Routine Fecal Occult Blood Screening and Colorectal Cancer Mortality in Sweden

Key Points Question Is routine screening with fecal occult blood test (FOBT) associated with reduced colorectal cancer (CRC) mortality? Findings In this cohort study of 379 448 individuals, there was a statistically significant 14% decreased CRC mortality among individuals who received early invitation to FOBT screening compared with individuals who received late or no invitation after a maximum of 14 years of follow-up. Meaning These findings suggest that population-based CRC screening with FOBT was associated with decreased CRC mortality.


Introduction
Secondary prevention of colorectal cancer (CRC) with screening has the potential to reduce deaths from the disease by detecting the cancer at an early, curable stage.Larger precursors, such as adenomatous polyps (adenomas), and cancer may bleed, enabling the measurement of invisible (occult) blood in the stool with fecal occult blood tests (FOBT) before disease symptoms occur.
In 2003, the European Commission issued recommendations to screen for CRC with FOBT in men and women aged 50 to 74 years, 1 and in 2006, national CRC screening programs started in some European countries, such as England and Italy. 2,35][6] In 2010, European Guidelines for Quality Assurance in CRC screening were issued, 7 and in 2022, fecal immunochemical testing (FIT) was recommended. 8T is a FOBT with higher sensitivity and adherence with invitation compared with gFOBT 9,10 and is expected to be at least as effective. 11Still, there is a lack of observational studies evaluating the association of CRC mortality with routine screening programs using FOBT.
In 2008, the region of Stockholm-Gotland, encompassing approximately 25% of the Swedish population, initiated a CRC screening program. 12Influenced by experiences from Finland, 2,13 the program gradually invited men and women aged 60 to 69 years to undergo biennial gFOBT.If results were positive, a referral for colonoscopy was undertaken.In 2015, gFOBT was replaced with FIT. 10 The aim of this study was to evaluate screening program effectiveness on CRC mortality by comparing birth cohorts invited early to screening with those not invited or invited late.

Methods
This cohort study was approved by the Ethics Review Board of Sweden and in accordance with the Declaration of Helsinki.Informed consent was waived because all data were deidentified.This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

The Screening Program
The screening program was centrally organized at the Stockholm-Gotland Regional Cancer Centre (RCC), Sweden, which was responsible for sending invitations, registration, and reporting outcomes of all parts of the screening process and ensuring quality control.Of 20 regional endoscopy clinics, 5 were contracted to perform all assessment colonoscopies.There were no other CRC screening activities in the region.The target group of screening comprised all residents in the region aged 60 to 69 years according to the Swedish population register, without any exclusion.In Sweden, all residents have a unique national registration number used in all population statistics, including health care.
An invitation to screening was sent from RCC to the home of the individuals, without involvement of primary health care physicians. 12The invitation included information on CRC screening, a test kit with 3 gFOBT test cards (Hemoccult-test; Beckman Coulter), instructions on how to take the test, and a prepaid return envelope.The test was not rehydrated before analysis and has demonstrated a screening program sensitivity of approximately 22% to 52%, although lower in women than in men. 14Participants with test results negative for occult blood (ie, 3 negative test cards) were informed by letter and, in case of false-negative test, advised to seek a physician if they had bowel symptoms.The individuals with test results positive for occult blood (ie, positive results on Ն1 of 2 panels of the 3 test cards) were electronically referred to the contracted endoscopy clinic that was responsible for assessment of individuals residing in the catchment area and that provided a colonoscopy within 2 weeks.Participants with invalid tests were sent new test kits, and invitees with no test results registered at the laboratory were sent a reminder after 8 weeks.Due to a higher level of interval cancers among women, 14  The invitations were sent biennially for 10 years, ie, 5 screening rounds, following the same procedure.Patients with cancer diagnosed at a screening episode were referred by the endoscopy clinic to surgery, while patients with advanced adenomas removed at screening colonoscopy, ie, adenomas of 10 mm or greater with high-grade dysplasia or villous histology, serrated polyps with dysplasia or 10 mm or greater in size or 3 or more low-risk adenomas, were referred to an adenoma surveillance program.

Study Cohort
The years).There were also birth cohorts never invited due to allocation to the no invitation group.Some birth cohorts were allocated to early start, ie, invitation to screening during 2008 to 2012 (exposure group), while the other birth cohorts never got an invitation or had their first invitation in 2013 to 2015 (control group) (Table 1).There were no other systematic differences between groups than year of invitation.

Data Retrieval
Data on the cohort individuals, including information on emigration, were retrieved from Statistics Sweden.By using the unique national registration number, the cohort data were then linked to the national cancer register and the cause of death register at the National Board of Health and Welfare to retrieve data on diagnoses of CRC from 1958 to 2020 and deaths and the underlying cause of death (UCD; in case of CRC) from 2008 to 2021. 15,16Data were further linked to the regional screening register at RCC Stockholm-Gotland to retrieve data on program performance, eg, dates of invitation, participation, and results of the tests and assessment colonoscopies.Revision (ICD-10), specifically coded as C18.X-C20.X (malignant tumor in colon or rectum), within the cause of death register.

Follow-Up
For the exposure group, the individual start of follow-up was defined as the date of the first invitation to the screening program, and for all individuals in the control group the start of follow-up was defined as January 1, 2008.All individuals were followed until possible emigration (the first emigration registered after start of follow-up), death, or December 31, 2021, whichever came first.

Data Cleaning Process
Individuals in the exposure group never invited or with first screening later than January 1, 2013 were excluded.Furthermore, individuals with CRC diagnosis before the start of follow-up were excluded, since they could not be affected by the screening program.There were 228 individuals with death certificate-only data, ie, individuals with CRC listed as the UCD, but they had no diagnosis of CRC in the national cancer register.They were excluded from the primary analysis but incorporated into a sensitivity analysis.More details of the data cleaning process are provided in Figure 1.

Statistical Analyses
The main end point of the study was death with CRC as UCD.The rate ratio (RR) of CRC mortality was calculated for the exposure group vs the control group.Since individuals with CRC diagnosis before the start of follow-up were removed, this is often called incidence-based mortality.We also determined the timing of the CRC diagnosis in relation to the most recent screening invitation for individuals who died from CRC in the exposure group.
The mortality was adjusted for follow-up year and attained age using Poisson regression.The follow-up was divided into cells with number of person-years and number of CRC deaths per follow-up year, year of attained age, and group.Poisson regression was performed with logarithm of the number of person-years as offset to estimate the mortality RR adjusted for follow-up year and attained age.The analysis was also extended by including sex.Determining a singular UCD in individual deaths, especially when there is a known diagnosis, like CRC, can be challenging.Excess mortality offers an alternative approach for calculating the cause of death independently of individual specifics.We assume the risk of death for a patient with CRC to be the normal mortality rate plus an additional mortality attributed to the disease.Subtracting the normal mortality provides an estimate of CRC mortality.The numerator, representing the excess number of deaths, was calculated by subtracting the expected number of deaths individuals would have had without CRC from the all-cause deaths among the individuals with CRC.The expected number of deaths was calculated as the product of the person-years among individuals with CRC and the population's all-cause mortality rate.The calculations were made by sex, age, and calendar year and then summarized.To determine excess mortality, the excess number of CRC deaths is then divided by person-years, following the standard mortality calculation approach.Excess mortality was analyzed in a similar manner to mortality based on the UCD, using Poisson regression.However, the Poisson analysis was adjusted due to the higher variance of the excess number of cases compared to its expected value; the distribution is not Poisson.

Results
After  Screening participation increased by individual round, with a mean of 63.3% and a pronounced increase from 2015, at the time of change from gFOBT to FIT (Table 2). 10

Main Outcome
There were 834 CRC deaths in 2 190 589 person-years in the exposure group and 889 CRC deaths in 2 249 939 person-years in the control group (Table 3).Individuals who underwent early CRC screening had reduced risk of CRC mortality in unadjusted analysis (RR, 0.96; 95% CI, 0.88-1.06)and after adjustment for follow-up years and attained age (RR, 0.86; 95% CI, 0.78-0.95).The main result did not change when sex was included in the model.However, women had a significantly lower CRC mortality compared with men (RR, 0.67; 95% CI, 0.61-0.74).There was no significant interaction between group and sex (RR for screening for women vs men, 0.94; 95% CI, 0.78-1.14).

Excess Mortality
There were 14 573 person-years and 1160 all-cause deaths among individuals with CRC in the exposure group and 15 102 person-years and 1283 all-cause deaths among individuals with CRC in the control group (Table 3).The resulting excess number of deaths was 890.8 in the exposure group and 975.4 in the control group, which is 6.8% higher than using the UCD in the exposure group and 9.7% higher than in the control group.Compared with the control group, the exposure group had reduced risk of excess mortality before adjustment (RR, 0.94; 95% CI, 0.86-1.03)and after adjustment for follow-up year and attained age (RR, 0.84; 95% CI, 0.75-0.93),ie, lower than the risk of CRC as UCD.

JAMA Network Open | Public Health
Routine Fecal Occult Blood Screening and Colorectal Cancer Mortality in Sweden study was performed on a cohort of 392 190 individuals who resided in the region of Stockholm-Gotland, Sweden, in 2008 to 2012 and were born between 1938 and 1954.In 2007, the program randomized birth years to determine the starting year for screening invitations, with 2008 as the initial year and 2015 as the final year for inviting individuals to commence screening.The number of screening invitations per individual varied due to age at first invitation, with 5 as maximum (ie, 10

8 ( 3 . 2 .
data cleaning, there were 379 448 individuals (193 436 [51.0%] female) in the cohort, including 203 670 individuals in the exposure group and 175 778 individuals in the control group.The maximum follow-up was 14 years, with a mean (SD) of 10.8 (2.7) years in the exposure group and 12.0) years in the control group.In the control group, 60 162 individuals (34.2%) were never invited for screening, while 115 616 individuals (65.8%) were invited to participate in at least 1 screening round.The time to first screening per group is illustrated in Figure The mean (SD) age at individual mid-follow-up was 68.9 (3.4) years for the exposure group 67.0 (5.6) years for the exposure group.

Figure 2 .
Figure 2. Cumulative Proportion of Invited to First Screening 1.00

Eiken JAMA Network Open | Public Health
the program changed from gFOBT to FIT (OC-Sensor; Downloaded from jamanetwork.comby guest on 03/10/2024 Chemical) in September 2015, with a cutoff level of 40 μg Hb/g feces for a positive result in women and 80 μg Hb/g for a positive result in men.

Table 1 .
Evaluation Group, Planned Year of Start of Screening, Age at Screening Start, Start of Follow-Up, Total Number, and Proportion of Women by Birth Year Routine Fecal Occult Blood Screening and Colorectal Cancer Mortality in Sweden Diagnosis and Cause of Death The Swedish national cancer register uses the International Classification of Diseases, Revision 7 (ICD-7) with CRC diagnosis code 153.X (malignant neoplasm of large intestine, except rectum) or 154.0 (malignant neoplasm of rectum) excluding the morphology (histology) codes C24; 091 (neuroendocrine tumor), 093 (lymphoma), 094 (adenoma), 144 (squamous cell carcinoma), or 793 (gastrointestinal stroma tumor).Death attributed to CRC as the underlying cause was determined using the International Statistical Classification of Diseases and Related Health Problems, Tenth a Exposure group: individuals invited to early start of screening (2008-2012).Control group: individuals invited to late start of screening (2013-2015) or were never invited.JAMA Network Open | Public Health The variance was adjusted by adding the expected number of deaths.We conducted a sensitivity analysis by including the 228 individuals with CRC as UCD on death certificates only but without diagnosis of CRC in the national cancer register.

Table 2 .
Invited and Participating Individuals per Test Method and Year

Table 3 .
Deaths With CRC as Underlying Cause of Death and Person-Years for the Total Cohort a The exposure group is individuals invited to early-start screening(2008-2012).The control group is individuals invited to late-start screening (2013-2015) or were never invited.