 5 972 CRCs were diagnosed. During screening, the overall age-adjusted incidence ratio for the gFOBT- and FIT-invited compared to the non-invited was 0.99 (95% CI 0.91–1.07) and 1.03 (95% CI 0.93–1.15) respectively. Post screening, 70–75 years of age, the overall incidence rate was 12% lower among the invited than the non-invited (RR 0.88, 95% CI 0.81–0.97). During FIT screening, the incidence for stage I and proximal CRC was 38 and 23% higher than in the non-invited (RR 1.38, 95% CI 1.09–1.76 and RR 1.23, 95% CI 1.02–1.48 respectively). The incidence post screening was 22% lower regarding stage I CRC, 13% lower in women, and 17% lower for distal CRCs as compared to the non-invited (RR 95% CI 0.78 0.63–0.95, 0.87 0.76-1.00 and 0.83 0.74–0.94 respectively). Conclusion In the Stockholm-Gotland screening program the shift to FIT significantly increased the incidence rate in early staged and proximal CRCs as compared to the uninvited, and the significant decrease in the overall CRC incidence post screening was mainly seen in distal, early staged CRCs in women. Colorectal cancer screening Fecal Occult Blood Test Fecal Immunochemical Test colorectal cancer incidence Figures Figure 1 Figure 2 Introduction Colorectal cancer (CRC) is attributed to more than 900 000 deaths worldwide every year and thus a major health concern ( 1 ). Biennial screening with guaiac-based Fecal Occult Blood Test (gFOBT) have shown an overall 15% decrease in CRC mortality in randomized controlled studies (RCTs) and is recommended as a screening test in European and American guidelines ( 2 – 5 ). It is believed that screening identifies CRC at an earlier stage than when diagnosed in symptomatic disease, and that the shift in stage is responsible for the mortality benefit. In all four RCTs a shift towards more early-staged CRCs (Dukes A) and fewer late-staged CRCs (Dukes D) was seen in the screening group as compared to the controls ( 2 ). A meta-analysis has shown a statistically significant pooled reduction of 8% in late-stage CRC (Dukes C or D or Stage III-IV) with gFOBT screening as compared to the controls ( 6 ). However, a systematic review revealed a poor correlation between late-stage CRC and mortality reductions in gFOBT screening RCTs ( 7 ). It is important to evaluate the effectiveness of CRC screening when introduced in a population-based screening program since the settings differ from that of an RCT. Previous studies of CRC incidence during FOBT screening implementation are limited by the lack of a population-based setting or a control group from the same time-period and demography with repeated screening ( 8 – 13 ). Moreover, changes in the CRC incidence with screening is likely different in subgroups of CRC. In a meta-analysis of gFOBT performance with colonoscopy-verified CRCs, the sensitivity for proximal cancer was significantly lower than for distal (63% vs 75%) ( 14 ). Hence, screen-detected CRCs are more likely to be located in the distal colon or rectum, and an advantage in stage distribution with screening might be limited to distal CRCs ( 15 ). The test sensitivity of the Stockholm-Gotland gFOBT screening program was considerably lower in women than in men, and warranted the switch to gender-based FIT screening in 2015, which may also be reflected in the stage distributions in men and women during gFOBT and FIT screening ( 16 ). The gFOBT screening in the Stockholm-Gotland region was implemented gradually for 60–69-year-olds in 2008–2015, by random invitation of birth cohorts born 1938–1954, to facilitate an evaluation of the effectiveness. Thus, half of the birth cohorts received early invitation to biennial gFOBT screening, and half late or no invitation to screening, and in 2015 gFOBT was replaced by Fecal Immunochemical Test (FIT) screening. The program is intended to expand to 74 years by 2026. An evaluation of the program has estimated a CRC mortality reduction of at least 14% after a maximum of 14 years of follow-up ( 17 ). The aim of this study was to evaluate the CRC incidence pattern overall and by gender, stage and colorectal localization before, during and up to five years after screening cessation in the colorectal cancer screening program in Stockholm-Gotland, Sweden, 2008–2021. Methods Study population The study population consisted of all residents born 1938–1954 (aged 60–69 years) living in the Stockholm-Gotland region of Sweden 2008 to 2012 according to the population register. In 2008, invitational population-based colorectal cancer screening with guaiac-based Fecal Occult Blood Test (gFOBT) was introduced stepwise in the birth cohorts 1940, 1942–1954 randomized to receive a first invitation to screening 2008–2015, Fig. 1. Biennial screening invitation continued until the age of 69, i.e., 1–5 rounds. The birth cohorts 1938, 1939 and 1941 were never invited to screening. From 2015 and onwards, the birth cohorts born 1947–1954 were invited to FIT screening. The follow-up period for CRC was 2008–2021. Invitations were sent by mail from the Regional Cancer Center (RCC) of Stockholm-Gotland that coordinated the screening program and included a panel of three gFOBT tests (Hemoccult, Beckman Coulter, U.S.A.) with information on CRC screening and instructions on how to perform the test. The FIT test kit included the invitation and one FIT test tube (OC Sensor, Eiken, Japan). The participants were instructed to note the date of the sample and to send the test in a prepaid envelope to the laboratory as soon as possible. The gFOBT samples were visually inspected by laboratory personnel. A sample was classified as positive if it exhibited an oxidase reaction in at least one of the three samples. In October 2015, the program changed to Fecal Immunochemical Test (FIT) with gender-based cut-off levels. Women with FIT ≥ 40µg Hemoglobin/g and men with FIT ≥ 80µg/g were considered FIT positive. A new kit was sent in case of an unanalyzable result, and a reminder was sent after 8 weeks in case of non-response. All participants with a positive test were offered colonoscopy at the nearest of five contracted endoscopy units. Those with a negative test were advised to consult the primary health care provider in case of bowel symptoms. There was no other CRC screening offered to the citizens of the region. Data sources All residents in Sweden have a unique personal ID number assigned at birth and used in all contacts with authorities and health care units and can thus be linked to various registers. The data on residents born 1938–1954 registered in the Stockholm-Gotland region and information on emigration were retrieved from Statistics Sweden. Record linkage was made to the screening register at RCC containing data on screening status and invitations, gFOBT/FIT- and colonoscopy results. Data were further linked to the National Cancer Register 1958–2020, where reporting of cancer cases is mandatory by law, for information on CRC diagnosis and date of diagnosis, and to the Swedish Colorectal Cancer Register (SCRCR) 2008–2021 that comprises information on CRC diagnosis for 2021, CRC stage and localization. The SCRCR has a coverage of 99% and an overall validity of 90% compared to hospital patient records ( 18 ). The National Cancer Register has a coverage of 96% ( 19 ). The data sources and linkage procedures are described in more detail in Blom et al ( 17 ). Colorectal cancers The CRC diagnosis included the International Classification of Diseases 7 (ICD-7) code 153.X (malignant neoplasm of large intestine, except rectum) or 154.0 (malignant neoplasm of rectum), excluding the codes C24; 091 (neuroendocrine tumor), 093 (lymphoma), 094 (adenoma), 144 (squamous cell carcinoma) and 793 (gastrointestinal stroma tumor). CRCs were classified according to the TNM system in stage I-IV: stage I (T1-2, N0, M0), stage II (T3-4, N0, M0), stage III (T1-4, N1-2, M0) and stage IV (M1) ( 20 ). Early CRC was defined as stage I-II and late CRC as stage as III-IV. The localization of CRCs was grouped into proximal CRC (caecum to splenic flexure) and distal CRC (descending colon to rectum). Data on stage and localization is recorded in the SCRCR. Statistics The study cohort consisted of individuals invited and not invited to screening. The follow-up for each individual was divided into four exposure categories: before first invitation including never invited, after first invitation to screening with gFOBT, after first invitation to screening with FIT and post screening, i.e., after the last screening round. Number of person-years and incident CRC cases were calculated by attained age and exposure category. The last invitation to screening occurred when the upper age limit for the program was reached (68 or 69 years), or when a CRC or an advanced adenoma that required polyp surveillance was detected, since that individual was admitted to surgery or the polyp surveillance program and not re-invited to the program, or if an invited individual migrated from the region. After the date of the last screening invitation which were either gFOBT or FIT, the exposure category was kept during the following two years of follow-up, corresponding to the biennial screening interval. Thus, the last screening round included up to 71-year-olds, and CRCs detected during the period two years after the last invitation was classified as a CRC in those invited. The incidence in previously invited age groups were compared with never invited of the same age and continued until the age of 75, since the effect of screening on the incidence is likely to diminish a few years after screening cessation. Those invited to FIT was kept as a separate exposure category from 2015. Due to the ageing of the study cohort and the biennial invitation scheme, birth cohorts 1938–1946 were never invited to the FIT program and birth cohorts 1947–1954 were older than 61 in 2015, hence the CRC incidence of invited and non-invited in the FIT program was estimated for 62–69-year-olds and continued until end of follow-up in 2021 or the age of 75, death or emigration, whichever came first. The CRC incidence rate was assessed according to invitational status, regardless of participation, and whether the CRC was screening-detected or an interval CRC (a CRC not detected at screening and diagnosed between screening rounds) and analyzed by stage, gender, and localization in colorectum. The CRC incidence was assessed by year of attained age. However, due to a small number of CRC cases and invited at the age 61, 63 and 67, ages with less than 5 000 person-years were omitted in Fig. 2 (Supplementary Table 1). Cumulative incidence was calculated for the three categories of individuals invited to gFOBT screening in age 60–69, individuals invited to FIT screening in age 62–69, and post-screening individuals aged 70–75, and compared to the cumulative incidence for not yet or never invited in the corresponding age intervals. Due to differences in age distribution, age-standardized incidence ratio (SIR) was calculated with the not yet or never invited category as reference ( 21 ). Similarly, SIR was calculated for FIT vs gFOBT. The CRCs diagnosed more than two years after their last screening invitation in the age category 60–69-year-olds, e.g. individuals included in the polyp surveillance program, were not included in the post screening comparisons. A p-vale of < 0.05 was considered statistically significant, and 95% Confidence Intervals (CI) were calculated. For all statistical analyses, the R statistical software version 4.2.2 was used (R project for statistical computing). Results In total, 320 989 and 151 533 were invited to a first gFOBT and FIT screening round respectively, of which 2 199 were screening naïve when they were invited to the FIT screening. The invitation schedule and number of screening round invitations in each birth cohort is illustrated in Fig. 1. The number of individuals invited to a first round of gFOBT and FIT screening at each attained age is listed in Supplementary Table 1. [Figure 1. Caption: Invitation schedule to gFOBT and FIT screening by birth year and attained age in the Stockholm-Gotland regional program 2008–2021. The vertical red line marks the shift to FIT screening in October 2015.] Overall, 5 972 CRCs were diagnosed. Within two years from the last gFOBT and FIT screening invitation 1 572 and 846 CRCs in 60–69-year-olds, and 46 and 31 in 70–71-year-olds were diagnosed. In 60-69-year-olds never or not yet invited to screening there were 970 CRCs. Furthermore, 1 762 CRCs were diagnosed post screening as compared to 653 in those never invited to screening and of the same attained age (Table 1 ). There were 92 (1.5%) CRCs diagnosed after two years from the last invitation to screening in the age category 60-69-year-olds during 57 375 person-years of follow up, corresponding to the CRCs detected in the polyp surveillance program or in those that migrated from the region. They were excluded from the SIR analyses. Table 1 Baseline characteristics of the study population Before screening or no screening Invited to gFOBT screening Invited to FIT screening Post screening, invited* Post screening, uninvited** Person-years, n 794 960 1 232 493 568 683 923 471 299 759 CRC, n 970 1572 846 1762 653 CRC, gender Men 562 891 483 978 358 Women 408 681 363 784 295 CRC stage I 170 337 213 330 138 II 244 390 175 448 171 III-IV 497 743 396 901 311 Unknown 59 102 62 83 33 CRC localization Proximal 286 527 296 736 250 Distal 651 991 518 976 380 Unknown 33 54 32 50 23 CRC = colorectal cancer. gFOBT = guaiac-based fecal occult blood test. FIT = Fecal immunochemical test. Post screening = age 70–75. Stage I = T1-T2 CRC with no regional lymph node metastases. Stage II = T3-T4 CRC with no regional lymph metastases. Stage III = CRC with regional lymph metastases. Stage IV = CRC with distant metastases. Proximal localization = caecum to splenic flexure, distal localization = descending colon to rectum. *) The last screening invitation occurs at the age 68 or 69, or when a CRC or high-risk adenoma is diagnosed in invitees aged < 69 since they are not reinvited to the program. In this column the CRCs in 60–69-year-olds are excluded. The CRCs diagnosed within two years from last screening invitation are considered attributed to the screening due to the biennial invitation scheme and thus not included. **) Post screening, uninvited, refers to the 70–75-year-olds that were never invited to screening at the age 60–69. [Table 1 ] The CRC incidence rate per person-years for each attained age is displayed in Fig. 2 for individuals invited to FIT and gFOBT and for the post screening and non-invited categories. The cumulative CRC incidence rate per 100 000 person-years was 122, 128, 149, 191 and 218 for non-invited or not yet invited, gFOBT invited 60–69 years-olds, FIT invited 62-69-year-olds, post screening invited and post screening non-invited individuals 70–75 years-olds, respectively. [Figure 2 . Caption: CRC incidence per 100 000 person-years and attained age in those invited and not invited to screening. The incidence is plotted for ages with > 5000 person-years of follow-up. Red line = Incidence in individuals not (yet) invited to screening. Green line = Incidence in those invited to gFOBT screening (from 2008). Blue line = incidence in those invited to FIT screening (from 2015). Purple line = Incidence two years after the last invitation to screening. CRC = colorectal cancer. gFOBT = guaiac-based fecal occult blood test. FIT = Fecal immunochemical test.] The age-adjusted incidence ratio (SIR) for the gFOBT- and FIT-invited compared to the non-invited was similar (RR 0.99 95% CI 0.91–1.07 and 1.03 95% CI 0.93–1.15). However, there was a 12% decrease (RR 0.88, 95% CI 0.81–0.97) in the incidence among previously invited 70–75-year-olds, as compared to the non-invited of the same age (Table 2 ). The age-adjusted incidence ratio post screening as compared to the non-invited remained in women (RR 0.87, 95% CI 0.76-1.00) but not significantly in men. Regarding CRC stage, there was an increase in stage I CRC of 38% (RR 1.38, 95% CI 1.09–1.76) for the FIT-invited, and a 22% decrease (RR 0.78, 95% CI 0.63–0.95) in incidence post screening as compared to the non-invited. The incidence in late-stage (III and IV) CRC was similar in invited and non-invited both during and after screening. The FIT screening increased the proximal CRC incidence by 23% (RR 1.23, 95% CI 1.02–1.48), but did not decrease the proximal CRCs incidence post screening (RR 0.98, 95% CI 0.84–1.13). There was no significant difference during the gFOBT screening in subgroups of CRC as compared to the non-invited. Distally located CRCs decreased with 17% post screening (RR 0.83, 95% CI 0.74–0.94) (Table 2 ). Table 2 Age-standardized CRC incidence ratio in invited to gFOBT and FIT screening, respectively, vs non-invited in the Stockholm-Gotland program. Age-standardized rate ratio (95% CI) Non-invited gFOBT FIT Post screening Overall 1 0.99 (0.91–1.07) 1.03 (0.93–1.15) 0.88 (0.81–0.97) Gender Men 1 0.99 (0.88–1.10) 1.05 (0.91–1.21) 0.89 (0.79–1.01) Women 1 0.99 (0.87–1.12) 1.01 (0.86–1.19) 0.87 (0.76-1.00) CRC stage I 1 1.17 (0.96–1.41) 1.38 (1.09–1.76) 0.78 (0.63–0.95) II 1 0.98 (0.83–1.15) 0.84 (0.68–1.05) 0.87 (0.73–1.04) III-IV 1 0.92 (0.81–1.03) 0.97 (0.83–1.13) 0.94 (0.83–1.07) CRC localization Proximal 1 1.13 (0.97–1.31) 1.23 (1.02–1.48) 0.98 (0.84–1.13) Distal 1 0.92 (0.83–1.02) 0.93 (0.81–1.06) 0.83 (0.74–0.94) gFOBT = guaiac-based Fecal Occult Blood Test. FIT = Fecal immunochemical test. The cumulative incidence for gFOBT screening is calculated for age 60–69 and that of FIT for age 62–69. Post screening refers to age 70–75. Distal colon = descending to rectum. Proximal colon = Caecum to splenic flexure. Stage I = T1-T2 CRC with no regional lymph node metastases. Stage II = T3-T4 CRC with no regional lymph node metastases. Stage III = CRC with regional lymph node metastases. Stage IV = CRC with distant metastases. Supplementary Table 1. Age and number of invited to the first gFOBT and FIT screening round in the Stockholm-Gotland screening program. [Table 2 ] Comparing FIT and gFOBT screening, the differences in incidences were non-significant; the overall age-adjusted incidence ratio was 1.03 (95% CI 0.94–1.12). For stage I CRC, the incidence ratio was 1.19% (95% CI 0.99–1.42) in FIT as compared to gFOBT screening. Moreover, the overall incidence in FIT-invited men was non-significantly higher than in gFOBT-invited men (RR 1.03, 95% CI 0.92–1.16). The difference between FIT and gFOBT incidences of stage II, III-IV, proximal and distal localization and in women was non-significant (RR 0.85 95% CI 0.70–1.02, RR 1.02 95% CI 0.90–1.16, RR 1.04 95% CI 0.90–1.21, RR 1.02 95% CI 0.91–1.14, and RR 1.02 95% CI 0.89–1.16 respectively). Discussion This evaluation of the population-based screening program in Stockholm-Gotland, Sweden, demonstrated a similar overall CRC incidence among those invited to the screening as compared to the non-invited, and a decreased incidence after screening cessation. This change in post screening incidence was significant for early-staged CRC and CRCs in women and differed by colorectal localization. However, we did not find a significant change in incidence in subgroups during the gFOBT program, nor a decrease in late-stage CRC from the screening program. Several previous studies have shown an increased CRC incidence when introducing population-based FIT screening, due to both incidence and prevalence screening in the first round, and thereafter a return to or decrease below pre-screening levels in subsequent rounds ( 12 , 22 , 23 ). At long-term follow-up of the randomized gFOBT screening trial in Minnesota there was a marked decline in incidence with multiple screening rounds as compared to controls ( 24 ). In the present study, we did not find a significant change in the incidence among those invited to the gFOBT program. However, the invited age cohorts consisted of both prevalent and incident screening rounds for each attained age (except the 60-years-olds), hence the net effect could be an unchanged incidence. Apart from this, approximately 40% of the gFOBT invitees did not participate in screening and could therefore not contribute to an increased CRC incidence ( 25 ). Furthermore, gFOBT, as compared to FIT, has a lower sensitivity for advanced adenoma; 10–15% vs 25–30%, hence it is not expected a large decline in CRC incidence post screening because of polypectomy in a gFOBT screened population ( 26 – 29 ). In the Minnesota trial the cumulative gFOBT positivity was approximately 30%, so the large decrease in incidence could partly be explained by the large number of colonoscopies (and polypectomies) performed in the intervention group. The positivity rate in the Stockholm-Gotland gFOBT program was approximately 2% ( 16 ). The gFOBT sensitivity for CRC is stage-dependent, with reported sensitivity rates of Dukes A 89%, Dukes B 79%, Dukes C 72%, and Dukes D 48% ( 15 ). A meta-analysis of FIT studies (cut-off-levels between 10–20 µg/g) estimated FIT sensitivity to 73% for stage I CRC, 80% for stage II, 82% for stage III, 79% for stage IV ( 30 ). The overall CRC sensitivity in the Stockholm-Gotland FIT program with cut-off levels 40 µg/g and 80 µg/g in women and men was estimated to 65%, as compared to 40% in the gFOBT program ( 16 , 31 ). The shift to FIT in the program generated an increased participation rate (69%), and a higher sensitivity for advanced adenomas and CRC, which contributed to the net increase in CRC incidence in subgroups of early-staged and proximal CRCs during screening and a decrease post screening due to the preventive effect of polypectomy. The decreased incidence post screening after an increase during screening as compared to the non-invited was only seen in stage I CRCs, probably due to the earlier detection of CRC with screening leading to a compensatory drop after screening cessation. The 14% reduction in CRC mortality recently reported from the Stockholm-Gotland screening program would most likely be explained by a shift from late to early-stage CRC ( 17 ). However, in the present study we did not a see a decreased incidence of stage III-IV CRC among the invited. Since the mortality is low in stage I CRC, the reduced stage I incidence post screening could not explain the reduced mortality ( 32 ). However, the invited included both the non-participants as well as prevalence screening rounds which could balance out a favorable stage shift in the participants. In the Dutch screening program, the incidence of late-stage CRC increased at screening implementation followed by a decrease when compared to the incidence rates prior to screening ( 8 ). Moreover, given the low number of CRCs stage III and IV in the present study they were combined and categorized into late-stage (III-IV). There might be a stage shift among the invited from IV to III or in subclassification of T stages that we were not able to detect albeit important for the prognosis ( 33 ). In the previously cited Danish study, there was an increased incidence of stage I-III CRC and no significant difference in stage IV CRC in the invited as compared to non-invited, but this study included only the prevalence round ( 12 ). On the other hand, it is not certain that a favorable stage shift due to screening directly translates into a disease specific mortality reduction, because this is dependent on the difference in survival between the early and late stages and the proportion of cancers that the screening is able to shift to earlier stages, and it also assumes that the late stage cancers among the invited have the same survival as the late staged cancers among the non-invited ( 34 ). Invitation to screening could raise the awareness of the disease and make the invited individuals more prone to seek health care and to life style changes, e.g., regarding smoking, than the non-invited, potentially affecting the disease mortality other than as a shift in stage ( 35 ). During the FIT screening, the incidence of proximal CRC increased. Proximal CRCs are more common in women, and the Stockholm-Gotland program applies lower cut-off-levels in women than in men, which might explain the increased incidence with FIT screening and the decreased incidence in women post screening, although gFOBT and FIT performs worse in proximal CRCs as compared to distal in gender-uniform screening ( 14 , 31 ). The increased incidence of early-stage proximal CRCs in women could have contributed to the decreased mortality of the program, since proximal CRCs confers a worse prognosis and are diagnosed clinically at a late stage ( 36 ). The overall incidence of proximal CRC was not decreased post screening. However, only birth cohorts 1948-51 (and part of 1947 cohort) were screened with FIT and reached post screening age at end of follow-up, hence gFOBT screening was over-represented in this group. Post screening, a significant decrease was seen only for distal localization reflecting the higher sensitivity for distal CRC of both gFOBT and FIT and the higher rate of distal CRC in men ( 14 ). The strengths of this study were the evaluation of a large population-based CRC screening program shifting from gFOBT to FIT screening, the linkage with individual data to validated cancer registers with low number of missing data enabling analyzation of CRC subgroups, and the assessment of CRC incidence of invited and non-invited individuals within the same time-period and in the same region. Moreover, evaluation of the invitation to screening precluded the self-selection bias from healthy participants. Nevertheless, this study has several limitations. The screening program implementation was made by randomization of birth cohorts into early, late or no screening invitation rather than individual randomization, making the comparisons between invited and non-invited biased by age. This problem was overcome when comparing age-adjusted incidence ratios, but we were unable to assess the incidence change over time when initiating screening and by subsequent screening rounds. Furthermore, we did not analyze stage III and IV CRCs separately due to a low number of cases, hence not capture any change in incidence in between the late-stage CRCs as discussed above. Moreover, the post screening comparisons of incidence were, due to the recent shift to FIT screening, dominated by gFOBT screened individuals, and additional studies are needed to fully address the effect of FIT in 70-75-year-olds, especially since the shift to FIT increased the participation rate by 12% ( 37 ). In conclusion, the shift to FIT in the population-based screening program of Stockholm-Gotland, Sweden, significantly increased the CRC incidence for early-staged and proximal CRCs, and the overall decrease post screening was mainly seen in distal, early staged CRCs in women as compared to the non-invited. The full effect of gender-based FIT screening on the incidence post screening needs further evaluation. Declarations The study was approved by the Ethics Review Board of Sweden (ref nb 2020-06757). Informed consent to participate in this study was not asked for, but information about the screening register and how to unregister was included in the invitation and reply letter. Informed consent was asked for at the endoscopy unit for the registration in the Swedish quality register for colonoscopies and colorectal cancer screening. Access to underlying research material can be obtained by email to the corresponding author. This study was not a clinical trial, hence not registered as such. The authors declare no conflict of interest with regards to this work. Authors contribution: H.R.W.: Design of the study, analysis and interpretation of data, and manuscript writing. H.J.: Design of the study, analysis and interpretation of data and critical revision of the manuscript J.B.: Design of the study, interpretation of data and critical revision of the manuscript. All authors have approved of the final version of the manuscript and consented to publication. Funding declaration This study was supported by The Swedish Cancer Society grant 21 1389 Pj, The Swedish Research Council grant 2021-03139 and Region Stockholm grant FoUI-961412. Acknowledgements Karolinska University Hospital, Division of Trauma & Reparative Medicine, is thanked for allocating working time for the realization of this study. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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The Lancet Oncology. 2021;22(7):1002-13. Hirai HW, Tsoi KK, Chan JY, Wong SH, Ching JY, Wong MC, et al. Systematic review with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies. Alimentary pharmacology & therapeutics. 2016;43(7):755-64. Morris EJ, Whitehouse LE, Farrell T, Nickerson C, Thomas JD, Quirke P, et al. A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme. British journal of cancer. 2012;107(5):757-64. Blom J, Tornberg S. Interval cancers in a guaiac-based colorectal cancer screening programme: Consequences on sensitivity. Journal of medical screening. 2017;24(3):146-52. Blom J, Saraste D, Tornberg S, Jonsson H. Routine Fecal Occult Blood Screening and Colorectal Cancer Mortality in Sweden. JAMA Netw Open. 2024;7(2):e240516. Moberger P, Skoldberg F, Birgisson H. Evaluation of the Swedish Colorectal Cancer Registry: an overview of completeness, timeliness, comparability and validity. Acta oncologica. 2018;57(12):1611-21. Barlow L, Westergren K, Holmberg L, Talback M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta oncologica. 2009;48(1):27-33. UJCC TNM Classification of Malignant Tumors, 8th Edition, p74-76. Brierley JD et al. Wiley Blackwell 2017. Breslow NE, Day NE. Statistical methods in cancer research. Volume II--The design and analysis of cohort studies. IARC Sci Publ. 1987(82):1-406. Breekveldt ECH, Lansdorp-Vogelaar I, Toes-Zoutendijk E, Spaander MCW, van Vuuren AJ, van Kemenade FJ, et al. Colorectal cancer incidence, mortality, tumour characteristics, and treatment before and after introduction of the faecal immunochemical testing-based screening programme in the Netherlands: a population-based study. The lancet Gastroenterology & hepatology. 2022;7(1):60-8. Zorzi M, Fedeli U, Schievano E, Bovo E, Guzzinati S, Baracco S, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut. 2015;64(5):784-90. Mandel JS, Church TR, Bond JH, Ederer F, Geisser MS, Mongin SJ, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. The New England journal of medicine. 2000;343(22):1603-7. Blom J, Kilpelainen S, Hultcrantz R, Tornberg S. Five-year experience of organized colorectal cancer screening in a Swedish population - increased compliance with age, female gender, and subsequent screening round. Journal of medical screening. 2014;21(3):144-50. Grobbee EJ, Wisse PHA, Schreuders EH, van Roon A, van Dam L, Zauber AG, et al. Guaiac-based faecal occult blood tests versus faecal immunochemical tests for colorectal cancer screening in average-risk individuals. The Cochrane database of systematic reviews. 2022;6(6):CD009276. Scholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle JD. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up. Gut. 2012;61(7):1036-40. Lindholm E, Brevinge H, Haglind E. Survival benefit in a randomized clinical trial of faecal occult blood screening for colorectal cancer. The British journal of surgery. 2008;95(8):1029-36. Brenner H, Haug U, Hundt S. Sex differences in performance of fecal occult blood testing. The American journal of gastroenterology. 2010;105(11):2457-64. Niedermaier T, Balavarca Y, Brenner H. Stage-Specific Sensitivity of Fecal Immunochemical Tests for Detecting Colorectal Cancer: Systematic Review and Meta-Analysis. The American journal of gastroenterology. 2020;115(1):56-69. Ribbing Wilen H, Blom J. Interval cancer after two rounds of a Swedish population-based screening program using gender-specific cut-off levels in fecal immunochemical test. Journal of medical screening. 2023:9691413231185722. https://cancercentrum.se/globalassets/cancerdiagnoser/tjock--och-andtarm-anal/kvalitetsregister/tjock--och-andtarm-2023/kolonrapport_2022.pdf Swedish Colorectal Cancer Register (SCRCR) quality report 2022. Accessed 8th Feb 2024. Foersch S, Lang-Schwarz C, Eckstein M, Geppert C, Schmitt M, Konukiewitz B, et al. pT3 colorectal cancer revisited: a multicentric study on the histological depth of invasion in more than 1000 pT3 carcinomas-proposal for a new pT3a/pT3b subclassification. British journal of cancer. 2022;127(7):1270-8. Owens L, Gulati R, Etzioni R. Stage Shift as an Endpoint in Cancer Screening Trials: Implications for Evaluating Multicancer Early Detection Tests. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022;31(7):1298-304. Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. International journal of cancer Journal international du cancer. 2009;124(10):2406-15. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-80. Blom J, Lowbeer C, Elfstrom KM, Sventelius M, Ohman D, Saraste D, et al. Gender-specific cut-offs in colorectal cancer screening with FIT: Increased compliance and equal positivity rate. Journal of medical screening. 2019;26(2):92-7. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4575023","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":321338572,"identity":"d2c37ce5-4213-46c3-8ea5-edbc1982bb43","order_by":0,"name":"Hanna Ribbing Wilén","email":"data:image/png;base64,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","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Hanna","middleName":"Ribbing","lastName":"Wilén","suffix":""},{"id":321338573,"identity":"4401b22b-6fb4-4d71-9220-584f983939ad","order_by":1,"name":"Håkan Jonsson","email":"","orcid":"","institution":"Umeå University","correspondingAuthor":false,"prefix":"","firstName":"Håkan","middleName":"","lastName":"Jonsson","suffix":""},{"id":321338574,"identity":"45e6e171-28df-477e-8ce8-0300bf218f2c","order_by":2,"name":"Johannes Blom","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Johannes","middleName":"","lastName":"Blom","suffix":""}],"badges":[],"createdAt":"2024-06-13 09:18:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4575023/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4575023/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12889-025-22771-8","type":"published","date":"2025-04-26T15:57:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60200687,"identity":"6ed61a72-d7a7-4a4e-85ba-94a2d0565105","added_by":"auto","created_at":"2024-07-13 02:34:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26895,"visible":true,"origin":"","legend":"\u003cp\u003eInvitation schedule to gFOBT and FIT screening by birth year and attained age in the Stockholm-Gotland regional program 2008-2021.\u003c/p\u003e\n\u003cp\u003eThe vertical red line marks the shift to FIT screening in October 2015.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4575023/v1/7fdd00aa57d89ebbde2a59e1.png"},{"id":60200688,"identity":"7b201d34-9fb8-41f1-9f89-876016c80e92","added_by":"auto","created_at":"2024-07-13 02:34:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":212590,"visible":true,"origin":"","legend":"\u003cp\u003eCRC incidence per 100 000 person-years and attained age in those invited and not invited to screening.\u003c/p\u003e\n\u003cp\u003eThe incidence is plotted for ages with \u0026gt;5000 person-years of follow-up. Red line = Incidence in individuals not (yet) invited to screening. Green line = Incidence in those invited to gFOBT screening (from 2008). Blue line = incidence in those invited to FIT screening (from 2015). Purple line = Incidence two years after the last invitation to screening. CRC = colorectal cancer. gFOBT= guaiac-based fecal occult blood test. FIT= Fecal immunochemical test.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4575023/v1/8b9a2a84be70cabd3993cf27.png"},{"id":81569663,"identity":"9d489d30-c226-4045-b8ca-d0999f0d5604","added_by":"auto","created_at":"2025-04-28 16:09:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":755883,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4575023/v1/1b5b8ab3-bb43-4be1-a818-c014dbe7558b.pdf"},{"id":60200689,"identity":"27d19453-1d32-48dd-9550-7f51846a381e","added_by":"auto","created_at":"2024-07-13 02:34:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14830,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4575023/v1/03bacff15d07dc5271dfaf46.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effect on colorectal cancer incidence and stage with population-based FOBT-screening in Sweden","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is attributed to more than 900 000 deaths worldwide every year and thus a major health concern (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Biennial screening with guaiac-based Fecal Occult Blood Test (gFOBT) have shown an overall 15% decrease in CRC mortality in randomized controlled studies (RCTs) and is recommended as a screening test in European and American guidelines (\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). It is believed that screening identifies CRC at an earlier stage than when diagnosed in symptomatic disease, and that the shift in stage is responsible for the mortality benefit. In all four RCTs a shift towards more early-staged CRCs (Dukes A) and fewer late-staged CRCs (Dukes D) was seen in the screening group as compared to the controls (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). A meta-analysis has shown a statistically significant pooled reduction of 8% in late-stage CRC (Dukes C or D or Stage III-IV) with gFOBT screening as compared to the controls (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, a systematic review revealed a poor correlation between late-stage CRC and mortality reductions in gFOBT screening RCTs (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is important to evaluate the effectiveness of CRC screening when introduced in a population-based screening program since the settings differ from that of an RCT. Previous studies of CRC incidence during FOBT screening implementation are limited by the lack of a population-based setting or a control group from the same time-period and demography with repeated screening (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMoreover, changes in the CRC incidence with screening is likely different in subgroups of CRC. In a meta-analysis of gFOBT performance with colonoscopy-verified CRCs, the sensitivity for proximal cancer was significantly lower than for distal (63% vs 75%) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Hence, screen-detected CRCs are more likely to be located in the distal colon or rectum, and an advantage in stage distribution with screening might be limited to distal CRCs (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The test sensitivity of the Stockholm-Gotland gFOBT screening program was considerably lower in women than in men, and warranted the switch to gender-based FIT screening in 2015, which may also be reflected in the stage distributions in men and women during gFOBT and FIT screening (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe gFOBT screening in the Stockholm-Gotland region was implemented gradually for 60\u0026ndash;69-year-olds in 2008\u0026ndash;2015, by random invitation of birth cohorts born 1938\u0026ndash;1954, to facilitate an evaluation of the effectiveness. Thus, half of the birth cohorts received early invitation to biennial gFOBT screening, and half late or no invitation to screening, and in 2015 gFOBT was replaced by Fecal Immunochemical Test (FIT) screening. The program is intended to expand to 74 years by 2026. An evaluation of the program has estimated a CRC mortality reduction of at least 14% after a maximum of 14 years of follow-up (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The aim of this study was to evaluate the CRC incidence pattern overall and by gender, stage and colorectal localization before, during and up to five years after screening cessation in the colorectal cancer screening program in Stockholm-Gotland, Sweden, 2008\u0026ndash;2021.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThe study population consisted of all residents born 1938\u0026ndash;1954 (aged 60\u0026ndash;69 years) living in the Stockholm-Gotland region of Sweden 2008 to 2012 according to the population register. In 2008, invitational population-based colorectal cancer screening with guaiac-based Fecal Occult Blood Test (gFOBT) was introduced stepwise in the birth cohorts 1940, 1942\u0026ndash;1954 randomized to receive a first invitation to screening 2008\u0026ndash;2015, Fig.\u0026nbsp;1. Biennial screening invitation continued until the age of 69, i.e., 1\u0026ndash;5 rounds. The birth cohorts 1938, 1939 and 1941 were never invited to screening. From 2015 and onwards, the birth cohorts born 1947\u0026ndash;1954 were invited to FIT screening. The follow-up period for CRC was 2008\u0026ndash;2021.\u003c/p\u003e \u003cp\u003eInvitations were sent by mail from the Regional Cancer Center (RCC) of Stockholm-Gotland that coordinated the screening program and included a panel of three gFOBT tests (Hemoccult, Beckman Coulter, U.S.A.) with information on CRC screening and instructions on how to perform the test. The FIT test kit included the invitation and one FIT test tube (OC Sensor, Eiken, Japan). The participants were instructed to note the date of the sample and to send the test in a prepaid envelope to the laboratory as soon as possible. The gFOBT samples were visually inspected by laboratory personnel. A sample was classified as positive if it exhibited an oxidase reaction in at least one of the three samples. In October 2015, the program changed to Fecal Immunochemical Test (FIT) with gender-based cut-off levels. Women with FIT\u0026thinsp;\u0026ge;\u0026thinsp;40\u0026micro;g Hemoglobin/g and men with FIT\u0026thinsp;\u0026ge;\u0026thinsp;80\u0026micro;g/g were considered FIT positive. A new kit was sent in case of an unanalyzable result, and a reminder was sent after 8 weeks in case of non-response.\u003c/p\u003e \u003cp\u003eAll participants with a positive test were offered colonoscopy at the nearest of five contracted endoscopy units. Those with a negative test were advised to consult the primary health care provider in case of bowel symptoms. There was no other CRC screening offered to the citizens of the region.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData sources\u003c/h2\u003e \u003cp\u003eAll residents in Sweden have a unique personal ID number assigned at birth and used in all contacts with authorities and health care units and can thus be linked to various registers. The data on residents born 1938\u0026ndash;1954 registered in the Stockholm-Gotland region and information on emigration were retrieved from Statistics Sweden. Record linkage was made to the screening register at RCC containing data on screening status and invitations, gFOBT/FIT- and colonoscopy results. Data were further linked to the National Cancer Register 1958\u0026ndash;2020, where reporting of cancer cases is mandatory by law, for information on CRC diagnosis and date of diagnosis, and to the Swedish Colorectal Cancer Register (SCRCR) 2008\u0026ndash;2021 that comprises information on CRC diagnosis for 2021, CRC stage and localization. The SCRCR has a coverage of 99% and an overall validity of 90% compared to hospital patient records (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The National Cancer Register has a coverage of 96% (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The data sources and linkage procedures are described in more detail in Blom et al (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eColorectal cancers\u003c/h2\u003e \u003cp\u003eThe CRC diagnosis included the International Classification of Diseases 7 (ICD-7) code 153.X (malignant neoplasm of large intestine, except rectum) or 154.0 (malignant neoplasm of rectum), excluding the codes C24; 091 (neuroendocrine tumor), 093 (lymphoma), 094 (adenoma), 144 (squamous cell carcinoma) and 793 (gastrointestinal stroma tumor). CRCs were classified according to the TNM system in stage I-IV: stage I (T1-2, N0, M0), stage II (T3-4, N0, M0), stage III (T1-4, N1-2, M0) and stage IV (M1) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Early CRC was defined as stage I-II and late CRC as stage as III-IV. The localization of CRCs was grouped into proximal CRC (caecum to splenic flexure) and distal CRC (descending colon to rectum). Data on stage and localization is recorded in the SCRCR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eThe study cohort consisted of individuals invited and not invited to screening. The follow-up for each individual was divided into four exposure categories: before first invitation including never invited, after first invitation to screening with gFOBT, after first invitation to screening with FIT and post screening, i.e., after the last screening round. Number of person-years and incident CRC cases were calculated by attained age and exposure category. The last invitation to screening occurred when the upper age limit for the program was reached (68 or 69 years), or when a CRC or an advanced adenoma that required polyp surveillance was detected, since that individual was admitted to surgery or the polyp surveillance program and not re-invited to the program, or if an invited individual migrated from the region. After the date of the last screening invitation which were either gFOBT or FIT, the exposure category was kept during the following two years of follow-up, corresponding to the biennial screening interval. Thus, the last screening round included up to 71-year-olds, and CRCs detected during the period two years after the last invitation was classified as a CRC in those invited. The incidence in previously invited age groups were compared with never invited of the same age and continued until the age of 75, since the effect of screening on the incidence is likely to diminish a few years after screening cessation.\u003c/p\u003e \u003cp\u003eThose invited to FIT was kept as a separate exposure category from 2015. Due to the ageing of the study cohort and the biennial invitation scheme, birth cohorts 1938\u0026ndash;1946 were never invited to the FIT program and birth cohorts 1947\u0026ndash;1954 were older than 61 in 2015, hence the CRC incidence of invited and non-invited in the FIT program was estimated for 62\u0026ndash;69-year-olds and continued until end of follow-up in 2021 or the age of 75, death or emigration, whichever came first.\u003c/p\u003e \u003cp\u003eThe CRC incidence rate was assessed according to invitational status, regardless of participation, and whether the CRC was screening-detected or an interval CRC (a CRC not detected at screening and diagnosed between screening rounds) and analyzed by stage, gender, and localization in colorectum. The CRC incidence was assessed by year of attained age. However, due to a small number of CRC cases and invited at the age 61, 63 and 67, ages with less than 5 000 person-years were omitted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e (Supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCumulative incidence was calculated for the three categories of individuals invited to gFOBT screening in age 60\u0026ndash;69, individuals invited to FIT screening in age 62\u0026ndash;69, and post-screening individuals aged 70\u0026ndash;75, and compared to the cumulative incidence for not yet or never invited in the corresponding age intervals. Due to differences in age distribution, age-standardized incidence ratio (SIR) was calculated with the not yet or never invited category as reference (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Similarly, SIR was calculated for FIT vs gFOBT. The CRCs diagnosed more than two years after their last screening invitation in the age category 60\u0026ndash;69-year-olds, e.g. individuals included in the polyp surveillance program, were not included in the post screening comparisons. A p-vale of \u0026lt;\u0026thinsp;0.05 was considered statistically significant, and 95% Confidence Intervals (CI) were calculated. For all statistical analyses, the R statistical software version 4.2.2 was used (R project for statistical computing).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn total, 320 989 and 151 533 were invited to a first gFOBT and FIT screening round respectively, of which 2 199 were screening na\u0026iuml;ve when they were invited to the FIT screening. The invitation schedule and number of screening round invitations in each birth cohort is illustrated in Fig.\u0026nbsp;1. The number of individuals invited to a first round of gFOBT and FIT screening at each attained age is listed in Supplementary Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e[Figure 1. Caption: Invitation schedule to gFOBT and FIT screening by birth year and attained age in the Stockholm-Gotland regional program 2008\u0026ndash;2021. The vertical red line marks the shift to FIT screening in October 2015.]\u003c/p\u003e \u003cp\u003eOverall, 5 972 CRCs were diagnosed. Within two years from the last gFOBT and FIT screening invitation 1 572 and 846 CRCs in 60\u0026ndash;69-year-olds, and 46 and 31 in 70\u0026ndash;71-year-olds were diagnosed. In 60-69-year-olds never or not yet invited to screening there were 970 CRCs. Furthermore, 1 762 CRCs were diagnosed post screening as compared to 653 in those never invited to screening and of the same attained age (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were 92 (1.5%) CRCs diagnosed after two years from the last invitation to screening in the age category 60-69-year-olds during 57 375 person-years of follow up, corresponding to the CRCs detected in the polyp surveillance program or in those that migrated from the region. They were excluded from the SIR analyses.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore screening or no screening\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInvited to gFOBT screening\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInvited to FIT screening\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePost screening, invited*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePost screening,\u003c/p\u003e \u003cp\u003euninvited**\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerson-years, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e794 960\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 232 493\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e568 683\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e923 471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e299 759\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1762\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e653\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC, gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e562\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e891\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e681\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e337\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e330\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e390\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e743\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e311\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC localization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e527\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e736\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e651\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e518\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e976\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e380\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCRC\u0026thinsp;=\u0026thinsp;colorectal cancer. gFOBT\u0026thinsp;=\u0026thinsp;guaiac-based fecal occult blood test. FIT\u0026thinsp;=\u0026thinsp;Fecal immunochemical test. Post screening\u0026thinsp;=\u0026thinsp;age 70\u0026ndash;75. Stage I\u0026thinsp;=\u0026thinsp;T1-T2 CRC with no regional lymph node metastases. Stage II\u0026thinsp;=\u0026thinsp;T3-T4 CRC with no regional lymph metastases. Stage III\u0026thinsp;=\u0026thinsp;CRC with regional lymph metastases. Stage IV\u0026thinsp;=\u0026thinsp;CRC with distant metastases. Proximal localization\u0026thinsp;=\u0026thinsp;caecum to splenic flexure, distal localization\u0026thinsp;=\u0026thinsp;descending colon to rectum.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*) The last screening invitation occurs at the age 68 or 69, or when a CRC or high-risk adenoma is diagnosed in invitees aged\u0026thinsp;\u0026lt;\u0026thinsp;69 since they are not reinvited to the program. In this column the CRCs in 60\u0026ndash;69-year-olds are excluded. The CRCs diagnosed within two years from last screening invitation are considered attributed to the screening due to the biennial invitation scheme and thus not included.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e**) Post screening, uninvited, refers to the 70\u0026ndash;75-year-olds that were never invited to screening at the age 60\u0026ndash;69.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe CRC incidence rate per person-years for each attained age is displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e for individuals invited to FIT and gFOBT and for the post screening and non-invited categories. The cumulative CRC incidence rate per 100 000 person-years was 122, 128, 149, 191 and 218 for non-invited or not yet invited, gFOBT invited 60\u0026ndash;69 years-olds, FIT invited 62-69-year-olds, post screening invited and post screening non-invited individuals 70\u0026ndash;75 years-olds, respectively.\u003c/p\u003e \u003cp\u003e[Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Caption: CRC incidence per 100 000 person-years and attained age in those invited and not invited to screening. The incidence is plotted for ages with \u0026gt;\u0026thinsp;5000 person-years of follow-up. Red line\u0026thinsp;=\u0026thinsp;Incidence in individuals not (yet) invited to screening. Green line\u0026thinsp;=\u0026thinsp;Incidence in those invited to gFOBT screening (from 2008). Blue line\u0026thinsp;=\u0026thinsp;incidence in those invited to FIT screening (from 2015). Purple line\u0026thinsp;=\u0026thinsp;Incidence two years after the last invitation to screening. CRC\u0026thinsp;=\u0026thinsp;colorectal cancer. gFOBT\u0026thinsp;=\u0026thinsp;guaiac-based fecal occult blood test. FIT\u0026thinsp;=\u0026thinsp;Fecal immunochemical test.]\u003c/p\u003e \u003cp\u003eThe age-adjusted incidence ratio (SIR) for the gFOBT- and FIT-invited compared to the non-invited was similar (RR 0.99 95% CI 0.91\u0026ndash;1.07 and 1.03 95% CI 0.93\u0026ndash;1.15). However, there was a 12% decrease (RR 0.88, 95% CI 0.81\u0026ndash;0.97) in the incidence among previously invited 70\u0026ndash;75-year-olds, as compared to the non-invited of the same age (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe age-adjusted incidence ratio post screening as compared to the non-invited remained in women (RR 0.87, 95% CI 0.76-1.00) but not significantly in men. Regarding CRC stage, there was an increase in stage I CRC of 38% (RR 1.38, 95% CI 1.09\u0026ndash;1.76) for the FIT-invited, and a 22% decrease (RR 0.78, 95% CI 0.63\u0026ndash;0.95) in incidence post screening as compared to the non-invited. The incidence in late-stage (III and IV) CRC was similar in invited and non-invited both during and after screening. The FIT screening increased the proximal CRC incidence by 23% (RR 1.23, 95% CI 1.02\u0026ndash;1.48), but did not decrease the proximal CRCs incidence post screening (RR 0.98, 95% CI 0.84\u0026ndash;1.13). There was no significant difference during the gFOBT screening in subgroups of CRC as compared to the non-invited. Distally located CRCs decreased with 17% post screening (RR 0.83, 95% CI 0.74\u0026ndash;0.94) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAge-standardized CRC incidence ratio in invited to gFOBT and FIT screening, respectively, vs non-invited in the Stockholm-Gotland program.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eAge-standardized rate ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-invited\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003egFOBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePost screening\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.91\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.03 (0.93\u0026ndash;1.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.88 (0.81\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.88\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.05 (0.91\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.89 (0.79\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.87\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 (0.86\u0026ndash;1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87 (0.76-1.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.17 (0.96\u0026ndash;1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.38 (1.09\u0026ndash;1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78 (0.63\u0026ndash;0.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98 (0.83\u0026ndash;1.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84 (0.68\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87 (0.73\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.92 (0.81\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97 (0.83\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.94 (0.83\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRC localization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.13 (0.97\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.23 (1.02\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98 (0.84\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.92 (0.83\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.93 (0.81\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.83 (0.74\u0026ndash;0.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003egFOBT\u0026thinsp;=\u0026thinsp;guaiac-based Fecal Occult Blood Test. FIT\u0026thinsp;=\u0026thinsp;Fecal immunochemical test. The cumulative incidence for gFOBT screening is calculated for age 60\u0026ndash;69 and that of FIT for age 62\u0026ndash;69. Post screening refers to age 70\u0026ndash;75. Distal colon\u0026thinsp;=\u0026thinsp;descending to rectum. Proximal colon\u0026thinsp;=\u0026thinsp;Caecum to splenic flexure. Stage I\u0026thinsp;=\u0026thinsp;T1-T2 CRC with no regional lymph node metastases. Stage II\u0026thinsp;=\u0026thinsp;T3-T4 CRC with no regional lymph node metastases. Stage III\u0026thinsp;=\u0026thinsp;CRC with regional lymph node metastases. Stage IV\u0026thinsp;=\u0026thinsp;CRC with distant metastases.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eSupplementary Table\u0026nbsp;1. Age and number of invited to the first gFOBT and FIT screening round in the Stockholm-Gotland screening program.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cp\u003e[Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eComparing FIT and gFOBT screening, the differences in incidences were non-significant; the overall age-adjusted incidence ratio was 1.03 (95% CI 0.94\u0026ndash;1.12). For stage I CRC, the incidence ratio was 1.19% (95% CI 0.99\u0026ndash;1.42) in FIT as compared to gFOBT screening. Moreover, the overall incidence in FIT-invited men was non-significantly higher than in gFOBT-invited men (RR 1.03, 95% CI 0.92\u0026ndash;1.16). The difference between FIT and gFOBT incidences of stage II, III-IV, proximal and distal localization and in women was non-significant (RR 0.85 95% CI 0.70\u0026ndash;1.02, RR 1.02 95% CI 0.90\u0026ndash;1.16, RR 1.04 95% CI 0.90\u0026ndash;1.21, RR 1.02 95% CI 0.91\u0026ndash;1.14, and RR 1.02 95% CI 0.89\u0026ndash;1.16 respectively).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis evaluation of the population-based screening program in Stockholm-Gotland, Sweden, demonstrated a similar overall CRC incidence among those invited to the screening as compared to the non-invited, and a decreased incidence after screening cessation. This change in post screening incidence was significant for early-staged CRC and CRCs in women and differed by colorectal localization. However, we did not find a significant change in incidence in subgroups during the gFOBT program, nor a decrease in late-stage CRC from the screening program.\u003c/p\u003e \u003cp\u003eSeveral previous studies have shown an increased CRC incidence when introducing population-based FIT screening, due to both incidence and prevalence screening in the first round, and thereafter a return to or decrease below pre-screening levels in subsequent rounds (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). At long-term follow-up of the randomized gFOBT screening trial in Minnesota there was a marked decline in incidence with multiple screening rounds as compared to controls (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study, we did not find a significant change in the incidence among those invited to the gFOBT program. However, the invited age cohorts consisted of both prevalent and incident screening rounds for each attained age (except the 60-years-olds), hence the net effect could be an unchanged incidence. Apart from this, approximately 40% of the gFOBT invitees did not participate in screening and could therefore not contribute to an increased CRC incidence (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Furthermore, gFOBT, as compared to FIT, has a lower sensitivity for advanced adenoma; 10\u0026ndash;15% vs 25\u0026ndash;30%, hence it is not expected a large decline in CRC incidence post screening because of polypectomy in a gFOBT screened population (\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In the Minnesota trial the cumulative gFOBT positivity was approximately 30%, so the large decrease in incidence could partly be explained by the large number of colonoscopies (and polypectomies) performed in the intervention group. The positivity rate in the Stockholm-Gotland gFOBT program was approximately 2% (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe gFOBT sensitivity for CRC is stage-dependent, with reported sensitivity rates of Dukes A 89%, Dukes B 79%, Dukes C 72%, and Dukes D 48% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). A meta-analysis of FIT studies (cut-off-levels between 10\u0026ndash;20 \u0026micro;g/g) estimated FIT sensitivity to 73% for stage I CRC, 80% for stage II, 82% for stage III, 79% for stage IV (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The overall CRC sensitivity in the Stockholm-Gotland FIT program with cut-off levels 40 \u0026micro;g/g and 80 \u0026micro;g/g in women and men was estimated to 65%, as compared to 40% in the gFOBT program (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). The shift to FIT in the program generated an increased participation rate (69%), and a higher sensitivity for advanced adenomas and CRC, which contributed to the net increase in CRC incidence in subgroups of early-staged and proximal CRCs during screening and a decrease post screening due to the preventive effect of polypectomy. The decreased incidence post screening after an increase during screening as compared to the non-invited was only seen in stage I CRCs, probably due to the earlier detection of CRC with screening leading to a compensatory drop after screening cessation.\u003c/p\u003e \u003cp\u003eThe 14% reduction in CRC mortality recently reported from the Stockholm-Gotland screening program would most likely be explained by a shift from late to early-stage CRC (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, in the present study we did not a see a decreased incidence of stage III-IV CRC among the invited. Since the mortality is low in stage I CRC, the reduced stage I incidence post screening could not explain the reduced mortality (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). However, the invited included both the non-participants as well as prevalence screening rounds which could balance out a favorable stage shift in the participants. In the Dutch screening program, the incidence of late-stage CRC increased at screening implementation followed by a decrease when compared to the incidence rates prior to screening (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Moreover, given the low number of CRCs stage III and IV in the present study they were combined and categorized into late-stage (III-IV). There might be a stage shift among the invited from IV to III or in subclassification of T stages that we were not able to detect albeit important for the prognosis (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In the previously cited Danish study, there was an increased incidence of stage I-III CRC and no significant difference in stage IV CRC in the invited as compared to non-invited, but this study included only the prevalence round (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the other hand, it is not certain that a favorable stage shift due to screening directly translates into a disease specific mortality reduction, because this is dependent on the difference in survival between the early and late stages and the proportion of cancers that the screening is able to shift to earlier stages, and it also assumes that the late stage cancers among the invited have the same survival as the late staged cancers among the non-invited (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Invitation to screening could raise the awareness of the disease and make the invited individuals more prone to seek health care and to life style changes, e.g., regarding smoking, than the non-invited, potentially affecting the disease mortality other than as a shift in stage (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDuring the FIT screening, the incidence of proximal CRC increased. Proximal CRCs are more common in women, and the Stockholm-Gotland program applies lower cut-off-levels in women than in men, which might explain the increased incidence with FIT screening and the decreased incidence in women post screening, although gFOBT and FIT performs worse in proximal CRCs as compared to distal in gender-uniform screening (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). The increased incidence of early-stage proximal CRCs in women could have contributed to the decreased mortality of the program, since proximal CRCs confers a worse prognosis and are diagnosed clinically at a late stage (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The overall incidence of proximal CRC was not decreased post screening. However, only birth cohorts 1948-51 (and part of 1947 cohort) were screened with FIT and reached post screening age at end of follow-up, hence gFOBT screening was over-represented in this group. Post screening, a significant decrease was seen only for distal localization reflecting the higher sensitivity for distal CRC of both gFOBT and FIT and the higher rate of distal CRC in men (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe strengths of this study were the evaluation of a large population-based CRC screening program shifting from gFOBT to FIT screening, the linkage with individual data to validated cancer registers with low number of missing data enabling analyzation of CRC subgroups, and the assessment of CRC incidence of invited and non-invited individuals within the same time-period and in the same region. Moreover, evaluation of the invitation to screening precluded the self-selection bias from healthy participants.\u003c/p\u003e \u003cp\u003eNevertheless, this study has several limitations. The screening program implementation was made by randomization of birth cohorts into early, late or no screening invitation rather than individual randomization, making the comparisons between invited and non-invited biased by age. This problem was overcome when comparing age-adjusted incidence ratios, but we were unable to assess the incidence change over time when initiating screening and by subsequent screening rounds. Furthermore, we did not analyze stage III and IV CRCs separately due to a low number of cases, hence not capture any change in incidence in between the late-stage CRCs as discussed above. Moreover, the post screening comparisons of incidence were, due to the recent shift to FIT screening, dominated by gFOBT screened individuals, and additional studies are needed to fully address the effect of FIT in 70-75-year-olds, especially since the shift to FIT increased the participation rate by 12% (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn conclusion, the shift to FIT in the population-based screening program of Stockholm-Gotland, Sweden, significantly increased the CRC incidence for early-staged and proximal CRCs, and the overall decrease post screening was mainly seen in distal, early staged CRCs in women as compared to the non-invited. The full effect of gender-based FIT screening on the incidence post screening needs further evaluation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe study was approved by the Ethics Review Board of Sweden (ref nb 2020-06757). Informed consent to participate in this study was not asked for, but information about the screening register and how to unregister was included in the invitation and reply letter. Informed consent was asked for at the endoscopy unit for the registration in the Swedish quality register for colonoscopies and colorectal cancer screening.\u003c/p\u003e\n\u003cp\u003eAccess to underlying research material can be obtained by email to the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was not a clinical trial, hence not registered as such.\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest with regards to this work.\u003c/p\u003e\n\u003cp\u003eAuthors contribution: H.R.W.: Design of the study, analysis and interpretation of data, and manuscript writing. H.J.: Design of the study, analysis and interpretation of data and critical revision of the manuscript J.B.: Design of the study, interpretation of data and critical revision of the manuscript.\u0026nbsp;All authors have approved of the final version of the manuscript and consented to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe Swedish Cancer Society grant 21 1389 Pj, The Swedish Research Council grant 2021-03139 and Region Stockholm grant FoUI-961412.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKarolinska University Hospital, Division of Trauma \u0026amp; Reparative Medicine, is thanked for allocating working time for the realization of this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA: a cancer journal for clinicians. 2018;68(4):250-81.\u003c/li\u003e\n\u003cli\u003eFitzpatrick-Lewis D, Ali MU, Warren R, Kenny M, Sherifali D, Raina P. Screening for Colorectal Cancer: A Systematic Review and Meta-Analysis. Clin Colorectal Cancer. 2016;15(4):298-313.\u003c/li\u003e\n\u003cli\u003eFeng X, Zahed H, Onwuka J, Callister MEJ, Johansson M, Etzioni R, et al. Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis. Jama. 2024.\u003c/li\u003e\n\u003cli\u003eBreekveldt ECH, Toes-Zoutendijk E, Spaander MCW, van de Schootbrugge-Vandermeer HJ, van Vuuren AJ, van Kemenade FJ, et al. Advanced-stage CRC incidence patterns following the phased implementation of the CRC screening programme in the Netherlands. European journal of cancer. 2023;178:60-7.\u003c/li\u003e\n\u003cli\u003eClark GR, Anderson AS, Godfrey TG, Strachan JA, Fraser CG, Steele RJ. Variation in changes in the incidence of colorectal cancer by age and association with screening uptake: an observational study. BMJ open. 2020;10(9):e037925.\u003c/li\u003e\n\u003cli\u003eMcClements PL, Madurasinghe V, Thomson CS, Fraser CG, Carey FA, Steele RJ, et al. Impact of the UK colorectal cancer screening pilot studies on incidence, stage distribution and mortality trends. Cancer epidemiology. 2012;36(4):e232-42.\u003c/li\u003e\n\u003cli\u003eTran TN, Hoeck S, De Schutter H, Janssens S, Peeters M, Van Hal G. The Impact of a Six-Year Existing Screening Programme Using the Faecal Immunochemical Test in Flanders (Belgium) on Colorectal Cancer Incidence, Mortality and Survival: A Population-Based Study. Int J Environ Res Public Health. 2023;20(2).\u003c/li\u003e\n\u003cli\u003eLarsen MB, Njor S, Ingeholm P, Andersen B. Effectiveness of Colorectal Cancer Screening in Detecting Earlier-Stage Disease-A Nationwide Cohort Study in Denmark. Gastroenterology. 2018;155(1):99-106.\u003c/li\u003e\n\u003cli\u003eCardoso R, Guo F, Heisser T, Hackl M, Ihle P, De Schutter H, et al. Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study. The Lancet Oncology. 2021;22(7):1002-13.\u003c/li\u003e\n\u003cli\u003eHirai HW, Tsoi KK, Chan JY, Wong SH, Ching JY, Wong MC, et al. Systematic review with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies. Alimentary pharmacology \u0026amp; therapeutics. 2016;43(7):755-64.\u003c/li\u003e\n\u003cli\u003eMorris EJ, Whitehouse LE, Farrell T, Nickerson C, Thomas JD, Quirke P, et al. 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Acta oncologica. 2009;48(1):27-33.\u003c/li\u003e\n\u003cli\u003eUJCC TNM Classification of Malignant Tumors, 8th Edition, p74-76. Brierley JD et al. Wiley Blackwell 2017.\u003c/li\u003e\n\u003cli\u003eBreslow NE, Day NE. Statistical methods in cancer research. Volume II--The design and analysis of cohort studies. IARC Sci Publ. 1987(82):1-406.\u003c/li\u003e\n\u003cli\u003eBreekveldt ECH, Lansdorp-Vogelaar I, Toes-Zoutendijk E, Spaander MCW, van Vuuren AJ, van Kemenade FJ, et al. Colorectal cancer incidence, mortality, tumour characteristics, and treatment before and after introduction of the faecal immunochemical testing-based screening programme in the Netherlands: a population-based study. The lancet Gastroenterology \u0026amp; hepatology. 2022;7(1):60-8.\u003c/li\u003e\n\u003cli\u003eZorzi M, Fedeli U, Schievano E, Bovo E, Guzzinati S, Baracco S, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut. 2015;64(5):784-90.\u003c/li\u003e\n\u003cli\u003eMandel JS, Church TR, Bond JH, Ederer F, Geisser MS, Mongin SJ, et al. The effect of fecal occult-blood screening on the incidence of colorectal cancer. The New England journal of medicine. 2000;343(22):1603-7.\u003c/li\u003e\n\u003cli\u003eBlom J, Kilpelainen S, Hultcrantz R, Tornberg S. Five-year experience of organized colorectal cancer screening in a Swedish population - increased compliance with age, female gender, and subsequent screening round. Journal of medical screening. 2014;21(3):144-50.\u003c/li\u003e\n\u003cli\u003eGrobbee EJ, Wisse PHA, Schreuders EH, van Roon A, van Dam L, Zauber AG, et al. Guaiac-based faecal occult blood tests versus faecal immunochemical tests for colorectal cancer screening in average-risk individuals. The Cochrane database of systematic reviews. 2022;6(6):CD009276.\u003c/li\u003e\n\u003cli\u003eScholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle JD. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up. Gut. 2012;61(7):1036-40.\u003c/li\u003e\n\u003cli\u003eLindholm E, Brevinge H, Haglind E. Survival benefit in a randomized clinical trial of faecal occult blood screening for colorectal cancer. The British journal of surgery. 2008;95(8):1029-36.\u003c/li\u003e\n\u003cli\u003eBrenner H, Haug U, Hundt S. Sex differences in performance of fecal occult blood testing. The American journal of gastroenterology. 2010;105(11):2457-64.\u003c/li\u003e\n\u003cli\u003eNiedermaier T, Balavarca Y, Brenner H. Stage-Specific Sensitivity of Fecal Immunochemical Tests for Detecting Colorectal Cancer: Systematic Review and Meta-Analysis. The American journal of gastroenterology. 2020;115(1):56-69.\u003c/li\u003e\n\u003cli\u003eRibbing Wilen H, Blom J. Interval cancer after two rounds of a Swedish population-based screening program using gender-specific cut-off levels in fecal immunochemical test. Journal of medical screening. 2023:9691413231185722.\u003c/li\u003e\n\u003cli\u003ehttps://cancercentrum.se/globalassets/cancerdiagnoser/tjock--och-andtarm-anal/kvalitetsregister/tjock--och-andtarm-2023/kolonrapport_2022.pdf Swedish Colorectal Cancer Register (SCRCR) quality report 2022. Accessed 8th Feb 2024.\u003c/li\u003e\n\u003cli\u003eFoersch S, Lang-Schwarz C, Eckstein M, Geppert C, Schmitt M, Konukiewitz B, et al. pT3 colorectal cancer revisited: a multicentric study on the histological depth of invasion in more than 1000 pT3 carcinomas-proposal for a new pT3a/pT3b subclassification. British journal of cancer. 2022;127(7):1270-8.\u003c/li\u003e\n\u003cli\u003eOwens L, Gulati R, Etzioni R. Stage Shift as an Endpoint in Cancer Screening Trials: Implications for Evaluating Multicancer Early Detection Tests. Cancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022;31(7):1298-304.\u003c/li\u003e\n\u003cli\u003eLiang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. International journal of cancer Journal international du cancer. 2009;124(10):2406-15.\u003c/li\u003e\n\u003cli\u003eDekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-80.\u003c/li\u003e\n\u003cli\u003eBlom J, Lowbeer C, Elfstrom KM, Sventelius M, Ohman D, Saraste D, et al. Gender-specific cut-offs in colorectal cancer screening with FIT: Increased compliance and equal positivity rate. Journal of medical screening. 2019;26(2):92-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Colorectal cancer screening, Fecal Occult Blood Test, Fecal Immunochemical Test, colorectal cancer incidence","lastPublishedDoi":"10.21203/rs.3.rs-4575023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4575023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003e To investigate colorectal cancer (CRC) incidence and stage of disease in the population invited vs not invited to the guaiac-based Fecal Occult Blood (gFOBT) and Fecal Immunochemical Test (FIT) colorectal cancer screening program in Stockholm-Gotland, Sweden, 2008\u0026ndash;2021 and to estimate the incidence rate by gender and localization in the colorectum.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study cohort consisted of all 60-69-years-old residents of the Stockholm-Gotland region 2008\u0026ndash;2012 according to the population register. Screening with biennial gFOBT was introduced in randomized birth cohorts from 2008 and replaced by FIT with cut-off level 40\u0026micro;g/g in women and 80\u0026micro;g/g in men for a positive test in 2015. Record linkage was made to the National Cancer Register and to the Swedish Colorectal Cancer Register (SCRCR). The age-standardized CRC incidence ratio was compared in invited and non-invited during screening and in 70-75-year-olds and assessed overall and by gender, CRC stage and localization.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 320 989 and 151 533 individuals were invited to a first gFOBT and FIT round, and 5 972 CRCs were diagnosed. During screening, the overall age-adjusted incidence ratio for the gFOBT- and FIT-invited compared to the non-invited was 0.99 (95% CI 0.91\u0026ndash;1.07) and 1.03 (95% CI 0.93\u0026ndash;1.15) respectively. Post screening, 70\u0026ndash;75 years of age, the overall incidence rate was 12% lower among the invited than the non-invited (RR 0.88, 95% CI 0.81\u0026ndash;0.97). During FIT screening, the incidence for stage I and proximal CRC was 38 and 23% higher than in the non-invited (RR 1.38, 95% CI 1.09\u0026ndash;1.76 and RR 1.23, 95% CI 1.02\u0026ndash;1.48 respectively). The incidence post screening was 22% lower regarding stage I CRC, 13% lower in women, and 17% lower for distal CRCs as compared to the non-invited (RR 95% CI 0.78 0.63\u0026ndash;0.95, 0.87 0.76-1.00 and 0.83 0.74\u0026ndash;0.94 respectively).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn the Stockholm-Gotland screening program the shift to FIT significantly increased the incidence rate in early staged and proximal CRCs as compared to the uninvited, and the significant decrease in the overall CRC incidence post screening was mainly seen in distal, early staged CRCs in women.\u003c/p\u003e","manuscriptTitle":"The effect on colorectal cancer incidence and stage with population-based FOBT-screening in Sweden","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-13 02:33:58","doi":"10.21203/rs.3.rs-4575023/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-26T06:49:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-25T07:27:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66086891016775331884295288770858188184","date":"2024-10-21T09:18:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294391505472842576084358640829814180299","date":"2024-10-09T04:54:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-07T16:46:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"322987293396528969278522062669391434427","date":"2024-09-30T10:16:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-01T04:48:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164128184994123201156732380241186410387","date":"2024-06-24T03:24:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145382056816674243912119355410111756030","date":"2024-06-23T16:46:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-23T08:21:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-17T04:34:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-14T23:51:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-14T23:50:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Public Health","date":"2024-06-13T09:16:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bf43525e-914c-41e2-b747-d592df51b6b8","owner":[],"postedDate":"July 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-28T16:02:25+00:00","versionOfRecord":{"articleIdentity":"rs-4575023","link":"https://doi.org/10.1186/s12889-025-22771-8","journal":{"identity":"bmc-public-health","isVorOnly":false,"title":"BMC Public Health"},"publishedOn":"2025-04-26 15:57:46","publishedOnDateReadable":"April 26th, 2025"},"versionCreatedAt":"2024-07-13 02:33:58","video":"","vorDoi":"10.1186/s12889-025-22771-8","vorDoiUrl":"https://doi.org/10.1186/s12889-025-22771-8","workflowStages":[]},"version":"v1","identity":"rs-4575023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4575023","identity":"rs-4575023","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}