Venous Thromboembolism Incidence and Impact on Survival in Patients with Brain Metastases

Background: Patients with brain metastases are considered especially high risk for venous thromboembolism (VTE). The incidence of VTE following a diagnosis of brain metastases and the impact of VTE on overall survival among patients with brain metastases have not been well characterized.

Methods: Using the linked Surveillance, Epidemiology and End Results (SEER) and Medicare databases between 2008-2015, we identified all patients ≥66 years with a primary diagnosis of lung, renal cell, breast cancer or melanoma and brain metastases (ICD-9-CM 198.3 present anytime in Medicare claims). Patients were required to have continuous Medicare part A and B enrollment from 12 months before and 12 months after diagnosis or until death. The primary outcome was incidence of VTE (deep vein thrombosis or pulmonary embolism or both) in the 12- months following a diagnosis of brain metastases. Patients with a VTE diagnosis prior to brain metastases were excluded. Incidence rates were calculated as VTE events per 100 patient years. Tumor specific multivariable Cox proportional hazards model adjusting for age, sex, race, time from primary cancer diagnosis to brain metastasis, comorbidities and VTE as a time varying covariate was used to assess the association of VTE and 12-month overall survival following a diagnosis of brain metastasis.

Results: Among 154,918 individuals with a primary cancer diagnosis of interest, 21,623 (14.0%) had a brain metastasis diagnosis. Majority of patients with brain metastases had a primary diagnosis of lung cancer (N=19,141 (88.5%)), followed by melanoma (N=1,607 (7.4%)), renal cell cancer (N=576 (2.7%)) and breast cancer (299 (1.4%)). The baseline characteristics are highlighted in Table 1. Among these patients, VTE was diagnosed in 3,432 (15.9%). In the year following a diagnosis of brain metastasis, the incidence of VTE per 100 patient-years was highest among those with a diagnosis of renal cell cancer (19.4), followed by breast (16.3), lung (16.0) and melanoma (12.5). The median time to VTE from a diagnosis of brain metastasis is 1 month (IQR 0-3 months) and the cumulative incidence of VTE stratified by tumor type and accounting for the competing risk of death over 12 months is illustrated in Figure 1.The median overall survival following a diagnosis of brain metastasis was 2.7 months (95% CI 2.1-3.1 months). In a multivariable Cox proportional hazards model, a diagnosis of VTE following brain metastasis was associated with increased risk of death in patients with lung cancer (HR 1.23 (95% CI 1.18-1.28)), renal cell cancer (HR 1.36 (95% CI 1.06-1.75)) and melanoma (HR 1.32 (95% CI 1.12-1.55)), but not breast cancer (HR 1.16 (95% CI 0.80-1.69)).

Conclusions: This large real-world retrospective cohort analysis demonstrates and quantifies the high tumor specific incidences of VTE among individuals with brain metastases. The VTE incidence rates observed are comparable to metastatic pancreatic cancer and highest in the initial 3 months following a diagnosis of brain metastasis. Furthermore, a diagnosis of VTE is associated with a reduced 12-month overall survival in this patient population. We are mindful to highlight the inherent limitations of claims data in identifying clinical events such as brain metastases and VTE, thus possible misclassification and selection biases should be considered when interpreting these findings. However, considering the complexity of managing VTE in this high-risk patient population and the high thrombotic burden demonstrated, these findings warrant further prospective validation.