External Validation of the Colon Life Nomogram for Predicting 12-Week Mortality in Dutch Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil in Daily Practice

Simple Summary Predicting prognosis in cancer patients is needed to guide decision making. In order to predict survival, nomograms can be used to estimate chances of survival based on clinical characteristics. In order to identify metastatic colorectal cancer (mCRC) patients with a very short life expectancy (less than 12 weeks) after receiving multiple standard treatments, the Colon Life nomogram was previously developed. Before a nomogram can be used in daily practice, it is essential to show that it accurately predicts survival in different real-life populations and can be used to guide clinical decision making. This is called external validation. We externally validated the Colon Life nomogram in a cohort of patients with refractory mCRC who were treated with a last treatment option, trifluridine/tipiracil, in daily practice. We demonstrated that the nomogram severely overestimated 12-week mortality and therefore should not be used in clinical practice in its present form. We also showed that quality of life reported by patients themselves can improve the prediction of survival, stressing the importance of patient-reported outcomes. We recommend conducting a study with a sufficiently large sample size to update the Colon Life nomogram or to develop a new model and include quality of life. Background: Predicting prognosis in refractory metastatic colorectal cancer (mCRC) patients is needed to guide decision making. The Colon Life nomogram was developed to predict 12-week mortality in refractory mCRC patients. The aim of this study is to validate the Colon Life nomogram in last line/refractory patients receiving trifluridine/tipiracil (FTD/TPI) in daily practice. Methods: The validation cohort consists of 150 QUALITAS study patients, an observational substudy of the Prospective Dutch CRC cohort, who were treated with FTD/TPI between 2016 and 2019. Model performance was assessed on discrimination, calibration, and clinical usefulness. The additional prognostic value of baseline quality of life (QoL) and thymidine kinase (TK1) expression in tissue was explored. Results: Of the 150 patients, 25 (16.7%) died within 12 weeks of starting FTD/TPI treatment. The C-statistic was 0.63 (95% C.I. 0.56-0.70). The observed/expected ratio was 0.52 (0.37-0.73). The calibration intercept and slope were -1.06 (-1.53 to -0.58) and 0.41 (0.01-0.81), respectively, which indicated overestimation of 12-week mortality by the nomogram. Decision curve analysis showed the nomogram did not yield a positive net benefit at clinically meaningful thresholds for predicted 12-week mortality. Addition of QoL to the nomogram improved the C-statistic to 0.85 (0.81-0.89). TK1 expression was associated with progression-free survival but not with overall survival. Conclusion: We demonstrated evident miscalibration of the Colon Life nomogram upon external validation, which hampers its use in clinical practice. We recommend conducting a study with a sufficiently large sample size to update the Colon Life nomogram or to develop a new model including QoL.