Divergent Detection Rates of FIT and QRA for Colorectal Adenomas

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Divergent Detection Rates of Fecal Immunochemical Test and Questionnaire-Based Risk Assessment for Detecting Proximal and Distal Advanced Colorectal Adenomas

Colorectal cancer (CRC) screening programs globally rely on tools such as fecal immunochemical tests (FITs) and questionnaire-based risk assessments (QRAs) to identify individuals at elevated risk of advanced adenomas and cancer. This study evaluated the divergent detection rates of proximal and distal advanced colorectal adenomas using these two screening modalities within the context of the TARGET-C trial, a population-based CRC screening initiative in China. The findings highlight significant variations in site-specific detection performance, particularly for FIT-based screening, which demonstrated a pronounced disparity in identifying distal versus proximal advanced adenomas.

Background and Rationale

FITs detect human hemoglobin in stool as a marker of colonic bleeding, a sign often associated with neoplasia. Previous studies have established that FIT sensitivity varies by anatomic location, with higher detection rates for distal colorectal lesions compared to proximal ones. This gradient may arise from differences in colonic transit time (affecting hemoglobin degradation) and adenoma morphology (e.g., pedunculated distal adenomas vs. flat or sessile proximal lesions). Conversely, QRAs stratify risk using demographic and lifestyle factors, such as age, sex, smoking, BMI, and family history of CRC. However, evidence suggests that certain risk factors may differentially influence proximal and distal CRC development, raising questions about QRA’s site-specific detection capabilities.

The TARGET-C trial, which enrolled 19,546 participants, provided a platform to compare the effectiveness of colonoscopy, FIT, and risk-adapted screening. This analysis focused on 3,825 participants who underwent colonoscopy during the baseline screening phase (2018–2019), stratified into three groups:

  1. Screening colonoscopy group (n = 1,665): Asymptomatic individuals undergoing routine screening.
  2. FIT-positive diagnostic colonoscopy group (n = 1,436): Participants with positive FIT results (≥100 ng Hb/mL).
  3. QRA-positive diagnostic colonoscopy group (n = 724): High-risk individuals identified via a modified Asia-Pacific Colorectal Screening (APCS) risk score.

Methodology

Risk Assessment Tools

  • FIT Protocol: A qualitative FIT (Pupu Tube, New Horizon Health Technology) with a positivity threshold of 100 ng Hb/mL (4 mg Hb/g feces) was used. Visual interpretation determined test results.
  • QRA Protocol: The modified APCS score incorporated five risk factors:
    • Age: 0 points (50–54 years), 1 point (55–65 years), 2 points (65–74 years).
    • Sex: 0 points (female), 1 point (male).
    • Family history of CRC: 0 points (absent), 1 point (present).
    • Smoking status: 0 points (non-smoker), 1 point (current/past smoker).
    • BMI: 0 points (<23 kg/m²), 1 point (≥23 kg/m²).
      Participants with cumulative scores ≥4 were classified as high-risk and referred for colonoscopy.

Outcomes and Definitions

  • Advanced adenoma: Lesions ≥1 cm, with high-grade dysplasia, or villous/tubulovillous histology.
  • Proximal colon: Segments proximal to the splenic flexure (cecum, ascending colon, transverse colon).
  • Distal colon/rectum: Segments distal to the splenic flexure (descending colon, sigmoid colon, rectum).
  • Detection rate: Number of cases divided by total participants in each group.

Key Findings

Advanced Adenoma Detection

  • Screening Colonoscopy Group:

    • Distal detection rate: 3.12% (95% CI: 2.39–4.07%).
    • Proximal detection rate: 2.52% (95% CI: 1.87–3.39%).
    • No significant difference in detection rates between sites (rate ratio [RR] = 1.24; 95% CI: 0.83–1.85).

  • FIT-Positive Group:

    • Distal detection rate: 8.64% (95% CI: 7.29–10.20%).
    • Proximal detection rate: 3.90% (95% CI: 3.01–5.03%).
    • Significant disparity favoring distal lesions (RR = 2.21; 95% CI: 1.63–3.00; P = 0.025 vs. screening colonoscopy).
    • Rate difference: 4.74% (95% CI: 2.97–6.50%).

  • QRA-Positive Group:

    • Distal detection rate: 6.91% (95% CI: 5.28–8.99%).
    • Proximal detection rate: 4.70% (95% CI: 3.38–6.49%).
    • Non-significant disparity (RR = 1.47; 95% CI: 0.96–2.24; P = 0.567 vs. screening colonoscopy).
    • Rate difference: 2.21% (95% CI: −0.20–4.62%).

Non-Advanced and Any Adenoma Detection

  • Non-Advanced Adenomas:

    • Screening colonoscopy group showed higher distal detection (12.43% vs. 9.19% proximal; RR = 1.35).
    • FIT-positive group mirrored this trend (15.88% vs. 11.56%; RR = 1.37).
    • QRA-positive group had non-significant differences (14.50% vs. 12.02%; RR = 1.21).

  • Any Adenoma:

    • FIT-positive group had the highest overall detection rates (24.51% distal vs. 15.46% proximal; RR = 1.59).
    • QRA-positive group showed moderate disparity (21.41% vs. 16.71%; RR = 1.28).

Mechanistic Insights and Implications

  1. FIT Performance Disparity:

    • The twofold higher detection of distal advanced adenomas by FIT aligns with prior observations. Distal lesions, often pedunculated, may bleed more readily than flat proximal adenomas. Hemoglobin degradation during colonic transit further reduces FIT sensitivity for proximal lesions.
    • Lowering FIT positivity thresholds (e.g., from 4 mg Hb/g feces) has been proposed to improve proximal detection, but this study found no evidence supporting such adjustments.

  2. QRA’s Site-Specific Limitations:

    • The modest, non-significant disparity in QRA detection rates may reflect variable risk factor associations with proximal versus distal CRC. For example, smoking and BMI show stronger links to proximal CRC, whereas distal lesions correlate more with familial factors.
    • Integrating genetic or molecular markers into QRAs could enhance site-specific risk prediction.

  3. Clinical and Policy Considerations:

    • FIT’s lower proximal detection rate underscores the need for complementary strategies (e.g., colonoscopy or CT colonography) in high-risk populations.
    • QRAs, while less site-specific, offer a cost-effective method for initial risk stratification but require refinement to address anatomic variations.

Limitations and Future Directions

  • Single-Round Screening: Longitudinal data are needed to assess cumulative detection rates over multiple screening rounds.
  • Sample Size Constraints: Limited advanced adenoma cases resulted in wide confidence intervals, particularly for QRA analyses.
  • Geographic Specificity: Findings from the Chinese population may not generalize to other ethnic or regional groups.

Conclusion

This study provides empirical evidence of divergent detection rates for proximal and distal advanced colorectal adenomas across screening modalities. FIT demonstrated a pronounced proximal-to-distal detection gradient, whereas QRA showed non-significant variations. These findings advocate for tailored screening strategies that address anatomic disparities, particularly in settings reliant on FIT-based programs. Future research should explore multimodal approaches, combining FIT, QRA, and emerging biomarkers, to optimize CRC screening efficacy across all colonic subsites.

doi.org/10.1097/CM9.0000000000001346

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