High-risk Khorana Score Research Articles

Assessing hypercoagulability and VTE risk using thromboelastography and Khorana score in women with cancers receiving chemotherapy.

Venous thromboembolism (VTE) is a common occurrence in cancer and chemotherapy increases thrombosis risk. Current risk assessment models such as the Khorana score (KS) and its modifications have limitations in female cancers. We assessed the coagulation profile of a group of women cancer patients under chemotherapy using thromboelastography (TEG) to determine if this can inform VTE risk assessment. Cancer patients who planned to receive chemotherapy were recruited. Baseline demographics, cancer data, BMI, Khorana Score (KS), and VTE risk factors were recorded and patients were followed for 6 months, for any thrombotic events. A total of 36 patients aged 35-85 (18 breast, 11 endometrial, 7 ovarian cancer) were evaluated. Hypercoagulability was detected in 63% of patients post-chemo cycle 1 and 75% post-cycle 2, with a significant increase in MA (maximum amplitude) and CI (clotting index), reduction in R (reaction time), K (clot kinetics), and LY30 (lysis time after 30 min of MA). KS showed only 7% of patients were high risk, 23% were low, and 70% were intermediate risk. MA and CI significantly increased in patients with intermediate and high-risk KS when compared with the low-risk patients and MA was positively correlated with KS. Five patients developed actual VTE; 100% of the tested ones were hypercoagulable either post-cycle 1 or 2 and 80% were KS intermediate risk. TEG is a hypercoagulability marker and TEG-MA and CI can potentially assess VTE risk. Larger studies are needed to assess the utility of TEG as an adjuvant to KS to better predict VTE in specific female cancers.

Using the Khorana risk score to predict venous thromboembolism and overall survival in a cohort of Hispanic patients with solid malignancies.

The Khorana risk score (KRS) for prognosis of venous thromboembolism (VTE) has been rarely explored in Hispanic populations. To determine the value of the KRS for prediction of VTE and overall survival (OS) among Hispanic individuals with cancer. We retrospectively evaluated all outpatients with newly diagnosed solid tumours receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. The 6-month cumulative VTE incidence according to the KRS categories was estimated using the Fine & Gray competing risk model. A Kaplan-Meier analysis was used to compare OS among KRS categories. The Cox regression analysis was performed to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI). The receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff value to predict VTE during follow-up. A total of 708 patients were included in the analysis. After a median follow-up of 8.13 months, the cumulative incidence of VTE at 6 months was 1.56% (95% CI: 0.83%-6.82%), 4.83% (95% CI: 2.81%-7.66%) and 8.84% (95% CI: 4.30%-15.42%) for low-, intermediate- and high-risk Khorana score categories, respectively (Gray's p value: 0.0178). The optimal cutoff for the KRS to predict VTE was 2 (area under the ROC curve: 0.65; 95% CI: 0.55-0.756). The KRS was independently associated with overall mortality (HR: 1.83; 95% CI: 1.46-2.29; p < 0.001, for the comparison of 'high-risk' and 'low-risk' KRS). The KRS is a valid tool to predict VTE and mortality in a cohort of Hispanic outpatients with newly diagnosed solid tumours.

Using machine learning to predict venous thromboembolism in patients with uterine cancer (081)

<b>Objectives:</b> Gynecologic cancers are traditionally associated with a high risk of venous thromboembolism (VTE). Recent ASCO clinical practice guidelines have expanded recommendations for pharmacological thromboprophylaxis in high-risk patients; however, high risk is not well defined for the endometrial cancer population. Both the Caprini and the Khorana scores are clinically validated to assess the risk of VTE - Caprini developed for surgical patients and Khorana for cancer patients undergoing chemotherapy. We sought to develop a better tool to assess endometrial cancer patients at high risk for VTE. <b>Methods:</b> A single-institution retrospective cohort study was performed from January 2016 through January 2020. All patients with uterine cancer were screened, and the patients with complete clinical information were included. VTE was evaluated from diagnosis through 90 days post-diagnosis. Both the Caprini and the Khorana scores were calculated for each patient. High-risk Caprini score was defined as ≥ 9 based on prior studies in cancer patients, whereas high-risk Khorana score was defined as ≥ 3. In addition to variables included in the risk assessment tools, additional variables included race/ethnicity, tumor grade, stage, and histology. Microsoft Azure Machine Learning Studio was utilized to develop a machine learning (ML) algorithm to predict VTE. Five different ML models were assessed, including random forest, extreme random trees (ERT), logistic regression, XGBoost classifier, and support vector machine. Data were split into 70% for ML training and 30% for validation. Models were analyzed based on classification accuracy, AUC, and sensitivity and specificity. <b>Results:</b> A total of 1000 patients were included. The majority of patients were White (93.5%), obese (mean BMI of 37.8 kg/m2) with an average age of 61.2 years. Most tumors were grade 1 (62.7%), endometrioid histology (79.3%), and stage I (76.4%). Most patients underwent a hysterectomy (95.4%). A minority received neoadjuvant (4.0%) and adjuvant chemotherapy (13.1%), whereas 269 patients received radiation (26.9%). Only 18 patients (1.8%) were diagnosed with a VTE within 90 days of diagnosis. The Khorana score had a sensitivity of 38.9% and a specificity of 80.1% for VTE. The Caprini score had a sensitivity of 66.7% and a specificity of 61.0%. Combining the features of the Khorana and Caprini scores, the best-performing ML algorithm had an accuracy of 67.3%, AUC of 83.8%, and the sensitivity improved to 100%, retaining specificity at 66.8% (ERT). To further improve the model, histology and grade were included, which performed better as a random forest model with an accuracy of 75.7%, AUC of 84.8%, sensitivity 100%, and specificity of 75.3%. Lastly, we added stage and race/ethnicity to the model (random forest model), which improved the accuracy to 83.7%, AUC 89.4%, sensitivity 100%, and specificity to 83.4%. In the final model, tumor grade and stage were the most weighted for importance, followed by age, platelet count, histology, and hemoglobin. <b>Conclusions:</b> The use of ML to enhance VTE prediction in endometrial cancer is promising. Using the same parameters as clinically validated tools, we were able to greatly improve prediction, and by adding clinically relevant variables (histology, grade, stage, race/ethnicity), we were able to further improve the model with 100% sensitivity and 83.4% specificity for VTE within 90 days of diagnosis. Using ML, VTE thromboprophylaxis could be more individualized for patients at the highest risk for VTE and minimize the potential risks associated with unnecessary anticoagulation.

Use of Khorana score to predict VTE in patients undergoing chemotherapy for uterine cancer.

5589 Background: Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a clinically-validated tool to assess risk of VTE in cancer patients (using disease site, BMI and blood counts). Recent ASCO clinical practice guidelines have recommended patients with a Khorana score of 2 or greater be offered pharmacologic thromboprophylaxis during systemic chemotherapy. For women with uterine cancer, the utility of the Khorana score is still unknown. Methods: A retrospective cohort study was performed from January 2016 to January 2020. All patients with uterine cancer were screened. Patients receiving chemotherapy, both neoadjuvant (NACT) and adjuvant (ACT), were included. VTE was evaluated for 12 months following the first cycle of chemotherapy. The Khorana score was calculated for each patient using both a high risk score of ≥2 and ≥3 and the patients were stratified based on NACT vs ACT. Logistic regression and chi-square were used to evaluate the prognostic utility of the Khorana score as well as other clinico-pathologic criteria on development of VTE. Results: A total of 265 patients were included. The majority of patients were obese (160, 60.4%) and 60 years or older (188, 70.9%). The most common histology was endometrioid (107, 40.4%) followed by serous (71, 26.8%) and the majority were advanced-stage (169, 63.8%). Most women underwent hysterectomy during treatment (243, 91.7%) followed by ACT (228, 86.0%). 14% (37) had NACT. 24 patients developed VTE (9.1%), which was higher, but not statistically different, with NACT vs ACT (13.5% vs 8.3%, p = 0.35). Demographics including age, race and BMI nor pathologic data including histology, grade or stage significantly correlated with development of VTE. Similarly, treatment factors including undergoing hysterectomy and radiation treatment were not statistically significant in regards to VTE. The proportion of patients with high Khorana score (both ≥2 and ≥3) was similar between groups. In the whole cohort, high Khorana score (defined either as ≥2 or ≥3) did not significantly predict VTE; however, the model using ≥3 was more predictive (OR 1.154, 95%CI 0.402-2.907, p = 0.7326). In the NACT cohort, neither model was predictive of VTE (both with OR &lt; 1). In the ACT group, Khorana ≥3 was a better prediction model, but was still not statistically significant (OR 1.557, 95%CI 0.480-4.343, p = 0.4213). Conclusions: Although validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in this population. A defined high risk Khorana score of ≥3 (per the original validation study) better predicted VTE than a score of ≥2 (per guidelines). Independent of the Khorana score, demographic and pathologic data were poor predictors of VTE. At this time, use of the Khorana score to guide routine thromboprophylaxis in patients undergoing chemotherapy for uterine cancer should be used with caution.

Validation of the Khorana Score for Prediction of Venous Thromboembolism After Robot-Assisted Radical Cystectomy.

Introduction: The Khorana score (KS) is used to predict the risk of venous thromboembolism (VTE) for cancer patients. We sought to assess the association between KS and VTE for patients who underwent robot-assisted radical cystectomy (RARC). Materials and Methods: We reviewed our prospectively maintained quality assurance RARC database between 2005 and 2020. KS was calculated for all patients (one point for each body mass index [BMI] ≥35 kg/m2, platelet count ≥350 × 109/L, leukocyte count >11 × 109/L, and hemoglobin level <10 g/dL, or use of erythropoiesis-stimulating agents). All patients received one point by default for the cancer type (bladder). Patients were divided into intermediate-risk (KS 1-2) or high-risk (KS ≥3) groups. Receiver operating characteristic curve was used to assess the ability of KS to predict VTE. Kaplan-Meier curves were stratified based on their KS risk and used to depict overall survival (OS). Multivariate analysis (MVA) was used to identify variables associated with VTE. Results: Out of 589 patients, 33 (6%) developed VTE (18 had deep vein thrombosis and 15 had pulmonary embolism). Five hundred forty-six (93%) patients had intermediate-risk KS and 30 (5%) of them developed VTE. Forty-three (7%) patients were classified as high-risk KS and 3 (7%) developed VTE. This difference was not significant (p = 0.73). The KS area under the curve for VTE prediction was 0.51. On MVA, BMI ≥35 kg/m2 (odds ratio [OR] 2.69, confidence interval [CI] 1.19-6.11, p = 0.02), longer inpatient stay (OR 1.04, CI 1.003-1.07, p = 0.03), and ≥pT3 disease (OR 2.29, CI 1.11-4.71, p = 0.03) were associated with VTE, whereas KS was not associated with VTE (p = 0.68). Five-year OS of patients with intermediate KS was 53% compared with 30% for high-risk KS (log rank p < 0.01). Conclusion: KS underestimated VTE risk after RARC and showed poor accuracy. This highlights the need to develop procedure-specific tools to estimate the risk of VTE after RARC.

Risk Assessment and Management of Venous Thromboembolism in Cancer Patients: A Population-Based Cohort Study

Introduction: The risk of venous thromboembolism (VTE) is increased in cancer patients, compared to subjects without cancer. The Khorana score (KS) is used to stratify VTE risk in cancer outpatients and recent society guidelines recommend thromboprophylaxis for patients with KS≥2. The burden of VTE in cancer, current use of thromboprophylaxis and performance of the KS in the Israeli setting are lacking. This data is needed to drive health-care policies regarding risk stratification and thromboprophylaxis. Aim: Define the clinical need for thromboprophylaxis in an Israeli population of cancer outpatients by determining the cumulative VTE incidence, VTE risk factors and anticoagulation (AC) use. Methods: This retrospective cohort study was conducted using the comprehensive computerized patient-level databases of Maccabi Healthcare Services (MHS), a nationwide healthcare insurer-provider organization for a quarter of the population in Israel, including 2.4 million members. All newly diagnosed cancer patients aged ≥18 years identified from the MHS cancer registry (excluding non-melanoma skin cancer) who initiated systemic anti-cancer treatment between 2010 and 2018 were included in the study. The cancer registry includes patients with cancer diagnostic codes from the Israel Ministry of Health, linked to cancer medication approvals and pathology reports. Subjects with prior VTE or AC within 3 months prior index were excluded. Patients were indexed on the first day of anti-cancer treatment and baseline variables were extracted, as well as data on AC post-index. The KS was used to stratify VTE risk as low (0-1) or high (≥2) at index. The main outcome was VTE at any site, defined using a validated algorithm based on diagnostic codes and AC prescription data (Sanfilippo et al, Thrombosis Research 135 (2015)). Cumulative incidence of VTE (95% confidence intervals [CI]) at 12 months was calculated and stratified for KS risk group. Univariate and multivariate analysis identified associations between baseline variables and VTE within 12 months. Results: The study cohort included 15,388 cancer patients of whom 35% were female with a mean age 58.8 (SD 13.6) years, 85% had a solid tumor, and 46% received chemotherapy as the index anti-cancer therapy. Of these, 338 (2.2%) had a VTE within one year after cancer diagnosis (24% pulmonary embolism with or without deep vein thrombosis [DVT], 76% DVT). Table 1 shows baseline characteristics according to VTE status at 12 months. The 12-month cumulative incidence of VTE (95% CI) was 2.3% (2.1%-2.6%) overall, 1.6% (1.3%-1.8%) in the low-risk KS group and 5.6% (4.7%-6.4%) in the high-risk KS group, as shown in Figure 1. A multivariate model considered baseline variables shown in Table 1, as well as socioeconomic status, year of diagnosis, district and use of granulocyte colony stimulating factors. In this multivariate model, the following variables were associated with increased risk of VTE in the first year since index date: females, subjects living in the south of Israel, older age, increasing co-morbidity, and high KS. All non-chemotherapy anti-cancer treatments were associated with decreased VTE risk, compared to chemotherapy. Table 2 shows the hazard ratios with 95% CI. A total of 2896 patients (19%) initiated prophylactic AC after index date (LMWH/unfractionated heparin (UFH) in 2452 (85%)). Among patients with a VTE at any time post-index, 574 (90%) started AC within a median of 2 days (IQR: 0,7) after VTE diagnosis. AC used to treat cancer-associated VTE (defined as AC class 30-days post VTE diagnosis) included LMWH/UFH in 341(74%), direct oral anticoagulant in 74 (16%) and vitamin K antagonists in 43 (9%). Median time on AC after index VTE was 22.1 months (95% CI 17.2-38.4). Conclusion: This study confirms that the Khorana score identifies a population of cancer outpatients at higher risk of VTE, and that patients receiving chemotherapy are at highest risk. The association between VTE risk and geographical location in Israel suggests possible health care disparities. The majority of cancer patients with VTE received long term therapy with LMWH. Funding: This research was sponsored by Pfizer Conflict of Interest Statement: A. Leader is an employee of Rabin Medical Center who was paid as a consultant to Pfizer in connection with this study. O. Friedman-Mazursky &amp; M. Tirosh are employees of Pfizer Israel. The remaining authors declare no conflict of interest. Disclosures Friedman: Pfizer Pharmaceuticals Israel Ltd.: Current Employment. Tirosh:Pfizer Pharmaceuticals Israel Ltd.: Current Employment. Chodick:Novartis Pharma AG: Other: Institutional grant. Leader:Bayer Healthcare: Other: personal fees ; Pfizer Pharmaceuticals Israel Ltd.: Consultancy, Honoraria, Other: personal fees .

Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis

AbstractGuidelines suggest thromboprophylaxis for ambulatory cancer patients starting chemotherapy with an intermediate to high risk of venous thromboembolism (VTE) according to Khorana score. Data on thromboprophylaxis efficacy in different Khorana score risk groups remain ambiguous. We sought to evaluate thromboprophylaxis in patients with an intermediate- to high-risk (≥2 points) Khorana score and an intermediate-risk score (2 points) or high-risk score (≥3 points) separately. MEDLINE, Embase, and CENTRAL were searched for randomized controlled trials (RCTs) comparing thromboprophylaxis with placebo or standard care in ambulatory cancer patients. Outcomes were VTE, major bleeding, and all-cause mortality. Relative risks (RRs) were calculated in a profile-likelihood random-effects model. Six RCTs were identified, involving 4626 cancer patients. Thromboprophylaxis with direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH) significantly reduced VTE risk in intermediate- to high-risk (RR, 0.51; 95% confidence interval [CI], 0.34-0.67), intermediate-risk (RR, 0.58; 95% CI, 0.36-0.83), and high-risk patients (RR, 0.45; 95% CI, 0.28-0.67); the numbers needed to treat (NNTs) were 25 (intermediate to high risk), 34 (intermediate risk), and 17 (high risk), respectively. There was no significant difference in major bleeding (RR, 1.06; 95% CI, 0.69-1.67) or all-cause mortality (RR, 0.90; 95% CI, 0.82-1.01). The numbers needed to harm (NNHs) for major bleeding in intermediate- to high-risk, intermediate-risk, and high-risk patients were 1000, −500, and 334, respectively. The overall NNH was lower in DOAC studies (100) versus LMWH studies (−500). These findings indicate thromboprophylaxis effectively reduces the risk of VTE in patients with an intermediate- to high-risk Khorana score, although the NNT is twice as high for intermediate-risk patients compared with high-risk patients.

Predictors of venous thromboembolism development before and during chemotherapy for advanced germ cell tumor.

We retrospectively analyzed the incidence and localization of venous thromboembolism in patients undergoing chemotherapy for advanced germ cell tumor and separately evaluated the risk factors for venous thromboembolism development before and during chemotherapy. We included 121 patients treated with cisplatin-based chemotherapy between 2005 and 2018. Venous thromboembolism was defined as venous thrombosis diagnosed using radiological imaging with or without thromboembolic symptoms. We analyzed the clinical parameters for identifying the possible venous thromboembolism risk factors. Khorana score was used to calculate the venous thromboembolism risk. Thirteen patients showed prechemotherapy venous thromboembolism and 13 developed venous thromboembolism during chemotherapy. The most common venous thromboembolism was deep vein thrombosis (10 patients), followed by inferior vena cava thrombus (eight patients) and pulmonary thrombus (six patients). Compared to the group without venous thromboembolism, the group with prechemotherapy venous thromboembolism showed higher proportion of patients with tumors originating in the right testis (10 out of 13), significantly higher lactate dehydrogenase levels (828IU/L versus 436IU/L, P=0.013), significantly higher proportion of patients with retroperitoneal lymph node (RPLN) metastases >5cm in diameter (76.9% versus 33.7%, P=0.003) and slightly higher proportion of patients with high-risk Khorana score (≥ 3; 30.8% versus 11.6%). No significant differences were observed between the clinical characteristics of patients with venous thromboembolism developed during chemotherapy and patients without venous thromboembolism. We show that both RPLN mass>5cm and high lactate dehydrogenase levels are significant risk factors for prechemotherapy venous thromboembolism but not for venous thromboembolism development during chemotherapy.

Khorana score and thromboembolic risk in stage II-III colorectal cancer patients: a post hoc analysis from the adjuvant TOSCA trial.

Background:The risk of venous thromboembolic events (VTE) during adjuvant chemotherapy for colorectal cancer (CRC) is unknown. We aim to evaluate if the Khorana score (KS) can predict this risk, and if it represents a prognostic factor for overall survival (OS) through a post hoc analysis of the phase III TOSCA trial of different durations (3- versus 6-months) of adjuvant chemotherapy.Methods:A logistic regression model was used to test the associations between the risk of VTE and the KS. The results are expressed as odds ratios (OR) with 95% confidence intervals (95% CI). To assess the effect of the KS on OS, multivariable analyses using Cox regression models were performed. The results are expressed as hazard ratios (HR) with 95% CI.Results:Among 1380 CRC patients with available data, the VTE risk (n = 72 events: 5.2%) was similar in the two duration arms (5.5% versus 4.9%), with 0.2% of patients belonging to the high-risk KS group. Rates of VTE were similar in the low- and intermediate-risk groups (4.8% versus 6.4%). KS did not represent an independent predictive factor for VTE occurrence. Chemotherapy duration was not associated with VTE risk. In addition, KS was not prognostic for OS in multivariate analysis (HR: 0.92, 95% CI, 0.63–1.36; p = 0.6835).Conclusions:The use of the KS did not predict VTEs in a low–moderate thromboembolic risk population as CRC. These data did not support the use of KS to predict VTE during adjuvant chemotherapy, and suggest that other risk assessment models should be researched.

Meta-Analysis and Cost-Effectiveness Analysis of Low-Dose Direct Oral Anticoagulant for the Prevention of Cancer Associated Thrombosis

Introduction: Randomized controlled trials (RCTs) have shown similar yet conflicting primary outcomes for the use of low-dose direct oral anticoagulant (DOAC), including rivaroxaban and apixaban, in the prevention of cancer-associated thrombosis (CAT). It remains unclear if this preventive strategy is consistent, robust, and cost-effective across different trial populations. Methods: We performed a systematic review of RCTs that compared DOAC vs. placebo for CAT prevention using EMBASE, MEDLINE, and CENTRAL. Two authors screened/reviewed articles and abstracted the data. Primary efficacy, sensitivity efficacy, and safety outcomes were uniformly defined and extracted from the studies. Meta-analysis was performed using random-effects model. Subgroup analysis was performed for patients with intermediate- and high-risk Khorana Score. Using inputs from the meta-analysis and relevant epidemiology and outcomes studies, we performed a cost-utility analysis using a Markov state-transition model over life time in a hypothetical cohort of 60-year-old high-risk patients with a similar distribution of cancers as the pooled RCTs. We calculated the differences in cost, quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER) and performed one-way and probabilistic sensitivity analyses to test the robustness of the results. Results: A total of 202 records were identified and 28 full-text articles were assessed. Two studies with 1415 participants were eligible to be included for meta-analysis (Table 1). For DOAC vs. placebo, the relative risk (RR) for overall VTE incidence by six months was 0.56 (0.35-0.89). The RR for major bleeding (MB) on-treatment was 1.96 (0.80-4.82). Patients with high-risk Khorana score (3+) derived the largest absolute risk reduction of VTE. Based on a Markov model, in patients at intermediate-to-high risk for VTE (Khorana Score 2+), prophylaxis with low-dose DOAC thromboprophylaxis for 6 months, compared to placebo, was associated with 32 per 1000 fewer CAT events and 11 per 1000 more MB over life-time. Prophylaxis was associated with an incremental cost increase of $1,445 and an incremental QALY increase of 0.12, resulting in an ICER of $11,947 per QALY gained (Figure 1). Key drivers of ICER variation included the relative risks of VTE and major bleeding as well as the cost of drug. Based on the cost-effectiveness acceptability curve, this preventive strategy was 94% cost effective at the threshold of $50,000. In a scenario sensitivity analysis, patients with the highest risk of VTE (Khorana Score 3+) derived the most benefit from low-dose DOAC thromboprophylaxis. Conclusion: Low-dose DOAC (rivaroxaban or apixaban) thromboprophylaxis for 6 months reduces the rate of overall VTE in higher-risk cancer patients starting systemic chemotherapy and may increase the likelihood of bleeding. It appears to be a cost-effective strategy for the prevention of CAT in intermediate-to-high risk ambulatory patients based on our analyses; however, the differential impact on QALY is small over lifetime. Future research should focus on a better understanding of the significance of these adverse events on longer term quality of life and their impact on delays in anti-cancer treatment. Disclosures Kuderer: Celldex: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Myriad Genetics: Consultancy; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Carrier:Leo Pharma: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Lyman:G1 Therapeutics, Halozyme Therapeutics, Partners Healthcare, Hexal, Bristol-Myers Squibb, Helsinn Therapeutics, Amgen Inc., Pfizer, Agendia, Genomic Health, Inc.: Consultancy; Amgen Inc.: Other: Research support, Research Funding; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific Affairs, LLC: Research Funding.

Bleeding Risk in a Cohort of Ambulatory Cancer Patients Receiving Outpatient Prophylactic Anticoagulation for Venous Thrombosis Prevention

Background: Recent clinical trials have evaluated the safety and efficacy of direct oral anticoagulant (DOAC) therapy for venous thromboembolism (VTE) prophylaxis in cancer outpatients at high risk for thrombosis. Bleeding risk in these trials were approximately 2% over the first 6 months of therapy. For individual patients, the utility of prophylactic anticoagulation (AC) depends on an acceptable safety profile between bleeding and thrombosis. We investigated whether ambulatory cancer patients on contemporary cancer-directed therapies and prophylactic AC had an increased risk of major bleeds over the first 6 months of therapy. Methods: As part of a single-center prospective cohort study, we assessed consecutive ambulatory patients initiating cancer-directed treatment, risk-stratified these patients for VTE using the Khorana score and educated them about VTE. High risk patients (Khorana score ≥3) were offered prophylactic AC. Major bleeding events and minor bleeding events (based on ISTH standard definitions) were prospectively captured via billing code screening and confirmed by physician review of the medical record. Logistic regression was used to compare the odds of developing a major bleed within 6 months in those who received prophylactic AC compared to those that did not. Results: A total of 1,210 patients were enrolled from October 2015 - June 2018, of which, 640 were women (52.9%). The most common cancers were gastrointestinal 270 (22%), lung 213 (18%), and breast 198 (16%). There were 393 patients (32%) with a Khorana score of 0, 706 (58%) with a Khorana score of 1-2, and 111 (9%) with a score of ≥3. A total of 421 patients received any AC (LMWH or DOAC). Of these, 282 received a prophylactic dose anticoagulant and 139 were receiving a full dose anticoagulant prior to enrolling for other medical reasons. Prophylactic dose anticoagulants prescribed included apixaban in 107 (41%), rivaroxaban in 6 (2.3%), enoxaparin in 119 (45.7%), and other heparin products in 50 (19.2%). A total of 27 (2.33%) major bleeds and 22 (1.81%) minor bleeds occurred within the first 6 months of starting therapy. Of these bleeding events, 8 (2.8%) occurred in those on prophylactic AC, and 6 (4.3%) occurred in those on full dose AC. The odds ratio (OR) of developing a major bleed on any type of AC was 1.78 [CI 0.817-3.88]. The OR of major bleeding on prophylactic AC was 1.49 [CI 0.64-3.479]. The OR of major bleed was highest in lung cancer patients on prophylactic AC (OR 2.81, CI 1.27-6.25). Men, when compared to women, were more likely to bleed on prophylactic AC in the first six month (OR 0.2; CI 0.07-0.52). The OR for major bleed with each 1 year increase in age was 1.02 (CI 0.99, 1.06). The OR of bleeding with a high risk Khorana score (≥3) compared to a lower score was 1.04 (CI 0.73-1.50). Conclusion: During the first six months of therapy, prophylactic AC was associated with an increased risk of major bleeding events in patients on cancer-directed therapy. In this study, the rate of major bleeding was similar as compared to published clinical trials. Neither age nor higher Khorana score were associated with an increased risk of major bleeds in patients on prophylactic AC. The finding that men, when compared to women, and patients with lung cancer may have an increased risk of major bleeding while on prophylactic AC and cancer-directed chemotherapy suggests these groups may warrant both increased education and monitoring to ensure safety while on prophylactic AC. Disclosures No relevant conflicts of interest to declare.

Incidence of venous thromboembolic disease (VTE) in a cohort of patients with colorectal cancer (CRC) according to KRAS, NRAS and BRAF status.

e15136 Background: A recent study has suggested that KRAS mutation could increase the risk of VTE in patients with CRC. The role of others biomarkers, such as BRAF, in this setting is unknown. The aim of this study is to analyze the incidence of cancer-associated thrombosis in a cohort of patients with CRC based on KRAS, NRAS and BRAF status. Methods: We performed a retrospective review of patients with metastatic CRC and KRAS/NRAS/BRAF status known, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) between January 2010 and January 2018. Results: 194 patients were identified and included in the analysis. The median age was 64 years (18-86). Most were metastatic at diagnosis (58.1%). Khorana’s predictive model: low-risk 67.7%, intermediate-risk 31.0%, high-risk 2.3%. The median follow-up was 35 months (2-240). 41 patients (21.1%) experienced VTE (11 pulmonary embolism, 15 lower extremity deep-vein thrombosis, 12 visceral vein thrombosis, 2 catheter-related thrombosis, 1 unknown). Most had metastatic disease at the moment of VTE (90.2%). 40% of the events occurred at the time of diagnosis or within the first 6 months. 65% were incidental events. Khorana’s predictive model in VTE patients: low-risk 63.4%, intermediate-risk 24.5%, high-risk 7.3%. According to biomarkers, the incidence was 19.1% (13/68) in KRAS/NRAS mutated patients, 28.6% (6/21) in BRAF mutated patients and 21% (22/105) in triple-wild-type patients. 6/38 patients (15.8%) developed recurrent thrombosis. In the univariate analysis, the presence of chronic kidney disease (p = 0.022), ECOG ≥ 2 (p = 0.038) and high-risk Khorana score (p = 0.011) were significantly associated with increased risk of VTE. Metastatic disease showed a trend towards the statistical significance (p = 0.053). In the multivariate model, including this variables, age, sex and biomarkers, only ECOG ≥ 2 remained independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). Conclusions: The biomarkers have not been associated with the risk of VTE. We have observed a high incidence of VTE in BRAF mutated patients that should be investigated in further studies.

The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis.

We aimed to evaluate the performance of the Khorana score in predicting venous thromboembolic events in ambulatory cancer patients. Embase and MEDLINE were searched from January 2008 to June 2018 for studies which evaluated the Khorana score. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. Additional data on the 6-month incidence of venous thromboembolism were sought by contacting corresponding authors. The incidence in each Khorana score risk group was estimated with random effects meta-analysis. A total of 45 articles and eight abstracts were included, comprising 55 cohorts enrolling 34,555 ambulatory cancer patients. For 27,849 patients (81%), 6-month follow-up data were obtained. Overall, 19% of patients had a Khorana score of 0 points, 64% a score of 1 or 2 points, and 17% a score of 3 or more points. The incidence of venous thromboembolism in the first six months was 5.0% (95%CI: 3.9-6.5) in patients with a low-risk Khorana score (0 points), 6.6% (95%CI: 5.6-7.7) in those with an intermediate-risk Khorana score (1 or 2 points), and 11.0% (95%CI: 8.8-13.8) in those with a high-risk Khorana score (3 points or higher). Of the patients with venous thromboembolism in the first six months, 23.4% (95%CI: 18.4-29.4) had been classified as high risk according to the Khorana score. In conclusion, the Khorana score can be used to select ambulatory cancer patients at high risk of venous thromboembolism for thromboprophylaxis; however, most events occur outside this high-risk group.

The Khorana Score for the Prediction of Venous Thromboembolism in Patients with Solid Cancer: An Individual Patient Data Meta-Analysis

Background: Guidelines suggest the use of the Khorana score to select patients with solid cancer receiving chemotherapy for thromboprophylaxis to prevent venous thromboembolism (VTE), but its performance in different types of cancers remains uncertain.Methods: The present analysis includes individual patient data from seven randomized controlled trials that had compared prophylactic (ultra)-low-molecular-weight heparin (LMWH) with placebo or observation in patients with solid cancer. The analysis addresses the performance of the continuous and dichotomized Khorana score in predicting the 6-month risk of VTE in the trial control groups, overall and in types of cancer studies, as well as the efficacy and safety of LMWH among patients with a high-risk Khorana score. Random effects meta-analysis provided the basis for summary estimates.Findings: In the 3,403 patients from the control groups included in the analyses, the mean age was 61 years, 59% were male, and 58% had lung cancer. During 6-months of follow-up, 188 patients (5.5%) developed VTE. Overall, the 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate risk patients (OR 1.6; 95%-CI 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95%-CI, 0.72-1.7) than in those with other types of cancer (OR 4.4; 95%-CI, 2.7-7.3; P interaction=0.002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared to placebo or observation (OR 0.36; 95%-CI, 0.22-0.58). In the group of patients with types of cancer other than lung cancer and a high-risk Khorana score (N=619), the 6-month VTE incidence was 3.3% (95% CI, 1.4 to 7.7) among LMWH recipients and 13% (95% CI, 6.8 to 24) among those not receiving LMWH (OR 0.23, 95% CI, 0.11 to 0.46; P <0.001). There was no difference in major bleeding (OR 1.2, 95% CI, 0.56 to 2.5).Interpretation: The Khorana score performs poorly in differentiating between those at high and low risk of VTE in patients with lung cancer, but is associated with a 4-fold increased risk of VTE in those with other types of cancer. Thromboprophylaxis is effective and safe in patients with a high-risk Khorana score.Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. DisclosuresVan Es:Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Crowther:Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth:Cancer Research UK: Research Funding; Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial. Griffiths:Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant > 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Streiff:Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno:Daiichi Sankyo: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; BMS-Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria. Bozas:PharmaMar: Honoraria. Maraveyas:Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi:Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project. McBane:Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Schünemann:Canadian Institutes of Health Research: Research Funding.

Risk Stratification for the Development of Venous Thromboembolism in Hospitalized Patients with Cancer

Introduction: No method of venous thromboembolism (VTE) risk stratification exists for hospitalized cancer patients. The Khorana score is a validated tool in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting development of VTE in cancer patients during admission to hospital.Methods: We conducted a retrospective analysis of data collected from healthcare records of consecutive, medically-ill cancer patients hospitalized between January and June 2010 in 3 academic medical centers in Canada. Objectively diagnosed symptomatic VTE during hospitalization, anticoagulant thromboprophylaxis (TP), and Khorana score variables were collected for every patient. Patients receiving therapeutic anticoagulation at admission, and those with incomplete data were excluded. The risk of VTE based on Khorana score category was evaluated using logistic regression. Continuous data were compared using a Student's t-test and expressed using the means and standard deviations. Categorical data were compared using the Pearson Chi-square test and were expressed as percentages. Statistical significance was defined as alpha less than 0.05.Results: 1398 patients were included. Mean age was 61.6 years, 51.2% were male, and mean BMI was 25.9 kg/m2. The most frequent tumor types were non-small cell lung carcinoma (12.7%) followed by lymphoma (10.9%). The median length of stay was 6 days (range 0-114 days). The most frequent reasons for hospitalization were chemotherapy (22.3%) followed by pain and palliation (21.4%). 34.5% received anticoagulant TP (n = 483/1398). The incidence of VTE was 2.9% (41/1398) overall, 5.4% (9/166) in high, 3.2% (26/817) in moderate, and 1.4% (6/415) in low Khorana score risk groups. High risk patients were significantly more likely than low risk patients to have VTE (p=0.016; OR 3.9, 95% CI 1.4-11.2). There was no difference in VTE incidence between patients who received anticoagulant TP and those who did not (3.5% vs 2.6%, p = 0.345). Patients with high risk Khorana score were more likely to receive anticoagulant TP than those with low risk Khorana score (46.4% vs. 23.9%, p <0.001, OR 2.8, 95% CI 1.9-4.0). Total incidence of major bleeding was 1.8% (25/1398). There was no difference in major bleeding between patients who received anticoagulant TP and those who did not (1.7% vs. 1.9%, p = 0.787).Conclusion: The Khorana score is predictive of VTE development in cancer patients who are hospitalized for medical illness and may be a useful tool for tailoring inpatient anticoagulant prophylaxis. DisclosuresLee:LEO: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Wu:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

EL-16 - Management of cancer-associated thrombosis

The development of VTE has been known to be one of cautious complications and associated with a worse QOL and survival outcome in cancer patients. Cancer patients have a 4∼7 fold increased risk of VTE compared with general population. Around 10% of the patients with unprovoked VTE have been reported to have hidden cancer. The high incidence of thrombosis is reported in patients with pancreas, ovary, lung, and brain tumor. On the other hand, relatively low risks are seen in patients with mammary or prostate cancer. While the mechanisms on development of VTE associated with cancer progression are actively studied recently, it remains unsolved. One of most attractive molecules is tumor-derived tissue factor-bearing microparticles (TMP) which are produced by cancer cells and spread out in circulating blood. TMP may attach to surface membrane of vascular endothelial cells and leukocytes via the interaction of adhesion molecules, and then blood coagulation system is activated and induces the formation of thrombosis on the phospholipid cell surface membrane. In cancer patients, VTE delays in surgery and administration of chemotherapy and increased risk of bleeding due to anticoagulation, and then results in worse QOL and increased mortality. Therefore, the prediction and adequate prevention of VTE should be essential. In 2008 Khorana et al proposed the predictive model for VTE in cancer patients, which included type of cancer, platelet count ( = >350,000/ml), Hb <10g/dl, WBC >11000/ml and BMI = >35. Recently, D-dimer is indicated to be predictive biomarkers of thrombosis. Several guidelines for prophylaxis and treatment of VTE in cancer patients are presented. Prophylaxis against VTE is generally accepted in cancer patients with high risk Khorana score for DVT. Low molecular weight heparin is mostly used as first line therapy, although it is not currently approved in Japan. The clinical usefulness of direct oral anticoagulants (DOACs) has not yet been concluded.

Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy.

Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk. The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre. The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio [OR], 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively). Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.