**2. Cancer as a risk factor for VTE**

The association between cancer and thrombosis is well-established since the first observation made by Armand Trousseau more than hundred years ago (Prandoni et al., 1992). Cancer and its treatment are recognized risk factors for VTE; in a population-based case-control study of 625 Olmsted County patients, the risk of VTE was six- fold higher in cancer patients compared to those without (Heit et al., 2000). Thrombosis is the most frequent complication and the second cause of death in patients with overt malignant diseases. Increasing evidence suggests that thrombotic episodes may also precede the diagnosis of cancer by months or years (Donati, 1995). The risk of VTE varies by cancer type; higher in patients with malignant brain tumors and adenocarcinoma of the pancreas, colon,

Venous Thromboembolism Prophylaxis in Cancer Patients 113

thrombotic events (Kabbinavar et al., 2007; Shah et al, 2005). Lower rates, however, wereobserved when different combination chemotherapy were used in the treatment of non-small cell lung cancer (Johnson et al., 2004). In addition to thrombosis, bevacizumab was associated with significant increase risk of bleeding; a fact that complicates decision making (Kabbinavar et al., 2003) . However, the highest incidence of VTE was observed in multiple myeloma patients treated with thalidomide, dexamethasone and doxorubicincontaining chemotherapy [Zangari et al., 2002). Higher VTE rates were also observed with thalidomide derivatives; lenalidomide and pomalidomide when used in combination with dexamethasone (Zonder et al., 2006 & Dimopoulos et al., 2007). Cancer-related risk factors

Different antithrombotics including low molecular weight heparin (LMWH), low-dose warfarin, full-dose warfarin with target international normalized ratio (INR) of 2 to 3, and aspirin (ASA) were all tried to reduce the risk of VTE in cancer patients undergoing such therapy (Baz et al., 2005; Cavo M et al., 2004; Minnema et al., 2004). Specific recommendations in these clinical settings are beyond the scope of this review. However, in a recent trial that included a total of 667 patients with previously untreated multiple myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), fixed-dose warfarin (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment; of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the warfarin group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, - 3.0% to 5.7%; *P* =.544) in the ASA group and +3.2% (95%

In addition to chemotherapy agents, drugs that are commonly used to support cancer patient while on active treatment may increase the risk of VTE. Erythropoiesis-stimulating agents (ESA); erythropoietin and darbepoietin are both associated with higher VTE rates. A meta-analysis of 35 trials in 6,769 cancer patients concluded that such treatment increased the risk of thromboembolic events by 67% compared with patients not receiving this therapy

Despite its proven success, many registry studies have shown low compliance rates with published VTE prophylaxis guidelines. In a national Canadian multi-center survey study (the CURVE study), the medical records of patients in 20 teaching and 8 community hospitals were reviewed to assess the adherence to the established sixth American College of Chest Physicians (ACCP) consensus guidelines for VTE prophylaxis. In this study, 1894 eligible patients were included; thromboprophylaxis was administered only to 23% of all patients and to 37% of patients who were bedridden for more than 24 hours. However, only 16% of the patients had appropriate prophylaxis; in particular, patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR = 0.40, 95% CI (0.24–0.68)

CI, - 1.5% to 7.8%; *P* = .183) in the warfarin group (Palumbo et al., 2011).

are summarized in table-1.

(Bohlius et al., 2006).

**3. Making the decision** 

stomach, ovary, lung, prostate, and kidney (Chew et al., 2006; Gerber DE, et al., 2006; Marras et al., 2000; Sallah et al., 2002; Thodiyil& Kakkar, 2002), but lower in sites like skin and breast (Andtbacka et al., 2006; Chew HK et al., 2007). In addition to primary tumor type, other cancer-related factors play important role in VTE rates; the risk of VTE is highest during the first 3–6 months after the initial diagnosis of cancer (Blom et al., 2005). Such risk also varies with the stage of the disease; much higher with advanced stage compared to early stage disease (Blom JW et al., 2005) and among cancer patients on active treatment with chemotherapy or radiotherapy (Haddad & Greeno, 2006).

Certain anti-cancer therapies are known to increase the risk of VTE in cancer patients. The rate of VTE increases by two to five folds in women with breast cancer treated with tamoxifen, a selective estrogen receptor modulator (SERM), and this risk was even higher when tamoxifen was combined with chemotherapy, a practice that was abandoned many years ago (Fisher et al., 2005; Pritchard et al., 1996). Aromatase inhibitors (AI), however, like anastrozole, letrozole and exemestane are less thrombogenic (Breast International Group (BIG) 1–98 Collaborative Group, 2005; ATAC (Arimidex Tamoxifen Alone or in Combination Trialists' Group), 2002).


Table 1. Cancer-related risk factors for thrombosis

The recent introduction of immune modulators and antiangiogenesis drugs in clinical practice resulted in higher rates of VTE among cancer patients receiving such therapy. Thalidomide, lenalidomide, bevacizumab, sorafenib and sunitinib are approved by the US Food and Drug Administration (FDA) for many types of cancers; all are associated with increased risk of VTE (Zangari et al., 2009). Up to 23% of patients using bevacizumab in combination with chemotherapy to treat colorectal and gastric cancers experienced

stomach, ovary, lung, prostate, and kidney (Chew et al., 2006; Gerber DE, et al., 2006; Marras et al., 2000; Sallah et al., 2002; Thodiyil& Kakkar, 2002), but lower in sites like skin and breast (Andtbacka et al., 2006; Chew HK et al., 2007). In addition to primary tumor type, other cancer-related factors play important role in VTE rates; the risk of VTE is highest during the first 3–6 months after the initial diagnosis of cancer (Blom et al., 2005). Such risk also varies with the stage of the disease; much higher with advanced stage compared to early stage disease (Blom JW et al., 2005) and among cancer patients on active treatment with

Certain anti-cancer therapies are known to increase the risk of VTE in cancer patients. The rate of VTE increases by two to five folds in women with breast cancer treated with tamoxifen, a selective estrogen receptor modulator (SERM), and this risk was even higher when tamoxifen was combined with chemotherapy, a practice that was abandoned many years ago (Fisher et al., 2005; Pritchard et al., 1996). Aromatase inhibitors (AI), however, like anastrozole, letrozole and exemestane are less thrombogenic (Breast International Group (BIG) 1–98 Collaborative Group, 2005; ATAC (Arimidex Tamoxifen Alone or in

High: Brain, Ovary, Pancreas, Colon, Stomach, Lung, Prostate, Kidney

Low: Aromatase inhibitors like letrozole, anastrozole and exemestene

The recent introduction of immune modulators and antiangiogenesis drugs in clinical practice resulted in higher rates of VTE among cancer patients receiving such therapy. Thalidomide, lenalidomide, bevacizumab, sorafenib and sunitinib are approved by the US Food and Drug Administration (FDA) for many types of cancers; all are associated with increased risk of VTE (Zangari et al., 2009). Up to 23% of patients using bevacizumab in combination with chemotherapy to treat colorectal and gastric cancers experienced

chemotherapy or radiotherapy (Haddad & Greeno, 2006).

High: Locally-advanced and metastatic disease

High: Chemotherapy, radiotherapy, surgery

**Antiangiogenesis and immune modulators:** 

Table 1. Cancer-related risk factors for thrombosis

Combination Trialists' Group), 2002).

Low: Skin, Thyroid, Breast **Duration since cancer diagnosis:**  High: First 6 months Low: After 12 months

Low: No active treatment

**Cancer type:** 

**Stage of disease:** 

**Hormonal therapy:**  High: Tamoxifen

> Thalidomide Lenalidomide Bevacizumab Sorafenib Sunitinib

Low: Early-stage **Anticancer therapy:** 

thrombotic events (Kabbinavar et al., 2007; Shah et al, 2005). Lower rates, however, wereobserved when different combination chemotherapy were used in the treatment of non-small cell lung cancer (Johnson et al., 2004). In addition to thrombosis, bevacizumab was associated with significant increase risk of bleeding; a fact that complicates decision making (Kabbinavar et al., 2003) . However, the highest incidence of VTE was observed in multiple myeloma patients treated with thalidomide, dexamethasone and doxorubicincontaining chemotherapy [Zangari et al., 2002). Higher VTE rates were also observed with thalidomide derivatives; lenalidomide and pomalidomide when used in combination with dexamethasone (Zonder et al., 2006 & Dimopoulos et al., 2007). Cancer-related risk factors are summarized in table-1.

Different antithrombotics including low molecular weight heparin (LMWH), low-dose warfarin, full-dose warfarin with target international normalized ratio (INR) of 2 to 3, and aspirin (ASA) were all tried to reduce the risk of VTE in cancer patients undergoing such therapy (Baz et al., 2005; Cavo M et al., 2004; Minnema et al., 2004). Specific recommendations in these clinical settings are beyond the scope of this review. However, in a recent trial that included a total of 667 patients with previously untreated multiple myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), fixed-dose warfarin (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment; of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the warfarin group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, - 3.0% to 5.7%; *P* =.544) in the ASA group and +3.2% (95% CI, - 1.5% to 7.8%; *P* = .183) in the warfarin group (Palumbo et al., 2011).

In addition to chemotherapy agents, drugs that are commonly used to support cancer patient while on active treatment may increase the risk of VTE. Erythropoiesis-stimulating agents (ESA); erythropoietin and darbepoietin are both associated with higher VTE rates. A meta-analysis of 35 trials in 6,769 cancer patients concluded that such treatment increased the risk of thromboembolic events by 67% compared with patients not receiving this therapy (Bohlius et al., 2006).
