Thrombosis Research 133 S2 (2014) S17–S22

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Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h o m r e s

Predicting recurrent venous thromboembolism in cancer: is it possible? Paul A. Kyrle Department of Medicine I, Medical University of Vienna; Karl Landsteiner Institute of Thrombosis Research, Vienna, Austria

ARTICLE

INFO

Keywords: Cancer Venous thromboembolism Recurrence Prediction

ABSTRACT

The association between cancer and venous thromboembolism (VTE) is well-established. Many clinical and laboratory risk factors of a first cancer-associated VTE have been identified. In contrast, the pathogenesis of recurrent VTE in cancer patients is less well studied. There is only very limited information on the importance of clinical risk factors and the role of biomarkers in this context has never been studied. Patients with cancer-associated VTE usually receive low-molecular-weight heparin for at least 3 to 6 months. Nevertheless, the recurrence risk during anticoagulation is as high as 10% and treatment-related major bleeding is more common in cancer-patient than in noncancer patients. Thus improvement of current treatment concepts is warranted. One important step to achieve this task is developing strategies that allow distinguishing patients with a high risk of recurrent VTE (who may benefit from prolonged or even intensified anticoagulation) from those with a low risk (i.e. patients in whom a shorter period of anticoagulant treatment at lower dose may be sufficient). Recently, a risk assessment model (RAM) for predicting recurrent VTE has been presented. By combining 4 clinical patient characteristics (sex, cancer type and stage, history of VTE), the Ottawa score allows stratification of cancer patients according to their VTE recurrence risk. The prediction tool was successfully validated in more than 800 patients from 2 prospective VTE treatment studies. Before this RAM can be introduced into routine clinical practice, however, management studies and impact analyses are required. © 2014 Elsevier Ltd. All rights reserved.

Introduction In 1865, 2 years before his death from stomach cancer (which noteworthy had been preceded by spontaneous deepvein thrombosis), Armand Trousseau from Paris published his important observation of the association between cancer and migratory superficial thrombophlebitis. Since then the association between cancer and venous disease is referred to as Trousseau´s syndrome [1]. Compared to non-cancer patients, the risk of venous thromboembolism (VTE) is - across all cancers - many-fold increased [2,3] and the clinical consequences for a cancer patient who develops VTE are often grave: VTE is one of the leading causes of death and a significant predictor of death for most cancer types and stages [4,5]. The incidence of VTE is highest among patients initially diagnosed with metastatic disease and varies with cancer type, with the highest risk in patients with brain tumours, adenocarcinomas of the lung, ovary, pancreas, colon, stomach, prostate, or kidney and in patients with hematologic malignancies [6]. The risk of VTE is higher in hospitalized than in ambulatory cancer patients and is highest within the first months after cancer diagnosis [3,7].

* Corresponding author at: Abteilung für Innere Medizin I, Medizinische Universitaet Wien, Waehringer Guertel 18-20, 1090 Wien, Austria. Tel.: 43-664-5080608; fax: 43-1-40400-4030. E-mail address: [email protected] (P.A. Kyrle). 0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.

Cancer-associated VTE is a typical example of a multi-causal disease and its occurrence depends upon the interaction of risk factors related to the patient (such as age, sex, race, comorbidities, congenital thrombophilia, prior history of VTE and performance status), to the cancer itself (such as cancer type and stage), and to the treatment (such as surgery, hospitalization, chemotherapy, use of anti-angiogenic substances, radiotherapy and central venous catheter insertion). Taking into account the multitude of risk factors, the likelihood of developing VTE varies considerably between patients and thus also between study populations [8-12]. VTE recurrence VTE is a chronic disease and tends to recur [13]. Several studies demonstrated that cancer is an important risk factor of VTE recurrence. Prandoni and co-workers determined the clinical course of 355 patients (of whom 58 had a cancer diagnosis) during the 8 years after cessation of anticoagulant therapy for a first episode of symptomatic deep-vein thrombosis and found that the presence of cancer increased the risk of recurrent VTE 1.7-fold [14]. Heit and co-workers followed 1,719 patients with a first VTE for an observation period of almost 12,000 patient-years. The diagnosis of cancer, in particular when patients received chemotherapy, was an independent predictor of recurrent VTE with a hazard ration (HR) of greater than 4.0 [15]. Using California hospital discharge records, White and

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co-workers determined the 6-months cumulative incidence of rehospitalisation for recurrent VTE in almost 37,000 patients with an incident deep-vein thrombosis and found a statistically significant association between recurrence and the presence of malignancy [16]. VTE prevention VTE is a preventable disease and this is also true for cancer patients. There is good evidence from primary prevention studies in surgical and medical cancer patients that VTE can to a large extent be prevented by anticoagulation at an acceptable risk of bleeding [17-20]. Hence, well-established concepts for prophylaxis in surgical and hospitalized cancer patients exist. With regard to ambulatory cancer patients receiving chemotherapy, the efficacy and safety of primary VTE prophylaxis was studied in 2 double-blind, placebo-controlled prospective trials [21,22]. Although anticoagulation significantly reduced the incidence of VTE in both studies, the over-all risk of VTE was low and the subset of patients that would benefit from primary prevention the most could not be identified. Major guideline panels do not recommend routine prophylaxis in ambulatory cancer patients with the exception of patients treated with thalidomide or lenalidomide together with steroids and/or chemotherapy [23-25]. With regard to secondary VTE prevention, there are 2 potential scenarios: (i) a patient with a history of VTE who receives a cancer diagnosis and is then either hospitalized for medical or surgical therapy, or treated as an out-patient; (ii) a patient with active cancer who develops VTE during the course of the malignant disease. As regards scenario (i), primary prevention studies of medical or surgical patients comprised only a small proportion of cancer patients and only few patients with a prior VTE were included in such studies. Hence, primary thromboprophylaxis usually does not differ between cancer patients with or without a history of VTE. Regarding scenario (ii), the risk of recurrent VTE appears to be higher among patients with active cancer as compared with non-cancer patients. In a retrospective analysis from the Netherlands, the risk of recurrent VTE during oral anticoagulation with a vitamin K antagonist was 3-fold higher among cancer patients than in non-cancer patients [26]. Palareti and co-workers compared the outcome of vitamin K antagonist therapy in 95 patients with malignancy with that of 733 patients without malignancy. They found a substantial albeit statistically non-significant higher rate of thrombotic complications in cancer patients than in non-cancer patients (6.8% vs. 2.5%) [27]. The most compelling evidence that cancer patients have higher risk of VTE recurrence during anticoagulation with a vitamin K antagonist comes from a prospective study carried out by Prandoni and co-workers. Of the 842 patients, 181 had cancer at entry. The 12-month cumulative incidence of recurrent VTE was 20.7% in cancer patients and 6.8% in non-cancer for a HR of 3.2 [28]. Importantly, in all studies the incidence of anticoagulationrelated bleeding was higher among patients with than without cancer. In a landmark study by Lee and co-workers [29], patients with cancer who had acute symptomatic proximal deep-vein thrombosis and/or pulmonary embolism were randomized to receive a therapeutic dose of dalteparin for 5 to 7 days followed by a vitamin K antagonist for 6 months or dalteparin alone for 6 months. The probability of recurrent VTE was 17% in patients receiving a vitamin K antagonist and 9% in the dalteparin group for a HR 0.48 (95% CI 0.30 to 0.77). There was no difference in major bleeding between the 2 groups. Similar findings were reported by other investigators [30-32]. Accordingly, patients with cancer-associated VTE should receive therapeutic

anticoagulation with a low-molecular-weight heparin at therapeutic dose for at least 3 to 6 months. Nevertheless, besides the choice of the “best” anticoagulant and the intensity of treatment, in particular the optimal duration of anticoagulation is still under debate. Current guidelines state that after 3 to 6 months termination or continuation of anticoagulation (lowmolecular-weight heparin or a vitamin K antagonist) should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity according to best clinical practice in the absence of data [25]. Over the last years, great efforts have been made (primarily in non-cancer patients, but also in patients with a malignant disease) to develop strategies that would allow distinguishing between high and low-risk patients with the objective to identify (cancer) patients in whom (i) VTE prevention is of benefit and (ii) if so, for how long VTE prevention is required. In the next sections of this article, I shall compare the importance of single clinical and laboratory risk factors in ambulatory cancer patients on the risk of a first or a recurrent VTE. I shall then focus in more detail on the performance and utility of risk assessment models (RAMs), which integrate clinical risk factors and laboratory biomarkers. Clinical risk factors in ambulatory cancer patients According to a large population-based, case-control study from the Netherlands including 3,220 consecutive patients with a first deep-vein thrombosis of the leg or pulmonary embolism, site of malignancy and the presence of distant metastases were identified as prominent risk factors of VTE [3]. The risk of VTE was highest in patients with a hematologic malignancy, lung cancer, gastrointestinal cancer or brain cancer. Compared to cancer patients without distant metastases, those with metastatic disease had an almost 20-fold increased risk of VTE. The incidence of VTE within 1 and 2 years of cancer diagnosis and the risk factors associated with VTE were determined on the basis of records of more than 235,000 cancer patients [5]. The strongest predictor of VTE was the presence of metastases. The highest incidence of VTE was found among patients with metastatic-stage pancreatic cancer, cancer of the stomach, bladder, uterus, kidneys or lung. In a population-based cohort study from Denmark, strong predictors for hospitalization for VTE were cancer site, stage and type of initial cancer treatment. The highest incidence of VTE was found in the first year after diagnosis with an 8-fold increase in VTE risk. The risk of developing VTE was highest in patients with pancreatic or brain cancer and in patients with multiple myeloma, According to registry data, a body mass index of 35 kg/m2 or more is an independent predictor of VTE in cancer patients with an OR of 2.5 [8]. Congenital thrombophilia also increases the risk of VTE in cancer patients. In one study, for instance, carriers of the factor V Leiden mutation who had cancer had a more than 2-fold increased risk compared with cancer patients without the mutation [3]. One of the most important treatment-related risk factor of VTE is systemic anti-cancer therapy. In one study, for instance, the risk of hospitalization for VTE was 19-fold increased in cancer patients receiving chemotherapy [33]. The risk of VTE is particularly high among multiple myeloma patients treated with chemotherapy or dexamethasone when given together with thalidomide [34,35]. In the Vienna Cancer and Thrombosis Study (CATS), surgery and radiotherapy were independent predictors of VTE (HR 2.4 and 2.3, respectively) [36]. As regards recurrence of VTE in non-cancer patients, the pivotal importance of clinical risk factors such as location of the thrombus in the proximal leg veins or in the lung, absence of a

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temporary risk condition including surgery or trauma, and male sex is well recognized [13]. In cancer patients, the association between clinical patient characteristics and the risk of recurrent VTE is less well established (Table 1). In a post-hoc analysis of the study by Lee and co-workers [29], lung cancer and metastatic disease were independent predictors of VTE recurrence during anticoagulation with a HR of 3.5 and 2.6, respectively [37]. In a systematic review, Louzada and co-workers sought to evaluate cancer characteristics that may influence the risk of VTE recurrence during anticoagulant treatment [38]. By the use of data from 4 retrospective and 6 prospective cancer patient cohorts with a sample size between 14 and 3,805 cancer patients per study, they found a 1.3-fold increased risk of recurrent VTE among patients with metastatic cancer as compared with patients with localized disease. They were not able to ascertain the relevance of tumour site and histology for the recurrence risk. From the studies included in this analysis, it appears that younger patients with adenocarcinoma, and patients with lung or gastrointestinal malignancy have the highest risk and that metastatic malignancy, or adenocarcinoma, or lung cancer confers a higher risk of VTE recurrence than localized malignancy, non-adenocarcinoma or breast cancer. Clinical risk factors that may influence the VTE recurrence risk of cancer patients after rather than during anticoagulation have never been systematically looked for. Biomarkers Pre-chemotherapy leukocytosis or thrombocytosis is associated with an increased risk of VTE. According to registry data, for instance, a high leukocyte or a high platelet count is an independent risk factor of a first VTE with an OR of 2.2 and 2.8, respectively [8]. Noteworthy, cancer patients with acute VTE and an elevated white blood cell count at baseline have a 1.6-fold increased incidence of recurrent VTE during anticoagulation [39]. Anaemia defined by a haemoglobin level of less than 100 g/l or the use of red cell growth factors was independently associated with cancer-related first VTE [8]. Anaemia or thrombocytosis has never been investigated in the context of recurrent VTE in patients with malignancy. In cancer patients, a high D-Dimer not only confers an increased risk of an incident VTE, but is also associated with poor overall survival [36,40]. The association between D-dimer levels and the risk of recurrence has never been studied. A factor VIII plasma concentration above 232% was reported to be associated with an almost 3-fold increased risk of first VTE in cancer patients [41], but again there are no data regarding high factor VIII and risk of VTE recurrence. In cancer patients, a high potential of plasma to generate thrombin in vitro upon stimulation with phospholipids and tissue factor conferred a 2-fold increased risk of a first VTE [42]. Data on its role to predict recurrent VTE are lacking. P-selectin mediates adhesion and migration of leukocytes at sites of inflammation and platelet-leukocyte interaction, and promotes fibrin formation and thrombus growth [43,44]. In cancer patients, increased levels of soluble P-selectin were independently associated with an increased risk of VTE [45], but it is unknown whether this holds also true for the risk of recurrence. In sum, there is currently no evidence whatsoever that cancer patients at risk of recurrent VTE can be identified by biomarker measurement. Risk assessment models (RAMs) RAMs integrate multiple risk factors associated with VTE, thereby assessing the overall thrombotic tendency of an individual patient and improving risk prediction. Khorana and coworkers developed a RAM for predicting a first VTE in ambulatory

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Table 1 Risk factors of VTE recurrence in cancer patients Clinical Younger age Female sex Prior VTE Adenocarcinoma Lung cancer Gastrointestinal cancer Metastasis Biomarkers Not assessed

cancer patients beginning a new chemotherapy regimen [8]. The patient population was divided into 2,701 patients in the derivation cohort and 1,365 patients in the validation cohort. In the derivation cohort VTE was recorded in 60 patients (2.2%). The following independent predictors of VTE were identified: very high-risk cancer (stomach or pancreatic cancer), high-risk cancer (lung cancer, lymphoma, gynaecologic cancer, genitourinary cancer excluding prostate), pre-chemotherapy platelet count > 350,000/l, hemoglobin < 100 g/l or use of red cell growth factors, pre-chemotherapy leukocyte count ≥ 11 x 109/L and body mass index ≥ 35 kg/m2. Very high-risk cancers were assigned 2 points, the remaining variables 1 point each. In the derivation cohort VTE was recorded in 0.8% of patients with a score of 0, in 1.8% of patients with a score of 1 or 2, and in 7.1% of patients with a score of > 3. Very similar incidence rates of VTE were seen in the validation cohort with an overall incidence of 2.1%. VTE occurred in 0.3% of patients with a score of 0, in 2% of patients with a score of 1 or 2, and in 6.7% of with a score of ≥ 3. The Khorana score was applied to the CATS population [10]. In this study the probability of VTE after 6 months was almost 18% in the patients with a Khorana score of > 3, 9.6% in patients with a score of 2, 3.8% in those with a score of 1, and 1.5% among patients with a score of 0. The score was also applied to large retrospective cohort of 932 patients treated with cisplatinbased chemotherapy [11]. 169 (18.1%) patients developed venous or arterial thromboembolism. The incidence of VTE for each Khorana risk group was higher than in the original study: 13% versus 0.3% for a score of 0, 17.1% versus 2% for a score of 1 or 2, and 28.2% versus 6.7% for a score of ≥ 3. At this time, there are 4 RAMs for estimating the risk of recurrent VTE, 3 in non-cancer patients and only 1 in patients with malignancy (Table 2). A cohort of women with unprovoked VTE at very low risk of recurrence could be identified by combining 4 risk factors, namely absence of symptoms suggestive for the post-thrombotic syndrome, D-dimer of less than 250  ng/ml measured during anticoagulation, body mass index below 30 kg/m2 and age less than 65 years [46]. In a prospective cohort study, 929 patients with a first unprovoked venous thrombosis or pulmonary embolism were followed for a median of 43 months after discontinuation of anticoagulation. Preselected clinical and laboratory variables including age, sex, thrombus location, body mass index, factor V Leiden, the prothrombin mutation, D-Dimer and in vitro thrombin generation were analysed in a Cox proportional hazards model, and those associated with recurrence were used to compute risk scores. Only the sex, thrombus location and D-Dimer levels were independently related to the recurrence risk. Using these variables the probability of recurrent VTE at various time points after cessation of anticoagulation can be calculated for an individual patient [47]. In an individual patient data metaanalysis of 7 prospective studies enrolling more than 1,800 patients with a first unprovoked VTE, abnormal D-Dimer after stopping anticoagulation, age ≤ 50 years, male sex and VTE not

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Table 2 Derivation cohorts of risk assessment models to identify patients at low risk of VTE recurrence Roger and co-workers [46]

Vienna prediction model [47]

DASH score [48]

Ottawa score [49]

Patient number

646

929

1818

543 cancer patients on anticoagulants

Cohort

Prospective cohort

Prospective cohort

Patient level meta-analysis

Retrospective

Predictive variables

Men: none Women: Age > 60 years Signs of PTS* BMI > 30 kg/m2 D-Dimer > 250 g/L during anticoagulation

Sex Location of first VTE D-Dimer after anticoagulation

Abnormal D-Dimer after anticoagulation Age < 50 years Male sex Hormonal therapy

Sex Cancer site Cancer stage Prior VTE

< 1 point 1.6% (95% CI 0.3%-4.6%)

< 180 points (nomogram) 4.4% (95% CI 2.7%-6.2%)

≤ 1 point 3.1% (95% CI 2.3-3.9)

< 0 points < 4.5%

Recurrence risk: Low risk

* post-thrombotic syndrome

associated with hormonal therapy (in women) were the main predictors of recurrence. The score attributes the following points: +2 for abnormal D-dimer, +1 for age ≤ 50 years, +1 for male sex, –2 for hormone use at time of initial VTE. The so-called DASH score allows stratification of patients into high, moderate or low risk categories as regards VTE recurrence [48]. The Ottawa score is the only RAM designed to predict VTE recurrence in cancer patients [49]. The derivation study was carried out in a retrospective cohort of 543 patients with active cancer and objectively diagnosed proximal deep-vein thrombosis of the leg or the upper extremity, pulmonary embolism, or unusual site thrombosis. 238 patients (44%) had distant metastases. Adenocarcinomas were present in the majority of the 485 patients with solid tumours. 200 patients (37%) were treated with a vitamin K antagonist and 343 patients (63%) with low-molecular-weight heparin. The primary outcome variable was objectively verified recurrence of VTE during an anticoagulation treatment period of 6 months. The predictors of VTE recurrence to be studied were sex, previous history of VTE, surgery, chemotherapy/hormone therapy (both within 3 months of VTE recurrence), primary cancer site, cancer stage, histology, and D-dimer level at the time of VTE recurrence. Within the first 6 months of anticoagulation, recurrent VTE occurred in 55 of the 543 patients. Of interest, the frequency of recurrent VTE did not differ between patients treated with low-molecular-weight heparin from those who received a vitamin K antagonist. After multivariate analysis only sex and cancer site were independent predictors of recurrence. The final model included also cancer stage and history of VTE as these 2 variables were close to significance regarding VTE prediction. The Ottawa score is depicted in detail in Table 3. In the low-molecular-weight heparin group, patients with a score of ≤ 0 had a significantly lower risk of VTE recurrence as compared with patients with a higher risk score (≤ 3.0% versus ≥ 17.5%). Similarly, patients in the vitamin K antagonist group who had a score of ≤ 0 had a significantly lower risk of VTE recurrence than patients with a higher score (≤ 5.6% versus ≥ 13.8%). After minor adjustment regarding cancer stage, the Ottawa score was successfully validated in 819 patients from 2 randomized prospective trials both comparing low-molecularweight heparin with a vitamin K antagonist in patients with acute cancer-associated VTE [29,30]. VTE recurrence developed in 86 of the 819 patients. Patients with a score < 0 (19% of the patient population) had a risk of VTE recurrence of 5.1%, patients with a score of 0 (42% of the patient population) had a risk of 9.8% and patients with a score of ≥ 1 (38% of the patient population) a risk of 15.8%. Dichotomizing the results gave a recurrence risk of 7.5% in patients with a score of ≤ 0 and a recurrence risk of 15.8% among patients with score of > 0.

Table 3 Risk assessment model for cancer-associated recurrent VTE: the Ottawa score [49] Risk factor Female sex Lung cancer Breast cancer TNM stage I Prior VTE

Regression coefficient

points

0.59 0.94 -0.76 -1.74 0.40

+1 +1 -1 -2 +1

-3 to 0 points: low VTE probability 1 to 3 points: high VTE probability

Summary and Conclusions It is well recognized that individuals who receive the diagnosis of cancer are at an increased risk of VTE. The pathogenesis of VTE in general, but especially in cancer patients in whom a multitude of disease-related risk factors exists, is multi-factorial. In cancer patients VTE can to a large extent be prevented by antithrombotic treatment. Large clinical trials have shown that hospitalized medical and surgical cancer patients benefit from anticoagulation and primary thromboprophylaxis has become routine in these patients. Patients with a cancer-associated VTE are nowadays treated with low-molecular-weight heparin at therapeutic dose for at least 3 to 6 months. Nevertheless, the probability of recurrent VTE during anticoagulation with heparin is still in the range of 10% after 3 to 6 months and hence better treatment strategies are required. One step forward to improved therapy would be a more personalized treatment approach by elucidating the relationship between VTE recurrence and patient management and to gain a better understanding of the different patient and cancer characteristics that may influence the risk of VTE recurrence. In contrast to the situation of VTE recurrence in non-cancer patients, there is only very limited information about clinical risk factors and the role of biomarkers in this context has never been investigated. Predicting the overall thrombotic risk can be improved by RAMs. Several RAMs have been developed in non-cancer patients, but there is only one prediction tool for cancer patients. In principal, RAMs are applied with the ultimate goal to identify patients who may benefit from treatment strategies deduced from the outcome of the model. The prerequisites for achieving such a task are as follows: (i) the prediction tool allows stratifying patients into different VTE risk categories; (ii) the prediction tool is generalizable in terms of its applicability to different patient populations; (iii) there is knowledge about the risk of bleeding

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related to anticoagulation when the prediction tool is applied in routine care. Louzada and co-workers developed a prediction score for VTE recurrence which is based on patient sex, cancer type and stage and history of VTE [49]. The first of the aforementioned prerequisites has indisputably been fulfilled as the Ottawa score allows stratification of cancer patient into high- and low-risk VTE categories. The model has also successfully been validated. The next step would be its application to different cancer patient populations with varying prevalences of VTE risk determinates to assess its generalizability. The ultimate challenge would then be to translate the risk estimates obtained by the model to clinical decision making on the basis of the results of management studies. In the case of patients with cancer-associated VTE, this would mean proving the concept that patients with a high propensity of VTE (as assessed by the model) benefit from extended and/ or more intense anticoagulation and, conversely, that in patients with a low recurrence risk anticoagulant treatment at a lower dose and/or for a shorter period of time is sufficient. Finally, impact analyses shall reveal as to what extent the rule influences physician behavior and patient outcomes [50,51].

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Conflict of interest statement

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The author states that has no conflicts of interest to declare in relation to this papers.

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Predicting recurrent venous thromboembolism in cancer: is it possible?

The association between cancer and venous thromboembolism (VTE) is well-established. Many clinical and laboratory risk factors of a first cancer-assoc...
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