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The Clinical Course of Venous Thromboembolism May Differ According to Cancer Site


We hypothesized that the clinical course of venous thromboembolism in patients with active cancer may differ according to the specificities of primary tumor site.

Aim and Methods

We used data from RIETE (international registry of patients with venous thromboembolism) to compare the clinical venous thromboembolism-related outcomes during the course of anticoagulation in patients with one of the 4 more frequent cancers (breast, prostate, colorectal, or lung cancer).


As of September 2014, 3947 cancer patients were recruited, of whom 938 had breast, 629 prostate, 1189 colorectal, and 1191 lung cancer. Overall, 55% had metastatic disease (42%, 36%, 53%, and 72%, respectively). During the course of anticoagulant therapy (mean duration, 139 days), the rate of thromboembolic recurrences was similar to the rate of major bleeding in patients with breast (5.6 [95% confidence interval (CI), 3.8-8.1] vs 4.1 [95% CI, 2.7-5.9] events per 100 patient-years) or colorectal cancer (10 [95% CI, 7.6-13] vs 12 [95% CI, 9.4-15] per 100 patient-years). In contrast, in patients with prostate cancer, the rate of venous thromboembolic recurrences was half the rate of major bleeding (6.9 [95% CI, 4.4-10] vs 13 [95% CI, 9.2-17] events per 100 patient-years), whereas in those with lung cancer, the rate of thromboembolic recurrences was twofold higher than the rate of major bleeding (27 [95% CI, 22-23] vs 11 [95% CI, 8.6-15] per 100 patient-years).


Significant differences in the clinical profile of venous thromboembolic-related outcomes were observed according to the site of cancer. These findings suggest the development of cancer-specific anticoagulant strategies as an area for further research.


Progress in the screening and treatment of cancer has resulted in improved survival of cancer patients and an increasing number of living patients in recent years.1 In parallel, the incidence of venous thromboembolism has been reported to progressively increase in cancer patients, in contrast to stable figures in venous thromboembolism incidence in the general population without cancer.2 In this context, optimal venous thromboembolism management as a common and potentially life-threatening complication in patients with cancer has become an issue of major concern that challenges clinicians and has a great impact on safety, quality of life, and cost of care.3

Current guidelines of anti-thrombotic therapy, based on the results of randomized clinical trials, recommend that cancer patients with acute venous thromboembolism be treated initially with low-molecular-weight heparin (LMWH), fondaparinux, or unfractionated heparin, followed by long-term treatment with LMWH rather than with vitamin K antagonists (VKA).456 These recommendations apply to all cancer patients, irrespective of the initial venous thromboembolic presentation, spread, and specific therapies according to primary tumor type. Nonetheless, numerous studies reported the highly different risk of venous thromboembolism per site of cancer, with relative low risk of venous thromboembolism for breast and prostate cancer as compared with lung and pancreas cancer.7 It appears that the more the cancers are biologically active (reflected by a high 1-year mortality and early metastatic spread), the higher the risk of developing venous thromboembolism.12789 On the other hand, fewer data are available with regard to the venous thromboembolism clinical course once the thrombotic event has been established. A number of studies revealed that a number of cancer variables (ie, advanced stage at venous thromboembolism diagnosis,1789 concomitant therapies, and comorbidities) may influence outcomes.19 However, there is uncertainty about the influence of the site of cancer on the risk of venous thromboembolism-related outcomes, including venous thromboembolic recurrences or major bleeding events during the course of anticoagulant therapy. It is likely that the biological and clinical heterogeneity among different types of malignancies might influence the balance between the rate of venous thromboembolic recurrences and major bleeding during follow-up. If this hypothesis is confirmed, it would suggest that cancer patients might likely benefit from different anticoagulant strategies according to primary tumor site. Overall, a cancer-per-cancer approach allows the practitioner to take into account the variety of natural history, anticancer treatment, and concomitant medications. In a first approach, in order to reliably assess the thromboembolic risk according to the cancer site, we have to consider cancer associated with a high number of thromboembolic events and with a life expectancy of more than 6 months.9 The most common malignancies associated with venous thromboembolism reported in the literature are those of the lung, breast, colon, or prostate, reflecting the prevalence of these malignancies in the general population.10111213

The RIETE (Registro Informatizado de Enfermedad TromboEmbólica) Registry is an ongoing, multicenter, international (Spain, Argentina, Belgium, Canada, Czech Republic, Ecuador, France, Greece, Israel, Italy, Latvia, Portugal, Republic of Macedonia, Switzerland and Venezuela), observational registry of clinical data of consecutive patients with objectively confirmed venous thromboembolism, including deep vein thrombosis and pulmonary embolism and their outcomes regarding major bleeding complications, recurrent venous thromboembolic events, and date and cause of death. Patients are managed according to treating physicians’ criteria in the real world. The RIETE Registry started in Spain in 2001, and 6 years later the database was translated into English with the aim to expand the Registry to other countries. Data from this registry have been used to evaluate short-term and long-term outcomes after acute venous thromboembolism, such as the frequency of recurrent venous thromboembolism, bleeding, and mortality, and risk factors for these outcomes.1415161718As of September 2014, 9646 patients out of 48,481 included in the RIETE registry had cancer. The aim of the present study was to assess the differences on epidemiology, clinical presentation, and outcome of patients with breast, prostate, colorectal, or lung cancer during the course of anticoagulant therapy for venous thromboembolism.

Patients and Methods

Consecutive patients with symptomatic, acute deep vein thrombosis or pulmonary embolism, confirmed by objective tests (compression ultrasonography or contrast venography for deep vein thrombosis; helical computed tomography [CT] scan or high-probability ventilation/perfusion lung scintigraphy for pulmonary embolism), were enrolled in RIETE. We considered as having pulmonary embolism all those patients with symptomatic pulmonary embolism, either with or without concomitant deep vein thrombosis. Patients were excluded if they were currently participating in a clinical trial with a blinded therapy. All patients (or their relatives) provided written or oral consent for participation in the registry, in accordance with local ethics committee requirements.

For the present analysis, only patients with active cancer defined as newly diagnosed cancer or cancer that is being treated (ie, surgery, chemotherapy, radiotherapy, hormonal, support therapy, or combined treatments), either localized or metastatic tumors of the breast, prostate, colon, or lung origin were included. These patients were receiving anticancer therapy (ie, surgery, chemotherapy, radiotherapy, hormonal, or combined treatments) or supportive or palliative care.

We certify that RIETE received institutional review board approval, always in accordance with the internal requirements of each of the centers participating. This analysis was approved by the institutional review board of Hospital Universitari Germans Trias i Pujol (Badalona, Spain) and the NorthShore University HealthSystem (Evanston, Ill.). As to the need for written consent, RIETE started in 2001; at that time, oral consent was sufficient. For France we got the approval of the Institut National de la Santé et de la Recherche Médicale (INSERM) Ethical committee for oral consent solely, as it is only an epidemiological study. However, as more and more centers have been joining us, most of them have obtained approval only if consent was written. We have the copies of these approvals.

Physicians participating in the RIETE registry ensured that eligible patients were consecutively enrolled. Data were recorded onto a computer-based case report form at each participating hospital and submitted to a centralized coordinating center through a secure Web site. The study coordinating center assigned patients with a unique identification number to maintain patient confidentiality and was responsible for all data management. Data quality was regularly monitored electronically, including checks to detect inconsistencies or errors, which were resolved by contacting the local coordinators. Data quality was also monitored by periodic visits to participating hospitals by contract research organizations that compared medical records with the submitted data.

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-Isabelle Mahé, MD, PhD, Jean Chidiac, MD, Laurent Bertoletti, MD, PhD, Carme Font, MD, PhD, Javier Trujillo-Santos, MD, PhD, Marisa Peris, MD, Cristina Pérez Ductor, MD, Santiago Nieto, MD, Elvira Grandone, MD, PhD, Manuel Monreal, MD, PhD the show RIETE investigators

This article originally appeared in the March 2017 issue of The American Journal of Medicine.

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