Esther Toes-Zoutendijk

Objective: Faecal haemoglobin (f-Hb) concentrations from two screening rounds improve colorectal cancer (CRC) risk prediction, but the value of longer longitudinal data remains uncertain. This study aimed to assess whether incorporating f-Hb data from three prior screening rounds improves risk stratification for CRC and advanced neoplasia (AN). Methods: Using data from four rounds of the Dutch national CRC screening programme (1 January 2014 and 31 December 2022), prognostic models combining age, sex, and f-Hb concentrations were developed to predict CRC and AN. Multiple representations of longitudinal f-Hb were evaluated. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration, and information criteria. Risk reclassification was quantified using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The policy impact of risk-based referral, expressed as additional colonoscopies, was examined. External validation used data from a Dutch faecal immunochemical test pilot study. Results: Among 1 171 070 participants included, 2357 (0.2%) had CRC and 14 543 (1.2%) had AN. Models incorporating categorised f-Hb values from three prior rounds, age, and sex achieved the highest discrimination (AUC: AN 0.76 (0.75–0.77); CRC 0.73 (0.72–0.74)) and significantly improved reclassification (NRI and IDI, p<0.001). Participants in the highest 15% predicted risk had a 6.8-fold (95% CI 6.4 to 6.9) increased risk of AN and a 5.9-fold (95% CI 5.4 to 6.6) increased risk of CRC. Risk-based referral enabled earlier detection with minimal additional colonoscopy for both CRC and AN. Conclusion: Including f-Hb data from three prior screening rounds improves CRC and AN risk prediction. Targeted referral of the highest risk individuals enables earlier detection with limited impact on colonoscopy capacity, supporting personalised CRC screening strategies.

The 5th edition of the European Code Against Cancer (ECAC5) recommends sustainable, organised screening programmes for: (a) colorectal cancer using biennial quantitative faecal immunochemical test (FIT) for individuals aged 50–74 years. As an alternative strategy, once‐only endoscopy may be considered within the same age range; (b) breast cancer using biennial digital mammography for women aged 50–69 years. Implementing this strategy for women aged 45–49 years and 70–74 years can be considered. Other screening strategies or additional examinations could be considered for women with high mammographic density; (c) cervical cancer using human papillomavirus (HPV) screening at intervals no shorter than 5 years for women aged 30–65 years. It is recommended to adapt policies according to vaccination status and screening history; and (d) lung cancer using annual low‐dose computed tomography (LDCT) for individuals considered to be at increased risk of lung cancer based on age, history of smoking or validated risk models, with biennial screening as an alternative. Screening should incorporate smoking cessation interventions.

Several medical therapies modify the risk of developing certain cancers in an individual. The aim of this paper was to provide the scientific justification for the 5th edition of the European Code Against Cancer (ECAC5) recommendation on the use of hormone replacement therapy (HRT) and other drugs used at population scale, such as hormonal contraceptives and aspirin. HRT modifies the risk of developing certain cancers in an individual. Except for vaginal oestrogens, all forms of HRT are associated with an increased breast cancer risk; the risk of serous ovarian cancer and endometrial cancer may also be increased. Despite such an increase in cancer risk, HRT often remains the only option for the management of certain menopausal symptoms for the restoration of quality of life and mental health. Therefore, the ECAC5 recommends using HRT for bothersome menopausal symptoms only after a thorough discussion with a healthcare professional and limiting its use for as short a duration as possible. On review of up‐to‐date evidence for hormonal contraceptives and aspirin, the ECAC5 Working Group elected not to make a recommendation for the average‐risk general population regarding the use of these therapies.

The most used primary colorectal cancer (CRC) screening tests are the fecal immunochemical test (FIT) and colonoscopy. However, colonoscopy is an invasive procedure with possible (fatal) complications and FIT has shortcomings in test sensitivity. Colon capsule endoscopy (CCE) could be an alternative, but long-term effects are unknown. We assessed the cost-effectiveness of CCE in CRC screening.We simulated a Dutch cohort born between 1938 and 1957 for eight strategies: biennial FIT screening with cutoffs of 15 (FIT15) and 47 (FIT47) micrograms of hemoglobin per gram feces (µg Hb/g); biennial and triennial CCE screening; CCE after a FIT-negative result of 15–47 µg Hb/g (CCE triage); CCE after positive FIT using 15 and 47 µg Hb/g cutoffs; and 10-yearly colonoscopy screening. Three adherence scenarios were considered. We estimated lifetime CRC incidence, mortality, life years gained, and number of tests required. A cost-effectiveness analysis was performed to determine cost-effectiveness of each strategy.Triennial CCE and CCE triage screening had similar long-term outcomes to biennial FIT47. At 100% adherence, biennial CCE screening reduced CRC incidence from 79 to 49 cases (38.0% reduction) and mortality from 36 to 17 deaths (52.8% reduction) per 1000 individuals versus no screening. Life years gained increased to 155 per 1000 individuals versus 115 with biennial FIT47 (34.8% increase). However, these increases came at high financial cost, and CCE cost-effectiveness was dominated by biennial FIT and 10-yearly colonoscopy.CCE was not cost effective for CRC screening compared with biennial FIT and 10-yearly colonoscopy.

This study investigates the impact of extended invitation intervals on the stage distribution of screen‐detected and interval colorectal cancers (CRCs) in the Netherlands' fecal immunochemical test (FIT)‐based screening program during the COVID‐19 pandemic. Using data from individuals with negative FIT results in 2017–2019 and subsequent screening round in 2019–2021, we examined whether delays of up to 6 months affected CRC stage at diagnosis. We performed multivariate logistic regression to assess the association between invitation intervals and cancer stage. Our analysis found no significant difference in stage distribution for both screen‐detected and interval CRCs despite the delays. Specifically, odds ratios for late‐stage cancer remained close to 1 across various intervals, indicating minimal impact of extended invitation times. These results suggest that the short‐term delays caused by the pandemic did not significantly affect the performance of the CRC screening program. This highlights the program's ability to adapt to temporary disruptions while maintaining effective early cancer detection. Our findings support the notion that such disruptions, when managed appropriately, do not substantially compromise the quality of screening outcomes, reinforcing the resilience and flexibility of CRC screening programs in the face of health crises.

Upper age limits are currently fixed for all fecal immunochemical test (FIT)‐based colorectal cancer (CRC) screening programs. A risk‐stratified upper age limit may be beneficial. Therefore, we assessed differences in interval CRC risk among individuals who had reached the upper age limit of screening (75 years). Individuals with a negative FIT (0 μg Hb/g feces. Among 305,761 individuals with a complete follow‐up (24 months), 661 were diagnosed with interval CRC (21.6 per 10,000 negative FITs). Individuals with detectable f‐Hb (15%) were 5 times more likely to be diagnosed with interval CRC than those without (HR 4.87, 95%CI: 4.19–5.65). Moreover, their cancers were more often detected at a late stage compared to individuals without detectable f‐Hb (OR 1.45, 95%CI: 1.06–2.01). Our results show that interval CRC risk among individuals aged ≥75 differs substantially by last f‐Hb concentration, indicating a uniform age to stop screening is suboptimal. Future research, taking into account multiple screening rounds and FIT results, should determine the optimal risk‐stratified screening strategy.

We are grateful for the detailed response from Larsen et al., which provides us with insights to further clarify the methodology that was chosen for our study on interval post-colonoscopy colorectal cancer (iPCCRC) in a fecal immunochemical test (FIT)-based screening program [11]. First, we acknowledge that the age distribution in our sample was skewed toward the older age groups, which will have affected our results; CRC incidence is higher in older age groups and therefore iPCCRC risk is expected to be higher. Nonetheless, the cancers detected in the older age groups should still be classified as post-colonoscopy CRCs according to the World Endoscopy Organization consensus statement [22]. In addition, a negative colonoscopy should provide justified reassurance to individuals, irrespective of age. Second, as colonoscopy registration is fallible, all negative colonoscopies with discrepant follow-up followed by an iPCCRC diagnosis and a random sample of 250 colonoscopies with discrepant follow-up without iPCCRC were extensively verified using pathology reports and excluded when the definition of a negative colonoscopy was not met. As described in the methods, we estimated the total number of negative colonoscopies based on the rate of negative colonoscopies in the random sample. The inquiry for an explanation of why iPCCRCs were relatively more common in the group with discrepant follow-up recommendation is valid, yet in our opinion does not undermine the conclusion of our study. Finally, there is indeed an immortal time period after a positive FIT result. However, this period of 6 months is recommended in the aforementioned consensus statement, and our analyses and results are reported in line with this statement [22]. The 6-month period allows for delays in the diagnosis of screen-detected cancers, for example due to repeat procedures following an inadequate colonoscopy. In that respect, our estimation of the risk of iPCCRC is conservative, but consistent with the guidelines. Article published online: 30 July 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany