Risks of Subsequent Primary Extracolonic Cancers for Colorectal Cancer Survivors: A Study Protocol for the Development and Validation of a Risk Prediction Model

BackgroundThe risk of developing a second cancer following colorectal cancer poses a significant challenge for colorectal cancer survivors, as 10-20% of survivors experience a subsequent primary cancer. These additional diagnoses are significantly associated with lower survival rates and increased morbidity compared with those who do not develop a subsequent primary cancer. Identifying survivors at the highest risk for subsequent primary cancers is imperative for preventive strategies and surveillance. This study protocol outlines the development and internal and external validation of risk prediction models, estimating individual risks of subsequent extracolonic cancer (cancers outside the colon and rectum) over 3-, 5-, 10-, and 15-year periods. MethodsThis study will include adult patients aged 18 years or older with a history of invasive colon, rectal, or colorectal cancer diagnosed within one year prior to recruitment; at least one year of follow-up post-recruitment; no prior nonskin cancers; and no genetic predispositions, such as Lynch syndrome. Data will be sourced from the Colon Cancer Family Registry Cohort, which recruits participants from population-based cancer registries. The primary outcome is the first diagnosis of a subsequent primary extracolonic cancer, excluding metastases or recurrence of any primary cancer. Candidate predictors will include sociodemographic factors, comorbidities, lifestyle factors, clinicopathological factors, and hormonal factors such as menopausal status and hormone use (in women). Initial predictor selection will be performed using five methods: backward stepwise elimination via flexible parametric regression, Cox regression, Fine and Gray subdistribution hazard regression, Lasso Cox regression, and elastic net regression. Predictive performance will be assessed through accuracy measures, discrimination (C and D statistics), R2 statistics, and calibration plots to select the best-performing final model. Internal validation will involve bootstrapping 500 samples to estimate optimism-corrected C statistics. We will calculate individualized risks for subsequent extracolonic cancer at 3-, 5-, 10-, and 15-year intervals using shrinkage-adjusted beta coefficients of the selected predictors in the final model, along with baseline hazards derived from two approaches--one that accounts for death as a competing risk, and one that does not. External validation will be performed by testing the final model on an independent cohort from the Melbourne Collaborative Cohort Study. DiscussionThis model may help clinicians identify colorectal cancer survivors at increased risk of subsequent extracolonic cancers, enabling early detection, lifestyle modifications, and personalized screening strategies. Early intervention could subsequently reduce morbidity and improve long-term outcomes for these colorectal cancer survivors.