The SCREESCO exam assessed two real-world cOral and rectal cancer screening strategiesIn a population-based setting in Sweden, a single initial colonoscopy and repeated fecal immunochemical testing (FIT) with colonoscopy in case of a positive result are performed against usual care without invitation for screening, with the aim of identifying both the potential benefits of early cancer detection and the short-term harms associated with diagnostic workup.
Title: Colonoscopy and Fecal Immunochemistry Testing and Usual Care in Colorectal Cancer Diagnostic Screening: The SCREESCO Randomized Controlled Trial
Authors: Marcus Westerberg, Jonas F. Ludvigsson, Chris Metcalfe, Ulf Strömberg, Johannes Blom, Lars Engstorm, Mikael Hellstrom, Christian Löwbeer, Robert Steele, Lars Holmberg & Anna Forsberg
background
Colorectal cancer (CRC) Although screening can detect cancer early and remove precancerous lesions and is recommended by many guidelines, there are trade-offs with any screening strategy, especially treatment-related harms. Although colonoscopy is often considered the most “sure-fire” test, many organized programs rely on a fecal immunochemical test (FIT) repeated every 1 to 2 years, followed by a colonoscopy only if there is a positive result.
A key evidence gap is how these approaches compare to usual care (no screening invitation) in a randomized setting, not only in cancer detection patterns but also in actual short- and medium-term adverse events. The Swedish SCREESCO randomized controlled trial was designed to quantify both benefits and harms by comparing only one initial colonoscopy and two low-cut-off FITs with usual care at the ‘diagnostic stage’, when screening procedures and downstream work-up are performed.
method
SCREESCO (Swedish Colon Screening; ClinicalTrials.gov NCT02078804) used Swedish population and medical registries to track outcomes for all randomized individuals, regardless of whether they actually participated in screening (intentional screening approach). The analysis focused on the diagnostic stage (2014-2020) and assessed:
- Incidence of CRC (overall and by stage). Includes cancers detected by screening and cancers diagnosed outside of the study through routine clinical care
- Adverse events – specifically gastrointestinal (GI) and cardiovascular events recorded in the medical register.
- All-cause mortality during follow-up as a widespread safety signal.
CRC staging was mainly divided into stages I-II and stages III-IV using data from national cancer registries and quality registries (with chart review of clinical trial-detected cases to confirm diagnosis/stage if necessary). Comparative effects were expressed as incidence rates per 100,000 person-years and incidence rate ratios (IRRs) with 95% confidence intervals (CIs).
research design
This was a large, pragmatic, population-based randomized trial covering 18 of 21 regions in Sweden (in a non-screened setting in the study area). In a randomized block design (unmasked due to the nature of the screening), 278,280 people aged 60 years were assigned to:
- Initial colonoscopy (one-time invitation only)
- FIT×2: We used an unusually low positive cutoff of 10 μg hemoglobin per gram of feces (positive if either sample reached the cutoff), performed 2 double stool FITs 2 years apart, and performed a colonoscopy after a positive FIT.
- Usual care controls (no invitation to screen, routine symptom-based assessments and existing surveillance pathways).
The final analysis population (after excluding individuals who died after randomization or were found to have prevalent colorectal cancer before assignment, and 2 unidentified controls) included 278,051 unique participants.
- 31,113 people in the colonoscopy department
- 60,267 for FIT×2 arms
- Of the 186,671 colonoscopy controls, 120,521 served as controls for the FIT×2 comparison (randomized to the same time period as FIT×2).
Participation reflected real-world uptake, with 35% having a colonoscopy in the colonoscopy group (median time to colonoscopy 349 days, IQR 253-446) and 55% in the FITx2 group returning at least one FIT (median time to first FIT 338 days, IQR 229-395). Baseline demographics and comorbidities were balanced between each intervention group and its control group. Of note, 92% had no previous history of gastrointestinal disease or cardiovascular events.
SCREESCO trial results
After a median follow-up of 4.8 years (up to 6.9 years), overall colorectal cancer incidence did not show a clear reduction compared with usual care during this early diagnosis period, but there were important changes in the timing and stage at which cancer was diagnosed.
Overall colorectal cancer incidence (per 100,000 person-years):
- Colonoscopy vs control: 107.9 vs 99.9; IRR 1.08 (95% CI 0.91 to 1.28).
- FIT×2 vs control: 96.0 vs 103.9; IRR 0.92 (95% CI 0.81-1.05).
The cumulative incidence at the end of follow-up was as follows:
- Colonoscopy: 0.69% (95% CI 0.66-0.71) vs control 0.72% (0.71-0.73).
- FIT×2: 0.61% (0.60 to 0.63) vs. control 0.73% (0.72 to 0.75).
Stage I-II colorectal cancer (early stage disease):
- Colonoscopy: 58.7 vs. 42.5 per 100,000 person-years. IRR 1.38 (95% CI 1.09 to 1.74).
- FIT×2: 52.7 vs 44.4; IRR 1.19 (95% CI 0.99–1.43).
This pattern indicates a shift toward early detection, particularly in invitations for colonoscopies. Importantly, the difference in incidence was most pronounced around the first year after randomization, coinciding with the timing of most screening procedures.
Stage III-IV CRC (late stage disease):
- Colonoscopy: IRR 0.86 (95% CI 0.67–1.11) versus control (less directional).
- FIT×2: IRR 0.71 (95% CI 0.58 to 0.86) versus control (significantly lower).
The cumulative curve suggests that the frequency of late-stage cancers decreased after approximately 4 years in the intervention group, especially in the FIT×2 group. This is consistent with the potential for early detection and prevention beginning to emerge, even if the net incidence reduction is not yet visible for less than 5 years.
How many cancers were detected by screening?
Of the CRCs diagnosed in the intervention group, 32% (colonoscopy group) and 38% (FIT×2 group) were classified as screen-detected. Very few colorectal cancers were diagnosed outside the trial among subjects who completed the screening procedure: 9 (0.03%) after post-colonoscopy screening in the colonoscopy group and 8 (0.01%) in the FIT x 2 group.
Safety and adverse events
For both intervention strategies, GI and cardiovascular event rates were slightly higher during the first year and became more similar to controls thereafter. At the end of the follow-up:
- Cardiovascular events: essentially identical for colonoscopy and controls (both 1,475.8 per 100,000 person-years; IRR 1.00, 95% CI 0.96 to 1.05).
- Venous thromboembolism was higher in the FIT×2 group than in controls: 60.1 vs. 43.3. IRR 1.39 (95% CI 1.16 to 1.66).
- Gastrointestinal events remained slightly higher in the FIT×2 group, primarily bleeding outcomes: iatrogenic bleeding IRR 1.18 (95% CI 1.05 to 1.32), unspecified gastrointestinal bleeding IRR 1.14 (95% CI 1.04 to 1.26).
The key safety evidence previously reported by SCREESCO was that serious adverse events directly related to screening colonoscopies were 0.2%, including 2 bowel perforations and 15 major bleeding events.
All-cause mortality:
- Colonoscopy: 554.6 vs. 579.0 per 100,000 person-years. IRR 0.96 (95% CI 0.89 to 1.03).
- FIT×2: 577.1 vs 601.8; IRR 0.96 (95% CI 0.91–1.01).
Main findings
- Screening invitations increased early colorectal cancer diagnosis, especially at initial colonoscopy (stage I-II IRR 1.38), showing a clear stage change compared to usual care.
- Late-stage CRC became less common over time, with the strongest signal occurring in the FIT×2 arm (stage III to IRR 0.71).
- The harm was concentrated early. Gastrointestinal and cardiovascular events increased slightly in the first year but were more closely matched to controls thereafter.
- FIT×2 showed certain safety signals, including increased venous thromboembolism and bleeding-related GI events compared to controls.
No excess all-cause mortality was observed with either screening strategy during follow-up at this stage of diagnosis.
conclusion
In the diagnostic phase of the Swedish SCREESCO randomized trial, invitation to an initial colonoscopy or two rounds of low cut-off FIT increased detection of early colorectal cancer compared with usual care, with slightly higher adverse event rates in the first year, which then converged to control rates over time.
In particular, the new reduction in stage III-IV CRC with FIT×2 suggests a possible long-term benefit that may become more apparent with extended follow-up. The trial’s final endpoint, colorectal cancer mortality, will be reported in a planned final analysis with follow-up through December 31, 2030, which will ultimately determine the net life-saving benefit of these screening strategies.