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December 2003

Principal Developer: M.F. Scully
Secondary Developers: W. Geerts, M. Kovacs, A. Lee

 Cancer & Thrombosis

Cancer and Venous Thrombo-Embolic Disease – A Significant Issue

  • Active cancer accounts for almost 20% of all new venous thrombo-embolic events occurring in the community
  • Most common cancers in patients with VTE are lung, breast, colorectal and prostate.
  • Patients presenting with unprovoked venous thrombo-embolic events have a 10% risk of developing cancer within the next two years
  • Occult malignancy is 3-4 times higher in patients who present with idiopathic thrombo-embolic disease versus patients with a secondary venous thrombo-embolic event
  • Patients who receive a diagnosis of cancer at the same time or within one year of an episode of a venous thrombo-embolic event have a shorter life expectancy than patients with cancer who do not have thrombosis
  • In cancer patients who undergo surgery the risk of a post-operative DVT is twice that of patients without cancer
  • Preliminary evidence suggests that prolonged prophylaxis with low molecular weight heparin after surgery for three weeks will significantly decrease the risk of venous thrombo-embolic disease
  • While on anticoagulant therapy, the risk of bleeding is six times higher and the risk of recurrent VTE is 2-3 times higher in cancer patients than in non-cancer patients

There is a very strong association between cancer and venous thromboembolism. This association was first suggested in 1865 by Dr. Armand Trousseau, who later developed unexplained deep vein thrombosis and then died of a gastric carcinoma.

The malignancies most frequently seen in patients with deep venous thrombosis or pulmonary emboli are lung, breast, colon and prostate cancer, the commonest malignancies seen in industrialized countries. However, certain malignancies are particularly associated with a high risk of venous thrombo-embolic disease. These include malignant brain tumours and adenocarcinoma, including ovary, pancreas, colon, stomach, lung and kidney. Risk factors for venous thrombo-embolic disease in patients with cancer include immobility, use of central venous access devices, hormonal therapy, chemotherapy and surgery.

Screening for Occult Malignancy in Idiopathic Venous Thrombo-Embolic Disease

Potentially 10% of patients who present with unprovoked idiopathic thrombosis are diagnosed with cancer within two years of their initial thrombotic event. The incidence of cancer is highest in the first 6-12 months after a diagnosis of idiopathic VTE and approximately 40% of patients already have metastatic disease when their cancer becomes clinically evident. Because there is no evidence that invasive screening in asymptomatic patients improves survival, we recommend that appropriate investigations for malignancy be performed only if indicated by history (e.g., unexplained weight loss), the presence of suspicious physical findings or abnormal routine bloodwork.

Prevention of Venous Thrombo-Embolic Disease in Cancer Patients

Central Venous Access Devices (CVAD) - The presence of a central venous access device alters the blood flow in the upper venous system and is an independent risk factor for upper extremity deep venous thrombosis. Low dose warfarin or low dose LMWH prophylaxis has been used for prevention of catheter-related thrombosis but recently completed randomized studies have shown no benefit from warfarin 1mg/day or dalteparin 5000 IU once daily compared to placebo. Furthermore, the risk of symptomatic thrombosis in adults is approximately 3%, which is much lower than previously reported. The risk of clinically relevant VTE is likely higher in children. It is possible that improvements in the manufacture of central venous access devices have decreased the risk of venous thrombo-embolic disease. The optimal prevention of venous thrombo-embolic disease in association with the use of these devices remains unclear and we cannot recommend low dose anticoagulation for routine prophylaxis.

Chemotherapy - Although one RCT has shown that low dose warfarin can safely reduce symptomatic VTE in women with stage IV breast cancer who are receiving chemotherapy, there is no recommendation for routine primary prophylaxis in ambulatory medical oncology patients. Prophylaxis may be considered in patients who have additional risk factors, such as previous history of VTE or known thrombophilia, if their risk of bleeding is low. Cancer patients who are hospitalized and who are immobile should receive prophylaxis according to guidelines appropriate for hospitalized medical patients.

Hormonal Therapy - Hormonal manipulation also affects venous thrombo-embolic risk. The risk of venous thrombo-embolic disease is increased 2-6 times among women with breast cancer receiving adjuvant tamoxifen therapy compared to patients taking placebo. When tamoxifen is used for the primary prevention of breast cancer, it is associated with an increased relative risk of deep venous thrombosis and pulmonary embolism of 1.6 and 3.0, respectively.  Aromatase inhibitors have a lower risk of VTE than tamoxifen and are a reasonable alternative in women with other risk factors for VTE. Studies have not been done to evaluate the efficacy or safety of primary prophylaxis in cancer patients receiving hormonal therapy.

Surgery – Cancer patients who require surgery are twice as likely as non-cancer patients to develop post-operative DVT and more than three times as likely to develop fatal PE. Patients with cancer are also more likely to develop venous thrombo-embolism despite prophylaxis. There is good evidence that low dose unfractionated heparin (5000 U three times a day) will reduce DVT and fatal PE following cancer surgery.  Low molecular weight heparin once daily is at least as effective as low dose unfractionated heparin in surgical oncology patients.  Two recently published clinical trials have shown that continuation of low molecular weight heparin prophylaxis for 3 weeks after discharge in patients who underwent cancer surgery reduced the risk of late venous thrombo-embolic disease by 62% based on venography. Further studies are necessary to evaluate whether extended prophylaxis will reduce symptomatic VTE. Patients who had protracted surgery or experience prolonged immobilization are likely to benefit.

Management of Patients with Venous Thromboembolic Disease

The diagnosis of a venous thrombo-embolic event in a patient with cancer is more challenging than in a non-cancer patient. Standard objective investigations (compression ultrasound, ventilation-perfusion lung scanning, spiral computed tomography) are all useful for diagnosing VTE in cancer patients. However, D-dimer tests are less reliable and less useful for excluding DVT in cancer patients as the D-dimer level is often raised in these patients. There is a higher risk of progressive and recurrent VTE and there is an increased risk of bleeding in cancer patients. Unfractionated heparin or LMWH should be considered as first-line treatment for acute VTE. LMWH is preferred because it can be given on an outpatient basis and is associated with a lower risk of HIT. Based on recent evidence from randomized clinical trials that LMWH is more effective and as safe as warfarin for prevention of recurrent VTE in cancer patients, LMWH should be considered for long term treatment. LMWH also obviates laboratory monitoring and has fewer drug interactions. In patients with significant GI disturbance and poor nutrition, LMWH also avoids the unpredictable anticoagulant responses associated with warfarin.

In patients with a major risk of bleeding, the use of a temporary or long-term inferior vena cava filter (IVC) may prevent pulmonary embolism in those with proximal DVT. However, IVC filters may increase the risk of recurrent DVT in the lower limbs and the risk of post-phlebitic syndrome.

Anticoagulant therapy should be continued while the patient is on active cancer therapy or has any evidence of active cancer. However, discontinuation should be considered when patients develop potentially life-threatening bleeding or has a very short life expectancy.

Summary of Recommendations
  • We recommend that appropriate investigations for malignancy be performed in patients with unprovoked VTE only if indicated by history, the presence of suspicious physical findings or abnormal routine blood work.
  • The optimal prevention of venous thrombo-embolic disease in association with the use of CVAD remains unclear and we cannot recommend low dose anticoagulation for routine prophylaxis.
  • Cancer patients who are hospitalized and who are immobile should receive prophylaxis according to guidelines appropriate for hospitalized medical patients. Studies have not been done to evaluate the efficacy or safety of primary prophylaxis in ambulatory cancer patients receiving chemotherapy or hormonal therapy.
  • Aromatase inhibitors have a lower risk of VTE than tamoxifen and are a reasonable alternative in women with other risk factors for VTE.
  • Patients who had protracted surgery or experience prolonged immobilization are likely to benefit from prophylaxis for 3 weeks or more post-discharge.
  • Standard objective testing is essential to confirm or refute a diagnosis of DVT or PE. D-dimer tests are less reliable and less useful for excluding DVT in cancer patients.
  • Monotherapy with LMWH should be considered as first-line therapy for acute treatment and secondary prevention of VTE. .

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