The long-term survival characteristics of a cohort of colorectal cancer patients and baseline variables associated with survival outcomes with or without time-varying effects

Abstract

Background: Colorectal cancer is the third most common cancer in the world. In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years.

Methods: The patient cohort included 738 incident cases diagnosed between 1999 and 2003. Cox models were used to analyze the association between the variables and a set of survival outcome measures (overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), metastasis-free survival (MFS), recurrence/metastasis-free survival (RMFS), and event-free survival (EFS)). Cox proportional hazard (PH) assumption was tested for all variables, and Cox models with time-varying effects were used if any departure from the PH assumption was detected.

Results: During the follow-up, ~ 61% patients died from any cause, ~ 26% died from colorectal cancer, and ~ 10% and ~ 20% experienced recurrences and distant metastases, respectively. Stage IV disease and post-diagnostic recurrence or metastasis were strongly linked to risk of death from colorectal cancer. If a patient had survived the first 6 years without any disease-related event (i.e., recurrence, metastasis, or death from colorectal cancer), their risks became very minimal after this time period. Distinct sets of markers were associated with different outcome measures. In some cases, the effects by variables were constant throughout the follow-up. For example, MSI-high tumor phenotype and older age at diagnosis predicted longer MFS times consistently over the follow-up. However, in some other cases, the effects of the variables varied with time. For example, adjuvant radiotherapy treatment was associated with increased risk of metastasis in patients who received this treatment after 5.5 years post-diagnosis, but not before that.

Conclusions: This study describes the long-term survival characteristics of a prospective cohort of colorectal cancer patients, relationships between baseline variables and a detailed set of patient outcomes over a long time, and time-varying effects of a group of variables. The results presented advance our understanding of the long-term prognostic characteristics in colorectal cancer and are expected to inspire future studies and clinical care strategies.

Keywords: BRAF Val600Glu mutation; Colorectal cancer; Cox model with time-varying effects; Early outcome markers; Late outcome markers; Long-term follow-up; MSI; Prognostic markers; Time-varying effects.

Fig. 1

a-f Kaplan-Meier curves of the survival outcomes. DSS, disease-specific survival; EFS, event-free survival; MFS, metastasis-free survival; OS, overall survival; RFS, recurrence-free survival; RMFS, recurrence/metastasis-free survival

Fig. 2

Associations between clinico-demographic/molecular markers and the survival outcomes. C, change of effect size; DSS, disease-specific survival; E, early-effect; EFS, event-free survival; L, late-effect; MFS, metastasis-free survival; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; OS, overall survival; RFS, recurrence-free survival; RMFS, recurrence/metastasis-free survival. X, variables that violated the PH assumption in the univariate Cox analyses or violated the PH assumption and found to have time-varying effects in the multivariate Cox analyses