Epidemiology of Cancer-Associated Thromboembolism

Introduction The link between cancer and venous thromboembolism (VTE) was established more than 150 years ago by Armand Trousseau.1 Since that time, multiple studies have provided evidence for a strong association between VTE and cancer. Understanding this link is of critical importance because VTE complicates management of cancer patients and has a negative impact on survival. Cancer is associated with a number of internal and external factors that increase risk for VTE. Established data indicate that cancer growth itself is associated with the development of a hypercoagulable state. Compounding the underlying pathophysiologic propensity for coagulation, patients with cancer also may have a number of underlying risk factors that contribute to the incidence of thromboembolic events, includingbut not limited to surgery, chemotherapy including anti-angiogenic therapy, hormonal therapy, long-term immobilization and central venous catheters. Emerging data have identified biomarkers that may be predictive of cancer-associated thrombosis. What is the risk for VTE in patients with cancer? Cancer is the strongest single risk factor for VTE. In fact, the population-based, case-control Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study found that the overall risk of VTE is increased 7-fold in patients with a malignancy.2 Using data from a population-based, nested, case-control study of 625 residents of Olmsted County, Minnesota, Heit and colleagues assessed risk factors for VTE.3 Of these cases, cancer (with or without chemotherapy) was responsible for 18% of cases of incident VTE. Cancer was the most important individual risk factor for VTE; for comparison, trauma, congestive heart failure, and prior central venous catheter or pacemaker placement were responsible for 12%, 10%, and 9% of VTE cases, respectively. The percentages of VTE cases attributable to various combinations of risk factors for VTE is shown in Figure 1. Notably, institutionalization with cancer accounted for approximately 65% of all cases of incident VTE.3 Figure 1. Percentages of VTE cases attributable to various combinations of risk factors3

Similar results were found in a much larger study conducted by White and colleagues using data from the California Discharge Data Set. In this population, there were 21 002 cases of incident VTE in 1996a crude incidence rate of 90 events per 100 000 adults.4 The percentage of incident VTE events accounted for by individual risk factors, broken down by racial/ethnic groups, is shown in Figure 2. Among cases of VTE that could be attributed to a specific condition, cancer and surgery were the 2 most prominent risk factors for VTE across races, accounting for approximately 21% of cases. Figure 2. Frequency distribution of VTE cases in a study of 21 002 cases of incident VTE in California, USA4

Increasing frequency of VTE in patients with cancer

Venous thromboembolism appears to be increasing in frequency over time. As part of a retrospective cohort study conducted by Khorana and colleagues, changes in the frequency of VTE in hospitalized neutropenic cancer patients were examined.5 Between 1995 and 2002, there was a 36% increase in the incidence of venous events and a 124% increase in arterial events (P<.0001) (Figure 3).

Figure 3. Increase in the proportion of patients with venous and arterial thromboembolism over time (P<.0001 for trend)5

Similarly, a second study using data from the National Hospital Discharge Survey (US) identified a substantial increase in the incidence of VTE in patients discharged with cancer between 1979 and 1989 (P<.001) (Figure 4).6 [POSTER SUMMARY] This increase substantially outpaced the increase in VTE incidence seen in noncancer patients. Over the same time period, there was also an increase in the incidence of pulmonary embolism (PE) among cancer patients that was greater than that seen in noncancer patients (Figure 5).

Figure 4. Change in incidence of VTE over time in cancer and noncancer patients, 197919996

Figure 5. Change in incidence of PE over time in cancer and noncancer patients, 1979-19996

Does the risk for VTE vary by cancer type?

The rate of VTE varies widely among cancer types, ranging from 16 per 10 000 patients with head/neck cancer to 120 per 10 000 patients with ovarian cancer (Table 1).7 As a group, malignancies with the highest incidence of VTE (kidney, stomach, pancreas, brain, ovary, lymphoma) were associated with a 4.126-fold increased risk for VTE compared with the group of cancers with the lowest risk for VTE (head/neck, bladder, breast, esophagus, uterus, and cervix) (P<.001).

Table 1. Rates of DVT/PE in different malignancies7

The MEGA study examined the risk for VTE by tumor site, the presence of distant metastases, and the carrier status of prothrombotic mutations.2 As summarized in Table 2, patients with hematologic malignancies had the highest risk for VTE, followed by patients with lung cancer and gastrointestinal cancer.

Table 2. Risk of VTE by type of malignancy in patients with a diagnosis of malignancy within 5 years before diagnosis of venous thrombosis2

How common is recurrent VTE in patients with cancer?

Data indicate that patients who develop thromboembolic disease in association with malignant disease are at higher risk for recurrent thromboembolic disease and death in comparison with patients with VTE who do not have an underlying malignancy.

The risk for recurrent VTE in patients with cancer was examined using Medicare hospital discharge data from 1988, 1989, and 1990.7 In this cohort of elderly patients, there were 8 177 634 admissions for nonmalignant disease, of which 46 848 (0.57%) were also diagnosed with DVT/PE, and 1 211 944 admissions for malignancy, of which 7238 (0.6%) were also diagnosed with DVT/PE.

In this study, the cumulative probability of readmission to the hospital with VTE within 183 days was highest among patients with a prior diagnosis of VTE and malignant disease (0.22), followed by those with a prior diagnosis of malignant disease (0.14), those with a prior diagnosis of nonmalignant disease (0.08), and those with a prior diagnosis of VTE alone (0.06). As shown in Figure 6, beginning at about 20 days, patients with concomitant VTE and malignant disease are at substantially higher risk for readmission for VTE.

Figure 6. Cumulative probability of hospital readmission with DVT/PE within 183 days of initial hospitalization by cohort (data from 1988 to 1990)7

What is the risk for death in patients with VTE and malignancy?

Patients with concurrent VTE and malignancy are at significantly higher risk for death than patients with VTE or malignancy alone.7 As shown in Figure 7, the cumulative probability of death within 183 days of initial hospitalization was also highest among patients with concurrent VTE and malignant disease (0.94), followed by patients with malignant disease without VTE (0.42), those with VTE alone (0.29), and those with a nonmalignant disease (0.26).7

Figure 7. Cumulative probability of death within 183 days of initial hospitalization by cohort (data from 1988 to 1990)7

Using data from the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files, Sorensen and colleagues found that, in patients with cancer at the time of VTE, the 1-year survival rate was 12%, as compared with 36% in the control group (P<.001) (Figure 8).8

Figure 8. Survival curves for patients with a diagnosis of cancer at the time of VTE and matched control patients with cancer8

What is the incidence of cancer in patients with VTE?

As summarized in module 7, cancers have long been known to be associated with the hypercoagulable state. It is reasonable to hypothesize that the presence of VTE may herald the presence of an "occult" malignancy. Several population-based studies have examined the risk for diagnosis of cancer after a primary thromboembolic event.

Population-based studies

Sorensen and colleagues examined whether there was an association between the occurrence of DVT or PE and a subsequent diagnosis of cancer by linking population-based data from the Danish National Registry of Patients to data from the Danish Cancer Registry. Cancer rates were estimated based on national age-, sex-, and site-specific rates of incidence.9 [POSTER SUMMARY]

The incidence ratio for all types of cancer was 1.3 in both patients with DVT and those with PE; this ratio was based on 1372 expected cases compared with 1737 cases observed in the

DVT cohort and 556 expected and 730 observed in the PE cohort. During the first 6 months of follow-up, the risk of cancer among patients with DVT and PE was 3 times the expected amount; risk declined to a constant level of ~1.0 one year after the thromboembolic event and throughout the study period (Figure 9). The strongest association between DVT and PE and cancer was seen in patients with pancreatic, ovarian, liver, and brain cancer.

Figure 9. Risk of cancer in relation to length of follow-up period in 26 653 patients with primary DVT or PE9

A second study, conducted by Murchison and colleagues, found that the risk for cancer remained significantly elevated for at least 2 years after a first episode of idiopathic VTE.10 The study, which used data from the National Health Service in Scotland, identified 77 572 patients with DVT, PE, or both who were diagnosed between 1981 and 2000, of whom 59 534 were included in the study. For all malignancies combined, there was a 4.2-fold increased risk for being diagnosed with cancer within 1 to 6 months of diagnosis of VTE. The risk for being diagnosed with cancer following VTE slowly declined through a follow-up period of 2 years to a level consistent with the general population. Of note, VTE was most strongly linked to subsequent diagnosis of ovarian cancer, Hodgkins lymphoma, and nonHodgkins lymphoma.

Similarly, a study conducted by Baron and colleagues, using data from the Swedish Inpatient Register and the nationwide Cancer Registry, found that the risk for cancer among patients admitted for thromboembolic disease was elevated at the time of first VTE admission or within the first year afterwards.11 For all cancers, the standardized incidence ratio (SIR) was 4.4. Among patients aged 65 years and >65 years, the SIRs were 6.7 and 3.9, respectively (P<.0001 for both). Patients with 2 admissions for VTE had a very high risk in the year after the second episode (SIR=8.2). SIRs were highest for polycythemia vera (12.9), followed by ovarian (11.4), pancreas (7.8), and brain (7.6) cancer, and Hodgkin lymphoma (7.4).

Meta-analysis

A recent meta-analysis examined the period prevalence of previously undiagnosed cancer within 1, 6, and 12 months after VTE diagnosis and to quantify the value of extensive cancer screening compared with more limited screening in patients admitted for an episode of VTE.12 Thirty-six studies that reported the prevalence of undiagnosed cancer up to 1 year after VTE diagnosis and 15 studies that assessed extensive versus limited cancer screening were identified. Across all studies, the period prevalence of previously undiagnosed cancer in patients with a first episode of VTE was 6.1% at baseline and 10.0% from baseline to 12 months. Is there value in prospectively screening patients with VTE for occult cancer?

The evidence summarized above suggests that the risk for clinically overt malignancy is increased among patients with idiopathic VTE. Thus, it is reasonable to suggest that cancer screening may be warranted in patients who present idiopathic VTE.

A prospective study conducted by Monreal and colleagues illustrates the potential value and limitations of screening of patients with VTE for occult cancer.13 All patients who presented confirmed DVT or PE (N=864) underwent routine examination for malignancy; of these, malignancies were detected in 34, a prevalence of cancer as identified by routine examine of 3.9%. Among the remaining 830 patients, diagnostic workup confirmed the presence of malignant disease in an additional 13 patients, a prevalence as identified by this workup of 1.6%. Among patients in whom no cancer was detected, cancer became symptomatic in 14 patients (1.7%), yielding a sensitivity for the limited diagnostic workup of 48.1%. Notably, however, malignancies identified by the limited diagnostic workup were generally earlier stage (61.5%) compared with those that developed during follow-up (14.3%). This study suggests that approximately half of occult malignancies can be detected with a limited

diagnostic workup following admission for idiopathic VTE. As importantly, it suggests that VTE may present an opportunity to diagnose cancers earlier.

The value of extensive screening for occult cancer in apparently cancer-free patients with acute idiopathic VTE was also examined in a recent study conducted by Piccioli and colleagues.14 Patients with a documented first episode of idiopathic symptomatic VTE were randomized to a strategy of extensive screening for cancer (n=99) or no screening (n=102). Extensive screening consisted of abdominal ultrasound and CT scanning, gastroscopy or double-contrast barium swallowing, colonoscopy or sigmoidoscopy, followed by barium enema, hemoccult, sputum cytology and tumor markers including carcinoembryonic antigen (CEA), -fetoprotein ( -FP) and CA125. Women received mammography and pap smear, and men received ultrasound of the prostate and total specific prostate antigen (PSA). Followup was for 24 months; the primary outcome measure was cancer-related mortality.

In the extensive screening group, occult cancer was detected in 13 (13.1%) patients at screening. During the follow-up period, 1 (1.0%) malignancy was detected in the extensive screening group, whereas 10 (9.8%) malignancies became symptomatic in the no-screening group. Thus, 13 of the 14 malignancies that occurred in the extensive screening group were detected at screening, yielding a sensitivity of 93%. Malignancies detected in the extensive screening group were, in general, less advanced than those that became clinically apparent during the 2-year follow-up in the no-screening group. Two patients in the extensive screening group and 4 in the no-screening group died from cancer.

In the previously mentioned meta-analysis conducted by Carrier and colleagues,12 the additional value of extensive cancer screening (limited screening plus imaging techniques or tumor marker measurement) compared with more limited screening (history, physical examination, and simple widely-available tests) was assessed using data from 15 studies. Across all studies, an extensive screening strategy using computed tomography of the abdomen and pelvis significantly increased the proportion of previously undiagnosed cancer from 49.4% to 69.7% in patients with idiopathic VTE.

Summary: Is there value in extensive screening in patients with idiopathic VTE?

These studies suggest that extensive screening, compared with no screening or only limited screening, can provide value in detecting occult cancers in patients presenting idiopathic VTE. However, complication rates from screening, cost-effectiveness, and differences in morbidity and mortality associated with extensive screening strategies have yet to be

sufficiently evaluated, so until further data are available extensive screening is not recommended. References (Click on reference for link to PubMed abstract)

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