Venous thromboembolism (VTE) represents one of the most important causes of morbidity and mortality in cancer patients. VTE commonly includes deep vein thrombosis and pulmonary embolism, but also includes thrombosis in other vascular territories. Trousseau first described the association between thrombosis and malignancy in 1885. The pathophysiology of venous thromboembolism is related to multiple factors including hypercoagulability, vessel wall damage and venous stasis. Age, surgery, the presence of central venous indwelling catheters, performance status, immobilisation, prolonged hospitalisation, acquired or congenital thrombophilia and other comorbidities also influence the overall likelihood of thrombotic complications, as they do in patients without cancer. 

The interrelationship between cancer and haemostasis is well known. Risk factors for thromboembolism in cancer patients include the cancer type, histology and the stage of the cancer. The risk of VTE is also increased in cancer patients by certain types of chemotherapy, hormonal therapy and anti-angiogenic regimens.

VTE development has serious clinical consequences and can have major impact on the clinical course of the disease, increasing both morbidity and mortality. The poor prognosis of VTE may reflect both a combination of fatal complications and higher disease agressiveness.¹

Incidence

According to population-based case-control studies, the two-year cumulative incidence of VTE is between 0.8% and 8%.² In a recent study of 17,284 patients undergoing chemotherapy in the ambulatory setting, VTE occurred in 12.6% of patients within 12 months of starting chemotherapy. The incidence of VTE in patients without cancer was 1.4% in the control cohort group.³

The increased risk of recurrent VTE in cancer patients is greatest in the first few months after malignancy is diagnosed and can persist for many years after an initial episode of symptomatic VTE. 

The most reliable evidence of the incidence of VTE in individuals with a specific malignancy comes from controlled clinical trials of systemic therapy in women with early-stage breast cancer. The B14 and B20 trials in the National Surgical Adjuvant Breast Project^4,5 involved women with oestrogen receptor-positive lymph node-negative breast cancer. It found the five-year incidences of VTE in women given placebo, tamoxifen, and tamoxifen plus chemotherapy were 0.2%, 0.9%, and 4.2%, respectively. In women with node-positive breast cancer on chemotherapy, the rate of thrombosis varies between 1% and 10%.⁶

A recent study found a 2.87% incidence of PE in a total of 13,783 outpatients with cancer in a single institution.⁷ The incidence of PE in the general population has been reported to be 0.11%.⁸

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Chemotherapy

Chemotherapy can increase the risk of VTE by at least four mechanisms including damaging vessel walls and endothelium, decreasing natural coagulation inhibitors (reduced level of C and S proteins or antithrombin III), and platelet activation.⁹ Antiangiogenic agents, such as bevacizumab, thalidomide and lenalidomide, also contribute to thrombosis.¹⁰ This thrombogenic effect is amplified by the co-administration of chemotherapy. In a recent meta-analysis of clinical trials of bevacizumab administered concomitantly with chemotherapy, the use of bevacizumab was associated with a 33% relative increase of VTE.¹¹ Among patients receiving bevacizumab, the overall incidence of any-grade and high-grade VTE was 11.9 and 6.3%, respectively. 

Tumours most strongly associated with thrombosis

Autopsy studies and retrospective reviews have shown that cancers of the pancreas, lung, stomach, and adenocarcinomas of unknown primary are most strongly associated with thrombosis. However, the rate appears to vary from study to study. 

In a large population-based study that used the discharge diagnoses of over 7,000 Medicare patients admitted to hospital with a diagnosis of both malignancy and VTE, Levitan et al found the highest rates of VTE in cases of ovarian cancer (1.2%), brain tumours (1.2%), and cancer of the pancreas (1.1%) when the data is adjusted for the prevalence of these tumour types. It found that lung cancer accounted for 21% of cases of VTE, colon cancer for 18%, and prostate cancer for 17%.¹²

Khorana et al recently reviewed over 17,000 patients and found an incidence ranging from 19.2% in pancreatic cancer to 8.2% in bladder cancer.³

Prognosis of patients with cancer and VTE

Patients with cancer who develop VTE have reduced life expectancy. On the basis of long-term follow-up data on patients with thrombosis, those with cancer have a four- to eight-fold higher risk of dying after an acute thrombotic event than patients without cancer.^13,14 Furthermore, patients with cancer and thrombosis have a lower survival rate than those with cancer without thrombosis. 

In a large population-based study, Sørensen et al examined the survival of patients with cancer and VTE compared with those without VTE matched for type of cancer, sex, age, and the year of diagnosis.¹⁵ The one-year survival rate for patients with thrombosis was 12% compared with 36% in control patients. The mortality ratio associated with VTE was 2.2 for the one-year follow-up period. 

The one-year mortality rate for PE has been reported as 24%. This high mortality probably reflects deaths due to both thromboembolism and a more aggressive course of malignancies associated with VTE.¹⁶

Thromboprophylaxis

The incidence of VTE is higher in cancer outpatients compared to inpatients (78% versus 22%; p < 0.0001).³ The National Comprehensive Cancer Network (NCCN) guidelines suggest that the option of thromboprophylaxis should be discussed with patients based on their individual risk profile for developing VTE. 

The Khorana model may be used to assess this risk.¹⁷ It uses certain parameters such as the site of the primary cancer, the platelet count, the haemoglobin level, the white cell count and body mass index (BMI) (see Table 1). A scoring system categorises patients into a low, intermediate or high-risk group for developing VTE. Patients with a Khorana score of three or higher are considered high risk for VTE and should be considered for outpatient VTE prophylaxis.

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A number of trials have continued to evaluate the benefit of outpatient thromboprophylaxis. The PROTECHT trial showed that the low-molecular-weight heparin (LMWH) nadroparin halved the rate of the composite end-point of symptomatic VTEs and arterial thromboembolic events, compared with placebo (20% versus 3.9%), with a number needed to treat of 53.¹⁸ In CONKO-004, the rate of VTE in pancreatic cancer receiving chemotherapy was reduced at three and 12 months with enoxaparin prophylaxis, however, there was no improvement in overall survival.¹⁹

In 2012, the SAVE-ONCO trial showed that the LMWH semuloparin significantly decreased the rate of symptomatic VTEs, compared with placebo (1.2% versus 3.4%), with a number needed to treat of 45. However, there was no survival advantage (43% versus 44.5%).²⁰

Current ASCO guidelines do not recommend routine thromboprophylaxis for outpatients with cancer.²¹ Thromboprophylaxis may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy should receive prophylaxis with either low-molecular-weight heparin (LMWH) or low-dose aspirin. 

Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least seven to 10 days. Extending prophylaxis up to four weeks should be considered in those with high-risk features. 

LMWH is recommended for the initial five to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term (six months) secondary prophylaxis. Novel oral anticoagulants do not currently carry the indication, and therefore are not currently recommended, for prophylaxis or treatment of VTE in malignancy.  

Novel oral anticoagulants should not be used for cancer treatment in the absence of other approved indications. Patients with cancer should be periodically assessed for VTE risk and patients should be educated about the signs and symptoms of VTE. 

Conclusion

Patients with cancer are at higher risk for developing thromboembolic disease. Further research will provide more reliable estimates of the thrombotic risk associated with different types of tumours, stages of disease, and antitumour treatments, which will help to improve the prophylactic and treatment strategies for VTE in these complex patients.

References

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