Venous thromboembolism is the leading cause of morbidity and mortality in cancer(1). Moreover, cancer is a major risk factor for venous thromboembolism, with an increased incidence of 4-7 times(2,3). The close association between cancer and venous thromboembolism is well known, it was first reported in 1865 by Trousseau(4).
At one in seven patients hospitalized and who died of cancer it was demonstrated at autopsy that the cause of death was pulmonary thromboembolism and also 60% of patients that had died by venous thromboembolism suffered from cancer in localized stage or metastatic limited(5).
The occurrence of venous thromboembolism in patients with cancer is caused by a hypercoagulable state by activation of coagulation by tumor cells, due to the synthesis of pro-coagulant factors, cytokines (TNF, IL-1b, VEGF) or by stimulating direct intercellular interaction with endothelial cells, leucocytes or platelets. Tumor cells constitutively express tissue factor, the main activator of coagulation, which initiates angiogenesis and vascular endothelial penetration by tumor cells(3,6). Another pro-coagulant factor produced by tumor cells is a cysteine proteinase that activates Factor X in a Factor VIIa independent manner. TNF and IL-1b stimulate endothelial expression of tissue factor and inhibit expression of thrombomodulin. VEGF stimulates angiogenesis and inhibits apoptosis. Also, tumor cells express cell surface adhesion molecules which fosters direct interaction with endothelial cells, platelets, white blood cells, fibronectin and von Willebrand factor(3,7,8).
The emergence of venous thromboembolism phenomena in patients with cancer severely affects disease prognosis, especially if this complication is experienced early (within the first month after diagnosis), highlighting an aggressive evolution of the disease or metastatic disease. Also, these patients have an increased risk of relapse of embolic phenomena, especially in the first months after diagnosis, and keep up even a few years(9). During chemotherapy, cancer patients show a 7 times higher risk of developing thromboembolism than patients without cancer(9).
Clinicians often underestimate the prevalence of embolic phenomena and their negative impact on patients. All patients known with venous thrombosis developed during neoplastic disease, who present at admission in the Departments of Oncology and Palliative Care in Romania, were in treatment with oral anticoagulants coumarins (acenocumarol), requiring frequent therapeutic dose adjustment. Most commonly, due to reduced accessibility of the patient to health care, especially in rural areas, the possibility of weekly assessment and precise adjustment of the dose of oral anticoagulants is reduced, resulting in increased risk of bleeding by overdosing, but also risk of ineffective therapeutics by suboptimal doses. In these conditions we wanted to evaluate the indications and benefits of the treatment with low molecular weight heparin compared with oral anticoagulant therapy in patients with cancer at increased risk of thromboembolic events or who have experienced at least one such event during the course of the disease.
Materials and method
We conducted a review of Anglo-Saxon literature and therapeutic international guidelines, by extensive research of Medline and Pubmed database, using the following search terms: thrombosis, venous thrombosis, cancer, Coumarin, Warfarin, Heparin, Low Molecular Weight Heparin, anticoagulant treatment, anti-thrombosis treatment. There were excluded from the review the articles that we could access only the abstract. We have identified major risk factors for thromboembolic events in cancer patients, and therapeutic indications (treatment initiation, type of treatment, period of treatment).
Results and discussion
The optimal approaches for preventing and treating thrombosis remains an open question regarding thromboprophylaxis in high-risk patients, treatment options and optimal treatment period in the acute or recurrent thrombotic events.
Many factors are associated with the risk of developing venous thrombosis and are classified into general causal factors (age, previous history of VTE, hospitalization and immobilization for longer than 3 days, major medical conditions, obesity, hereditary thrombophilia), cancer related factors (primary site - high risk: stomach, pancreas; intermediate risk: lung, lymphomas, gynaecological; low risk: breast, colorectal, head and neck; cancer stage: metastatic)(9,10,11) and treatment - related factors: surgery, chemotherapy, hormonal therapy, antiangiogenic agents - bevacizumab, thalidomide, lenalidomide, erythropoiesis stimulating factors, transfusions(9,11).
VTE rate was up to 34% in patients with myeloma treated with thalidomide and doxorubicin and also in patients with relapsed myeloma treated with lenalidomide and high dose dexamethasone. The use of bevacizumab was associated with 33% relative increase of thrombotic events(9).
Recently, in determining the risk of VTE, some biomarkers were associated: leukocyte count, platelet count, low hemoglobin level, high D-dimer level, elevated soluble P-selectin level, high C-protein reactive level(11,12).
In current clinical practice, the routine thromboprophylaxis in ambulatory patients with cancer with chemotherapy,even with high risk factors, is not recommanded. An exception is made for patients with multiple myeloma who have received thalidomide or lenalidomide and dexamethasone regimens(1,9).
The PROTECHT study (Prophylaxis of Thromboembolism during chemotherapy) of 1150 ambulatory cancer patients showed a 50% reduction in venous and arterial events in patients treated with nadroparin versus placebo group(1).
The initial therapy of VTE in cancer patients is low-molecular-weight heparin (LMWH) followed by oral anticoagulant (warfarin or related oral anticoagulants). The long-term use of warfarin or acenocoumarol is problematic due to achieving and maintaining the international normalized ratio (INR) of 2-3.
The analysis of 33 studies of patients with VTE who received oral anticoagulant therapy longer than 3 months indicates a case fatality for major bleeding of 9.1% and the cancer patients have higher risk of major bleeding - hazard ratio of 4.07 compared with patients without cancer(5,13,14). The therapeutic levels in the treatment with oral anticoagulants may not be reached due to drug interactions (ex.: Warfarin - fluorouracil infusions(15)), vomiting, liver dysfunction or malnutrition and subsequently increasing the risk of overdose and bleeding.
Several trials have compared LMWHs with anticoagulants for long term prevention of VTE. A study of 146 cancer patients with VTE who received 3 months of LMWH or warfarin showed a risk of major bleeding or recurrent VTE of 10.5%, respectively 21.1%(5,16) and a meta-analysis demonstrated also a reduction of recurrence of VTE and major bleeding in favor of LMWHs(17). But, this were not statistical significant.
The benefits of using the LMWHs are: more predictable bioavailability, dose-independent renal clearance, not affected by diet, other drugs, anorexia or vomiting; greater flexibility when the treatment must be interrupted, less likely to cause heparin-induced thrombocytopenia(5,9).
The higher cost of the treatment with LMWHs can be annihilated by reducing hospitalization costs necessary to adjust the warfarin dose(3,5).
In the Malignancy and Low Molecular Weight Heparin Therapy (MALT), trial reported by Klerk et al., approximately 300 patients with incurable solid tumors were randomly assigned to the low molecular weight heparin or placebo for 6 weeks. A statistically significant improvement in overall survival was observed for LMWH relative to placebo. The reduction in mortality was also in favor of LMWH in the subgroup of patients who were identified as having a life expectancy of greater than 6 months(18).
The CONKO-004 trial found a 87% risk reduction of VTE using enoxaparin at 1 mg/kg once daily for 3 months compared to no prophylaxis (9.9% vs. 1.3%), while the FRAGEM study reported a 62% risk reduction in VTE using the CLOT therapeutic regimen of dalteparin (31% vs. 12%)(11,19,20).
A multicentre study demonstrated that a high prophylactic dosage of LMWH( 2500UI versus 5000UI) increases the protective effect without enhancing the bleeding risk(9,21).
A recent meta-analysis evaluated the anticoagulant treatment on survival in cancer patients without VTE, finding a significant reduction in overall mortality with anticoagulant therapy. The clinical effect was most pronounced for LMWH, which produced a relative risk reduction in mortality of 13.3% compared with a non-significant reduction with warfarin of 5.8%(9,22).
The aim of the anticoagulant treatment in cancer patients is to prevent recurrence, extension and complications of venous thromboembolism while minimizing the risk of major bleeding.
In cases carefully selected, long-term therapy with LMWH is the alternative for the oral anticoagulation therapy.