Thrombosis Research 129, Supplement 1 (2012) S10S15

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Risk assessment for cancer-associated thrombosis: What is the best approach?

Alok A. Khorana *
James P. Wilmot Cancer Center, and the Department of Medicine, University of Rochester, Rochester, NY, USA

A R T I C L E

I N F O

A B S T R A C T Venous thromboembolism (VTE) is an increasingly frequent complication of cancer and its treatments. One in ve cancer patients are estimated to develop venous and arterial events during the natural history of their illness. However, the risk for VTE varies widely between various subgroups of cancer patients and even in the same cancer patient over time. This narrative review focuses on risk factors, biomarkers and risk assessment tools and attempts to clarify approaches to risk stratication. Clinical risk factors include primary site of cancer, chemotherapy, anti-angiogenic therapy, surgery and hospitalization. Predictive and candidate biomarkers include platelet and leukocyte counts, hemoglobin, D-dimer and tissue factor. However, single risk factors or biomarkers have not, in general, been able to identify suciently high-risk populations. A clinical risk score, incorporating 5 simple clinical and laboratory variables, has now been studied in over 10,000 patients and can successfully categorize patients at low- and high-risk for VTE. Recent trials have shown that outpatient prophylactic anticoagulation is both safe and effective, but event rates have been highly variable. Targeted thromboprophylaxis provides an optimal riskbenet ratio and the best opportunity to reduce the burden of VTE and its consequences for patients with cancer. 2012 Elsevier Ltd. All rights reserved.

Keywords: Venous thromboembolism Prevention Risk factors Cancer

1. Introduction Cancer patients frequently experience thromboembolic events (TEEs) and the risk of such events is increased several-fold in the cancer population when compared to the general population [1]. Additionally, the frequency of both venous and arterial events has increased substantially in the past decade [2]. However, the risk varies widely between subgroups of cancer patients and in individual patients over time [3,4]. Even if we are to accept the conventional estimate that one in ve cancer patients will develop venous thromboembolism (VTE) during the natural history of their illness, this implies that four in ve cancer patients will not suffer from VTE. VTE is largely preventable with the appropriate use of prophylactic anticoagulants [5]. However, unlike other settings where prophylactic anticoagulation is successful and widely used, the risk for VTE in cancer can persist over a period of several weeks to months. Identifying cancer patients at highest risk for VTE, therefore, is of crucial importance to avoid the burden and potential complications of long-term anticoagulants in patients who do not need them and, conversely, to provide these drugs to patients truly at risk. This narrative review will focus on reviewing recent data on clinical risk factors, predictive biomarkers and risk assessment tools with an emphasis on identifying best practice approaches to assessing risk of VTE in the cancer patient.

2. A note on rates of TEE A host of publications in the past decade have provided contemporary information regarding the incidence, prevalence and burden of TEEs in the cancer population (reviewed in [3]). However, rates of VTE reported across these studies vary widely even when similar populations are studied. This has been a source of frustration for clinicians and investigators focused on study design of prophylaxis studies, since sample size determinations rest heavily on anticipated VTE rates. It is important, therefore, to understand the context within which rates are reported and discussed in the literature as well as the reasons for these disparities in reported rates (Table 1). Firstly, the study endpoint varies across studies; more recent studies utilize what has been described [6] as an extended denition of TEE, which includes visceral thromboses, arterial events and incidentally discovered events. There is good scientic rationale to support such an extended denition since thrombotic events are linked pathophysiologically and because incidental and similar adverse outcomes are noted for visceral events as for symptomatic events [7,8]. However, such a denition needs to be standardized. Secondly, rates are generally higher if TEE constitute the primary or secondary endpoint of the study and TEE rates are often underestimated when events are recorded as toxicity data for clinical trials. Indeed, in one analysis of a clinical trial in advanced colorectal cancer, 90% of VTE cases were not identied by usual toxicity reporting and only discovered on subsequent chart review [9]. In a meta-analysis of TEE endpoints in cancer studies, incidence rates of VTE outcomes were 355 times higher for active surveillance than for passive surveillance [10]. Next, the

* Correspondence to: Alok A. Khorana, MD, 601 Elmwood Ave, Box 704, Rochester, NY 14642, USA. Tel.: +1 (585) 273-4150; fax: +1 (585) 273-1042. E-mail address: alok_khorana@urmc.rochester.edu (A.A. Khorana). 0049-3848/$ see front matter 2012 Elsevier Ltd. All rights reserved.

A.A. Khorana / Thrombosis Research 129, Supplement 1 (2012) S10S15 Table 1 Reasons for disparities in rates of TEEs across studies. Study endpoints Higher rates if incidental events included Higher if visceral thromboses included Higher if arterial events included Higher if screening studies conducted Higher if TEE primary or secondary endpoint; lower if TEE collected as part of toxicity reporting Higher for active versus passive surveillance Study population Higher rates in North America; lower in Asia Higher in retrospective studies; lower in clinical trials Higher if studies focused on high-risk populations (on systemic therapy, specic sites of cancer); lower in large, heterogeneous study populations Higher in more contemporaneous reports Duration of follow-up Table 2 Selected clinical risk factors and biomarkers for cancer-associated thrombosis. Patient-associated risk factors Older age Race Gender Medical comorbidities Obesity Past history of thrombosis Cancer-associated risk factors Primary site Stage Cancer histology (higher for adenocarcinoma than squamous cell) Time after initial diagnosis (highest in rst 36 months) Treatment-associated risk factors Chemotherapy Anti-angiogenic agents (thalidomide, lenalidomide) Hormonal therapy Erythropoiesis-stimulating agents Transfusions Indwelling venous access devices Radiation Surgery Biomarkers Currently widely available Platelet count (350,000/mm3 ) Leukocyte count (>11,000/mm3 ) Hemoglobin (<10 g/dL) D-dimer Investigational or not widely available Tissue factor (antigen expression, circulating microparticles, antigen or activity levels) Soluble P-selectin (>53.1 ng/mL) Factor VIII Prothrombin fragment F 1 + 2 (>358 pmol/L)

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composition of the study population can greatly affect reported rates since the case mix is in and of itself an important risk factor for VTE. Thus, studies that are population-based and involve heterogeneous cancer sites generally report lower rates than studies focused on specic cancers (e.g., pancreas or lung [11,12]) or specic chemotherapy regimens (e.g., cisplatin-based therapy [13]). Finally, the duration of follow-up can inuence rates as well. An excellent illustration of such disparities is the difference in rates reported for high-risk patients in the development and validation of a clinical risk score. In the original report [14], high-risk patients had a risk of VTE of 6.77.1% but this was based on a median follow-up of approximately 2.5 months; in addition, VTE reporting was not a primary or secondary endpoint of the study. In an external validation of this risk score performed by the Vienna CATS group [15], rates in the high-risk cohort were much greater at 17.7% but this was reported at a 6 month follow-up period and VTE was in fact a primary endpoint of this study. It is important to keep all of these considerations in mind when conducting cross-study comparisons and when utilizing these data to estimate rates for the design of future studies. 3. Clinical risk factors Clinical risk factors for VTE include patient-related, cancerrelated and treatment-related risk factors (Table 2). Patient-related risk factors include demographics such as older age and African American race [2]. Comorbid conditions are strongly associated with VTE, particularly infection, pulmonary disease, renal disease and obesity [16]. Cancer patients with a prior history of VTE have a 67 fold increased risk of developing VTE compared to cancer patients with no history of VTE [17]. The primary site of cancer has historically been considered the most important clinical risk factor. Highest rates of VTE are observed in patients with brain, pancreas, stomach, kidney, ovary and lung cancers [3]. Patients with hematologic malignancies are also at high risk (in one study, odds ratio [OR] 28, 95% CI 4.0199.7) [4]. The rate of VTE is especially high during the initial period after diagnosis. In the populationbased study discussed above, risk of VTE was highest in the rst 3 months after initial diagnosis of cancer (OR 53.5, 95% CI 8.6334.3), with some degree of elevated risk persisting for several years [4]. Therapeutic interventions further enhance the risk of VTE. The use of systemic chemotherapy is associated with a 2- to 6-fold increased risk of VTE compared to the general population [18,19]. VTE risk may further be inuenced by specic anti-neoplastic agents and regimens. For instance; in an analysis of patients with metastatic gastric and gastro-esophageal junction cancers, thromboembolism rates were 15.1% in patients receiving cisplatin compared to 7.6% in patients receiving oxaliplatin [20]. Antiangiogenic agents, particularly thalidomide and lenalidomide, have

been associated with high rates of VTE when given in combination with dexamethasone or chemotherapy. Bevacizumab-containing regimens have been associated with increased risk for an arterial thromboembolic event (hazard ratio [HR] 2.0, 95% CI 1.053.75) but the data for risk of VTE are conicting [21,22]. The anti-angiogenic multiple tyrosine kinase inhibitors sunitinib and sorafenib, have also been associated with elevated risk for arterial events [RR 3.03 (95% CI, 1.25 to 7.37)] but not for VTE [23]. The use of central venous access devices adds to this risk, although recent studies have demonstrated an overall low risk with contemporary catheters [24]. Supportive care agents can also add to the risk For instance, erythropoietin and darbopoetin are associated with a signicantly increased risk of VTE (RR = 1.57; 95% CI, 1.31 to 1.87) and mortality (HR = 1.10; 95% CI, 1.011.20) [25]. Cancer patients undergoing surgery have a two-fold increased risk of postoperative VTE as compared to non-cancer patients; elevated risk can persist for up to 7 weeks [26]. Hospitalization substantially increases the risk of developing VTE in cancer patients (OR 2.34, 95% CI 1.633.36) [27]. 4. Biomarkers Recent studies have identied several predictive and candidate biomarkers (Table 2). Baseline (i.e., pre-chemotherapy) elevated platelet and leukocyte counts, and low hemoglobin levels have all been demonstrated to be risk factors for chemotherapy-associated VTE [14,20]. In a prospective study of cancer patients receiving chemotherapy, rates of VTE were 4% in patients with elevated platelet counts as compared to 1.3% for those without (adjusted OR 2.8, 95% CI 1.65) [28]. The Vienna Cancer and Thrombosis Study (CATS) also found high platelet count to be an independent risk factor for VTE (HR = 3.50; 95% CI, 1.52 to 8.06, p = 0.0032) in 665 cancer patients undergoing chemotherapy. Patients with platelet counts in the 95th percentile or above (platelet count of 443 109 /L) had a 34.3% cumulative probability of developing VTE

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in contrast to only 5.9% in the group with counts below the designated threshold [29]. Similarly in a prospective analysis of 4,405 ambulatory cancer patients initiating chemotherapy VTE occurred in 25 of 561 patients (4.5%) with baseline leukocytosis compared to 68 of 3,830 (1.8%) without leukocytosis (p <0.0001) [30]. D-dimer is also a widely studied biomarker that is also widely available clinically. In colorectal cancer, patients with elevated D-dimer (dened as >0.3 mg/L) had a 20% (95% CI, 12 to 31%) one-year incidence of DVT versus 5% (95% CI, 2 to 12%) for other patients (adjusted HR 6.53; 95% CI, 1.58 to 27.0) [31]. Elevated D-dimer in addition to prothrombin split products (as dened by a cutoff set at the 75th percentile of the total study population) were associated with increased risk of VTE (HR = 1.8; 95% CI, 1.0 to 3.2; p = 0.048 and HR = 2.0; 95% CI, 1.2 to 3.6; p = 0.015 respectively) in the Vienna CATS registry [32]. Tissue factor (TF), the physiologic initiator of hemostasis, is widely expressed across a variety of human malignancies [33]. Unfortunately, there is currently no consensus on a standard assay to evaluate TF. Reports initially suggested a signicant association of elevated TF with subsequent VTE; for instance, a retrospective analysis revealed a 1-year cumulative incidence of VTE of 34.8% in patients with tissue factor-bearing microparticles versus 0% in those without detectable tissue factor-bearing microparticles (p = 0.002) [34]. However, the majority of data have been derived from patients with certain cancers, particularly pancreas [35] and ovary [36]. Initial reports suggested a signicant association of elevated TF with subsequent VTE [34,37]. More recently, in a recent large study of cancer patients with a heterogeneous mix of cancer patients, elevated procoagulant microparticles (not TF-specic) were not found to be predictive of VTE [38]. Further, in a prospective analysis of subgroups of the Vienna CATS registry, TF was predictive of VTE in pancreatic but not brain or colorectal cancers [39]. TF must therefore still be considered an investigational biomarker awaiting standardization prior to clinical use, with potential value in select malignancies, such as pancreatic cancer. 5. Risk assessment tools Oncology treatment paradigms are moving toward individualization or personalization of therapy. Such a therapeutic approach acknowledges that risk for various cancer-related outcomes and complications varies signicantly between individual patients and that a one size ts all approach does not benet individual patients. In supportive oncology, for instance, prophylactive myeloid growth factors are only recommended if the risk of febrile neutropenia is estimated to be 20% or higher. Such an approach has two major advantages: it allows targeting of patients truly at risk, and it reduces adverse effects and resource utilization in low-risk patients. As is evident from the preceding discussion of risk factors and biomarkers, cancer-associated VTE is a multi-factorial illness. A clinical risk score can identify cancer patients at high-risk for VTE by utilizing a combination of easily available clinical and laboratory variables (Table 3) [14]. The risk score for VTE was derived from
Table 3 Predictive model for chemotherapy-associated VTE [14]. Patient characteristics Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular) Prechemotherapy platelet count 350,000/mm3 or more Hemoglobin level less than 10 g/dl or use of red cell growth factors Prechemotherapy leukocyte count more than 11,000/mm3 Body mass index 35 kg/m2 or more * Risk scores: High risk 3; intermediate risk = 12; low risk = 0. Risk score * 2 1 1 1 1 1

a development cohort of 2,701 patients and then validated in an independent cohort of 1,365 patients from a prospective registry. The stage-adjusted multivariate model identied ve predictive variables. Observed rates of VTE in the development and validation cohorts were 0.8% and 0.3% in the low-risk category, 1.8% and 2% in the intermediate-risk category and 7.1 and 6.7% in the high-risk category, respectively. This model was initially externally validated by the prospective Vienna CATS study in 819 cancer patients [40]. The 6-month cumulative probabilities of developing VTE in this study population were 1.5% (score of 0), 3.8% (score of 1), 9.4% (score of 2) and 17.7% (score 3). Multiple other retrospective and prospective studies have further validated this Risk Score, including in populations quite different from the original cohort (Table 4). Mandal and colleagues evaluated risk factors for VTE in 1,415 patients enrolled in phase I studies conducted in Southern Europe [41]. Fifty-six patients (4%) developed a VTE. At univariate analysis, the risk score, the combination of an antiangiogenic agent with a cytotoxic drug, and the time from rst cancer diagnosis were associated with VTE. The multivariate analysis, however, conrmed only a statistically signicant association for the risk score. The hazard ratio of VTE occurrence was 7.88 (95% CI 2.8621.70) and 2.74 (95% CI 1.275.92) for the high (3) and intermediate (12) scores as compared with low-risk (score = 0). Similarly, in 932 patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008, the risk score remained signicantly associated with TEE after adjusting for multiple variables, including performance status [13]. Including all studies that have evaluated ecacy of this risk score, it has now been studied or validated in over 10,000 patients. Furthermore, the Vienna group has described expansion of this original risk score with the inclusion of two additional biomarkers: D-dimer and soluble P-selectin. In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200). This expanded risk score, while promising, requires further validation in other studies. Use of the expanded score is further limited by the lack of wide availability of the P-selectin assay and the small number of patients at the highest risk levels. Patients with myeloma are at very high risk for VTE, particularly when treated with specic regimens. A risk assessment algorithm has recently been proposed by the International Myeloma Working Group [42]. Aspirin, warfarin or LMWH are recommended based on the level of risk identied by this algorithm. It is important to note that this risk assessment tool is based on expert consensus and has not been validated. 6. Lessons from prophylaxis studies Multiple randomized controlled trials (RCTs) and meta-analyses have demonstrated the safety and ecacy of anticoagulants in reducing the incidence of VTE in several high-risk settings. In the cancer population, recent studies have focused on cancer outpatients receiving chemotherapy although thromboprophylaxis is largely only recommended in the inpatient setting. 6.1. Hospitalized medical cancer patients Three large RCTs in acutely ill medical patients have demonstrated reduced rates of VTE with the use of prophylactic LMWH or fondaparinux [4345]. Unfortunately, no cancer-specic RCTs have been conducted and in the medical studies, cancer patients (including those with previous history of cancer) represented only a small minority (515%) of the study population. Despite this lack of cancer-specic evidence, current guidelines recommend

A.A. Khorana / Thrombosis Research 129, Supplement 1 (2012) S10S15 Table 4 Rates of VTE according to risk score in various studies. Study Khorana et al. [14], 2008 Khorana et al. [14], 2008 Kearney et al. [52], 2009 Price et al. [53], 2010 Ay et al. [40], 2010 Khorana et al. [54], 2010 Moore et al. [13], 2011 Mandala et al. [41], 2011 George et al. [51], 2011 Type, f/u Development cohort, 2.5 mos Validation cohort, 2.5 mos Retrospective, 2 yrs Retrospective, pancreatic, NA Prospective, 643 days Prospective **, 3 mos Retrospective, cisplatin-based chemotherapy only, NA Retrospective, phase I patients only, 2 months Subgroup analysis of SAVE-ONCO (placebo arm), 3.5 months N 2,701 1,365 112 108 819 30 932 1,415 1,604 Low risk (score = 0) 0.8% 0.3% 5% * 1.5% *** 13% 1.5% 1.3% Intermediate risk (score = 12) 1.8% 2% 15.9% 14% 9.6% (score = 2) 3.8% (score = 1) 17.1% 4.8% 3.5%

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High risk (score 3) 7.1% 6.7% 41.4% 27% 17.7% 27% 28.2% 12.9% 5.4%

NA = not available. * Pancreatic cancer patients are assigned a score of 2 based on site of cancer and therefore there were no patients in the low-risk category. ** Included 4-weekly screening ultrasonography. *** Enrolled only high-risk patients.

thromboprophylaxis based on the known high risk of VTE in the hospitalized cancer population and extrapolation from the data in medical patients [46,47]. Predictors of VTE in hospitalized cancer patients have been identied and include site of cancer, use of chemotherapy and comorbid conditions [2]. However, risk assessment is not routinely conducted nor recommended for hospitalized cancer patients although it may be argued that such an approach is necessary in the future. 6.2. Outpatient chemotherapy Most VTE now occurs in the outpatient setting and major recent RCTs have focused on outpatient thromboprophylaxis for solid tumor patients receiving systemic therapy. In the context of this review of risk assessment, it is instructive to evaluate study designs for these RCTs since they utilized very different approaches to risk assessment. The two largest prophylaxis studies dened high risk eligibility based on 3 risk factors: primary site of cancer, advanced stage and concomitant chemotherapy. The Prophylaxis of Thromboembolism during Chemotherapy Trial (PROTECHT) study evaluated the ecacy of daily nadroparin, a LMWH, in locally advanced or metastatic lung, gastrointestinal, pancreatic, breast, ovarian, and head/neck cancers actively receiving chemotherapy [48]. Event rates were low: 2% of the treatment group and 3.9% of the placebo group developed a TEE (one-sided 95% CI 0.303%, p = 0.02) with a non-signicant increase in major bleeding. It should be noted that in the contemporary era, breast and head/neck cancer patients have not been typically considered high-risk for VTE and their inclusion in this study may have reduced the overall event rate. The second and largest study thus far in a broad cancer population was SAVE-ONCO, a prospective, double-blind, multicenter study of 3,212 patients with locally advanced or metastatic solid tumors (lung, pancreas, stomach, colorectal, bladder or ovary) randomized to daily subcutaneous semuloparin (a novel ultra-LMWH) or placebo [49]. Patients receiving prophylactic semuloparin had 64 % relative risk reduction of VTE (hazard ratio: 0.36; 95% CI [0.21, 0.60]; p < 0.0001) but a lower absolute risk reduction (1.2 vs. 3.4%). There was no signicant increase in major bleeding. Semuloparin awaits FDA approval for the indication of preventing VTE in cancer patients receiving chemotherapy and is not currently available. Two other RCTs focused on a much narrower but also high-risk population: pancreatic cancer. In the CONKO-004 study (currently only available in abstract form), VTE occurred in 5.0% (8 of 160) of patients randomized to enoxaparin (1 mg/kg daily for 3 months, then 40 mg daily) versus 14.5% (22 of 152) in the observation arm (p < 0.01) [50]. In the FRAGEM study, a phase II randomized trial, patients were assigned to full therapeutic doses of dalteparin versus observation. All-type VTE during the dalteparin treatment

period (<100 days from randomization) was reduced from 23% to 3.4% (p = 0.002), an 85% risk reduction. All-type VTE throughout the whole follow-up period was also reduced from 28% to 12% (p = 0.039), a 58% risk reduction. Lethal VTE (at <100 days) was seen only in the control arm, 8.3% versus 0% (p = 0.057), RR = 0.092, 95% CI (0.0051.635) but overall survival was no different between the two arms. These latter studies show that in high-risk patients, extremely high event rates of VTE occur and can safely be reduced but their ndings apply only to a small niche of the cancer population (advanced pancreatic cancer patients receiving chemotherapy). Which, then, of these two approaches to risk assessment is best? The former is more broad-based but leads to a high number needed to treat (44, in SAVE-ONCO). The latter approach is narrower but its applicability to other cancer populations and its ability to meaningfully reduce the public health burden of VTE in this setting is limited. Subgroup analyses of PROTECHT and SAVEONCO suggest that the risk assessment tool discussed previously may be a useful compromise. In SAVE-ONCO, when the risk score was applied (Table 4), 550 (17.4%) of patients enrolled were dened to be at high risk of VTE, 1,998 (63.2%) were at moderate risk, and 614 (19.4%) were at low risk (VTE risk score of 3, 12, or 0 points, respectively) [51]. Risk reduction was indeed greater in the highrisk subgroup (5.4% in the placebo arm vs 1.4% in the semuloparin arm, for score 3 [HR = 0.27] compared to the low-risk subgroup (1.3% vs. 1% respectively for score = 0 [HR = 0.71]). Currently ongoing research efforts are focused on outpatient prophylaxis of ambulatory cancer patients based on novel approaches to risk assessment. The University of Rochester and Duke University are conducting an NIH-sponsored prospective study based on the previously discussed risk score in which cancer outpatients at high risk for VTE (risk score 3) are randomized to observation or dalteparin for 12 weeks (Clinicaltrials.gov NCT00876915). In a biomarker-based approach, the MicroTEC study is investigating enoxaparin in patients with pancreatic, lung and colorectal cancer with elevated plasma TF microparticles (Clinicaltrials.gov NCT00908960) and is expected to be reported in 2012. These data, along with ongoing biomarker studies and risk factor registries, will further clarify the best approach to risk assessment for VTE in the cancer population. For now, however, targeted thromboprophylaxis is consistent with current therapeutic personalized medicine paradigms in oncology, provides an optimal risk-benet ratio for individual patients, and remains the best opportunity to reduce the burden of VTE and its consequences for patients with cancer.

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Acknowledgements Dr. Khorana is supported by grants from the National Cancer Institute (K23 CA120587), the National Heart, Lung and Blood Institute (R01HL095109) and the V Foundation Conict of interest statement Dr. Khorana has received research support from Pharmacyclics, Leo Pharma, sano-aventis and Eisai; consulting fees and honoraria from Roche/Genentech, Bristol Myers Squibb, sano-aventis, Johnson and Johnson, Isis Pharmaceuticals, Boehringer-Ingelheim, Daiichi-Sankyo and Leo Pharma. References
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