REVIEWARTICLE

Thromboembolic disease in cancer patients

Nadia Hindi & Nazaret Cordero & Enrique Espinosa

Received: 3 May 2012 /Accepted: 4 February 2013 /Published online: 21 February 2013# Springer-Verlag Berlin Heidelberg 2013

Abstract Thromboembolic events are common amongpatients with cancer as a consequence of cancer- andtreatment-related factors. As these events are the secondmost frequent cause of death in this population, their pre-vention and treatment are important. Venous ultrasonogra-phy is the technique of choice for diagnosis, with sensitivityand specificity above 95 % in symptomatic thrombosis.Routine prophylaxis is not recommended for ambulatorypatients, although it could be useful in selected cases. Onthe other hand, all inpatients should receive prophylactictherapy unless contraindicated. Therapy of thromboembolicdisease is based on anticoagulants. Clinical trials demon-strate that the use of low-weight heparins is associated witha lower incidence of bleeding and recurrent thrombosis ascompared with non-fractionated heparin or warfarin.Options for recurrent thrombosis include change to anotheranticoagulant agent, increasing doses of the same agent andcava filters.

Keywords Cancer . Thrombosis . Thromboembolicdisease . Heparin . Anticoagulant

Introduction

Thromboembolic disease—including deep vein thrombosisand pulmonary embolism—is common both in the generalpopulation and in patients with cancer. A cohort study in thegeneral population of subjects aged ≥45 showed that the

incidence of this disease is 1.92 per 1,000 inhab/year [1].There is a sevenfold increase in the risk of thrombosisamong cancer patients, but the incidence may be 28 timeshigher in patients with haematological tumours [2]. Solidtumours mostly associated with venous thromboembolism(VTE) include gliomas and carcinomas of the pancreas,stomach, lung and ovary [3]. VTE is the second mostcommon cause of death in cancer patients after the tumouritself, which underscores the need for proper prophylaxisand management [4].

Pathophysiology and risk factors

Endothelial damage, alterations in the blood flow and thepresence of pro-coagulants contribute to the development ofVTE. These risk factors can be present in cancer patientsdue to the tumour itself or to anticancer therapy (Table 1).

Common analytical alterations found in patients withcancer include increased expression of intrinsic factor andactivation of factors VII and XII [5], as well as impairmentof fibrinolysis and platelet aggregation [6]. Surgery is an-other well-known factor for VTE, and patients who undergosurgery to treat a cancer have a higher risk to present thiscomplication as compared with those having other kinds ofsurgical procedures [7].

Cancer therapy increases the risk of VTE. A large cohortstudy with more than 66,329 cancer patients found a two-fold increase in those receiving chemotherapy (relative risk,2.2) [8]. Hormonal agents are also associated with the de-velopment of thrombosis, for instance tamoxifen in breastcancer [9] and progesterone in endometrial cancer. VTE is aside effect of drugs having anti-angiogenic activity, particu-larly thalidomide [10], which benefits patients with multiplemyeloma, and bevacizumab [11], which is used in the treat-ment of colorectal, breast, lung and ovarian carcinomas.Other anti-angiogenic agents less commonly associated with

N. Hindi : E. Espinosa (*)Service of Oncology, Hospital La Paz, Paseo de la Castellana,261-28046 Madrid, Spaine-mail: eespinosa00@hotmail.com

N. CorderoService of Oncology, Hospital Virgen de la Salud, Toledo, Spaine-mail: letecordero@hotmail.com

Support Care Cancer (2013) 21:1481–1486DOI 10.1007/s00520-013-1742-6

this complication include sunitinib and sorafenib. Finally,cisplatin, bleomycin and erythropoietins may favour theappearance of VTE [12, 13].

All these risk factors were confirmed in a meta-analysisfocused in cancer patients [14]. The study also pointed outthe role of central vein catheters, particularly those withperipheral access as compared with reservoir catheters.

Diagnosis

Deep vein thrombosis produces pain, oedema and erythema,although no single symptom can be regarded as definitivefor diagnosis. High or low probability of deep vein throm-bosis is defined according to validated predictive models,which usually include D-dimer. If D-dimer is not elevatedand the model predicts a low probability of thrombosis, thiscan reasonably be ruled out [15]. However, cancer patientshave been under-represented in clinical studies, and D-dimerelevation in the absence of thrombosis is more commonamong these patients than in the general population [16].As a consequence, predictive models can help in diagnosis,but further studies are required to clarify their role in thefield of oncology.

Ultrasonography is the method of choice for the diagno-sis of deep vein thrombosis. This technique is cheap andnon-invasive, and has high sensitivity (96 %) and specificity(98 %) to detect acute and symptomatic thrombosis.Sensitivity lowers to 60 % in the case of distal and asymp-tomatic thrombosis [17]. If ultrasonography is not definitiveand there is still clinical suspicion, flebography allows directvisualisation. However, this technique is invasive, moreexpensive and uses iodine contrast. Magnetic resonanceimaging is used less commonly, but it can evaluate theinferior cava vein and iliac veins without nephrotoxic con-trast [18]. With regard to pulmonary embolism, angio-computed tomography confirms the presence of the

thrombus and also allows the evaluation of other lunglesions, so it is preferred over ventilation–perfusion scan inpatients with cancer.

Therapy

Anticoagulation remains the cornerstone of VTE treatment.The aims of therapy are to improve symptoms, reduce theincidence of new episodes of VTE and reduce the incidenceof post-thrombotic syndrome. One out of four cancerpatients develop post-thrombotic syndrome in the first yearafter the diagnosis of VTE, even with appropriate anticoag-ulant therapy, and up to one third have recurrent thrombosisin the first 5 years [19]. In fact, the presence of a tumourincreases the incidence of recurrent thrombosis (relativerisk, 1.97) [20, 21, 22].

Therapy for VTE includes the immediate phase (first 5–10 days) and the chronic phase (up to 6 months). In the firstphase, low molecular weight heparins (LMWH) and non-fractionated heparin are the therapies of choice, whereas inthe second phase, oral anticoagulation can also be used.

The indication for LMWH in the acute and delayedphases has been established in randomised clinical trials,so these drugs are the preferred option for some experts.Heparins have been suggested to have anti-tumour activityby interfering with the union of growth factors and theirreceptors and also by reducing the activity of vascularendothelial growth factor and heparinases. On the otherhand, LMWH inhibit the adhesion of leukocytes to theendothelium and increase natural killer cell activity, whichcould enhance the effectiveness of the immune systemagainst the tumour [23, 24].

LMWH could improve survival in the acute phase ofVTE as compared with non-fractionated heparin. This hasbeen suggested by a meta-analysis of 11 studies, whereLMWH significantly reduced mortality (relative risk, 0.71)[25]. This benefit was restricted to cancer patients, and theauthors concluded that further studies were needed to con-firm it. Some clinical guidelines recommend just LMWH,whereas others admit non-fractionated heparin as an optionto LMWH [26].

In the chronic phase of treatment, LMWH are more effec-tive than oral anticoagulants. Most clinical guidelines recom-mend these drugs for long-term therapy [26]. A randomisedtrial in cancer patients compared dalteparin in the acute phasefollowed by coumarin in the chronic phase versus dalteparinin both phases of treatment [27]: continuous dalteparin re-duced by 52 % the risk of recurrent and symptomatic throm-bosis, and no differences were seen in mortality and incidenceof haemorrhage. The CANTHANOX study, prematurelyclosed because of low recruitment, indicated that haemorrhageand recurrent thrombosis were more common with an oral

Table 1 Risk factors for thrombosis in cancer patients

Risk factor Mechanism

Vascular stasis Tumour compression

Surgery

Platelet/coagulation activation Increased intrinsic factor

Activation of factors VII and XII

Thrombin overproduction

Plasminogen activators

Cancer therapy Chemotherapy: RR 2.2

Hormonal therapy: RR 1.6

Antiangiogenics

Erythropoietin (RR 1.57)

RR relative risk with regard to patients not receiving these therapies

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anticoagulant (21.1 %) than with enoxaparin (10.5 %), al-though differences were not significant (p=0.09) [28]. In theLITE trial, recurrent thrombosis at 12 months was 16 % withwarfarin and 7 % with tinzaparin (hazard ratio, 0.44), and nodifferences were detected in the incidence of haemorrhage andmortality [29]. Other studies have suggested a survival benefitof LMWH, particularly in patients without metastatic disease[30–32]. Ongoing clinical trials will try to confirm a survivalbenefit of LMWH in cancer patients: ABEL (bemiparin insmall cell lung cancer), TILT (tinzaparin in lung cancer) andSYRINGES (enoxaparin in small cell lung cancer).

Finally, a recent study in the general population assessedthe role of additional thrombolysis to reduce the incidenceof post-thrombosis syndrome [19]. The authors concludethat catheter-guided thrombolysis should be considered inpatients with proximal vein thrombosis and low risk ofhaemorrhage.

LMWH dosage

Four LMWH—dalteparin, bemiparin, tinzaparin and enoxa-parin—are widely used in clinical practice. Table 2 showsdosage schedules. Comparison of tinzaparin and dalteparinwas performed in a clinical trial that included cancer patients,and no differences in efficacy or toxicity were found [33].

Dose adjustment for patients with renal failure has beendescribed for enoxaparin on the basis of body weight, serumcreatinine and gender to reach a target anticoagulation levelassessed by maximal anti-Xa activity. Although no recom-mendation can be made in patients with mild or moderaterenal impairment, patients with severe renal failure (creati-nine clearance under 30 ml/min) should not receive dosesabove 20 mg in prophylaxis or 1 mg/kg/24 h in therapy.

In the case of thrombocytopenia, the dose of LMWHshould be reduced by 50 % if the platelet count is lower

than 50×109/L, and therapy should be stopped if lower than20×109/L. Some guidelines recommend beginning with 75–80 % of the initial dose for long-term therapy [34].

Fondaparinux is a selective inhibitor of factor Xa thatbinds to anti-thrombin III and has demonstrated similaractivity to enoxaparin in the treatment of deep vein throm-bosis. Experience in cancer patients is scarce. One study(including 10 % of patients with cancer) showed similarefficacy of fondaparinux versus LMWH and oral anticoagu-lants in the initial phase of VTE therapy [35].

Cancer patients should receive therapy for at least 3–6 months. If the tumour or other risk factors persist, perma-nent therapy should be considered. There is no evidence thatanticancer therapy modifies the pharmacokinetics ofLMWH. However, oral anticoagulants not only requireclose monitoring and frequent dose adjustment, but can beaffected by food and the concomitant use of other drugs:some anti-inflammatory drugs and antibiotics may potenti-ate their effect, whereas rifampicin, metronidazole or anti-convulsant agents, for instance, accelerate their metabolism.

Management of recurrent thrombosis

Recurrent thrombosis appears in 10 % of patients. A cohortstudy in patients with cancer demonstrated that increasing thedose of heparin or changing to a LMHW (if the patient wasreceiving warfarin) is an effective strategy to prevent newthrombotic events [36]. In this study, 6 out of 70 patientshad a new recurrence after 3 months and 3 patients had ahaemorrhage after increasing the dose of heparin. With regardto dose adjustment, international normalized ratio (INR)should not exceed 3–3.5 in the case of oral anticoagulants,and the initial dose of a LMWH should not be increasedbeyond 25 %. Tumour progression should be ruled out, andbleeding complications should be carefully monitored.

Table 2 Dosage of low molec-ular weight heparins and fonda-parinux for the treatment of deepvein thrombosis

Dalteparin Bemiparin Tinzaparin Enoxaparin Fondaparinux

100IU/kg/12 h or 200 IU/kg/24 h(max,18,000 IU/day)

115 IU anti-Xa/kg/day

175 IU/kg/day

1 mg/kg/12 h or1.5 mg/kg/day

<50 kg, 5 mg/kg/day

50–100 kg,7.5 mg/kg/day

<50 kg,5,000 IU/day

50–60 kg, 60 mg/12 h

>100 kg,10 mg/kg/day

46–56 kg,10,000 IU/day 50–70 kg,7,500 IU/day

61–80 kg, 80 mg/12 h

>70 kg,10,000 IU/day

>80 kg, 100 mg/12 h

57–68 kg, 12,500 IU/day >100 kg,115 IU/kg/day

1 mg=100 IU69–82 kg, 15,000 IU/day

≥83 kg, 18,000 IU/day

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Cava filters

Filters are recommended to prevent pulmonary embolism inpatients with any contraindication for anticoagulant therapy orin those who have recurrent VTE in spite of adequate antico-agulant therapy [37]. Up to 32 % of patients with cava filterssuffer recurrent thrombosis, so LMWH should be maintainedafter the insertion of the filter [38]. Few studies have evaluatedthe efficacy of filters in patients with cancer, so further inves-tigation should be performed in this field [39].

Catheter-related thrombosis

The incidence of catheter-related symptomatic thrombosis inadults varies between 0.3 and 28%, being higher in the case ofpartial and asymptomatic thrombi. The rate of thrombosis islower in implanted ports as compared with peripherallyimplanted central venous catheters [14]. There are no prospec-tive randomised studies about the treatment of catheter-relatedthrombosis. Guidelines recommend anticoagulant therapy forat least 3 months if the catheter is not withdrawn, or a fewweeks otherwise [26]. Withdrawal of the catheter is advised ifit does not work correctly or if there is contraindication foranticoagulant therapy. One study of dalteparin followed bywarfarin (INR, 2–3) in patients with cancer did not findrecurrent thrombosis after a 3-month-period follow-up [40].

Prophylaxis

Oral anticoagulants and heparins are the main options for theprophylaxis of VTE. An important distinction is whether thepatient is ambulatory or not. In ambulatory patients, the litera-ture offers contradictory results. Low-dose warfarin (INR, 1.5)was more effective than placebo in a series of patients withmetastatic breast cancer, with a reduction of 85 % in the risk ofthrombosis [41]. Two randomised trials—TOPIC II in non-small cell lung cancer and PRODIGE in glioma—did not showany advantage of the LMWH certorapin and dalterapin, respec-tively, over placebo [42, 43]. However, the PROTHECT trial,which included over 1,000 patients with advanced cancer,demonstrated a significant reduction in the risk of thrombosiswith nadroparin [44]. Overall, results suggest that LMWHcould be useful in some patients, although type of drug anddose remain undetermined. With regard to oral inhibitors offactor X, results of clinical trials have not been published yet.

Cancer surgery increases the risk of VTE. An observationalstudy including over 40,000 patients undergoing cancer sur-gery showed that 1.6 % had a thrombotic event [45]. One thirdof these episodes occurred after hospital discharge, whichsupports long-term prophylaxis. Prolonged surgery, age >65,obesity, thrombocytosis, leucocytosis and anaemia were

identified as risk factors for thrombosis in this study. Unlesscontraindicated, hospitalised patients should receive prophy-laxis of VTE with non-fractionated heparin or LMWH [46].

Clinical guidelines

The above-mentioned recommendations about the treatmentand prophylaxis of VTE are included in clinical guidelines,such as the European Society of Medical Oncology [34], theNational Comprehensive Cancer Network [47], the AmericanSociety of Clinical Oncology [48] and the American Collegeof Chest Physicians [49]. Even when these guidelines areimportant in clinical practice, some studies have shown thatthey are not followed very commonly. The observationalstudy ENDORSE, which included data on 68,000 hospitalisedpatients in several countries (over 3,000 of them cancerpatients), reported that anticoagulant prophylaxis was pre-scribed in less than 60 % of surgical patients and less than50 % of medical patients with risk factors [50]. Similar resultswere seen in the IMPROVE study [51]. The FRONTLINEstudy surveyed over 3,000 oncologists, haematologists andcancer surgeons about prescription habits regarding VTE pro-phylaxis [52]. Approximately 50 % of surgeons administeredprophylaxis to their patients, which coincides with previousdata, but this percentage dropped to 5 % among oncologists.LMWH were the therapy of choice for 70 % of doctors,although 24 % of oncologists used aspirin, which is ineffec-tive in this indication. These data indicate the need to spreadthe content of guidelines among professionals dealing withcancer patients.

Conclusions

VTE appears commonly in cancer patients and is the secondleading cause of death. There is consensus about the need toadminister prophylactic therapy in high-risk patients andalso about treatment once VTE is established. However,many professionals treating patients with cancer do notfollow guidelines, so it is important to insist on this topic.

Acknowledgments We thank Dr. Paula Jiménez (Hospital CentralUniversitario de Asturias) for her comments.

Conflict of interest The authors do not have any conflict of interestregarding the present manuscript.

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