Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions (AU)

Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence.

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions.

Incidence of venous thromboembolism in patients with colorectal cancer according to oncogenic status.

BACKGROUND: There are conflicting data regarding the role of KRAS mutation on the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients. Moreover, the role of other biomarkers such as NRAS or BRAF has not been studied. PURPOSE: To analyze the incidence of VTE in a cohort of patients with CRC based on KRAS, NRAS, and BRAF status. METHODS: We performed a retrospective review of patients with unresectable locally advanced and metastatic CRC (mCRC) and known KRAS/NRAS/BRAF status, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain). The primary outcome was VTE defined as any venous thromboembolic event that occurred either 6 months before or at any time after the diagnosis of CRC. The biomarker status (KRAS, NRAS, and BRAF) and other predictors of thrombosis were collected. RESULTS: One hundred and ninety-four patients were identified and included in the analysis. Forty-one patients (21.1%) experienced VTE. The incidence was 19.1% in RAS-mutated patients, 28.6% in BRAF-mutated patients and 21% in triple wild-type patients (p = NS). In multivariate analysis, ECOG ≥ 2 was the only independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). CONCLUSIONS: In our study, biomarkers have not been associated with an increased risk of VTE in CRC patients. A high incidence of VTE in BRAF-mutated patients has been observed and should be explored in further studies.

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019).

In 2011, the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of venous thromboembolism (VTE) and cancer. This guideline was updated in 2014, and since then, multiple studies and clinical trials have changed the landscape of the treatment and prophylaxis of VTE in cancer patients. To incorporate the most recent evidence, including data from direct oral anticoagulants (DOACs) randomized clinical trials, SEOM presents a new update of the guideline.

Monitoring anti-Xa levels in patients with cancer-associated venous thromboembolism treated with bemiparin.

OBJECTIVE: To analyze the relationship between therapeutic (weight-adjusted) dose of bemiparin and anti-Xa activity in patients with venous thromboembolism (VTE) and cancer in comparison with a cohort of patients with VTE without cancer, and its relationship with outcomes. MATERIALS AND METHODS: This is a prospective cohort study that comprised a cohort of patients with cancer-associated VTE and a cohort of non-cancer patients with VTE, all of them treated with bemiparin. The ethics committee approved the study and informed consent was obtained from the patients. RESULTS: One hundred patients were included (52 with cancer and 48 without cancer), with a median follow-up of 9.8 months. Mean anti-Xa activity was 0.89 (± 0.33) UI/mL in oncological patients and 0.83 (± 0.30) UI/mL in non-cancer patients (mean difference - 0.05 95% CI - 0.18; 0.06). A multiple linear regression model showed that anti-Xa peak was associated with the dose/kg independently of possible confounding variables (presence of cancer, age, sex and eGFR-estimated Glomerular Filtration Rate), in a way that for every 1 UI of dose/kg increase, the anti-Xa peak activity increased 0.006 UI/mL (95% CI 0.003; 0.009) (p < 0.001). The predictive capacity of anti-Xa peak in the oncology cohort showed an area under the ROC curve of 0.46 (95% CI 0.24-0.68), 0.70 (95% CI 0.49-0.91) and 0.74 (95% CI 0.44-0.94) for death, first bleeding and recurrence of VTE, respectively, and none was statistically significant. CONCLUSION: In patients with venous thromboembolism treated with bemiparin, anti-Xa levels were not influenced by the presence of cancer.

Pleiotropic effects of heparins: does anticoagulant treatment increase survival in cancer patients?

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed.

Pancreatic ductal adenocarcinoma: metastatic disease.

The treatment of choice of metastatic PADC is systemic chemotherapy. In the last decade, there have been significant advances in this area. New combination poli-chemotherapy schemes have shown a significant increase in overall survival and progression-free survival without impairing quality of life. In addition, the value of second-line chemotherapy treatment has consolidated and a new concept called "therapeutic sequencing" has also emerged. The aim of this article is to review the different therapeutic options in metastatic PDAC based on patient's characteristics.

FOTROCAN Delphi consensus statement regarding the prevention and treatment of cancer-associated thrombosis in areas of uncertainty and low quality of evidence.

INTRODUCTION: Decision-making in cancer-related venous thromboembolism (VTE) is often founded on scant lines of evidence and weak recommendations. The aim of this work is to evaluate the percentage of agreement surrounding a series of statements about complex, clinically relevant, and highly uncertain aspects to formulate explicit action guidelines. MATERIALS AND METHODS: Opinions were based on a structured questionnaire with appropriate scores and were agreed upon using a Delphi method. Questions were selected based on a list of recommendations with low evidence from the Spanish Society of Oncology Clinical Guideline for Thrombosis. The questionnaire was completed in two iterations by a multidisciplinary panel of experts in thrombosis. RESULTS: Of the 123 statements analyzed, the panel concurred on 22 (17%) and another 81 (65%) were agreed on by qualified majority, including important aspects of long-term and prolonged anticoagulation, major bleeding and rethrombosis management, treatment in special situations, catheter-related thrombosis and thromboprophylaxis. Among them, the panelists agreed the incidental events should be equated to symptomatic ones, long-term and extended use of full-dose low-molecular weight heparin, and concluded that the Khorana score is not sensitive enough to uphold an effective thromboprophylaxis strategy. CONCLUSION: Though the level of consensus varied depending on the scenario presented, overall, the iterative process achieved broad agreement as to the general treatment principles of cancer-associated VTE. Clinical validation of these statements in genuine practice conditions would be useful.

Clinical guide SEOM on venous thromboembolism in cancer patients.

Venous thromboembolism (VTE) is a common event in cancer patients and one of the major causes of cancer-associated mortality and a leading cause of morbidity. In recent years, the incidence rates of VTE have notably increased; however, VTE is still commonly underestimated by oncologists. VTE is considered an adverse prognostic factor in cancer patients in all settings. In 2011 the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of prophylaxis and treatment of VTE in cancer patients. In an effort to incorporate evidence obtained since the original publication, SEOM presents an update of the guideline for thrombosis and cancer in order to improve the prevention and management of VTE.

Incidence of venous thromboembolism (VTE) in ambulatory pancreatic cancer patients receiving chemotherapy and analysis of Khorana's predictive model.

PURPOSE: To evaluate the incidence of venous thromboembolism (VTE) in ambulatory pancreas cancer patients receiving chemotherapy and analyze Khorana's predictive model of chemotherapy-associated thrombosis. METHODS/PATIENTS: We performed a retrospective review to determine the incidence of VTE in the gastrointestinal cancer unit of our center. Between 2008 and 2011, 84 consecutives patients diagnosed with pancreas adenocarcinoma were identified and included in the analysis. Pancreatic neuroendocrine tumors were excluded. RESULTS: Thirty patients experienced VTE (35.7 %) and 66 % of the events were diagnosed during the first 6 months after diagnosis. Khorana's score: 33.3 % of the intermediate category patients developed a venous thromboembolic event and 37.5 % in the high-risk category. CONCLUSIONS: The high incidence of VTE observed in this study is consistent with prior reports. Specific predictive model for chemotherapy-associated thrombosis in pancreatic cancer must be investigated.

Bevacizumab in combination with biweekly capecitabine and irinotecan, as first-line treatment for patients with metastatic colorectal cancer.

BACKGROUND: Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treatment for metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the efficacy and safety of this regimen in combination with bevacizumab (BV), as first-line treatment for mCRC. PATIENTS AND METHODS: A total of 46 consecutive patients received a combination of BV (5 mg kg⁻¹, day 1), irinotecan (175 mg m⁻², day 1) and capecitabine (1000 mg m⁻² twice daily on day 2-8), every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary objective was to determine the progression-free survival (PFS) and safety profile. RESULTS: The overall response rate (ORR) was 67.4%, with a disease control rate (ORR+stable disease) of 93.5%. Median PFS and overall survival (OS) were 12.3 months (95% confidence interval (CI): 6.5-18.1 months) and 23.7 months (95% CI: 16.7-30.6 months), respectively. The most frequent grade 3/4 treatment-related adverse events were asthenia (7%), diarrhoea (7%), nausea (9%) and vomiting (7%). CONCLUSION: Bevacizumab combined with biweekly XELIRI is a highly active first-line regimen for mCRC treatment, showing encouraging PFS, ORR and OS with a good tolerability.

Acquired ichthyosis as a paraneoplastic syndrome in Hodgkin's disease

An 80-year-old man was admitted to hospital with low-grade fever, weight loss, asthenia and anorexia. Physical examination revealed generalised ichthyosis with palmoplantar hyperkeratosis. CT scan showed retroperitoneal and inguinal lymph node enlargement. An inguinal lymph node biopsy revealed Hodgkin's disease (nodular-sclerosing subtype). The patient received chemotherapy, showing a clear improvement of both skin lesions and lymph nodes (AU)

First-line treatment of advanced gastric cancer and hepatic dysfunction with oxaliplatin, 5-fluorouracil and cetuximab

There is no standard chemotherapy regimen in advanced gastric cancer with poor performance status and hepatic dysfunction. New chemotherapeutical agents and targeted therapy have demonstrated promising results in terms of efficacy and safety in phase II clinical trials. We report the case of a 68-year-old man with stage IV gastric cancer and severe hepatic dysfunction due to liver metastases treated with a combination of oxaliplatin, 5-fluorouracil and cetuximab (AU)

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