Thrombosis Research 129 (2012) 353–359

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Thrombosis Research

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Review Article

Anticancer treatment and thrombosis

Anna Falanga ⁎, Marina MarchettiDivision of Immunohematology and Transfusion Medicine, Ospedali Riuniti di Bergamo, Bergamo, Italy

⁎ Corresponding author at: Division of Immunohemacine, Ospedali Riuniti di Bergamo, Largo Barozzi n.1, 24035 269 492; fax: +39 035 266 659.

E-mail address: annafalanga@yahoo.com (A. Falanga

0049-3848/$ – see front matter © 2011 Elsevier Ltd. Alldoi:10.1016/j.thromres.2011.10.025

a b s t r a c t

a r t i c l e i n f o

Article history:Received 22 September 2011Received in revised form 21 October 2011Accepted 24 October 2011Available online 25 November 2011

Keywords:cancerchemotherapyhormonal therapyvenous thromboembolismprophylaxis

Venous thromboembolic (VTE) complications are common in patients with cancer and represent the secondcause of death in this disease. The risk of VTE varies according to the type of malignancy and with the extentof the cancer. Patients with VTE and more advanced, metastatic disease face worse clinical outcomes. Impor-tant in this setting is the triggering role of antitumor therapies, including cancer surgery and active treat-ments such as chemotherapy, hormonal and anti-angiogenic therapy, which further increase the cancer-associated thrombotic risk. Predictive models for VTE in cancer patients are now available and will allowthe possibility of improving outcomes for patients under chemotherapy by identifying those who would ben-efit most from thromboprophylaxis.

© 2011 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353Anticancer treatments and thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

Central venous catheters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354Chemotherapy and hormonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354Antiangiogenic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Supportive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

Evaluation of thrombotic risk in cancer patients undergoing non-surgical cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Thromboprophylaxis recommendations in cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Introduction

Venous thromboembolism (VTE) is a common complication in can-cer patients which significantly impacts on mortality and quality of lifeof the affected subjects [1]. Indeed, patients with cancer and VTE aremore frequently hospitalized than patients with VTE without cancer,and are more prone to experience side effects related to anticoagulanttreatment. VTE in cancer is associated with a unfavorable effect on sur-vival. A reciprocal link exists between cancer and thrombosis, andmany efforts have been done in the last decades to understand the un-derlying pathophysiological mechanisms [2]. Thromboembolic disease

tology and Transfusion Medi-128 Bergamo, Italy. Tel.: +39

).

rights reserved.

can be the earliest clinical sign of a tumor, conversely, patients alreadydiagnosed with cancer have a significantly higher risk of developing“secondary” thrombosis in specific conditions. Approximately 20% of pa-tients presenting with idiopathic VTE have an active cancer. Further-more, even in the absence of overt thrombosis, cancer patientscommonly present with abnormalities in laboratory coagulation tests,underlying a subclinical hypercoagulable condition, characterized byvarying degrees of blood clotting activation [3].

The incidence of VTE in cancer populations has been estimated atapproximately 1 in 200, 5-fold higher than that of the general popu-lation [4], and active malignant disease has been shown to be an inde-pendent risk factor for VTE [5,6]. Overall, 18–29% of all VTE events inthe community have been shown to be associated with cancer [7–9].The incidence of VTE among hospitalized cancer patients is progres-sively increasing. Several large retrospective analyses of hospital dis-charge data have reported a significant 28–36% increase in VTE eventsover the period 1995–2003 [1,10].

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VTE in cancer is a multifactorial disease, and various risk factorscan interact in the same patient. Risk factors for VTE in cancer canbe at least classified in three main categories, i.e. those related to:1) patient characteristics, 2) the type and the extent of malignancy,and 3) the therapeutic interventions for cancer. The first group in-clude many VTE risk factors that are common among cancer patients,for example advanced age, prolonged immobility, a prior history ofVTE, leukocyte and platelet count, and obesity, but also comorbidconditions such as acute infection, heart disease, and respiratory dis-ease [5,10–12]. As regard to the second category of risk factors, largeepidemiological studies have identified malignant brain tumors, he-matological malignancies, and adenocarcinoma of the pancreas, uter-us, ovary, stomach, lung and kidney as having the highest risk of VTE[1,10,12–17]. Myeloma, non-Hodgkin's lymphoma, and Hodgkin'sdisease showed the highest incidence of VTE among hematologicalmalignancies [1]. In addition to the type, also the extent of the malig-nant disease affects the likelihood of developing VTE. Advanced, met-astatic cancer has been shown to be associated with an increased riskof VTE compared to localized tumors [10,13,14,16,18,19]. Finally, hos-pitalization, anticancer surgery, and active treatment regimens fur-ther increase the risk of thrombosis in cancer [1,5,20]. To complicatethe scenery, several novel anti-cancer agents have been associatedwith VTE, thereby bringing this issue to the forefront of cancermedicine.

In this review, we will focus on the role of the anti-tumor thera-pies as risk factors for thrombosis in cancer patients, and will brieflygive an overview of the current VTE prevention strategies in thissetting.

Anticancer treatments and thrombosis

Many standard anticancer treatment strategies have been shownto increase the risk of VTE complications. These include surgery, hos-pitalization, central venous catheters (CVC), anti-tumor drugs, as wellas supportive therapies (Fig. 1).

Major surgery, defined in the American Society of Clinical OncologyGuidelines as laparotomy, laparoscopy or thoracotomy lasting greaterthan 30 minutes, is known to increase the risk of VTE (16). Cancer pa-tients undergoing surgery have a two-fold increased risk of postopera-tive VTE as compared to non-cancer patients, and this elevation canpersist for a period up to 7 weeks following the procedure, as alsoreported by the Italian surgical @RISTOS observational registry [20].There are two reasons at least that can explain the increased VTE com-plications in patients who undergo cancer-related surgery: 1. cancer-related surgery tends to be more extensive and often involves venous

Supportive therapies

Major surgery

Hospitalization

Central venous catheter

Chemotherapy, hormonal therapy and anti-angiogenic agents

THROMBOSIS

Fig. 1. Schematics of the principal anti-tumor strategies contributing to the thromboticrisk in cancer. Most of the therapeutic interventions for the cure of cancer can increasethe VTE risk associated with this disease. These include major surgery, hospitalization,pharmacological anti-tumor therapies, CVC and supportive therapy (i.e. use of erythro-poiesis stimulating agents).

trauma, and 2. the tendency of these patients to be immobilized for pro-longed periods. In addition, cancer treatments, the use of central venouscatheters (CVC), and the hypercoagulable state associated with malig-nancy also heighten the VTE risk in surgery for cancer.

Hospitalization substantially increases the risk of developing VTEin cancer patients as well [15]. The average risk of VTE per hospitali-zation is 4.1%, but it varies widely and can be as high as 12–18% inspecific subgroups [1]. Of note, the rate of VTE per hospitalizationhas increased by 47% in patients receiving chemotherapy between1995 and 2003 raising the possibility that newer cancer regimensmay be more thrombogenic [1].

Non-surgical anticancer treatment strategies are also associatedwith a high incidence of VTE [21–26]. Active treatments, includingchemotherapy, adjuvant chemotherapy, hormonal therapy, anti-angiogenic agents, and combination regimens all have a pro-thrombotic effect in cancer patients. In a population-based studyof VTE risk factors among 625 patients, malignant disease wasshown to increase the risk of VTE 4.1-fold but malignant diseasewith chemotherapy increased the risk 6.5-fold [5]. This study alsoindicated the presence of an indwelling CVC as a significant riskfactor for the development of VTE [5]. By contrast, however, itshould be noted that radiotherapy has not been proven to increasethe risk of VTE complications [16,23].

Central venous catheters

Themajority of cancer patients have a long-termCVC inserted for thedelivery of chemotherapy, transfusions, parenteral nutrition, and bloodsampling. CVC present with a number of advantages, however frequentcomplications such as CVC-related upper limb deep vein thrombosis(DVT) or infections have been described [27]. The incidence of asymp-tomatic CVC-related DVT is estimated to be about 20%, while the rateof clinically overt DVT of upper limbs ranges between 2% and 4%. Somefeatures of the catheter may influence the occurrence of VTE complica-tions. CVC are thought to promote thrombosis by inducing a trauma tovessel walls either directly or through high drug concentrations at theCVC site [28]. A number of retrospective studies have indicated a high-risk of catheter-related thrombosis in malignancy affecting 12–66% ofcancer patients, depending on the type of cancer and its treatment, aswell as the type, position, and duration of catheterization involved[29,30]. However, recent randomized controlled trials in cancer patientshave reported lower rates of CVC-related thrombosis inwhich the use ofeither warfarin (1 mg/day), dalteparin (5000 IU), or enoxaparin(40 mg/day) did not reduce the incidence of catheter-related DVT[31–33]. Accordingly guidelines do not recommend routine thrombo-prophylaxis with use of a CVC [30,34]. A recent analysis of the RIETE reg-istry revealed that among patients diagnosed with an objectively-confirmed symptomatic DVT, the upper-extremity DVT ismore frequentin patients with cancer than in those without (38 vs 20%, respectively;OR, 2.46; 95% CI, 2.04–2.95; Pb .001) [35]. In addition, from the samestudy, it comes out that among patients with upper-extremity DVT, a di-agnosis of cancer is associated with significantly (pb0.05) higher ratesof VTE recurrences (6.1 vs 2.8%) and overall mortality (22 vs 3.5%).

Chemotherapy and hormonal therapy

Chemotherapy for cancer, either as primary or adjuvant therapy, isassociated with a 2-to 6-fold increased risk of VTE compared to thegeneral population [1,5,19,23,24,36,37]. The rate of VTE among hospi-talized patients receiving chemotherapy is 5.7% [10]. Several con-trolled clinical trials of systemic chemotherapy in women withbreast cancer have shown a clear link between chemotherapy and in-creased incidence of VTE. Recently, a prospective study of nearly4,500 patients receiving outpatient chemotherapy reported a 2.7-fold increase in arterial thrombosis, and a 47-fold increase in the mor-tality rate from VTE compared with the general population [38].

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The reasons for this increase in risk are complex and poorly under-stood, but the direct injury of endothelial cells by the chemotherapeuticagents or by tumor derived products leading to a loss of antithromboticproperties is likely (Fig. 2). In this setting, many studies have tested thedirect in vitro effect of some chemotherapeutic agents on the hemostat-ic properties of different blood cell types, including endothelial cells,monocytes, myeloid leukemic cells, and blood cells. An important find-ing is the elevation in the expression of procoagulant tissue factor and/or phosphatidylserine exposure and the release of microparticles aftertreatment with cisplatin or gemcitabine [39], cyclophosphamide [40],doxorubicin and epirubicin [41–43] and daunorubicin [44].

At present, it is unknown if any of chemotherapeutic agent carriesa higher risk of thrombosis than another. Among chemotherapeuticagents, cisplatin-based regimens particularly have been associatedwith a wide range of thromboembolic complications. A direct role ofcisplatin in thromboembolic toxicity has been suggested by both ret-rospective and prospective studies. The results of one of the prospec-tive studies found a VTE incidence of 7.8% in patients treated with acisplatin-based therapy compared to 0.9% in patients treated with aoxaliplatin-based therapy [45]. Recently, a large retrospective analy-sis of patients treated with cisplatin-based chemotherapy confirmedthe high incidence of thromboembolic events in patients treatedwith this type of chemotherapy [46].

Direct cause–effect relationship between treatment with L-asparaginase, an enzyme used in the treatment of acute lymphoblas-tic leukemia, and increased thrombogenic risk have been reported[47,48]. High-dose corticosteroids, which are sometimes given to can-cer patients to counteract the nausea associated with chemotherapy,are by themselves associated with a 3.5-fold increase in the odds ofdeveloping VTE [49].

Hormone therapy, either as monotherapy or in combination withchemotherapy, has also been shown to increase thrombotic risk in pa-tients with breast cancer. Studies have reported that compared withplacebo or no treatment, women who received the selective estrogenreceptor modulator tamoxifen had a 1.5–7.1-fold increase in risk ofdeveloping symptomatic VTE [50]. Although the ongoing efforts to es-tablish the mechanism which explains the thrombogenic effect of ta-moxifen, the reason for this adverse effect is still unknown. Accordingto some studies, tamoxifen induces reduction in plasma antithrombin

Fig. 2. Prothrombotic mechanisms of anti-tumor drugs. Chemotherapeutic agents can inducposed to anti-tumor drugs increase the expression on their surface of the tissue factor, and rprostacyclin, thrombomodulin, heparan sulfate, tissue-factor pathway inhibitor, and plasminproinflammatory and proangiogenic factors released from tumor cells damaged by chemotupregulating the expression of tissue factor, cell adhesion molecules and plasminogen activ

and protein S levels, and promote the production of superoxide byplatelets, thus generating a prothrombotic status [51,52]. Similarly,reduced levels of proteins C and S have been reported during chemo-therapy with cyclophosphamide, methotrexate, and 5-fluorouracil[36].

The most extensive studies on the relationship between VTE andchemotherapy or chemo-hormonal therapy have been performed inpatients diagnosed with early breast cancer who are receiving adju-vant therapy. The reported incidence of VTE in women with earlystage, node-negative or node-positive breast cancer on chemotherapytreatment is 0.9–9.6% [36], with the greatest risk seen in older post-menopausal women [53]. The results of a randomized multicentertrial that compared 12 weeks of combined chemotherapy and hor-mone therapy versus 36 weeks of chemotherapy alone in womenwith stage II breast cancer [21] found that VTE events occurred duringactive treatment. No thrombotic events occurred after treatmentstopped in the shorter treatment arm, and no VTE events occurredduring the follow-up period. The B14 study of the National SurgicalAdjuvant Breast and Bowel Project (NSABP) reported in womenwith estrogen-receptor positive, node-negative breast cancer a VTEincidence of 0.9% in those who received tamoxifen for 5 years, com-pared with 0.2% in women in the placebo group [54]. In a follow-upstudy (B20), the incidence of VTE increased from 0.8% to 4.2% inthose receiving tamoxifen plus chemotherapy, compared with thosereceiving tamoxifen alone [55]. Anastrozole, a third generation aro-matase inhibitor may be associated with a lower risk of VTE complica-tions than tamoxifen [56], and represents an alternative agent foradjuvant treatment in women with early breast cancer and a low-risk of recurrent tumors [36].

Acquired and inherited risk factors for VTE and the incidence ofsymptomatic VTE were prospectively investigated in a group of pa-tients on adjuvant chemotherapy for breast or gastrointestinal cancer[57]. Overall, 30 VTE events (7.87%) were recorded. Thrombocytosisand history of thrombosis were identified as risk factors for develop-ment of a thrombotic event during adjuvant chemotherapy.

Regarding the association between VTE and chemotherapy in ad-vanced cancer, a review of the medical records of 206 cancer patientswho received chemotherapy reported the highest incidence of VTE inpatients treated with a combination of fluorouracil and leucovorin

e the expression of prothrombotic phenotype by endothelial cells. Endothelial cells ex-elease procoagulant microparticles. In parallel, these agents can reduce the synthesis ofogen activators, all of which inhibit hemostasis and thrombus formation. Furthermore,herapy can act on endothelial cells and induce a prothrombotic phenotype as well byator inhibitor.

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calcium for inoperable colorectal cancer [23]. These findings supportthe 17% incidence of VTE cited in an earlier study of patients with ad-vanced colon cancer treated with an active regimen of fluorouracil,leucovorin, and granulocyte-macrophage colony-stimulating factor[58]. In gastrointestinal cancers, 9.2% of patients receiving chemo-therapy developed symptomatic VTE [24], and was 3.5-times greaterin patients with advanced disease undergoing chemotherapy, than inthose patients with advanced disease not given chemotherapy [24].Studies of patients with high-grade glioma treated with chemothera-py have reported VTE events in 19–26% of patients [59].

Antiangiogenic agents

Tumorigenesis is a complex multistep process involving also se-lective supportive conditions of the deregulated tumor microenviron-ment. One key compartment of the microenvironment is the vascularniche. The role of angiogenesis in solid tumors but also in hematologicmalignancies is nowwell established. New therapeutic agents that in-hibit angiogenesis, thereby restricting the growth and spread of tu-mors, are being developed as treatments for various solid tumors(non-small-cell lung cancer, breast cancer, and colon cancer) andmultiple myeloma. At today several antiangiogenic agents includingthalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesiro-limus, and everolimus have been approved for the clinical use. Beva-cizumab the monoclonal antibody to vascular endothelial growthfactor, have shown efficacy in improving survival rates among pa-tients with advanced disease, however, the addition of bevacizumabto chemotherapy regimens is associated with a high incidence ofthrombotic events [60]. Similarly, cancer treatment regimens involv-ing thalidomide or lenalidomide are associated with very high rates ofVTE [60]. These antiangiogenic agents appear to increase further theVTE risk associated with the chemotherapy, although it is difficult toseparate their effects from those of the chemotherapy drugs. It hasbeen hypothesized that perturbation of tumor-associated endothelialcells might mediate the activation of systemic coagulation in cancerpatients rendering them even more susceptible to thrombosis.

Combination therapy

Anti-tumor treatment regimens involving combinationof chemother-apy plus immunomodulatory agents or antiangiogenic agents (i.e. vascu-lar endothelial growth factor inhibitors) are associated with increasedVTE risk. In patientswith advanced non-small-cell lung cancer, combinedtreatment with the matrix metalloproteinase inhibitor prinomastat pluschemotherapy has been reported to double the risk of VTE [61]. In meta-static colon cancer, addition of bevacizumab to a fluorouracil-based che-motherapy regimen increased the reported incidence of VTE from 16.2%to 19.4% [62]. Pooled analysis of data from five randomized, controlledclinical trials involving patients with metastatic cancer (predominantlymetastatic colorectal cancer) has shown that the addition of bevacizumabto chemotherapy regimens is associatedwith an increased risk of arterialthrombosis (HR 2.0, 95% CI , 1.05-3.75; P=0.031) but not VTE (HR 0.89,95% CI, 0.66-1.20; P=0.44) [63].

Similarly, in multiple myeloma, treatment regimens involving eitherthalidomide or lenalidomide in combinationwith dexamethasone, or ananthracycline such as doxorubicin together with thalidomide have beenassociated with up to a 7-fold increases in VTE incidence [64]. A recentmeta-analysis showed thatmultiplemyeloma patients receiving combi-nation therapy with dexamethasone and thalidomide were 8-timesmore likely to develop VTE than patients not on active treatment [26].

In combination treatment, the addition of doxorubicin appears to beassociated with an increase in VTE risk, independently of the thrombo-genic effects of other agents in the regimen. Zangari et al. have reportedthe incidence of VTE in 232 patients with multiple myeloma that weretreated using a combination regimen of chemotherapy and thalidomide.Two treatment regimens were studied, differing only in the addition of

doxorubicin to one protocol. The incidence of VTE was significantlyhigher in patients who received doxorubicin (16 vs 3.5%, P=0.02)[65]. These findings are supported by a later study of the thrombogeniceffects of different combination regimens by the same group in whichthe addition of doxorubicin was found to be associated with 4.3-fold in-crease in the incidence of VTE [66].

Supportive therapy

Supportive cancer therapy is the use of medications to counteractunwanted effects of cancer treatment, like nausea or vomiting, anemia,thrombocytopenia and leukopenia. Among these agents, the use of re-combinant human erythropoietin and other hematopoietic growth fac-tors, such as granulocyte-macrophage colony-stimulating factor andgranulocyte-colony stimulating factor, as supportive therapy in cancerpatients is increasing. These treatments improve quality-of-life in pa-tients with cancer by reducing anemia and fatigue, and can improveoutcomes by reducing tumor hypoxia and thereby improving the re-sponse to chemotherapy. However, a study in 147 patients with non-metastatic cervical or vaginal cancer has shown that erythropoietin in-creases the risk of thrombosis 15-fold (OR, 15.3; 95% CI, 3.1–76.7) [67].The use of erythropoietin andwhite cell growth factors has been shownto be independently and significantly associated with VTE risk amongpatients on chemotherapy [23]. A recently published analysis of datafrom Phase 3 trials involving erythropoietin for the treatment of anemiain patientswith cancer reported a increased risk of VTE (RR 1.57; 95% CI,1.31-1.87) and an increased risk of mortality (HR 1.10; 95% CI, 1.01-1.20) associated with erythropoietin therapy compared with placeboor standard of care [68].

Evaluation of thrombotic risk in cancer patients undergoing non-surgical cancer treatment

As discussed in this review, the risk of developing symptomatic VTEduring cancer treatment is influenced by many patient-, cancer- andtreatment-related factors. Therefore, the interaction and relative effectsof the risk factors associated with VTE in cancer patients is highly com-plex, and makes the pre-treatment assessment of VTE difficult. In the re-cent years, risk predictionmodels for chemotherapy-associated VTE havebecome available and include many of the risk factors listed above, butalso begin to incorporate biomarkers [69,70]. A simple scoring system isthe Khorana's model, which is based on baseline clinical and laboratorydata. This model has been shown to accurately predict the short-termrisk of symptomatic VTE in patients undergoing chemotherapy-basedtreatments. The inclusion of plasma hemostatic biomarkers, such as D-Dimer and soluble P-selectin, in a validated risk assessmentmodel signif-icantly increased the capacity to predict for VTE [23,71,72], and allowed abetter stratification of the thrombotic risk. In particular, the hazard ratiofor VTE in patientswith the highest comparedwith thosewith the lowestscore was 25.9 [73].

Thromboprophylaxis recommendations in cancer patients

The efficacy of prophylactic strategies to prevent VTE in at riskhospitalized patients has been well demonstrated. However, VTEprevention in cancer patients is more complicated compared tonon cancer patients, as they are prone to greater recurrence ratesand a higher incidence of bleeding complications [11,74]. It hasbeen shown that cancer patients undergoing surgery benefit from ef-fective pharmacological prophylaxis [75], and that extended dura-tion of thromboprophylaxis with low molecular weight heparin(LMWH) is beneficial to patients undergoing major abdominal orpelvic surgery [76]. This is reflected in current guidelines which rec-ommend that all cancer patients undergoing major surgery shouldreceive heparin-based prophylaxis for a minimum of 7–10 days,with supportive mechanical prophylaxis in those patients at highest

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risk [77]. Clinical trials have demonstrated the benefit of VTE pro-phylaxis in hospitalized general medical patients, including patientswith cancer [78] .

Differently from hospitalized cancer patients, still debate is the pri-mary prevention of thrombosis in ambulatory cancer patients. Althoughthere is evidence that LMWH is effective in reducing VTE in selectedoutpatients receiving chemotherapy, the optimal dose, duration andspecific patient populations remain to be defined. The two most recenttrials, conducted in patients with advanced pancreatic cancer who re-ceive systemic chemotherapy, have shown positive results withLMWH prophylaxis. In particular, the CONKO-004 trial found a 87%risk reduction of VTE using the LMWH enoxaparin compared with noprophylaxis [79,80]; while the FRAGEM study reported a 61% risk re-duction of VTE (31 vs 12%; p=0.02) [81]. Results from these trials are,however, in contrast with other studies evaluating LMWHgiven at pro-phylactic doses in ambulatory cancer patients (i.e. TOPIC-1 and TOPIC-2in patients with advanced breast cancer or non-small cell lung cancer(NSCLC), respectively), which did not show statistically significant re-duction of VTE rate with the use of LMWH compared to placebo [82].In the PRODIGE study, the VTE rate in patients with malignant gliomatreatedwith LMWHwas lower compared to placebo but not statisticallysignificant [83]. The results of a large Italian study (i.e. the PROTECHTstudy) on the efficacy of thromboprophylaxis with LMWH in reducingthe rate of VTE in ambulatory cancer patients receiving chemotherapy,showed a 50% reduction of VTE in patients treated with nadroparincompared to placebo [84]. Overall, there is sound evidence thatLMWH is effective in reducing clinically important VTE in selected out-patients receiving chemotherapy, but the optimal dose, duration andspecific patient populations have to be further defined.

Based on the well-established VTE risk and emerging evidence show-ing the benefits of prophylaxis, a number of guidelines and consensusstatements have been published on the use of VTE prophylaxis for cancerpatients. Most notably are the ACCP [34], the International Union ofAngiology (IUA) [85], the National Comprehensive Cancer Network(NCCN)[86], the Italian Association of Medical Oncology (AIOM) [19],French National Federation of the League of Centers Against Cancer(FNCLCC) [87], European Society of Medical Oncology (ESMO) [88], andthe most recent guidelines from the American Society of Clinical Oncolo-gy (ASCO) [89]. Areas thatwarrant further research include the benefit ofprophylaxis in the ambulatory setting, the risk/benefit ratio of prophylax-is for hospitalized patients with cancer, an understanding of incidentalVTE, and the impact of anticoagulation on survival.

Conclusions

The risk of VTE cancer patients varies according to the type of malig-nancy and its disease stage. Hospitalization, surgical and non-surgicalcancer treatments, particularly chemotherapy and combination regimensinvolving hormonal or immunosuppressive agents in conjunction withchemotherapy, further increase the risk of VTE in these patients. Support-ive therapy with erythropoietin and white cell growth factors appears tobe associated with an increased risk of VTE complications. However,thromboprophylaxis is not currently recommended for ambulatory pa-tients with cancer (with exceptions). New and validated predictivemodels for VTE in cancer are becoming available. Risk stratification bythese models will help clinicians to identify those patients at highestrisk for VTE, who may benefit most from thromboprophylaxis.

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