**2.2 The incidence of venous thromboembolism in cancer patients**

The first description of deep vein thrombosis (DVT) in patients with cancer was made by Bouillard in 1823(12) although this was popularly first credited to Armand Troussean, the French Physician, in 1865 (13-14). Since that time, hundreds of studies have provided solid data on the clinical association between VTE and cancer, and delineated the elevated risk for VTE particularly during the first few months following the diagnosis of cancer and in the presence of distant metastasis (15-18).

The incidence of DVT or PE in patients with cancer varies widely because of the heterogeneity of the patients' population and the difficulty of conducting large epidemiological studies. Based on a prospective medical database in the United States, the annual incidence of a first episode of DVT or PE in the general population is 0.1% (15), while the estimated annual incidence of VTE in the cancer population is 0.5%. (19-21) The prevalence of cancer-associated thrombosis may be underestimated by more than 10-fold as autopsy studies in cancer patients have demonstrated even higher rates of VTE (17-22). In a large population-based epidemiological study, approximately 20% of all new cases of VTE are associated with underlying cancer, whereas 26% of incident cases had idiopathic VTE (15).

The risk of VTE associated with different malignancies has more recently been quantified in NHL (23), colonic cancer (24) ovarian (25) lung (26) and breast cancer (27). It was generally thought that solid tumors, such as pancreatic, ovarian and brain cancer carry a much higher risk for VTE than haematological malignancies. However, recent studies suggest that the incidence of VTE in patients with haematological malignancies may be similar to that observed in patients with solid tumors (28). In a population based case-control study of patients with a first episode of VTE, Blom et al found that the odds ratio of developing VTE among patients with haematological malignancies was approximately 26 compared to the general population (18). Similar results were also reported by other authors (29-31).

Prospective studies has shown that VTE have inflicted a higher risk of several adverse complications on patients with cancer including recurrent VTE, bleeding complications while on anticoagulant treatment, increase in both short-term and long-term mortality (32- 33) and increased mortality during first 3 month of therapy. The risk of VTE is markedly different for cancer patients throughout the course of the disease and this variable incidence of VTE comorbidity in cancer patients can be attributed to a combination risk factors related to the patient, the cancer itself and treatment (34).

Venous Thromboembolism in Cancer Patients 77

d. **Rate of metastatic spread:** The incidence of VTE has been reported to correlate with the rate of growth and spread of the cancer cells. Fast growing cancer such as colonic and ovarian, has been associated with a higher rate of VTE (24-25, 41-42) and patients with advanced and metastatic disease had a higher risk of VTE (OR 19.8, CI 2.6–149). The observed incidence of VTE in ovarian, colorectal, pancreatic, lung and breast cancer supports the finding that advanced stage increases the risk of cancer associated VTE

Chemotherapy is one of the most important treatment-related factors in the aetiology of cancer-associated VTE as cancer alone is associated with a four-fold risk of thrombosis,

Several different mechanisms have been reported to explain the prothrombotic states induced by chemotherapy including (a) damage to the vascular endothelium (48-49), (b) reduction of endogenous, physiological, anticoagulant factors (56-59), (c) increase of levels of procoagulants (54-57), (d) induction of tumor and endothelial level apoptosis and cytokine release that, in turn, lead to increased expression and hence activity of TF (56-57), (e) induction of platelet activation (58) and (f) direct induction of expression of monocyte-

Weiji et al (60), in a retrospective review of VTE in germ cell cancer patients treated with cisplatin and bleomycin-based chemotherapy reported an estimated risk of thrombosis of 8.4%. In a prospective study of VTE in non-small cell lung cancer patients treated with

The mechanisms by which cisplatin induces thrombosis is not well known but in vitro studies suggest increase in the level of TF (48), platelet activation (50) and increased levels of von Willebrand factor suggesting endothelial injury (58). The latter perhaps explain the cisplatin induced arterial thrombosis. Moore et al (62) conducted a large retrospective analysis to determine the incidence of venous and arterial thromboembolic events in patients treated with cisplatin-based chemotherapy and confirmed the unacceptable incidence of those events and recommend randomized studies to examine the question of

L-Asparaginase (ASNase) has been a mainstay in the treatment of paediatric patients with acute lymphoblastic leukemia since the 1960's and there are several reports of ASNase containing regimen used in the treatment of paediatric ALL achieving a higher survival rate than non-ASNase treatment regimens used for ALL in adults and adolescents (63-65).

The following chemotherapeutic agents are associated with high risk for VTE:

cisplatin and gemcitabine, Numico et al (61) reported VTE incidence of 17.6%.

prophylactic anticoagulation in patients with cancer treated with chemotherapy.

of cancer diagnosis (42-43).

**2.5 Cancer Treatment-related factors and risk of VTE** 

while chemotherapy increases the risk by six-fold (45-47)

(24-25, 44).

macrophages TF (59).

• **L-Asparaginase** 

• **Cisplatin based regimens** 

**2.5.1** 

of diagnosis is a strong independent risk factor for developing VTE within the first year
