Sage Journals: Discover world-class research

Abstract

Venous thromboembolism (VTE) is the second leading cause of death and a major cause of morbidity in patients with cancer. Pharmacologic thromboprophylaxis is recommended in all hospitalized cancer patients without contraindications to anticoagulants. The role of thromboprophylaxis in outpatients undergoing chemotherapy is less certain because of the diversity of the tumor types and their associated risks of VTE and bleeding. Thromboprophylaxis should only be considered in patients at high risk for VTE. Cancer patients with a newly diagnosed VTE should be preferably treated with low-molecular-weight heparin for a minimum of 3–6 months. Treatment duration should be individualized based on the clinical status and stage of the cancer, the risk of recurrent VTE, the risk of bleeding, and personal preference of the patient. Further research is required to assess the role of the new oral anticoagulants (direct Xa and thrombin inhibitors) for this high-risk population.

Keywords

anticoagulants low-molecular-weight heparins neoplasm thromboprophylaxis venous thromboembolism

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) are common in cancer patients. Patients with cancer have a fourfold increased risk of developing VTE when compared with the general population [Blom et al. 2005; Heit et al. 2002]. Systemic chemotherapy, cancer hormonal therapy and other supportive measures (e.g. erythropoietin stimulating agents) have been shown to increase that risk further [Bohlius et al. 2006; Blom et al. 2005]. More recently, anti-angiogenic agents (e.g. bevacizumab) and immunomodulatory agents (e.g. thalidomide and lenalidomide) have also been shown to increase the risk of VTE in patients with a variety of solid tumors (colorectal, breast, renal cell and non-small cell lung carcinoma [NSCLC] and multiple myeloma [MM]) [Carrier et al. 2011; Nalluri et al. 2008]. Cancer-associated thrombosis can delay or interfere with anticancer therapy, precipitate or prolong hospitalization, and utilize scarce healthcare resources. Therefore, effective thromboprophylaxis and appropriate treatment of VTE are important strategies for minimizing morbidity and mortality for cancer patients and potentially reducing healthcare costs.

Cancer-associated thrombosis, death and prognosis

Thromboembolism is the second leading cause of death in patients with cancer [Khorana et al. 2007b]. The annualized death rate for VTE in cancer patients is approximately 500 per 100,000 patients which is 47-fold higher than in the general population. VTE seems to lead to an increased mortality rate in both hospitalized and ambulatory cancer patients [Fotopoulou et al. 2008; Khorana et al. 2007a, 2006]. A recent analysis of 1,824,316 patients including 1,015,598 cancer patients showed that mortality was significantly increased among patients who developed VTE as compared with those who did not (16.3% versus 6.3%; p < 0.0001) [Khorana et al. 2007a]. Similarly, cancer patients with VTE hospitalized with febrile neutropenia were demonstrated to have greater in-hospital mortality compared with those without thrombosis [Khorana et al. 2006]. Finally, a significant decrease in overall survival was reported in a pooled analysis of 2743 women with ovarian cancer undergoing platinum paclitaxel-based chemotherapy following primary surgical resection (29.8 months in women with VTE versus 36.2 months without VTE; p = 0.03) [Fotopoulou et al. 2008].

VTE appears to have an effect on both short- and long-term prognosis [Kuderer et al. 2008; Sorensen et al. 2000]. A recent study has suggested that cancer-associated thrombosis was associated with early mortality in cancer patients undergoing chemotherapy. A total of 4458 patients with solid tumors or malignant lymphoma were followed for a median of 75 days. A total of 93 patients had a VTE at a median of 38 days following initiation of chemotherapy. Multivariate analyses showed that VTE was a significant predictor of early mortality (hazard ratio [HR] 4.5, 95% confidence interval [CI] 1.61–12.53; p < 0.004) [Kuderer et al. 2008]. Similarly, a Danish Cancer registry comparing 668 cancer patients with DVT with 5371 matched control cancer patients reported a significant reduction of the 1-year overall survival rates (12% versus 36%; p < 0.0001) and the mortality ratio for the entire follow-up period was 2.2 (95% CI 2.05–2.40) [Sorensen et al. 2000]. A more recently published study including 235,149 cancer patients from the California Cancer registry has also suggested that VTE was associated with a worse long-term prognosis in cancer patients. In that study, a total of 3775 (1.6%) of cancer patients were diagnosed with a VTE over a 2-year period. VTE was associated with an increased risk of mortality for all stages and cancer types except for regional and metastatic renal cancer with an overall HR of 3.7 (95% CI 1.3–14.4) [Chew et al. 2006]. Although the effect of VTE on mortality in studies involving multiple sites might be partly attributed to the worse prognosis of more thrombogenic tumor types (e.g. pancreatic cancer) or the presence of a more advanced disease state (e.g. metastatic disease), numerous studies have assessed the association within specific tumor types, stage, or histology. A recent analysis of 108,255 patients with breast cancer demonstrated that VTE was a significant predictor of decreased 2-year survival (HR 2.3; 95% CI 2.1–2.6) and stratification by initial cancer stage showed that the effect was highest in patients with localized (HR 5.1; 95% CI 3.6–7.1) or regional stage (HR 3.5; 95% CI 2.5–4.8) cancer compared with patients with metastatic disease (HR 1.9; 95% CI 1.5–2.4) [Chew et al. 2007]. In a risk-adjusted model including 68,142 colorectal-cancer patients, VTE was also a significant predictor of death within 1 year of cancer diagnosis among patients with local (HR 1.8; 95% CI 1.4–2.3) or regional-stage disease (HR 1.5; 95% CI 1.3–1.8) but not among patients with metastatic disease (HR 1.1; 95% CI 1.0–1.2) [Alcalay et al. 2006]. Finally, another analysis of the California Cancer Registry assessing 91,933 patients with newly diagnosed lung cancer, the 1-year and 2-year cumulative VTE incidences were 3.0% and 3.4%, respectively. Multivariate analyses showed that VTE was a significant predictor of death within 2 years independent of histology (non-small cell lung cancer or small cell lung cancer) [Chew et al. 2008]. Therefore, the association between VTE and increased mortality cannot be solely attributed to cancer types and staging. However, the association is likely multifactorial and might be a surrogate for adverse tumor biology leading to a worse prognosis. More research is needed to investigate the mechanism behind clinical hypercoagulable state and tumor biology.

Risk stratification for cancer-associated thrombosis

Given the high prevalence of VTE in cancer patients and its associated detrimental effect on mortality and morbidity, a risk assessment score to predict the development of cancer-associated thrombosis in cancer patients undergoing chemotherapy has been proposed. This risk assessment score was developed using the Awareness of Neutropenia in Chemotherapy Study registry using cancer patients who had completed at least one cycle of chemotherapy [Khorana et al. 2008]. Five predictive variables were identified to assess the risk of symptomatic VTE during the first cycle of chemotherapy: (1) site of cancer; (2) platelet count; (3) hemoglobin level and or/use of erythropoiesis-stimulating agents; (4) leukocytes counts; and (5) body mass index (Table 1) [Khorana et al. 2008]. A total of 27% of patients were stratified within the low-risk group in both derivation and validation cohorts whereas 13% and 11% were categorized in the high-risk group in the derivation and validation cohort, respectively. Rates of VTE in the derivation and validation cohorts were 0.8% and 0.3% in the low-risk group, 1.8% and 2% in the intermediate-risk group and 7.1% and 6.7% in the high-risk group, respectively [Khorana et al. 2008]. The Khorana’s risk assessment score was recently validated [Ay et al. 2009]. Incorporating additional variables including biomarkers (e.g. D-dimer, tissue factor, soluble P selectin, thrombin generation) has been proposed and seem to potentially improve the risk assessment score [Ay et al. 2011, 2010, 2009; Zwicker et al. 2009]. A prospective and observational cohort study of 819 patients with newly diagnosed cancer or progression of disease after remission was conducted to assess an expanded version of Khorana’s risk assessment score by incorporating two biomarkers (soluble P selectin and D-dimer). A total of 61 VTEs occurred over a median of 656 days. Rates of VTE in the original and expanded version of the risk assessment scores were 17.7% and 35% in the high-risk group, 9.6% and 10.3% in the intermediate-risk group and 1.5% and 1% in the low-risk group, respectively. The HR of patients with the highest compared with those with the lowest score was 25.9 (95% CI 8.0–84.6). However, only 4% (n = 30) of the entire sample was classified within the highest-risk group. Although biomarkers are promising and seem to improve the risk stratification of VTE in cancer patients undergoing chemotherapy, it is important to recognize these assays are not uniformly standardized and different assays might not yield similar accuracy. Studies assessing the use of VTE risk assessment scores to determine the need for pharmacological thromboprophylaxis in ambulatory cancer patients undergoing chemotherapy are ongoing and might be able to provide clinicians with more insight to tailor the risk–benefit ratio of thromboprophylaxis in this high-risk population.

Table 1.

Khorana’s risk assessment score.

Patient characteristic		Risk score
Site of primary cancer
• Very high risk (stomach, pancreas)		2
• High risk (lung, lymphoma, gynecologic, bladder, testicular)		1
Prechemotherapy platelet count 350 × 10⁹/l or higher		1
Hemoglobin level less than 10 g/l or erythropoiesis-stimulating agents		1
Prechemotherapy leukocyte count higher than 11 × 10⁹/l		1
BMI 35 kg/m² or higher		1
Total Score	Risk category	Risk of symptomatic VTE
0	Low	0.3–0.8%
1, 2	Intermediate	1.8–2.0%
3 or higher	High	6.7–7.1%

BMI, body mass index; VTE, venous thromboembolism.

Prevention of cancer-associated thrombosis in medical patients

Hospitalized medically ill cancer patients

Cancer patients who are hospitalized for medical problems have an increased risk of VTE. A large study using hospital discharge databases showed that up to 5.4% of patients requiring hospitalization for chemotherapy will develop thrombotic complications [Khorana et al. 2006]. Furthermore, the incidence of VTE is rising in the hospitalized oncology population [Khorana et al. 2006; Stein et al. 2006]. Unfortunately, data from large randomized trials assessing pharmacological thromboprophylaxis in hospitalized patients with cancer are not available and the risk–benefit ratio of thromboprophylaxis has never been formally studied in this population. Large randomized, double-blind, placebo-controlled trials evaluating a low-molecular-weight heparin (LMWH; enoxaparin 40 mg or dalteparin 5000 U daily) or fondaparinux (2.5 mg daily) in hospitalized medical patients have included approximately 5–15% of patients with a diagnosis of cancer [Francis, 2007; Cohen et al. 2006; Leizorovicz et al. 2004; Samama et al. 1999]. Therefore, it is probable that cancer patients would benefit from pharmacological prophylaxis [Francis, 2007]. A post hoc analysis of one of the trials has reported no difference between cancer patients receiving thromboprophylaxis and placebo [Alikhan et al. 2003]. The study sample was small and the analysis was underpowered. Consensus guidelines are supporting the use of pharmacological thromboprophylaxis [Geerts et al. 2008; Lyman et al. 2007b]. However, compliance is poor in hospitalized cancer patients [Geerts et al. 2008; Amin et al. 2007; Lyman et al. 2007b]. A randomized controlled trial has recently showed that an electronic alert system was able to increase physician compliance in prescribing thromboprophylaxis and resulted in a significant reduction of symptomatic VTE by 41% [Kucher et al. 2005]. Computerized prompts have also been shown to increase compliance and decrease VTE specifically in hospitalized oncology patients [Candelario et al. 2010]. Hence, effective thromboprophylaxis in hospitalized cancer patients could have an important impact on overall survival.

Hospitalized medically ill cancer patients with a contraindication to pharmacological thromboprophylaxis should be considered for mechanical thromboprophylaxis. Intermittent pneumatic compression (IPC) devices and/or graduated compression stockings (GCSs) are reasonable alternatives. However, few studies have addressed the efficacy of such mechanical prophylactic devices in hospitalized cancer patients. A recent systematic review showed a lower crude cumulated DVT rate with IPC compared with GCSs in patients following abdominal surgery [Morris and Woodcock, 2010]. The use of mechanical thromboprophylaxis is limited by improper fit and patient’s noncompliance. Furthermore, combination of pharmacological and mechanical thromboprophylaxis has shown a significantly decreased incidence of both symptomatic PE and DVT when compared with mechanical modalities alone [Kakkos et al. 2008]. Thus, once a patient’s contraindication to thromboprophylaxis with an anticoagulant resolves, the addition of pharmacological thromboprophylaxis should be considered.

Outpatients undergoing chemotherapy

Several studies have assessed the use of LMWH or ultra-LMWH for thromboprophylaxis in outpatients undergoing chemotherapy (Table 2) [Agnelli et al. 2011, 2009; Haas et al. 2005; Maraveyas et al. 2011; Perry et al. 2010; Reiss et al. 2009]. Whereas some studies have showed a significant difference in overall or symptomatic VTE between the treatment groups, others have not. The CONKO-004 trial and the FRAGEM study have both showed a significant relative risk reduction of VTE in patients with advanced pancreatic adenocarcinoma [Maraveyas et al. 2011; Reiss et al. 2009]. The PROTECHT study has also shown that thromboprophylaxis using nadroparin significantly decreases the risk of venous and arterial thrombosis in patients with locally advanced or metastatic cancers [Agnelli et al. 2009]. More recently, the SAVE-ONCO trial evaluated the use of the ultra-LMWH semuloparin in patients with locally advanced or metastatic disease [Agnelli et al. 2011]. Semuloparin was shown to significantly decrease the risk of symptomatic VTE (HR 0.36; 95% CI 0.21–0.6) without increasing the risk of bleeding [Agnelli et al. 2011]. Although the PROTECHT and SAVE-ONCO have reported significant relative risk reduction in their respective primary efficacy outcome measure, the absolute risk reduction is modest at 1.8% and 2.2%, respectively. In contrast, the TOPIC 1 and 2 studies have failed to show any significant difference between the treatment groups in patients with advanced breast cancer and non-small cell lung cancer respectively [Haas et al. 2005]. Similarly, the PRODIGE study did not show any significance difference in symptomatic VTE in patients with grade III/IV malignant glioma receiving prophylactic doses of dalteparin [Perry et al. 2010]. However, the PRODIGE study was stopped prematurely (186 out of 512 required patients) as a result of expiration of the study drug. These conflicting results suggest that pharmacological thromboprophylaxis might be effective in preventing VTE in only certain types of tumors (e.g. advanced pancreatic adenocarcinoma) or patients with high-risk features. Hence, identifying high-risk cancer patients who would be more likely to potentially benefit from thromboprophylaxis remains an important and unresolved clinical question. Unfortunately, none of the previously discussed trials used a risk assessment score to stratify patients according to their underlying risk of VTE. Finally, the incidence of bleeding episodes observed in the control groups varied considerably amongst the different studies suggesting that the risk–benefit ratio of thromboprophylaxis might vary for different tumor sites and stages [Kuderer et al. 2009]. Consensus guidelines from the ASCO and ACCP are currently not recommending routine thromboprophylaxis in ambulatory cancer patients undergoing chemotherapy [Geerts et al. 2008; Amin et al. 2007]. However, the most recent version of the NCCN guidelines suggest to consider using thromboprophylaxis in cancer patients with additional risk factors (i.e. high-risk tumor site, high platelet count, low hemoglobin or use of erythropoietin agents, high BMI, etc.).

Table 2.

Pharmacological thromboprophylaxis for outpatient undergoing chemotherapy.

Study	Type of cancer	Design	Numberofpatients	Intervention	Primary outcome measure	Primary outcome	Conclusions
Haas et al. [2005]	Advanced breast cancerNon-small cell lung carcinoma	Double-blind RCT	353547	Certoparin 3000 U OD versus observationCertoparin 3000 U OD versus observation	Symptomatic and asymptomatic thrombosis	4.0% versus 3.9%4.5% versus 8.3%	No differenceNo difference
Reiss et al. [2009]	Advanced pancreatic cancer	Open RCT	312	Enoxaparin 1 mg/kg daily × 3 monthsthen 40 mg daily versus observation	Symptomatic VTE	5.0% versus 14.5%	Favoring enoxaparin
Maraveyas et al. [2010]	Advanced pancreatic cancer	Open RCT	123	Dalteparin 200 U/kg daily × 1 months then 150 U/kg daily × 3 months versus observation	Overall VTE	12% versus 31%	Favoring dalteparin
Agnelli et al. [2009]	Locally advanced or metastatic solid tumors	Double-blind RCT	1166	Nadroparin, 3800 U daily up to 4 months versus placebo	Composite of symptomatic VTE or arterial thromboembolic events	2.0% versus 3.8%	Favoring nadroparin
Perry et al. [2010]	Grade III/IV malignant glioma	Double-blind RCT	186	Dalteparin 5,000 U OD × 6–12 months versus placebo	Symptomatic VTE	11.0% versus 15.0%	No difference
Agnelli et al. [2011]	Locally advanced or metastatic solid tumors	Double-blind RCT	3212	Semuloparin 20 mg daily × at least 3 months versus placebo	Symptomatic VTE	1.2% versus 3.4%	Favoring semuloparin

RCT, randomized controlled trial; U, units; VTE, venous thromboembolic events; OD, once daily.

Pharmacological thromboprophylaxis should be considered in patients with multiple myeloma who are receiving thalidomide- or lenalidomide-based chemotherapy. Aspirin, LMWH or warfarin may be effective agents in reducing symptomatic VTE [Carrier et al. 2011]. Given the high incidence of VTE specifically and the absence of level 1 data, randomized-controlled trials are urgently required to identify effective and safe thromboprophylactic regimen.

Finally, only one phase II study has evaluated the use of the oral direct Xa inhibitor apixaban in cancer patients. A total of 125 patients with metastatic cancer receiving first- or second-line chemotherapy were randomized to different doses of apixaban or placebo for 12 weeks [Levine et al. 2009]. Apixaban was well tolerated in patients with advanced cancer on chemotherapy. Further research on the role of the new oral direct antithrombin and anti-Xa inhibitors are also most needed.

Treatment of VTE in cancer patients

Treating DVT and PE in patients with cancer can be more complex than treating noncancer patients. There are many reasons why treatment is less straightforward. Chemotherapy can cause nausea and diarrhea, impairing oral medication absorption, and can be associated with thrombocytopenia (potentiating the bleeding risk). Chemotherapy itself and indwelling long-term intravenous catheters increase the risk of recurrent VTE. Surgical resection of the cancer necessitates careful anticoagulant management, with minimal time off anticoagulant therapy due to the high-risk nature of the surgery.

A proportion of patients with both cancer and acute VTE have very poor prognosis. The 30-day mortality of cancer patients with VTE in a Swiss prospective registry and the RIETE database was 11.4% [Spirk et al. 2011] and 13% [Trujillo-Santos et al. 2011], respectively. The severity of the underlying cancer might influence a patient’s opinion regarding the method of treatment, hospitalization and potential risks. When treating cancer patients with VTE, it is important to understand the potential risks and benefits of anticoagulant therapy. The three main aims of therapy are to reduce progression and recurrence of VTE, with minimal increase in bleeding risk, and to improve survival.

Risk of recurrent VTE in cancer patients

There is evidence that cancer patients have a higher risk of recurrent VTE than noncancer patients. In a prospective cohort of 842 patients with acute DVT treated with warfarin [Prandoni et al. 2002], the 12-month cumulative incidence of recurrent VTE in cancer patients was 20.7% (95% CI 15.6–25.8%) versus 6.8% (95% CI 3.9–9.7%) in noncancer patients. A second analysis of two prospective cohorts totaling 1303 patients treated with warfarin for acute VTE [Hutten et al. 2000] has reported an incidence of recurrent events of 27.1 per 100 patient-years (95% CI 14.8–45.4) in cancer patients as compared with 9.0 per 100 patient-years (95% CI 5.6–13.8) in those without cancer. Finally, the RIETE registry reported a 4.6% VTE recurrence rate at 3 months despite anticoagulant therapy in women with cancer [Trujillo-Santos et al. 2009]

There is little evidence on how to stratify cancer patients according to their individual risk of recurrent VTE. A systematic review has previously shown that patients with metastatic cancer have an increased risk of recurrent VTE as compared with patients with localized disease (RR 1.36; 95% CI 1.06–1.74) [Louzada et al. 2009]. Unfortunately, there was insufficient data to report the risk of recurrent VTE per tumor type or histology. A prospectively cohort study of patients with DVT managed with warfarin has reported a higher hazard ratio for recurrent VTE in patients with lung (HR 6.9; 95% CI 3.0–15.9) and colorectal cancer (HR 5.1; 95% CI 2.3–11.3) [Prandoni et al. 2002]. DVT in women with breast cancer was associated with a lower risk of recurrence (HR 0.7; 95% CI 0.1–4.9) [Chew et al. 2007; Prandoni et al. 2002]. In a recent registry study including 2474 women with cancer-associated VTE, fatal recurrent PE within 30 days of follow up was more common in women with breast, colorectal, lung or pancreatic cancer [Trujillo-Santos et al. 2011]. It appears that some cancer types are associated with a greater probability of recurrence; however, there is insufficient data to produce any tailored therapeutic management at present. Further studies identifying risk factors for recurrent VTE in patients with cancer-associated thrombosis are required.

Risk of bleeding in cancer patients

Patients with cancer have a higher risk of bleeding while treated with anticoagulant therapy than those without cancer. A retrospective-population study from 1987–1989 [Gitter et al. 1995] reported cumulative incidences of major hemorrhage at 12 and 24 months of 5.3% and 10.6%, respectively, among patients with treated with warfarin. Malignant disease was associated with major hemorrhage in all patients regardless of indication for anticoagulation. A prospectively cohort study of patients with DVT managed with warfarin has reported a rate of major bleeding episodes of 15.7/100 patient-years in cancer patients compared with 8.6/100 patient-years in noncancer patient [Prandoni et al. 2002]. The incidence of bleeding correlated with cancer stage. Similarly, a post hoc analysis of 1303 patients enrolled into two multicenter randomized-controlled clinical trials on the initial treatment of VTE showed that the rates of bleeding on warfarin was 13.3/100 patient-years (95% CI 5.4–27.5) and 2.1/100 patient-years (95% CI 0.7–5.0) for patients with and without cancer, respectively [Hutten et al. 2000]. Finally, an analysis of the international RIETE registry [Prandoni et al. 2010] shows that 36% of patients who had a major bleeding complication during treatment of VTE had cancer versus 20% of those who did not have a bleeding complication. Bleeding was fatal in 25% of cases; however, even after survival of the bleeding episode, these patients remained more likely to die in the 3 months after diagnosis of VTE. In contrast to these older trials, the more recent Swiss registry [Spirk et al. 2011] recorded 30-day bleeding rates of 7.2% and 6.0% in cancer and noncancer patients treated for VTE. However, the treatment regimens for patients with cancer and without cancer were different (i.e. more LMWH use in patients with cancer)

Therefore, it is clear that patients with both cancer and VTE are at a higher risk of bleeding complications than those who do not have cancer. Furthermore, those who have a major bleeding episode are more likely to die either from the bleed, or following recovery from the bleed.

Initial anticoagulant therapy for cancer-associated thrombosis

LMWH is the preferred approach for the initial 5–10 days of anticoagulant treatment [Lyman et al. 2007a]. A recent Cochrane review [Akl et al. 2011] analyzed 16 randomized-controlled trials comparing treatments for the initial anticoagulation of cancer patients during the first week after diagnosis of acute VTE. Eleven studies compared initial treatment with unfractionated intravenous heparin (UFH) with LMWH. The pooled analysis showed a statistically significant mortality reduction at 3 months in patients treated with LMWH compared with those treated with UFH (RR 0.71; 95% CI 0.52–0.98). The pooled analysis for recurrent VTE did not show a significant advantage of LMWH over UFH (RR 0.78; 95% CI 0.29–2.08). No difference was found between fondaparinux and heparin, or between tinzaparin and dalteparin.

Long-term anticoagulant therapy forcancer-associated thrombosis

As discussed above, cancer patients with VTE are more likely to have recurrent VTE or major bleeding episodes while on long-term anticoagulant therapy using warfarin. Cancer patients receiving warfarin therapy are less likely to stay in the therapeutic international normalized ratio (INR) range [Rose et al. 2007; Hutten et al. 2000] than VTE patients without cancer. Furthermore, cancer patients are more likely to have recurrent VTE when subtherapeutic (INR < 2.0) on warfarin therapy as compared with noncancer patients (estimated excess risk of recurrence 35 versus 9/100 patients-years) [Rose et al. 2007; Hutten et al. 2000].

Studies have compared the rate of recurrent VTE, bleeding and death in cancer patients treated with warfarin or LMWH (Table 3). Compared with warfarin, LMWH treatment results in fewer episodes of VTE recurrence. The CLOT study [Lee et al. 2003] compared long-term anticoagulant therapy using dalteparin with warfarin for cancer-associated thrombosis. Patients receiving dalteparin received 200 U/kg once per day for the first month followed by 150 U/kg for the following 5 months. The trial showed a relative risk reduction of 52% in symptomatic VTE at 6 months in patients receiving long-term anticoagulant therapy with dalteparin (p = 0.002) [Lee et al. 2003]. There were no differences in the rates of bleeding episodes (major and any bleeding episodes) or death between the two groups. In the LITE study, cancer patients randomized to LMWH received therapeutic doses of tinzaparin (175 U/Kg once per day) for the 3-month treatment period. Although a significant difference in recurrent VTE between the two groups was observed at 12 months, there was no difference detected after the 3-month study treatment of LMWH [Hull et al. 2006]. A study randomizing patients with cancer-associated thrombosis to receive either therapeutic doses of tinzaparin for 6 months or warfarin is currently underway. Finally two small trials have assessed the use of enoxaparin as long-term anticoagulant therapy [Deitcher et al. 2006; Meyer et al. 2002]. Both trials have shown no difference in the rates of recurrent VTE but they were underpowered to detect a significant difference. A Cochrane review [Akl et al. 2008] reported a pooled hazard ratio for recurrent VTE of 0.47 (95% CI 0.32–0.71) favoring LMWH, but no difference on overall mortality rate, HR 0.96 (95% CI 0.81–1.14). There was no statistical difference between the incidence of bleeding events or thrombocytopenic episodes.

Table 3.

Long term treatment of cancer patients with VTE.

Study	Design	Number of patients	Intervention	Primary outcome measure	Primary outcome	Conclusions
Meyer et al.[2002]	Open label RCT	67	Enoxaparin 1.5 mg/kg once per day versus	Recurrent VTE at 3 months	3.0% versus 4.2%	No difference
	Cancer patients with acute VTE	71	Enoxaparin 1.5 mg/kg once per day for first 4 days then warfarin	Major bleed at 3 months	7.0% versus 16.0%	No difference
	25 centers		(Both treatments for 3 months)	Mortality at 3 months	11.9% versus 23.9%	No difference
Lee et al.[2003]	Open label RCT	336	Dalteparin 200 U/kg for first month followed by 150 U/kg for next 5 months	Recurrent VTE at 6 months	8.0% versus 15.8%	Favors dalteparin
	Cancer patients with acute VTE		versus	Major bleed at 6 months	5.6% versus 3.6%	No difference
	48 centers	336	Dalteparin 200U/kg for first 5 days then either warfarin for 6 months	Any bleed at 6 months	14% versus 19%	No difference
Deitcher et al. [2006]	Open label RCT		All received enoxaparin 1 mg/kg twice daily for 5 days, then randomized to :	Recurrent VTE at 7 months	6.9% versus 6.3% versus 10.0%	No difference
	Cancer patients with acute VTE	29	Enoxaparin 1 mg/kg once per day versus	Minor bleed at 7 months	61.3% versus 55.6% versus 50.0%	No difference
		32	Enoxaparin 1.5 mg/kg once per day vs.	Major bleed at 7 months	6.5% versus 11.1% versus 2.9%	No difference
	27 centers	30	Warfarin (all for 175-180 days)
Hull et al.[2006]	Open label RCT	100	Tinzaparin 175U/kg once per day vs.	Recurrent VTE at 3 months	6% versus 10%	No difference
	Cancer patients with acute proximal DVT with or without PE	100	UFH for first 6 days then warfarin	Recurrent VTE at 12 months	7% versus 16%	Favors tinzaparin
	23 centers		(both treatments for 12 weeks)	Minor bleed	20% versus 17%	No difference
				Major bleed	7% versus 7%	No difference
				Mortality at 3 months	20% versus 19%	No difference
				Mortality at 12 months	47% versus 47%	No difference
van Doormaal et al. [2010]	Post hoc subgroup analysis of open label RCT	220	Idraparinux 2.5 mg weekly vs.	Recurrent VTE at 3 months	2.5% versus 5.5%	No difference
	Cancer patients with acute DVT	201	LMWH or UFH for 5 days followed by warfarin	Clinically relevant bleed at 3 months	6.8% versus 11.9%	No difference
	318 centers		(Both treatment for 3 or 6 months depending on physician)	Mortality at 9 months	22.7% versus 22.4%	No difference

RCT, randomized-controlled trial; U, units; VTE, venous thromboembolic events; LMWH, low-molecular-weight heparin; UFH, unfractionated intravenous heparin; DVT, deep vein thrombosis; PE, pulmonary embolism.

The evidence suggests that LMWH therapy is superior to warfarin therapy for long-term anticoagulation therapy for cancer-associated thrombosis in terms of preventing VTE recurrences [Lyman et al. 2007b]. The more predictable dose response obtained with LMWH compared with warfarin, can partly be explained by administration via the subcutaneous route and independence from dietary vitamin K intake. This makes the treatment more effective than warfarin during periods of nausea, vomiting, diarrhea and poor oral intake. Furthermore, the dose of LMWH seldom requires alteration which may improve patient compliance in comparison with warfarin which necessitates regular INR checks and dose alterations. Cessation of anticoagulation prior to surgical intervention is less complicated with LMWH which may further reduce the incidence of recurrent VTE.

It is unclear whether LMWH should be given at a therapeutic dose for the entire duration of the anticoagulation period or not. As discussed above, the CLOT study treated patients with therapeutic doses of dalteparin for the first month, followed by 75–80% therapeutic dose for the following 5 months [Lee et al. 2003]. However, other trials have given therapeutic doses of LMWH (tinzaparin and enoxaparin) for a total duration of 3 months [Hull et al. 2006; Meyer et al. 2002]. It is difficult to compare the individual study outcomes given the differences in the follow-up period and relatively small sample sizes of the studies, and relate these outcomes to drug dosing alone. One prospective cohort study reported outcomes of 203 consecutive patients with cancer-associated thrombosis treated with 10,000 U of dalteparin once per day for 3 months regardless of weight [Monreal et al. 2004]. All patients had metastatic cancer. A total of 21 patients (10%) had recurrence within 3 months, 11 (5%) had a major bleed and 65 (32%) died within 3 months. As yet, there have been no studies comparing doses of LMWH for cancer-associated thrombosis. Given the heightened risk of recurrent VTE and major bleeding episodes in cancer patients with VTE, dose reduction of the LMWH following the first month of treatment should be made on an individual patient basis. A trial using 6 months of full dose tinzaparin treatment versus warfarin in cancer patients with VTE is currently recruiting, and may provide more insight on this important clinical issue.

There is a dearth of evidence to guide physicians when treating VTE in the presence of chemotherapy induced thrombocytopenia. Several cancer-associated thrombosis studies have used dose reduction protocols during episodes of severe thrombocytopenia. The CLOT study [Lee et al. 2003] withheld LMWH if the platelet count dropped below 50,000, and reduced the dose of LMWH with platelet counts of 50,000–100,000. Of the 19 patients treated with dalteparin who had a major bleed, two were thrombocytopenic. In contrast, Monreal and colleagues continued dalteparin therapy at a dose of 5000 U with a platelet count <50,000 and 2500 U if the platelets dropped below 10,000 [Monreal et al. 2004]. Thrombocytopenia was associated with 7/16 patients with minor bleeding and 0/11 patients with major bleeding. Although it is impossible to quantify the risk of bleeding in patients with chemotherapy-induced thrombocytopenia it appears appropriate to reduce the dose of LMWH with platelet counts of 50,000 or less. In the setting of acute VTE, consideration should be given to temporary inferior vena cava filter insertion to protect against further pulmonary embolism. The decision to omit anticoagulation should be made on an individual patient basis.

Newer anticoagulants have been tested for the treatment of VTE. A subgroup analysis of the van Gogh study has shown that idraparinux might be as efficacious and safe as warfarin for the treatment of cancer-associated DVT but not PE [van Doormaal et al. 2010]. The new oral anticoagulant drugs dabigatran (a direct thrombin inhibitor), apixaban and rivaroxaban (factor Xa inhibitors) may also be potential therapies for cancer patients with VTE in the future. Studies to date recruited all patients treated for VTE with a very small number of cancer patients (approximately 5%), and compared the efficacy of the new drug to warfarin. We have established that LMWH is the current standard of care for treating cancer related VTE, so more relevant research would compare the rate of VTE recurrence and bleeding in cancer patients treated with either LMWH or a new oral anticoagulant. These new drugs do not require blood monitoring, dose alterations, or self-injection; however, it is unclear whether the oral route would be associated with less predictable drug absorption in cancer patients, or whether the bleeding rate would differ from LMWH. Their use cannot be recommended in this population at present.

Duration of anticoagulation therapy

The American Society of Clinical Oncology [Lyman et al. 2007a] and The American College of Chest Physicians [Kearon et al. 2008] are currently recommending a minimum of 3–6 months of treatment with LMWH. Patients should continue anticoagulant therapy for as long as they are receiving anticancer therapy. Patients with metastatic disease should receive indefinite anticoagulant therapy. The choice of anticoagulant agent (LMWH or warfarin) to use after the initial 3–6 months of LMWH should be made on a case-by-case basis.

Two recent publications suggest that despite these recommendations, a large proportion of cancer patients are still treated with warfarin instead of LMWH. The RIETE Registry database started in 2001. An analysis in 2010 showed that 34% of women with cancer had been treated with warfarin rather than LMWH. The more recent Swiss registry from 2009 to 2010 recorded that only 39% of cancer patients were treated with LMWH alone.

Treatment of incidentally diagnosed pulmonary embolism

Most cancer patients undergo CT scanning for tumor staging and evaluation of disease response. PE is diagnosed on routine chest CT scanning, in patients who have no symptoms of embolus, in around 1–4% of patients [Browne et al. 2010; Douma et al. 2010]. In a retrospective analysis of 113 patients with lung cancer and incidental PE diagnosed on CT [Sun et al. 2010], the median survival for patients who were anticoagulated (with warfarin) was 40 months compared with 6 months for patients who were not treated with anticoagulation (p < 0.001). A second retrospective cohort of 51 cancer patients with incidental PE, all of whom were anticoagulated with LMWH or warfarin, demonstrated that 1-year mortality and VTE recurrence was the same as for cancer patients who were treated for symptomatic PE [den Exter et al. 2011]. These small studies suggest that cancer patients with incidental PE diagnosed on CT, in the absence of symptoms, benefit from anticoagulation and should be treated.

Treatment of recurrent VTE

There is little published research to guide the approach to cancer patients who have been diagnosed with a recurrent VTE while on anticoagulant therapy for cancer-associated thrombosis. There is no evidence supporting the use of temporary inferior vena cava (IVC) filters in cancer patients. One open-label, randomized-controlled trial has studied the efficacy of inserting a permanent IVC filter in addition to standard anticoagulation for preventing VTE recurrence in patients with acute VTE [PREPICT Study, 2005]. The study reported a significant reduction in PE (HR 0.37; 95% CI 0.17–0.79) at 8-year follow up in patients with a permanent IVC filter. However, there was no reduction in overall mortality and an increased incidence of DVT was demonstrated in the IVC filter group [PREPICT Study, 2005]. A retrospective cohort study has also reported a high rate of DVT (32%) in cancer patients with IVC filters [Elting et al. 2004]. Therefore, IVC filters do not seem to provide any advantage to VTE patients receiving anticoagulation. Given the absence of survival advantage with permanent IVC filter insertion in patient receiving anticoagulation, the lack of safety data using the different types of temporary IVC filter and the increased risk of DVT in cancer patients with IVC, their use should be kept for patients with contraindications to anticoagulation. A retrospective cohort of 70 cancer patients with recurrent VTE while on LMWH reported 3-month follow-up results using dose escalation of LMWH [Carrier et al. 2009]. Patients with recurrent VTE had their dose increased by 20–25% for 4–6 weeks. During 3-month follow up, 9% had a second recurrent VTE and 4% developed a bleeding complication. A recent narrative review recommends dose escalation of LMWH by 20–25% in cancer patients with recurrent VTE while on LMWH [Lee, 2010]. Clinical evaluation should be performed after 5–7 days. If the patient has no clinical improvement, clinicians should aim for a peak anti-Xa level of 1.6–2.0 U/ml for once-daily LMWH and 0.8–1.0 U/ml for twice-daily dosing [Lee, 2010]. Cancer patients with recurrent VTE while on therapeutic warfarin (INR 2.0–3.0) should be switched to therapeutic levels LMWH with clinical reassessment within 5–7 days.

Conclusion

VTE is associated with increased morbidity and mortality in cancer patients. All cancer patients admitted to hospital should be evaluated to receive pharmacological thromboprophylaxis. Despite the recent clinical trials, more research is required to evaluate the risk–benefit ratio of thromboprophylaxis in ambulatory cancer patients undergoing chemotherapy. The best evidence for treatment at present time suggests that commencing initial treatment with LMWH is superior to UFH and long-term anticoagulation should preferably be done using LMWH rather than warfarin for up to 6 months. All cancer patients should have an assessment of their risk of VTE recurrence as well as their risk of bleeding on anticoagulation. The total length of anticoagulation should be tailored to each individual patient. Dose escalation of LMWH seems effective and safe for cancer patients with recurrent VTE despite anticoagulation. IVC filter insertion should be reserved for cancer patients with contraindication to anticoagulant therapy.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. M. Carrier is a recipient of a Research Chair in Thrombosis and Cancer from the University of Ottawa. K. Hogg is the recipient of a Department of Medicine Fellowship Award from the Ottawa Hospital and a Postgraduate Fellowship Award for the University of Ottawa.

The authors declare no conflicts of interest in preparing this article.

References

Agnelli

George

Fisher

Kakkar

A.K.

Lassen

M.R.

Mismetti

(2011) The ultra-low molecular weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in patients with cancer receiving chemotherapy: SAVE ONCO study. J Clin Oncol 29: abstract LBA9014.

Agnelli

Gussoni

Bianchini

Verso

Mandala

Cavanna

(2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10: 943–949.

Akl

E.A.

Barba

Rohilla

Terrenato

Sperati

Muti

(2008) Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2: CD006650.

Akl

E.A.

Vasireddi

S.R.

Gunukula

Barba

Sperati

Terrenato

(2011) Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 4: CD006649.

Alcalay

Wun

Khatri

Chew

H.K.

Harvey

Zhou

(2006) Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol 24: 1112–1118.

Alikhan

Cohen

A.T.

Combe

Samama

M.M.

Desjardins

Eldor

(2003) Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis 14: 341–346.

Amin

Stemkowski

Lin

Yang

(2007) Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost 5: 1610–1616.

Chiriac

Dunkler

Vormittag

Simaken

Quenhenberger

(2009) Biomarkers improve the risk scoring model for prediction of cancer-associated thrombosis. J Thromb Haemost 5: OC-Tu-016 [Abstract].

Dunkler

Marosi

Chiriac

A.L.

Vormittag

Simanek

(2010) Prediction of venous thromboembolism in cancer patients. Blood 116: 5377–5382.

10.

Dunkler

Simanek

Thaler

Koder

Marosi

(2011) Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna cancer and thrombosis study. J Clin Oncol 29: 2099–2103.

11.

Blom

J.W.

Doggen

C.J.

Osanto

Rosendaal

F.R.

(2005) Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293: 715–722.

12.

Bohlius

Wilson

Seidenfeld

Piper

Schwarzer

Sandercock

(2006) Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 3: CD003407.

13.

Browne

A.M.

Cronin

C.G.

English

Nimhuircheartaigh

Murphy

J.M.

Bruzzi

J.F.

(2010) Unsuspected pulmonary emboli in oncology patients undergoing routine computed tomography imaging. J Thorac Oncol 5: 798–803.

14.

Candelario

G.D.

Francis

C.W.

Panzer

McAdam

K.S.

Cockrell

Baird

(2010) A computerized prompt for thromboprophylaxis in hospitalized cancer patients. Thromb Res 126: 32–34.

15.

Carrier

G.G.

Cho

Tierney

Rodger

Lee

A.Y.

(2009) Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 7: 760–765.

16.

Carrier

G.G.

Tay

Lee

A.Y.

(2011) Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 9: 653–663.

17.

Chew

H.K.

Davies

A.M.

Wun

Harvey

Zhou

White

R.H.

(2008) The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost 6: 601–608.

18.

Chew

H.K.

Wun

Harvey

Zhou

White

R.H.

(2006) Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 166: 458–464.

19.

Chew

H.K.

Wun

Harvey

D.J.

Zhou

White

R.H.

(2007) Incidence of venous thromboembolism and the impact on survival in breast cancer patients. J Clin Oncol 25: 70–76.

20.

Cohen

A.T.

Davidson

B.L.

Gallus

A.S.

Lassen

M.R.

Prins

M.H.

Tomkowski

(2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332: 325–329.

21.

Deitcher

S.R.

Kessler

C.M.

Merli

Rigas

J.R.

Lyons

R.M.

Fareed

(2006) Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 12: 389–396.

22.

den Exter

P.L.

Hooijer

Dekkers

O.M.

Huisman

M.V.

(2011) Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 29: 2405–2409.

23.

Douma

R.A.

Kok

M.G.

Verberne

L.M.

Kamphuisen

P.W.

Buller

H.R.

(2010) Incidental venous thromboembolism in cancer patients: prevalence and consequence. Thromb Res 125(6): e306–e309.

24.

Elting

L.S.

Escalante

C.P.

Cooksley

Avritscher

E.B.

Kurtin

Hamblin

(2004) Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 164: 1653–1661.

25.

Fotopoulou

Dubois

Karavas

A.N.

Trappe

Aminossadati

Schmalfeldt

(2008) Incidence of venous thromboembolism in patients with ovarian cancer undergoing platinum/paclitaxel-containing first-line chemotherapy: an exploratory analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. J Clin Oncol 26: 2683–2689.

26.

Francis

C.W.

(2007) Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med 356: 1438–1444.

27.

Geerts

W.H.

Bergqvist

Pineo

G.F.

Heit

J.A.

Samama

C.M.

Lassen

M.R.

(2008) Prevention of venous thromboembolism: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th edn). Chest 133(6): 381S–453S.

28.

Gitter

M.J.

Jaeger

T.M.

Petterson

T.M.

Gersh

B.J.

Silverstein

M.D.

(1995) Bleeding and thromboembolism during anticoagulant therapy: A population- based study in Rochester, Minnesota. Mayo Clin Proc 70: 725–733.

29.

Haas

Kemkes-Matthes

Freud

Gatzemeier

Heilmann

Von Tempelhoff

(2005) Prevention of venous thromboembolism with low-molecular-weight heparin in patients with metastatic breast or lung cancer – results of the TOPIC Studies. J Thromb Haemost 3: OR059 [Abstract].

30.

Heit

J.A.

O’Fallon

W.M.

Petterson

T.M.

Lohse

C.M.

Silverstein

M.D.

Mohr

D.N.

(2002) Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 162: 1245–1248.

31.

Hull

R.D.

Pineo

G.F.

Brant

R.F.

Mah

A.F.

Burke

Dear

(2006) Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 119: 1062–1072.

32.

Hutten

B.A.

Prins

M.H.

Gent

Ginsberg

Tijssen

J.G.P.

Buller

H.R.

(2000) Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved International Normalized Ratio: A retrospective analysis. J Clin Oncol 18: 3078–3083.

33.

Kakkos

S.K.

Caprini

Geroulakos

G.E.A.

(2009) Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Eur J Vasc Endovasc Surg 37: 364–365.

34.

Kearon

Kahn

S.R.

Agnelli

Goldhaber

Raskob

G.E.

Comerota

A.J.

(2008) Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133 >6 Suppl. 6): 454S–545S.

35.

Khorana

A.A.

Francis

C.W.

Culakova

Fisher

R.I.

Kuderer

N.M.

Lyman

G.H.

(2006) Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 24: 484–490.

36.

Khorana

A.A.

Francis

C.W.

Culakova

Kuderer

N.M.

Lyman

G.H.

(2007a) Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 110: 2339–2346.

37.

Khorana

A.A.

Francis

C.W.

Culakova

Kuderer

N.M.

Lyman

G.H.

(2007b) Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 5: 632–634.

38.

Khorana

A.A.

Kuderer

N.M.

Culakova

Lyman

G.H.

Francis

C.W.

(2008) Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111: 4902–4907.

39.

Kucher

Koo

Quiroz

Cooper

J.M.

Paterno

M.D.

Soukonnikov

(2005) Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 352: 969–977.

40.

Kuderer

N.M.

Francis

C.W.

Culakova

Khorana

A.A.

Ortel

(2008) Venous thromboembolism and all-cause mortality in cancer patients receiving chemotherapy.

41.

Kuderer

N.M.

Khorana

A.A.

Francis

C.W.

Lyman

G.H.

Falanga

Ortel

(2009) Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients. A meta-analysis. Blood 114: 490 [Abstract].

42.

Lee

A.Y.

(2010) Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulants. Hematology Am Soc Hematol Educ Program 150–152.

43.

Lee

A.Y.Y.

Levine

M.N.

Baker

R.I.

Bowden

Kakkar

A.K.

Prins

(2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349: 146–153.

44.

Leizorovicz

Cohen

A.T.

Turpie

A.G.G.

Olsson

C.G.

Vaitkus

P.T.

Goldhaber

S.Z.

(2004) Randomized, placebo-controlled trial of Dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 110: 874–879.

45.

Levine

M.N.

Deitchman

Julian

J.A.

Liebman

Escalante

O’Brien

(2009) A randomized phase II trial of a new anticoagulant, apixaban, in metastatic cancer. J Clin Oncol 27: e20514 [Abstract].

46.

Louzada

M.L.

Majeed

H.H.M.

Dao

V.V.D.

Wells

P.P.W.

(2009) Evaluating risk for recurrent venous thromboembolism (VTE) according to malignancy characteristics in patients with cancer-associated-thrombosis: A systematic review of observational and intervention studies. J Thromb Haemost 7: PP-WE-500 [Abstract].

47.

Lyman

G.H.

Khorana

A.A.

Falanga

Clarke-Pearson

Flowers

Jahanzeb

(2007a) American Society of Clinical Oncology 2007 clinical practice guideline recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Oncol Practice 3: 326–329.

48.

Lyman

G.H.

Khorana

A.A.

Falanga

Clarke-Pearson

Flowers

Jahanzeb

(2007b) American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 25: 5490–5505.

49.

Maraveyas

Waters

Roy

R.E.A.

(2010) Gemcitabine with or without prophylactic weight-adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial (the UK FRAGEM study). Thromb Research 125: OC-02 [Abstract].

50.

Meyer

Marjanovic

Valcke

Lorcerie

Gruel

Solal-Celigny

(2002) Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: A randomized-controlled study. Arch Intern Med 162: 1729–1735.

51.

Monreal

Zacharski

Jimenez

J.A.

Roncales

Vilaseca

(2004) Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: A prospective cohort study. J Thromb Haemost 2: 1311–1315.

52.

Morris

R.J.

Woodcock

J.P.

(2010) Intermittent pneumatic compression or graduated compression stockings for deep vein thrombosis prophylaxis? A systematic review of direct clinical comparisons. Ann Surg 251: 393–396.

53.

Nalluri

S.R.

Chu

Keresztes

Zhu

(2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300: 2277–2285.

54.

Perry

J.R.

Julian

J.A.

Laperriere

N.J.

Geerts

Agnelli

Rogers

L.R.

(2010) PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 8: 1959–1965.

55.

Prandoni

Lensing

A.W.A.

Piccioli

Bernardi

Simioni

Girolami

(2002) Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100: 3484–3488.

56.

Prandoni

Trujillo-Santos

Sanchez-Cantalejo

Dalla

V.F.

Piovella

Pesavento

(2010) Major bleeding as a predictor of mortality in patients with venous thromboembolism: Findings from the RIETE Registry. J Thromb Haemost 8: 2575–2577.

57.

PREPICT Study (2005) Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation 112: 416–422.

58.

Reiss

Pelzer

Deutschinoff

Opitz

Stauch

Reitzig

(2009) A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC). Results of the CONKO 004 trial. J Clin Oncol 27: LBA4506 [Abstract].

59.

Rose

A.J.

Sharman

J.P.

Ozonoff

Henault

L.E.

Hylek

E.M.

(2007) Effectiveness of warfarin among patients with cancer. J Gen Intern Med 22: 997–1002.

60.

Samama

M.M.

Cohen

A.T.

Darmon

J.Y.

Desjardins

Eldor

Janbon

(1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 341: 793–800.

61.

Sorensen

H.T.

Mellemkjaer

Olsen

J.H.

Baron

J.A.

(2000) Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343: 1846–1850.

62.

Spirk

Ugi

Korte

Husmann

Hayoz

Baldi

(2011) Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. Thromb Haemost 105: 962–967.

63.

Stein

P.D.

Beemath

Meyers

F.A.

Skaf

Sanchez

Olson

R.E.

(2006) Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 119: 60–68.

64.

Sun

J.M.

Kim

T.S.

Lee

Park

Y.H.

Ahn

J.S.

Kim

(2010) Unsuspected pulmonary emboli in lung cancer patients: the impact on survival and the significance of anticoagulation therapy. Lung Cancer 69: 330–336.

65.

Trujillo-Santos

Casa

J.M.

Casado

Samperiz

A.L.

Quintavalla

Sahuquillo

J.C.

(2011) Thirty-day mortality rate in women with cancer and venous thromboembolism. Findings from the RIETE Registry. Thromb Res 127(Suppl. 3): S1–S4.

66.

Trujillo-Santos

Ruiz-Gamietea

Luque

J.M.

Samperiz

A.L.

Garcia-Bragado

Todoli

J.A.

(2009) Predicting recurrences or major bleeding in women with cancer and venous thromboembolism. Findings from the RIETE Registry. Thromb Res 123(Suppl. 2): S10–S15.

67.

van Doormaal

F.F.

Cohen

A.T.

Davidson

B.L.

Decousus

Gallus

A.S.

Gent

(2010) Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: a subgroup analysis of the Van Gogh DVT trial. Thromb Haemost 104: 86–91.

68.

Zwicker

J.I.

Liebman

H.A.

Neuberg

Lacroix

Bauer

K.A.

Furie

B.C.

(2009) Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 15: 6830–6840.

Prevention and treatment of venous thromboembolism in patients with cancer

Abstract

Keywords

Introduction

Cancer-associated thrombosis, death and prognosis

Risk stratification for cancer-associated thrombosis

Prevention of cancer-associated thrombosis in medical patients

Hospitalized medically ill cancer patients

Outpatients undergoing chemotherapy

Treatment of VTE in cancer patients

Risk of recurrent VTE in cancer patients

Risk of bleeding in cancer patients

Initial anticoagulant therapy for cancer-associated thrombosis

Long-term anticoagulant therapy forcancer-associated thrombosis

Duration of anticoagulation therapy

Treatment of incidentally diagnosed pulmonary embolism

Treatment of recurrent VTE

Conclusion

Footnotes

References