Interval colorectal cancer risk by haemoglobin concentration in Australia’s National Bowel Cancer Screening Program
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Background
Interval colorectal cancers (CRCs) are an important measure of screening performance. We assessed interval CRC risk after negative faecal immunochemical testing (FIT), its association with faecal haemoglobin (f-Hb) concentration, and differences by age and sex in Australia s National Bowel Cancer Screening Program (NBCSP).
Methods
We conducted a population-based retrospective cohort study linking Queensland screening and cancer registry records for NBCSP participants aged 50-74 years screened in 2018-2022. Eligible episodes had f-Hb below 20 ug/g in both samples. We excluded episodes with CRC diagnosed on or before follow-up start. Follow-up ended at CRC, the next screening episode, death, 24 months, or December 31, 2023. We estimated adjusted cause-specific hazard ratios (HRs), accounting for repeated episodes within participants, and cumulative incidence with death and subsequent screening as competing events.
Findings
Among 1,083,149 negative screening episodes from 700,734 participants, 586 interval CRCs occurred over 2,056,405 person-years. The incidence rate was 28.5 per 100,000 person-years, and 24-month cumulative incidence was 57.6 per 100,000 episodes (95% CI 53.1-62.5). Risk increased with age and was higher in males (adjusted HR 1.28, 95% CI 1.08-1.50). The complete-case quantitative cohort included 326,931 episodes and 138 cancers. Compared with maximum f-Hb of 0-5 ug/g, concentrations >15-<20 ug/g were associated with an adjusted HR of 14.93 (9.02-24.70). Corresponding 24-month risks were 35.7 (28.5-44.7) and 504.5 (323.4-787.0) per 100,000 episodes. Higher negative-range f-Hb concentrations were more common in older participants and males. The quantitative cohort showed no clear sex difference after adjustment for f-Hb.
Interpretation
CRC risk varies substantially among people with a negative screening result. Quantitative F-Hb levels may help identify who is at higher risk of interval CRC. Further research is needed to confirm these findings and assess the benefits, harms and costs of changing screening intervals.
Research in context
Research in context
Evidence before this study
We searched PubMed October 2026, for Australian studies and international systematic reviews and meta-analyses, using combinations of “colorectal”, “bowel”, “interval cancer”, “interval cancers”, “interval colorectal”, “negative FIT”, “faecal haemoglobin”, “fecal hemoglobin”, “faecal immunochemical”, and “fecal immunochemical”, combined with “Australia”, “Australian”, “systematic review”, or “meta-analysis”. Additional searches examined international cohort studies published from January 1, 2020, to October 25, 2026. Australian national monitoring and a study in Western Australia showed that interval CRC was uncommon but more frequent among males and older participants. Both analyses were based on the 2018 screening cohort, before biennial screening had been fully implemented for all eligible people aged 50-74 years. Neither examined interval CRC risk across the negative f-Hb range. International reviews documented substantial variation in interval CRC incidence between screening programmes. More recent Danish and Dutch cohort studies showed that higher f-Hb concentrations below the positivity threshold were associated with greater interval CRC risk, including after successive negative screening rounds. A dose-response meta-analysis of 13 studies supported the prognostic value of negative-range f-Hb, but combined evidence on interval cancers, cancers detected at subsequent screening, and adenomas. These outcomes do not provide interchangeable estimates of risk before the next screen. The evidence therefore supported further investigation of quantitative f-Hb, but did not establish concentration-specific interval CRC risks for the NBCSP’s two-sample protocol and 20 µg/g positivity threshold.
Added value of this study
This study extends Australian evidence through longitudinal linkage of Queensland screening and cancer registry records from 2018-2022, including repeated screening episodes from more than 700,000 participants. It estimates interval CRC risk overall and by age and sex, and examines how that risk varies within the negative f-Hb range. Follow-up ended at the next screening episode, allowing interval cancers to be distinguished from cancers detected at later screening. The quantitative analysis showed a substantial concentration gradient in both relative and absolute risk, despite all included results being classified as negative. By providing absolute risks within the Australian screening setting, the study offers evidence directly relevant to evaluating whether participants with different negative f-Hb concentrations could benefit from different screening intervals.
Implications of all the available evidence
A negative FIT result provides reassurance, but does not indicate the same level of interval CRC risk for every participant. Together, the international evidence and our findings support evaluating screening strategies that use quantitative f-Hb rather than relying solely on a positive or negative result in the Australian program. They do not establish which screening intervals or thresholds should be adopted. Further evaluation should determine whether tailoring screening reduces interval cancers and advanced disease without disproportionate increases in colonoscopy use, harms, or inequalities in access and outcomes.
