Venous thromboembolism and cancer: Guidelines of the Italian Association of Medical Oncology (AIOM)

Abstract

Thromboembolic complications represent one of the most important cause of morbidity and mortality in cancer patients. Although several data have been published demonstrating the strong association between cancer and venous thromboembolism (VTE), there is poor perception, among oncologists, of the level of risk of thrombosis and of relevance of managing VTE in these patients. The Associazione Italiana di Oncologia Medica (AIOM) has provided some recommendations to direct clinical practice according to evidence-based data concerning cancer and VTE. In fact, we conducted an extensive literature review (1996–2005) to produce evidence-based recommendations to improve perceptions of the magnitude of this risk among Italian medical and surgical oncologists and alert on the new approaches to prophylaxis and treatment of VTE in cancer patients. Levels of evidence are given according to a five-point rating system, and similarly for each key recommendation a five-point rating system suggests if the evidence is strong and indicate that the benefits do, or do not, outweigh risks and burden.

Introduction

The strict two-way clinical relationship between cancer and VTE has been evaluated since Trousseau's time [1]. This author described the high incidence of venous thromboembolism (VTE) in a cohort of patients with gastrointestinal carcinoma. Thereafter it has been extensively recognised that VTE is a common complication of patients with malignancy [2].

Even though the association between cancer and hypercoagulability is well established, the pathogenesis of VTE in these patients is not entirely elucidated. While coagulation activation is encountered in up to 90% of cancer patients, only 4–15% of them develop deep venous thrombosis (DVT) and/or pulmonary embolism (PE) [3].

Thromboembolic disease can also act as an epiphenomenon of a hidden cancer. Several studies have demonstrated that patients with idiopathic thrombosis have a substantial likelihood to develop cancer [4]. It is noteworthy that local growth and metastatic dissemination of malignancies are influenced by the coagulation system [5], [6]. Tissue factor, thrombin, fibrin, platelets and other hemostatic components can all play a role in tumor progression. Chemotherapy and hormone therapy may further impair the hemostatic balance by causing alterations of blood vessel walls or regulatory proteins of the coagulation cascade [7], [8]. The incidence of VTE in solid tumors, and particularly for each histotype is difficult to establish because most clinical studies presented in current literature show a great variability based on the type of diagnostic procedure utilized to diagnose VTE, the most frequent tumor histotype, the medical or surgical procedures, and finally the presence or not of an indwelling central venous catheter, which in itself increases the risk of thrombosis of the axillary/subclavian vein. In addition, most data in the literature have been derived from retrospective and prospective studies not specifically designed to evaluate the issue. No studies have been able to definitively quantify the risk of developing a VTE for each histotype and/or site of the primary tumor.

Even in absence of symptomatic thrombosis most cancer patients present with abnormalities of coagulation tests, underlying a subclinical hypercoagulable state, including thrombin–antithrombin complex, prothrombin fragments 1 + 2, fibrinopeptide A, and D-dimer [9].

The developing of VTE is a multifactorial event involving several mechanisms. General mechanisms include inflammation due to necrosis or release of acute phase reactants and hemodynamic disorder such as stasis. Tumor-specific mechanisms include the capacity of tumor cells to activate the coagulation cascade by several ways. The tumor cells are able to interact with host blood cells, such as platelets, leukocytes, and endothelial cells, by releasing inflammatory cytokines (IL-1, TNF, VEGF) or by direct cell-to-cell interactions. As a final result, a downregulation of anticoagulant and an upregulation of procoagulant properties of these cells occur in the host, contributing to the general hypercoagulable condition of these subjects [9]. Cancer cells also produce a number of procoagulant substances including tissue factor [10], [11], [12] and cancer procoagulant [13], [14]. Therefore, tumor tissue can directly activate the clotting cascade, leading to thrombin generation and fibrin formation. It is now well demonstrated that tissue factor and other hemostatic proteins, including thrombin and fibrin, besides favouring thrombotic phenomenon, are also involved in the neoplastic dissemination and metastasis [10].

Albeit the pathophysiology of VTE in cancer has been extensively studied and VTE commonly occurs in patients with cancer, however most oncologists underestimate the prevalence of VTE and its negative impact on their patients. With this background in mind the Associazione Italiana di Oncologia Medica (AIOM) decided to draft recommendations for clinical practice in order to improve perceptions about the magnitude of VTE risk in patients with malignancy and to improve prophylaxis and treatment of VTE in cancer patients among Italian medical and surgical oncologists. For this purpose, we performed an extensive “Medline” and Cancerlit literature review (1996–2005) to produce evidence-based recommendations. Various combinations of search terms were used depending on the requirements of the database being searched. These terms included: “Thrombosis”, “Thromb*”, “Venous Thrombosis”, “Coagulation”, “Cancer”, “Tumor”, “prophylaxis*”, “therapy”, “Surgery”, “Chemotherapy”, “Hormonotherapy”, “Occult Cancer”, “Prognosis”, “Survival”, “Heparin”, “Coumarin”, “Warfarin*”. Relevant references in each article were scanned and we also did manual searches of abstracts from the annual meetings of the American Society of Hematology (1993–2004), American Society for Clinical Oncology (1993–2004), and European Haematology Association (1993–2004).

We focused on five distinct issues: (1) VTE and occult cancer; (2) prophylaxis of VTE in cancer surgery; (3) prophylaxis of VTE during chemotherapy or hormonal therapy; (4) prophylaxis of VTE and central venous catheters; (5) treatment of VTE in patients with cancer and VTE; (6) anticoagulation and prognosis of cancer patients.

For this purpose, the AIOM established a panel of experts in clinical oncology, clinical research, and clinical hematology. The panel included three academically affiliated and four community-based practicing hematology/oncology specialists. The panel used a systematic review of the evidence as its foundation for making recommendations. This process included a systematic weighting of the level of evidence and a systematic grading of the evidence for making a recommendation. In order to design a hierarchical grading system we gave greater weight to well-designed randomised controlled trials and meta-analyses and progressively less weight to studies with weaker internal validity. We considered with particular interest, and scored as high quality results those derived from studies with false positive rate ≤5% and false-negative rate ≤20%. Furthermore the concordant findings of controlled studies that have not been subject to meta-analysis were highly considered in order to score the levels of evidence. When evidence was lacking, the panel determined that it was appropriate to reach conclusions based on expert opinion. The strength of evidence and grade of recommendations are reported in Table 1, Table 2 and the scheme is identical to that in use by American Society of Clinical Oncology and European Society of Medical Oncology.