Long-Term Risk Factors for Occult Cancer Detection in Patients with Unprovoked Venous Thromboembolism: A Post-Hoc Analysis of the Reverse Study

Background: The diagnosis of an unprovoked (i.e., in the absence of any risk factors) venous thromboembolism (VTE) may be a sign of an underlying cancer. Previous estimates of the incidence rate of occult cancer in patients with unprovoked VTE are as high as 5-10%. However, screening methods to detect cancer early in these patients are of limited clinical value and previous identification of risk factors focused on short-term cancer diagnosis. Therefore, this study will assess the long-term incidence and risk factors of cancer in unprovoked VTE patients.

Methods: This retrospective study is a post-hoc analysis of the REVERSE (Recurrent Venous Thromboembolism Risk Stratification Evaluation) study. Patient data was collected following an initial six-month course of anticoagulation therapy and were followed for a mean time period of 5.0 years (range 1 month-8 years). We performed univariable analysis to test the strength of association between each potential predictor variable and occult cancer diagnosis. Furthermore, using forward model selection we created a multivariable model with optimal predictive value for cancer diagnosis.

Results: Among 663 patients presenting with unprovoked VTE, 38 (5.7%) subsequently developed a new cancer diagnosis during the follow-up period. The most common types of cancers diagnosed were prostate (21%) and colorectal cancer (16%). Univariate analysis revealed age > 65 (OR 2.59; 95% CI 1.31-4.49, P= 0.0036), elevated D-Dimer (OR 2.71; 95% CI 1.38-5.31, P=0.026) and pulmonary vein obstruction (PVO) score (OR 4.34 95% CI 1.26-14.92, P=0.023) as the strongest predictors of occult cancer. Only D-Dimer (Adj.-OR 2.72 95% CI 1.39-5.32) remained in the multivariate model and no other factor significantly improved the model's fit.

Conclusion: Patients with an unprovoked VTE remain at an elevated risk of developing cancer following anticoagulation therapy. Age > 65 years old, elevated D-Dimer, and PVO in pulmonary embolism patients are among potential risk factors for developing occult cancer. More studies are needed to validate these potentially important risk factors.