Gregory C. Connolly

Assessing Risk of Venous Thromboembolism in the Patient With Cancer

PURPOSE Patients with cancer are increasingly at risk for venous thromboembolism (VTE). Rates of VTE, however, vary markedly among patients with cancer. DESIGN This review focuses on recent data derived from population-based, hospital-based, and outpatient cohort studies of patients with cancer that have identified multiple clinical risk factors as well as candidate laboratory biomarkers predictive of VTE. RESULTS Clinical risk factors for cancer-associated VTE include primary tumor site, stage, initial period after diagnosis, presence and number of comorbidities, and treatment modalities including systemic chemotherapy, antiangiogenic therapy, and hospitalization. Candidate predictive biomarkers include elevated platelet or leukocyte counts, tissue factor, soluble P-selectin, and D-dimer. A recently validated risk model, incorporating some of these factors, can help differentiate patients at high or low risk for developing VTE while receiving chemotherapy. CONCLUSION Identifying patients with cancer who are most at risk for VTE is essential to better target thromboprophylaxis, with the eventual goal of reducing the burden as well as the consequences of VTE for patients with cancer.

Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States†

Recent studies suggest that thromboprophylaxis is beneficial in preventing venous thromboembolism (VTE) in cancer outpatients, but this is not widely adopted because of incomplete understanding of the contemporary incidence of VTE and concerns about bleeding. Therefore, the authors examined the incidence and predictors of VTE in ambulatory patients with bladder, colorectal, lung, ovary, pancreas, or gastric cancers.

Emerging risk stratification approaches to cancer-associated thrombosis: risk factors, biomarkers and a risk score

Cancer patients are well-known to be at increased risk of venous thromboembolism (VTE). However, the risk varies widely between patients and over the natural history of malignancy. Recent data have identified multiple clinical risk factors as well as biomarkers predictive of VTE. Risk factors include patient-associated factors such as age, obesity and medical comorbidities, cancer-associated factors such as site and stage of cancer, and treatment-associated factors, particularly chemotherapy and anti-angiogenic therapy. Biomarkers associated with increased risk of cancer-associated VTE include leukocyte count, platelet count, and levels of tissue factor, P-selectin and D-dimer. This review focuses on the evidence for risk stratification of cancer patients, based on these risk factors and biomarkers, as well as a recently validated predictive model which can be used to identify patients at highest risk. Targeted thromboprophylaxis utilizing model-based and/or biomarker-based approaches may provide an optimal risk-benefit ratio and is currently the focus of ongoing clinical trials.

Inhibition of Mrp2- and Ycf1p-mediated transport by reducing agents: evidence for GSH transport on rat Mrp2

Mammalian Mrp2 and its yeast orthologue, Ycf1p, mediate the ATP-dependent cellular export of a variety of organic anions. Ycf1p also appears to transport the endogenous tripeptide glutathione (GSH), whereas no ATP-dependent GSH transport has been detected in Mrp2-containing mammalian plasma membrane vesicles. Because GSH uptake measurements in isolated membrane vesicles are normally carried out in the presence of 5-10 mM dithiothreitol (DTT) to maintain the tripeptide in the reduced form, the present study examined the effects of DTT and other sulfhydryl-reducing agents on Ycf1p- and Mrp2-mediated transport activity. Uptake of S-dinitrophenyl glutathione (DNP-SG), a prototypic substrate of both proteins, was measured in Ycf1p-containing Saccharomyces cerevisiae vacuolar membrane vesicles and in Mrp2-containing rat liver canalicular plasma membrane vesicles. Uptake was inhibited in both vesicle systems in a concentration-dependent manner by DTT, dithioerythritol, and beta-mercaptoethanol, with concentrations of 10 mM inhibiting by approximately 40%. DTTs inhibition of DNP-SG transport was noncompetitive. In contrast, ATP-dependent transport of [(3)H]taurocholate, a substrate for yeast Bat1p and mammalian Bsep bile acid transporters, was not significantly affected by DTT. DTT also inhibited the ATP-dependent uptake of GSH by Ycf1p. As the DTT concentration in incubation solutions containing rat liver canalicular plasma membrane vesicles was gradually decreased, ATP-dependent GSH transport was now detected. These results demonstrate that Ycf1p and Mrp2 are inhibited by concentrations of reducing agents that are normally employed in studies of GSH transport. When this inhibition was partially relieved, ATP-dependent GSH transport was detected in rat liver canalicular plasma membranes, indicating that both Mrp2 and Ycf1p are able to transport GSH by an ATP-dependent mechanism.

Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States.

Background This study examines venous thromboembolism (VTE)-associated resource utilization and real-world costs in ambulatory patients initiating chemotherapy for selected common high-risk solid tumors. Methods Health care claims data (2004–2009) from the IMS/PharMetrics® Patient-Centric database were collected for propensity score-matched adult cancer (lung, colorectal, pancreatic, gastric, bladder, or ovarian) patients initiating chemotherapy with VTE (n = 912) and without VTE (n = 2736). Health care resource utilization (inpatient, outpatient, and outpatient prescription drug claims) and costs were compared between the two cohorts during the 12-month follow-up period after the index VTE event. Incremental costs were adjusted for demographic and clinical covariates. Results Cancer patients with VTE had approximately three times as many all-cause hospitalizations (mean 1.38 versus 0.55 per patient) and days in hospital (10.19 versus 3.37), and more outpatient claims (331 versus 206) than cancer patients without VTE (all P < 0.0001). Cancer patients with VTE incurred higher overall all-cause inpatient costs (mean USD 21,299 versus USD 7459 per patient), outpatient costs (USD 53,660 versus USD 34,232 per patient), and total health care costs (USD 74,959 versus USD 41,691 per patient) than cancer patients without VTE (all P < 0.0001). Total mean VTE-related health care costs were USD 9247 per patient over 12 months. Adjusted mean incremental all-cause health care costs of VTE were USD 30,538 per patient for cancer overall, ranging from USD 11,946 for gastric to USD 38,983 for pancreatic cancer. Conclusion: VTE is associated with significant inpatient and outpatient resource utilization, and increased all-cause (in addition to VTE-related) health care costs among ambulatory cancer patients. Measures to prevent outpatient cancer-associated VTE may reduce health care utilization and costs in this population.

Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer

BACKGROUND The incidence and economic impact of lung cancer-associated venous thromboembolic (VTE) events in a contemporary ambulatory setting is unknown. PATIENTS AND METHODS We conducted a retrospective cohort analysis utilizing the IMS Patient-Centric database of US healthcare claims and recorded VTE events occurring 3-12 months after chemotherapy initiation. RESULTS Lung cancer (n=6732) and control (n=17 284) cohorts had 51% women, with a mean age of 64 years. VTE occurred in 13.9% of the lung cancer cohort (odds ratio [OR], 3.15; 95% confidence interval [CI] 2.55, 3.89), and 1.4% of the control cohort (P<0.0001). Charlson Comorbidity Index ≥ 5 (CCI; OR, 2.56; 95% CI 1.02, 6.39; P=0.045), the use of erythropoiesis-stimulating agents (ESAs; OR, 1.63; 95% CI 1.40, 1.89; P<0.0001), and congestive heart failure (CHF; OR, 1.29; 95% CI 1.01, 1.66; P=0.045) were associated with VTE. Bleeding occurred in 22.1% of the lung cancer cohort and 7.0% of the control cohort (P<0.0001). Among lung cancer patients the average total healthcare payment was

Prevalence and Clinical Significance of Incidental and Clinically Suspected Venous Thromboembolism in Lung Cancer Patients

84,187 in patients with VTE compared to

Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer

56,818 in patients without VTE (P<0.0001). CONCLUSIONS VTE is common among lung cancer patients receiving chemotherapy and is associated with increased healthcare utilization.

Pattern of Frequent But Nontargeted Pharmacologic Thromboprophylaxis for Hospitalized Patients With Cancer at Academic Medical Centers: A Prospective, Cross-Sectional, Multicenter Study

BACKGROUND It is unclear what proportion of VTE events in lung cancer patients are incidentally discovered and whether incidental events affect mortality. PATIENTS AND METHODS We conducted a retrospective cohort study of lung cancer patients seen at the University of Rochester between January 1, 2006 and December 31, 2008 with the goal of quantifying and characterizing VTE events. Multiple clinical variables and mortality outcomes were compared using Kaplan-Meier survival analysis and multivariate Cox proportional hazards. RESULTS The study population consisted of 207 subjects with lung cancer. The median age was 66 years and 55% were female (n = 115). Thirty-one patients (14.9%) experienced at least 1 VTE event with 32.2% (10/31) of these incidentally discovered. Incidental events comprised 29.4% (n = 5) of pulmonary embolisms, 11.1% (n = 2) of deep vein thrombosis, and 100% (n = 3) of visceral events. The median survival for patients with incidental VTE was 23.4 months (95% confidence interval [CI], 4.8-32.1) compared with 45.8 months (95% CI, 34.1-56.8) in patients without VTE (HR 2.4; 95% CI, 1.2-4.9; P = .01), but in a subgroup analysis of stage IV patients overall survival was not significantly different (HR, 0.94; P = .33). Patients with clinically suspected VTE had the lowest median survival at 13.1 months (95% CI, 6.4-18.9) which was significantly lower than patients without VTE (HR, 2.7; 95% CI, 1.6-4.5; P = .002), but not significantly different from patients with incidental VTE (HR, 1.2; 95% CI, 0.4-2.0; P = .7). In multivariate analysis, occurrence of VTE (HR, 2.3; 95% CI, 1.3-3.8; P = .002) was significantly associated with mortality when adjusting for age, stage, and histology. CONCLUSIONS One-third of VTE events in lung cancer patients are incidentally discovered and VTE has negative clinical effect in lung cancer patients.

Risk stratification for cancer-associated venous thromboembolism

Background:Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.Methods:Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg−1, GEM 1000 mg m−2 (10 mg m−2 min−1) and OX 85 mg m−2 on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.Results:Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.Conclusions:The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.