Characteristics and Impacts of Venous Thromboembolism in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in cancer patients, and is associated with worse prognosis in such population. Hepatocellular carcinoma (HCC) poses high risk for VTE; however, data is scarce regarding the characteristics and consequences of VTE in HCC patients. METHOD: We retrospectively reviewed the electronic medical records (EMR) of 270 patients diagnosed with HCC from 2000 to 2015 in Cook County Health and Hospitals System. We report the cumulative incidence of VTE in the present cohort, and identified through multivariate logistic regression the independent risk factors of the development of VTE. Overall prognosis of patients with and without VTE were presented and compared. RESULTS: Sixteen cases (5.93%) of VTE were documented in the present study. In multivariate analysis, obesity, Child B cirrhosis, intra-hepatic lesions more than 3, and multi-organ extrahepatic metastasis were significantly associated with VTE development (p < 0.05). The presence of VTE was an independent risk factor for mortality in multivariate analysis (HR = 3.62, p = 0.021), together with male gender, Child C cirrhosis, and extrahepatic metastasis. CONCLUSIONS: Obesity, Child B cirrhosis, more intra-hepatic lesions, and multi-organ extrahepatic metastasis are associated with cancer-associated VTE. VTE will adversely affect the prognosis of patients with HCC; therefore, primary thromboprophylaxis may be warranted in such population.

Venous Thromboembolism Is an Independent Predictor of Mortality Among Patients with Gastric Cancer.

BACKGROUND: Venous thromboembolism (VTE) is an independent predictor of death among patients with cancer. Patients with gastric cancer (GC) are at higher risk for VTE when compared to other solid tumors, and if one considers its prevalence, GC may be responsible for one of the highest incidences of cancer-associated thrombosis. The impact of VTE on mortality is not well defined among patients with GC. AIM: The aim of this study is to measure the impact of VTE as independent predictor of GC mortality. METHODS: Chart review of patients with GC treated in the Department of Oncology at John Stroger Hospital between the years of 2010 and 2015. VTE events were objectively confirmed with imaging in all cases. Active GC was defined as biopsy-proven metastatic disease or on active chemotherapy. Along with cancer-specific data, we abstracted risk assessments tools, non-GC-specific, validated for VTE and mortality prediction cancer, including the Khorana score (KRS), platelet lymphocyte ratio (PLR), and neutrophil lymphocyte ratio (NLR). Continuous variables are expressed by the median as appropriate according to normality. Categorical variables are expressed as percentages. SPSS version 22 was used and chi-square, Mann-Whitney U, Kaplan-Meier curve, and Cox proportional hazard with forward modeling were applied. RESULTS: We included 112 patients in the analysis. The patients were predominantly men (66%), 58-year-old, with adenocarcinoma (84%) and advanced disease (59%). The median follow-up was 21.3 months (IQR 8.9-42.4). Cumulative incidence of VTE at 1 year was 9%. The median time from diagnosis to VTE occurrence was 59 days (IQR 36 to 258). Patients with VTE had worse OS when compared to the non-VTE group (medians 11.87 vs 29.97 months, p = 0.02). Patients stratified as high risk by the PLR had worse OS (medians 22.6 vs 42.77 months, p = 0.02). There was no statistical difference in OS among patients stratified as high risk by the KRS (medians 23.7 vs 42.5, p = 0.16) and NLR (medians 24.1 vs 42.7 months, p = 0.21). In multivariate analysis, the independent predictors of mortality were VTE (hazard ratio (HR), 2.9; 95% CI, 1.4 to 6.6; p < 0.01), adenocarcinoma (HR, 3.1; 95% CI, 1.1 to 9.0; p = 0.03), advanced disease (HR, 2.8; 95% CI, 1.4 to 5.8; p < 0.01), and PLR (HR, 2.2; 95% CI, 1.3 to 3.8; p < 0.01). CONCLUSION: VTE is associated with worse survival among patients with GC along with adenocarcinoma, advanced disease, and PLR. Moreover, these findings were independent of other cancer- and treatment-specific variables. Although potentially predictive in other cancer types, NLR and KRS were not associated with worse survival in this cohort.

Performance of Current Thromboembolism Risk Assessment Tools in Patients With Gastric Cancer and Validity After First Treatment.

Patients with gastric cancer (GC) are at higher risk of thromboembolism when compared to other solid tumors. We aim to determine the predictive performance of current venous thromboembolism (VTE) predictive tools and their variability and validity after first treatment. Single institution cohort of GC-treated patients (2010*15). We abstracted predictive tools, validated for VTE prediction in patient with cancer; including the Khorana Score (KRS), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ratio (NLR). The primary outcome was CAT prediction. We included 112 patients who were predominantly men (66%), 58 (51-64)-year-olds, with adenocarcinoma (84%) and advanced disease (59%). The median follow-up was 21.3 months (9.5-42.6). The VTE occurrence was 12%. The median time from diagnosis to VTE occurrence was 59 days (36-258). In our cohort, performance status (PS; hazard ratio [HR], 8.02; 95% confidence interval [CI], 2.37-27.14; P < .01) was an independent predictor of VTE whereas KRS (univariate HR, 2.3; 95% CI, 0.7-7.4; P = .17), PLR (univariate HR, 0.8; 95% CI, 0.2-3.1; P = .8), and NLR (univariate HR, 0.8; 95% CI, 0.3-2.5; P = .8) at baseline were not associated with VTE risk. The posttreatment KRS was an independent predictor of VTE (HR, 3.69; 95% CI, 1.17-11.65; P = .25) along with PS (HR, 7.58; 95% CI, 2.27-25.33; P = .01). Posttreatment KRS appears as a valid tool to identify patients with GC at high risk of VTE after first cancer treatment.

Performance of Khorana Risk Score for Prediction of Venous Thromboembolism in Patients With Hepatocellular Carcinoma.

Cancer-associated venous thromboembolism (VTE) is one of the leading causes of mortality and morbidity among patients with malignancy. The Khorana risk score (KRS) is currently the best validated risk assessment model to stratify risks of VTE development in ambulatory patients with cancer. In the current study, we assessed the performance of KRS in patients with hepatocellular carcinoma (HCC). We retrospectively analyzed patients with diagnosis of HCC (screened by International Classification of Diseases [ ICD-9] and ICD-10 code, confirmed with radiographic examination and/or histopathology) at a large public hospital over 15 years (January 2000 through July 2015). Cases with VTE were identified through radiographic examination and blindly adjudicated. Khorana risk score was calculated for each patient, and its association with VTE development and mortality was assessed. Among 270 patients with HCC, 16 (5.9%) cases of VTE were identified, including 7 (43.8%) pulmonary embolism, 4 (25%) peripheral deep vein thrombosis, and 6 (37.5%) intra-abdominal thrombosis. One hundred eighty-four (68.1%) patients had a KRS of 0 and 86 (31.9%) patients had a KRS >0. Most of the thrombotic (n = 9, 56%) events occurred in the low-risk group. In univariate analysis, only prechemotherapy leukocyte count equal to or greater than 11 000/µL was statistically significant in the prediction of VTE incidence. After adjusting for confounding factors in multivariate analysis, KRS >0 was not predictive of VTE (hazard ratio [HR] = 1.83, 95% confidence interval [CI] = 0.81-4.15, P = .15) or mortality (HR = 1.61, 95% CI = 0.92-2.81, P = .09). Khorana risk score did not predict VTE development or mortality in patients with HCC. Design of HCC-specific risk assessment model for VTE development is necessary.

Meta-analysis on anticoagulation and prevention of thrombosis and mortality among patients with lung cancer.

BACKGROUND: Venous thromboembolism (Wickham et al., 2012 [1]) is a leading cause of morbidity and mortality among patients with cancer; however, primary thromboprophylaxis is not routinely recommended. We performed a systematic review and meta-analysis of randomized control trials (RCTs) to measure the impact of primary VTE prevention and its effect on mortality among patients with lung cancer. METHODS: With assistance from a master librarian, we searched Ovid, Scopus, DARE, CINAHL, MEDLINE, EMBASE, EBM reviews-Cochrane database of systematic reviews, EBM reviews-ACP journal, and EBM Reviews-Databases for relevant studies following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included articles addressing the role of anticoagulation in patients with lung cancer for primary VTE prevention for outpatients. The clinical outcomes were VTE occurrence, all-cause mortality, major and clinically relevant non-major bleeding. The results are presented as odds ratio (OR) and data were analyzed using R and R META package (Version 0.8-2, Author: Guido Schwarzer). RESULTS: Eleven studies with 5107 patients were included for the final analysis. We found 50% lower VTE occurrence in the prophylaxis group with low molecular weight heparin (LMWH) (OR: 0.50; 95% Confidence Interval (CI): 0.38-0.66; I2: 0%) without an increased bleeding risk (OR: 2.03; 95% CI: 0.78-5.25; I2: 71.1%). We found a mortality benefit when we grouped all VTE prevention modalities [LMWH, Warfarin, unfractionated heparin (UFH)] (OR: 0.75; 95% CI: 0.58-0.96; I2: 18.4%), but no significant difference when LMWH (OR: 0.74; 95% CI: 0.49-1.11; I2: 56.9%) and warfarin were analyzed individually (OR: 0.75; 95% CI: 0.47-1.21; I2: 0%). We found higher odds of bleeding combining all treatment modalities (OR: 3.06; 95% CI: 1.64-5.72; I2: 64.4%) with the greatest occurrence in the warfarin group (OR: 5.42; 95% CI: 3.48-8.45; I2: 45.7%). CONCLUSION: Primary VTE prophylaxis with LMWH reduces the occurrence of VTE among ambulatory patients with lung cancer, without apparent increase in bleeding risk. There is a measurable mortality benefit of anticoagulation strategies that remains elusive when the analysis is restricted to a single agent.

Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer.

UNLABELLED: Essentials Venous thromboembolism (VTE) prevention strategies require effective risk assessment models. We sought to validate the Khorana Risk Score (KRS) in patients with lung cancer. A high KRS was not predictive of VTE but was independently associated with all-cause mortality. Our findings stress the need for a lung cancer-specific VTE risk assessment model. SUMMARY: Objectives Lung cancer is strongly associated with venous thromboembolism (VTE), but primary prevention against VTE is not a validated management strategy. Risk assessment models will be necessary for efficient implementation of preventative strategies. Materials and methods Utilizing a prospectively collected lung cancer database, we aimed to validate the Khorana Risk Score (KRS) in the prediction of VTE among patients with lung cancer. VTE events were retrospectively identified by reviewers unaware of the clinical prediction score calculation. The association between KRS and the risk of VTE was examined using cumulative incidence function with competing risk models. Mortality prediction was evaluated as a secondary outcome. Results We included 719 patients in our review. The patients were predominantly older men with non-small cell lung cancer and 40% had metastatic disease at inception. The median follow-up was 15.2 months. There were 83 VTEs (11.5%) and 568 (78.8%) patients died. A high KRS (cumulative incidence, 12.4%; 95% confidence interval [CI], 6.4-20.5%) was not associated with VTE compared with an intermediate score (cumulative incidence, 12.1%; 95% confidence interval, 9.5-15.0%) in both univariate and multivariable analyses. However, a high KRS was a predictor of mortality (hazard ratio, 1.7; 95% CI, 1.4-2.2). Conclusions Among patients with lung cancer, the KRS did not stratify the patients at the highest risk of VTE. Improved risk stratification methods are needed for this group of patients prior to implementing a primary prevention strategy.

Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials.

INTRODUCTION: Venous thromboembolic events (VTEs) are a significant cause of death in patients with cancer. The incidence of VTE is not well characterized in early phase clinical trials of novel antineoplastic agents, or in hepatic dysfunction studies designed for patients with varying degrees of liver test abnormalities. We compared the incidences of VTE in phase 1 clinical trials (P1CTs) and hepatic dysfunction trials (HDCTs) sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) of the United States. MATERIALS & METHODS: We reviewed individual patient records of 1841 subjects for symptomatic VTE diagnosed while on study: 1328 subjects on 42 P1CTs, and 513 subjects on 9 HDCTs. The NCI's Organ Dysfunction Working Group definitions were used to categorize patients. The incidences of VTEs between patients were compared by the Chi square test. Confounders were evaluated with the Cochran-Mantel-Haenszel method. RESULTS & CONCLUSIONS: There were 43 VTEs identified among all subjects (2.3%). There were significantly more VTE observed in the subjects on P1CTs (n=38, 2.9%) than in the subjects on HDCTs (n=5, 1.0%; RR 0.341, 95% 0.13-0.86, p=0.015). For patients on HDCTs, those with severe dysfunction had a high incidence of VTE (RR 10.5 (1.12-93.6), p=0.021) that remained significant in a multivariate model. VTEs were observed less frequently in patients who were enrolled in HDCT than those who were enrolled in P1CT; however, patients with severe hepatic dysfunction were more likely to experience VTE. Severe liver test abnormalities may not be protective against VTE in patients with malignancies receiving chemotherapy.

Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis.

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.

Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients.

BACKGROUND: Patients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known. PATIENTS AND METHODS: Two thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding. RESULTS: Compared with patients without cancer, active cancer patients (n=493) had more venous thromboembolism (VTE) complications (1.2% versus 0.2%; P=0.001), major bleeding (3.4% versus 1.7%; P=0.02) and reduced survival (95% versus 99%; P<0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2% versus 0.16%; P=0.002) and major bleeding (3.7% versus 0.6%; P<0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5% versus 1%; P=0.03) without impacting the VTE rate (0.7% versus 1.4%, P=0.50). CONCLUSIONS: Cancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.