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I. INTRODUCTION. Cancer patients have a 5- to 7-fold increased risk of developing venous thromboemboli (VTE) compared with noncancer patients (JAMA 2005;293:715), with cancer-associated VTE accounting for 20% to 30% of all VTEs (J Thromb Haemost 2007;5:692). Patients with cancer-associated VTE had decreased survival compared with their thrombosis-free counterparts matched by cancer type and stage. When treated with anticoagulation, cancer patients have higher rates of major bleeding events compared with patients with VTE without cancer (Blood 2002;100:3484).
II. PATHOPHYSIOLOGY AND RISK FACTORS. A clearer understanding of the complex pathophysiology of cancer-associated thrombosis is beginning to emerge. In response to cancer-induced inflammatory cytokines, tissue factor (TF) or cancer procoagulants are aberrantly expressed on the surface of cancer cells, monocytes, and endothelial cells, promoting a hypercoagulable state, angiogenesis, and tumor metastasis. Secondly, decreased patient activity due to the disease or therapy leads to increased venous stasis. In addition, vascular injury from surgery, chemotherapy, radiation, and central venous catheters (CVCs) are major risk factors for VTE, completing Vichow’s triad. Thus, cancer is a heterogeneous disease, with varying VTE risk based on cancer subtype and stage, patient-associated factors, and cancer-specific therapy.
A. Type of cancer. A higher VTE risk has been noted in biologically aggressive malignancies with early metastatic potential and short overall survivals. Cancers associated with the highest risk of VTE include lung, pancreas, brain, ovary, and hematologic malignancies (myeloma, lymphoma, leukemia) (JAMA 2005;293:715).
B. Stage of cancer. As expected, more advanced stage is associated with higher risk (JAMA 2005;293:715).
C. Timing related to cancer diagnosis. Patients are at highest risk for VTE in the time period immediately following cancer diagnosis. This is hypothesized to be due to the presence of the largest disease burden; in addition, this period correlates with initiation of therapy (i.e., chemotherapy/surgery). In a study by Blom et al., VTE risk was highest in the 3 months after diagnosis (53-fold risk) and decreased over time (JAMA 2005;293:715).
D. Patient-associated risk factors. These are similar to those in noncancer patients and include age, race, obesity, presence of medical comorbidities, surgery, history of VTE, presence of hereditary thrombophilia, and leukocytosis and/or thrombocytosis.
E. Cancer treatment. Recent surgery is a well-documented risk factor for VTE in both cancer and noncancer patients. Pathophysiology is attributed to direct vascular damage, prolonged immobility, and presence of an inflammatory state. It should be assumed that all patients receiving chemotherapy or hormonal therapy are at increased risk of VTE. Plausible mechanisms for this prothrombotic state include decreased activity of physiologic anticoagulants, release of procoagulants from apoptotic cancer cells, and drug-induced injury to endothelial cells. Some of the specific therapies that have been associated with increased risk of VTE in randomized, prospective trials include cisplatin therapy, hormonal therapy, antiangiogenic agents, erythrocyte-stimulating agents (ESAs), and immunomodulatory agents (i.e., lenalidomide and thalidomide).
The knowledge of these potential risk factors for VTE in cancer patients can guide clinicians to identify patients with increased risk of VTE.
Several risk prediction models have been generated to identify cancer patients at greatest risk of developing VTE. The 2013 American Society of Clinical Oncology (ASCO) VTE guidelines recommend the use of the model proposed by Khorana et al., given that it has been validated in a large population of cancer patients (Blood 2008;111:4902). The model was generated using a cohort of 4,066 ambulatory cancer patients initiated on chemotherapy. Several important risk factors for VTE were identified in multivariate analysis, including site of cancer, prechemotherapy platelet and leukocyte counts, hemoglobin or use of red cell growth factors, and body mass index (BMI). Each risk factor was assigned a corresponding score in the point system. Patients were then divided into three groups: high risk ($3 points), intermediate risk (1 to 2 points), and low risk (0 points), with VTE rates of 6.7%, 2%, and 0.3%, respectively, over a 2.5-month period. While the clinical utility of such models remains poorly defined beyond patient education, incorporation of these tools in the future will allow identification of patients at highest risk of VTE and potential consideration for thromboprophylaxis.
III. VENOUS THROMBOSES AND OCCULT CANCER. About 20% to 30% of all newly diagnosed VTE are cancer associated. The majority of these cases will present with thrombosis following diagnosis of an established malignancy. However, a significant percentage of patients with seemingly idiopathic VTE will subsequently be diagnosed with cancer. This association has raised the question of the clinical benefit of cancer screening in patients who present with idiopathic VTE.
In a landmark study by Prandoni et al. (N Engl J Med 1992;327:1128), 260 consecutive outpatients with objectively diagnosed deep vein thrombosis (DVT) were followed for 2 years. Development of cancer in patients was compared between the idiopathic (n = 153) and secondary DVT (n = 107) groups. History, physical, and routine laboratory testing were performed at VTE diagnosis in each group, identifying 3.3% (n = 5) of patients in the idiopathic (2 lung cancers, 1 multiple myeloma, 1 chronic lymphocytic leukemia, and 1 osteosarcoma) compared to no patients in the secondary DVT group with an underlying malignancy. During the 2-year follow-up in the remaining patients, symptomatic malignancies were diagnosed in 11 of 145 patients (7.6%) with idiopathic DVT compared to 2 of 105 patients (1.9%) with secondary DVT. The majority of malignancies (77%) were diagnosed in the first 12 months of follow-up, with all cases diagnosed by 18 months. A similar association between occult malignancy and idiopathic VTE is further supported by findings from retrospective studies using hospital discharge administrative databases.
Given the association, oncologists may be asked to evaluate patients with idiopathic VTE for occult cancer. Limited prospective data are available for guidance. In the SOMIT trial, 233 patients with newly diagnosed, idiopathic VTE were randomized to receive cancer screening (abdominal/pelvic ultrasound or computed tomography [CT], endoscopy, colonoscopy, hemoccult testing, sputum cytology, serum tumor markers, mammogram, and pelvic exam with cytology for women and prostate ultrasonography for men) or routine follow-up (J Thromb Haemost 2004;2:884). At baseline, all patients underwent history, physical, and routine laboratory tests, during which 32 cancers were diagnosed (14%). An additional 13 of 99 patients (13%) in the screening group were diagnosed with cancer based on the additional procedures. During the 2-year follow-up, one cancer was diagnosed in the screening arm compared to 10 cases in 102 patients in the control arm, with no significant difference in mortality between the arms (2% vs. 3.9%, respectively). However, the study was closed early due to poor accrual, failing to meet a target enrollment of 1,000 patients. A cost-effective analysis of the trial concluded that abdominal/pelvic CT was the most cost-effective test, and tumor markers were associated with high false-positive rates generating additional unnecessary testing.
In a second, large prospective cohort study (J Thromb Haemost 2004;2:876), the impact of cancer screening was also assessed in new, idiopathic VTE. In this trial, 864 patients were initially evaluated with history, physical (including rectal), breast and pelvic exam in women, routine laboratory tests (in addition to erythrocyte sedimentation rate and serum protein electrophoresis), and chest X-ray (CXR), at which time a total of 34 cancers were detected, the majority of which were limited in stage (61%). Patients who did not have a cancer diagnosed in step 1 (n = 830) underwent a “limited” workup consisted of an abdominal/pelvic ultrasound, Carcinoembryonic antigen (CEA), and Prostate-specific antigen (PSA) in men and CA-125 in women, revealing an additional 13 cancers. The remaining patients (n = 817) were followed for 12 months for the occurrence of cancer. During the 12-month follow-up, 14 additional malignancies were diagnosed, of which 14% were limited stage for a total of 61 malignancies. The results of this study suggest that in adults with idiopathic VTE, more than 50% of underlying occult malignancies can be detected with a limited initial evaluation, followed by age/sex appropriate cancer screening. Patients diagnosed at the time of presentation tend to be diagnosed with earlier stage cancers compared with those diagnosed during follow-up. Despite diagnosis at early stage, data have not yet indicated a proven survival benefit for cancer screening in patients with idiopathic VTE.
In summary, 20% to 30% of all newly diagnosed idiopathic VTEs are cancer associated. While a significant proportion of cancers are known at the time of VTE diagnosis, the majority of the remaining cases will be established between presentation and the following 12 months. Aggressive screening for occult cancers in asymptomatic patients with idiopathic VTEs has not been associated with improvement in survival and is thus not recommended. However, limited evaluation with history, physical, routine labs, and age/gender appropriate cancer screening is a reasonable strategy.
IV. PREVENTION OF VTE IN PATIENTS WITH CANCER. Cancer patients have a sevenfold increased risk of VTE compared to persons without cancer, with risk highest in the first 3 months after cancer diagnosis (53-fold increased risk) (JAMA 2005;293:715). One of the main reasons for this high risk of VTE is due to surgical, chemotherapy, and hormonal interventions, and can be reduced by employing prevention strategies.
A. Prophylaxis against VTE in patients with cancer in the perioperative setting.
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