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Keywords:

  • cancer;
  • deep venous thrombosis and pulmonary embolism;
  • venous thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

Summary.  Patients with cancer are at increased risk of venous thromboembolism (VTE). In these patients VTE is associated with substantial morbidity and complicates the clinical management of cancer. Emerging research indicates a probable detrimental effect of VTE on cancer survival. Although VTE may develop at any stage of cancer disease, the risk of VTE is particularly high in association with three clinical settings including surgery for cancer, use of a central vein catheter (CVC) and chemotherapy. Guidelines recommend post-operative prophylaxis (for at least 7–10 days) for patients undergoing elective cancer surgery. A prolonged prophylaxis (for upto four post-operative weeks) is recommended in cancer patients at high risk for VTE. The role of antithrombotic prophylaxis in the prevention of CVC-related thrombosis remains controversial. The PROTECHT study has recently evaluated the benefit of antithrombotic prophylaxis in cancer patients receiving chemotherapy, showing a statistically significant 50% relative risk reduction in symptomatic thromboembolic events. The international guidelines currently agree in non-recommending routine prophylaxis in ambulatory patients who receive anticancer chemotherapy but suggest an individual risk-based evaluation. To better identify cancer patients at high risk for VTE, simple predictive models have been validated. Further intervention studies are currently on-going to explore the benefit of antithrombotic prophylaxis in individual high-risk groups of patients. The long-term treatment of cancer-related VTE is based on therapeutic doses of LMWH in preference to warfarin. The optimal duration of antithrombotic treatment in cancer patients remains to be fully defined.


The clinical burden of venous thromboembolism in patients with cancer

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

The association between venous thromboembolism (VTE) and cancer has been evaluated in recent years with increasing interest [1]. Patients with cancer are at 4- to 7-fold higher risk for VTE than patients without cancer, and about 15% of patients with cancer suffer a VTE episode. On the other hand, approximately 20% of patients presenting with VTE have an active cancer. Patients with VTE and cancer are hospitalised more frequently than VTE patients without cancer, are sicker and more prone to suffer side effects related to anticoagulant treatment. Patients with cancer have more frequently a bilateral DVT of the lower limbs and venous thrombosis in unusual sites.

In patients with cancer, VTE is associated with considerable morbidity with emerging research indicating a detrimental effect on survival. Based on Danish administrative data, Sorensen et al. [2] reported a reduced survival in patients with cancer and concomitant VTE in comparison to control cancer patients matched for age, gender, cancer type, and time since diagnosis. Cases and controls were not matched for cancer stage. In a retrospective analysis based on the California cancer registry, Chew et al. [3] found that the occurrence of VTE during the first year since cancer diagnosis was a predictor of death for all of the 12 cancer types which were analysed. The effect of VTE on survival was similar in patients with localised, regional, or metastatic disease. Kuderer et al. [4] reported a hazard ratio for death of 4.90 (95% CI, 2.27–10.60) among 4458 cancer patients with VTE. Pulmonary embolism was the cause of death in 5.4% of patients. In an analysis by Chew et al. [5] in patients with breast cancer, an increased mortality was associated with VTE, even after adjusting for comorbid conditions. This effect of VTE was most pronounced in patients with early-stage cancer and when VTE occurred in the first months after cancer diagnosis. Alcalay et al. [6] found that the 2-year cumulative incidence of death in patients with colon cancer and concomitant VTE was 52% in comparison to 35% in those cancer patients who never had VTE (P < 0.0001). When analysed by cancer stage, patients with local or regional cancer and VTE were 1.7 times more likely to die than patients without VTE. This difference was not observed in patients with metastatic disease. In a second study published by Chew et al. [7] in patients with lung cancer, the diagnosis of VTE was associated with a high risk of death within 2 years. The risk was 2.3 and 1.5 times higher in patients with non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) respectively. The risk of death was further increased in male patients and in those with squamous carcinoma. Consistently with the other cancer sites, the effect of VTE on survival was more pronounced in lung cancer patients with local or regional disease. VTE is found to be an adverse predictive factor also in patients with gastro oesophageal, pancreatic, bladder, ovarian, uterine and cervical cancer [8–11]. In patients with cancer, older than 75 years, a concomitant VTE is associated with increased risk of death in several types of cancers but not in patients with breast or prostate cancer [12].

Taken together, these findings consistently show that in patients with cancer the occurrence of VTE is associated with a reduced survival. Whether the increased mortality is due to VTE or to a more aggressive course of cancer when this is associated with VTE or to both is unclear as well as whether preventing VTE in cancer patients would result in an improved survival.

Although patients with cancer may develop a thromboembolic complication at any stage of their disease, the risk of VTE is particularly high in association with three clinical settings: surgery for cancer, use of a central vein catheter (CVC) and chemotherapy.

Prophylaxis of VTE in cancer patients

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

Prevention of postoperative VTE

For a relatively similar type of surgery, post-operative VTE occurs 2–3 times more frequently in cancer patients than in non cancer patients. In cancer patients undergoing surgery without prophylaxis, the incidence of lower limb deep vein thrombosis (DVT), as shown by venography, ranges from 40% to 80% and that of proximal DVT from 10% to 20%. The risk of fatal post-operative pulmonary embolism is about four times higher in cancer surgery in comparison to non cancer surgery. In a large multicentre study including patients undergoing abdominal surgery, the incidence of fatal pulmonary embolism was 1.6% in cancer patients and 0.5% in patients without cancer (P = 0.05). A prospective study, focused on the incidence of clinically overt VTE in patients undergoing surgery for cancer, found an incidence of 2.1% at the 30th post-operative day despite most of the patients being on antithrombotic prophylaxis [13]. About 40% of VTE events occurred beyond 2 weeks after surgery. The 30-day mortality was 1.7% and approximately half of the deaths were due to pulmonary embolism. Extensive abdominal or pelvic surgery, age older than 60 years, obesity, previous VTE and prolonged immobility make patients with cancer at particularly high risk for post-operative VTE.

In patients undergoing surgery for cancer, the most commonly used prophylactic regimen consists in the pre-operative subcutaneous injection of heparin, followed by continued administration starting 12–24 h after surgery. Typically, unfractionated heparin (UFH) is given two or three times daily while low molecular weight heparin (LMWH) is given once-daily. Based on a meta-analysis, once-daily LMWH is as safe and effective as multiple daily-injections of UFH in reducing the incidence of post-operative VTE [14]. A randomised, controlled trial that compared LMWH (enoxaparin 40 mg once-daily) with UFH given for 10 days showed a non significant risk reduction in favour of enoxaparin (14.7% vs. 18.2%, respectively) [15]. The ACCP, ASCO, NCCN, ESMO and AIOM guidelines recommend antithrombotic prophylaxis for cancer surgery for at least 7–10 post-operative days [16–20].

The benefit of extended prophylaxis for VTE after cancer surgery was first demonstrated by the ENOXACAN II study [21]. This study reported a statistically significant reduction from 12% to 4.8% in the rate of DVT after extended prophylaxis (4 weeks) compared with prophylaxis given in the first post-operative week. The protective effect of prolonged prophylaxis was maintained until the third month of follow-up. A Cochrane review, including cancer patients undergoing abdominal, pelvic or thoracic surgery, showed that extended prophylaxis reduces the overall rate of DVT by more than 50% and that of proximal DVT by 75% compared with prophylaxis given for 7–10 days [22]. The rate of haemorrhagic complications was similar in the two groups. More recently, a randomised, double-blind study in patients with abdominal and pelvic surgery for cancer, shown that prolonged prophylaxis with bemiparin decreases the rate of major VTE without increasing the rate of bleeding complications [23]. The ESMO and AIOM guidelines [19,20] recommend extended prophylaxis for all patients undergoing elective cancer surgery. ASCO and NCCN panels [17,18] recommend to extend prophylaxis for up to 4 weeks in patients undergoing major abdominal or pelvic cancer surgery in presence of high thromboembolic risks as residual or advanced cancer disease, age 60 year or older, obesity previous history of VTE, duration of surgery longer than 2 h and prolonged post-operative immobilisation.

In the Pegasus study, fondaparinux was found to be at least as effective as dalteparin in preventing VTE in high risk abdominal surgery [24]. Nearly 68% of 2048 included patients had cancer. A post-hoc analysis showed a statistically significant 40% risk reduction of VTE in the subgroup of patients who underwent abdominal surgery for cancer.

Mechanical methods of thromboprophylaxis, in absence of pharmacological prophylaxis, reduce the rate of DVT by 66% but achieve only a non statistical significant 33% risk reduction in the rate of pulmonary embolism. A combined strategy of pharmacological and mechanical prophylaxis may improve the efficacy in the very high risk patients. A Cochrane review shows that a combination of low dose UFH with graduated compression stockings is four times more effective for VTE prevention than UFH alone [25].

Prevention of VTE related to long-term CVC

Currently, most of the patients with cancer have a long-term CVC inserted for chemotherapy. CVC offers several advantages that are potentially out-weighed by complications such as CVC-related upper limb DVT or infections [26]. The incidence of asymptomatic CVC-related DVT is estimated to be about 20%, while the rate of clinically overt DVT of upper limbs ranges between 2% and 4%. Some features of the catheter may influence the occurrence of VTE complications [27,28].

The role of antithrombotic prophylaxis in the prevention of CVC-related thrombosis is controversial. Although some initial open studies [29,30] showed a benefit in the prevention of CVC-related VTE with both LMWH and warfarin, more recent randomised, placebo controlled trials and meta-analysis [31–35], where either symptomatic or venography-detected thrombosis was measured, did not confirm this benefit.

A multicentre, randomised, double-blind, placebo-controlled study assessed the efficacy and safety of enoxaparin, given for 6 weeks, for the prevention of VTE in 385 cancer patients with CVC [31]. In this study, a 22% non-statistically significant risk reduction in the rate of CVC-related VTE was seen in patients receiving enoxaparin compared to those receiving placebo. The international guidelines do not recommend routine prophylaxis for this indication [16–20]. The French guidelines emphasise the importance of correct positioning of CVC tip at the junction between superior vena cava and right atrium [36].

Prevention of chemotherapy-associated VTE

Chemotherapy for cancer is associated with a 2- to 6-fold increased risk for VTE compared with the general population. Among hospitalised patients receiving chemotherapy, the reported rate of VTE is 5.7% [37]. Specific chemotherapeutic agents may be associated with particularly high rates of VTE. In a prospective study, platinum-based regimens were significantly associated with VTE [38]. Regimens containing antiangiogenic agents are associated with increased risk of venous thrombotic events [39]. The risk of VTE associated with chemotherapy is dependent on many contributing factors including cancer stage, age, co-morbidities, bed rest, patient performance status and type and intensity of therapeutic regimens. Most of the earlier data on the incidence of chemotherapy-associated VTE derive from studies in women with breast cancer. In these patients, the risk of VTE ranges from 4% to 15% and is even higher in patients with metastatic cancer. An incidence of VTE of approximately 10% per year has been reported in patients with different types of cancer including cancer of the colon, lung, breast and genitourinary [40].

The benefit of antithrombotic prophylaxis in cancer patients receiving chemotherapy has been evaluated in several studies. In the earliest randomised study, low dose of warfarin was reported to be safe and effective in reducing VTE complications in patients receiving chemotherapy for stage IV breast cancer, the relative risk reduction vs. placebo being 85% [41].

In the recently published PROTECHT study [42], ambulatory cancer patients receiving chemotherapy for advanced cancer of breast, lung, gastrointestinal, pancreas, ovary and head and neck were randomly assigned to receive either nadroparin, 3800 IU once daily or placebo for up to 4 months. The study showed a statistically significant 50% relative risk reduction in symptomatic thromboembolic events (2.0% vs. 3.9%) in favour of nadroparin group. No statistically significant difference in major bleeding was found.

The TOPIC-1 and TOPIC-2 studies evaluated prophylaxis with certoparin 3.000 International Units (IU) once daily in patients with metastatic breast cancer (TOPIC-1) and in patients with advanced NSCLC (TOPIC-2) [43]. Patients were randomly assigned to receive certoparin or placebo for 6 months, and had ultrasonography every 4 weeks. A non-significant trend toward efficacy was observed in lung cancer patients with a VTE rate of 4.5% in the treated group, compared with 8.3% in the placebo group (P = 0.07). The rate of major bleeding complications was not statistically different in the two cancer populations.

A recent combined analysis of data from PROTECHT and TOPIC-2 in metastatic or locally advanced lung cancer patients receiving chemotherapy showed that LMWHs significantly reduce the rate of thromboembolic events [44]. In the 811 included patients (279 in the PROTECHT study, and 532 in the TOPIC-2 study), 15 thromboembolic events occurred in the 467 LMWHs patients (3.2%) and 22 events in the 344 patients in the placebo group (6.4%) (relative risk: 0.50; 95% CI 0.25–0.95). Twelve of 472 patients in the LMWHs group (2.5%) and six of 353 patients in the placebo group (1.7%) suffered a major bleeding (P = ns).

The international guidelines agree in non recommending routine prophylaxis in ambulatory cancer patients who receive anticancer chemotherapy [16–20]. Currently, VTE prophylaxis in this setting is recommended only for patients with multiple myeloma receiving thalidomide or lenalidomide-based combination chemotherapy. More data will be available after the completion of on-going studies designed to assess the clinical benefit of antithrombotic prophylaxis to prevent chemotherapy associated VTE. Common anticoagulant regimens used for antithrombotic prophylaxis are listed in Table 1.

Table 1.   Recommended anticoagulant regimens for venous thromboembolism prophylaxis and treatment in patients with cancer
ManagementDrugRegimen
  1. *Avoid in patients with creatinine clearance < 35 mL min−1 or adjust dose on base of antifactor Xa levels.

ProphylaxisUnfractionated heparin5.000 IU SQ, every 8 h
Dalteparin5.000 IU SQ, daily
Enoxaparin40 mg SQ, daily
Tinzaparin2.5 mg SQ, daily
Fondaparinux75 IU kg−1 SQ, daily
Initial treatmentUnfractionated heparin80 IU kg−1, i.v., bolus, then 18 IU kg−1 per hour i.v.
Dalteparin*100 IU kg−1 SQ, every 12 h or 200 IU kg−1 SQ, every 24 h
Enoxaparin*1 mg kg−1 SQ, every 12 h or 1.5 mg kg−1 SQ, daily
Tinzaparin175 IU kg−1 SQ, daily
Fondaparinux*< 50 kg: 2.5–5 mg SQ, daily 50–100 kg: 5–7.5 mg SQ, daily > 100 kg: 7.5–10 mg SQ, daily
Long-term treatmentDalteparin200 IU kg−1 SQ, daily × 1 month, then 150 IU kg−1 SQ, daily
Warfarin5–10 mg os daily, adjust dose to INR of 2.0–3.0

To reduce the clinical burden of VTE associated with anticancer treatment, it is important to identify patients with cancer at highest risk for VTE for whom prophylaxis may be beneficial. In addition, about 30% of patients with cancer are at low risk of developing VTE (estimated VTE rate ≤ 1%), and thus, it is equally important to exclude such low-risk patients from prophylaxis studies. Khorana et al. [45] proposed a simple predictive model based on five clinical and laboratory variables to predict chemotherapy-associated VTE risk in outpatients with cancer. The identified variables in the risk assessment score include site of cancer, pre-chemotherapy platelet and leukocyte count and haemoglobin level or use of erythropoietic stimulating agents and body mass index. The major advantage of this model is the easy availability of these common clinical markers, while the major limitation is the generalisability of the results. This model identifies about 7% of cancer patients receiving chemotherapy in ambulatory setting as high risk of VTE. Furthermore, the model is able to identifying about 30% of patients as low-risk for VTE.

More recently, in order to increase the predictive value of the Khorana score the addition of biomarker such as P-selectin, tissue factor and D-dimer has been evaluated [46,47].

Intervention trials are on-going to evaluate the clinical benefit of antithrombotic prophylaxis in high risk group of cancer patients.

Diagnosis of VTE in cancer patients

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

The management of VTE in patients with cancer requires maintaining a high suspicion for thrombotic disease, particularly immediately after cancer diagnosis and during anticancer treatment, and confirms the diagnostic suspicion with objective testing. Risk factors for VTE include age, primary cancer site, histological type and stage, hospitalisation or serious medical illness, immobility, concomitant use of erythropoietic stimulating agents, as well as the presence of molecular thrombophilia or history of VTE.

D-dimer testing

Although the studies that evaluated the accuracy of non-invasive diagnostic methods included also patients with cancer, the value of D-dimer measurement in cancer patients with clinically suspected VTE is controversial and probably reduced. Indeed, both cancer [48] and its treatment [49] can reduce the specificity of D-dimer measurement. It has been observed that D-dimer levels differ significantly in relation to the site of cancer: the highest D-dimer levels are observed in patients with pancreatic cancer and the lowest in patients with prostate cancer [50]. In a retrospective study, Lee et al. [51] reported that a negative result of the D-dimer assay does not reliably exclude DVT in patients with active cancer. More recently, two prospective studies showed that D-dimer assay, used in association with clinical probability scores, has a high negative predictive value for VTE in patients with cancer [52,53].

Baseline D-dimer value in cancer patients scheduled for chemotherapy might predict the occurrence of VTE and could be used to identify patients at low risk for VTE. The CATS study showed that patients with cancer who had both elevated D-dimer and elevated prothrombin fragment 1 + 2 had the highest risk of developing VTE (3.6-fold increased risk). The probability of developing VTE after 6 months was 15.2% in patients with both elevated D-dimer and elevated prothrombin fragment 1 + 2 compared with 5.0% in patients without elevation of D-dimer and prothrombin fragment 1 + 2 [47]. In a relatively small study, D-dimer was measured at baseline in 124 cancer patients scheduled for their first chemotherapy cycle [54]. Multivariate analysis found that baseline D-dimer levels were correlated with the subsequent occurrence of VTE.

High levels of D-dimer have been also evaluated as a prognostic factor, either for VTE recurrence or mortality [55]. Legnani et al. [56] reported that D-dimer levels and residual venous thrombosis measurements at 6 months from acute VTE are independent risk factors for VTE recurrence in cancer patients.

Treatment of VTE and its optimal duration

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

When VTE is objectively confirmed, anticoagulant therapy is required. According to the current guidelines, treatment is started with adjusted-dose UFH or fixed dose LMWH for 5–7 days and continued with vitamin K antagonists, such as warfarin, for 3–6 months [16–20]. The aim of this treatment is to prevent the extension of DVT, the occurrence of pulmonary embolism and the recurrence of VTE. In comparison with the general medical patients, the treatment of VTE in patients with cancer is more challenging, particularly in patients with advanced disease. Recurrence of VTE is more common in cancer patients than in non-cancer patients [57–59] and occurs despite an appropriate anticoagulation more often than in VTE patients without cancer. On the other hand, cancer patients seem to be prone to have more frequently bleeding complications while receiving anticoagulant treatment [57,60,61]. Most bleeding events are observed in the first months of anticoagulation and are not necessarily related to a high International normalised ratio (INR) [62].

Four open-label multicentre randomised controlled trials [63–66] compared long-term LMWH with warfarin for the secondary prevention of VTE in patients with and without cancer. In three studies, the randomisation method and power calculation for recurrent VTE and bleeding as the primary endpoints were clearly stated. The fourth study was a feasibility study for recruitment and compliance, with recurrent VTE and bleeding as secondary endpoints. The four studies differed in the way they dealt with recurrent VTE and bleeding as combined or separate endpoints, the duration of treatment and follow-up. About half of the patients included in the four studies had metastatic disease (range 47–67%). However, all studies excluded patients on the basis of a prognosis of < 3 months or of an ECOG performance status of more than 2. These criteria might have led to a substantial number of patients with advanced cancer and VTE being excluded from the studies. All four studies showed LMWH to be more effective than warfarin in the prevention of recurrent VTE, with an overall risk ratio (RR) of 0.51 (95% CI; 0.35–0.74). There was no significant difference in the risk of bleeding between patients on LMWH or warfarin, with an overall RR of 1.10 (95% CI; 0.77–1.58). The anticoagulant regimens used in these trials are reported in Table 1.

A randomised, controlled study in cancer patients demonstrated the efficacy and safety of secondary prevention of VTE with long-term administration of LMWH. In this study, dalteparin was shown to be more effective than oral anticoagulants in reducing the risk of VTE recurrence of about 50%, without increasing the risk of bleeding [67]. The option of increasing the dose of LMWH in cancer patients with recurrent VTE has been recently explored [68].

Interactions between warfarin and several chemotherapeutic agents such as fluoropyrimidine, 5-fluorouracil have been reported [69,70]. More recently, interactions between warfarin and capecitabine, erlotinib or sorafenib have been also reported [71–74]. These interactions produce an elevation of the INR value and an increased risk of clinically relevant bleeding.

Current clinical guidelines recommend LMWH for the long-term treatment of cancer-related VTE in preference to full doses warfarin [16–20]. The optimal duration of the anticoagulant treatment in cancer patients remains to be defined. The eight ACCP Consensus Conference [16] recommends an indefinitely or ‘as long as cancer is active’ anticoagulation for VTE occurring in cancer patients.

Outpatient management is feasible for carefully selected patients with cancer and DVT of lower limbs or low-risk pulmonary embolism [75–77]. Ageno et al. [75] reported their clinical experience on home treatment of DVT in 321 cancer patients. The results of this study show that home treatment of DVT in cancer patients is safe and feasible. Of interest, almost two thirds of cancer patients received LMWH only.

Retrospective series reported that up to 32% of cancer patients with inferior vena cava filters inserted for thrombosis develop recurrent VTE [78–84]. There is only one open-label randomised trial of inferior vena cava filters in VTE patients (most of them without cancer) [85]. In this trial the vena cava filter was permanent and all patients received standard anticoagulant therapy. Long-term follow-up suggested that filter insertion was associated with a reduction of pulmonary embolism (recurrence), but it was counterbalanced by an increased risk of DVT recurrence. In addition, no effect on mortality was observed. According to published guidelines [16–20,86] interruption of the inferior vena cava by filter should be limited to patients for whom anticoagulation is contraindicated or for those with recurrent emboli despite therapeutic anticoagulation. If anticoagulation is contraindicated temporarily, it should be resumed as soon as possible. If retrievable filters are used, they should be removed within 3 months from insertion or left in situ permanently. Research is needed to study the use of filters in cancer patients.

Treatment of specific situation

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References

CVC-thrombosis

The natural history and management of CVC-related thrombosis have not been completely assessed. In particular, it is not completely defined the risk of clinically relevant pulmonary embolism after CVC-related thrombosis and its reduction by anticoagulant therapy. No randomised, controlled trials have been published to evaluate long-term outcomes of treatment of CVC-related thrombosis or to compare different treatment strategies in patients with a CVC-related thrombotic complications. Indeed, in clinical practice, CVC-related DVT is treated as a VTE complication in other site with therapeutic doses of LMWH for at least 3 months. It is not completely defined if CVC should be removed in patients with mural venous thrombosis [26]. It is reasonable to remove the catheter if it is not required for at least 3 months or it is occluded by a thrombus. If the CVC should be removed, then it is suggested to remove it after at least 5–7 days of heparin treatment in order to reduce the risk of thrombotic embolisation during the procedure [26].

Incidental pulmonary embolism

In routine helical computed tomography scans, unsuspected pulmonary embolism in non cancer population is relatively low, being observed in up to 1.5% of patients [87]. This prevalence is higher in cancer patients with a reported prevalence of asymptomatic VTE (both pulmonary embolism and DVT) of up to 6.3% [88]. Gladish et al. [89] found an incidental VTE in 4% of oncology patients at re-evaluation of the computed tomography scans, of which only a quarter had been reported at initial clinical computed tomography image interpretation. Most of cancer patients with incidental VTE had advanced disease.

Finding an incidental VTE poses the treating physician in front of the dilemmas on what is the adequate anticoagulant treatment and if the anticancer therapy should be discontinued. It is not clear if the occurrence of an asymptomatic VTE has an adverse prognostic value similar to those of the symptomatic VTE. A recent study suggested that cancer patients with asymptomatic and symptomatic VTE have a similar mortality rate at 6 months, which is higher compared to cancer patients without VTE [90]. Noteworthy, in this study, all patients with asymptomatic VTE were treated with anticoagulants.

Thrombolysis for patients with high risk pulmonary embolism

Cancer patients with pulmonary embolism should be distinguished as haemodynamically stable or unstable. In the case of cancer patients with haemodynamically stable pulmonary embolism standard treatment with therapeutic doses of LMWH is recommended. Haemodynamically unstable pulmonary embolism is characterised by systolic hypotension (< 90 mmHg) and sign of right ventricular dysfunction and it is associated with a short term mortality of about 15%. Pooled data from randomised clinical trials in non cancer patients showed that the administration of thrombolytic therapy significantly reduce mortality and pulmonary embolism recurrence. A number of thrombolytic agents are used in high risk patients with pulmonary embolism but the agent more commonly used is the recombinant tissue plasminogen activators (r-tPA) at the dose of 100 mg over 2 h [91]. In addition to thrombolysis, intravenous heparin should be started immediately as a bolus followed by infusion at the rate to maintain aPTT ratio between 1.5 and 2.5 times control. Until further data will emerge in cancer patients, the recommendation for thrombolysis remains the same as for non cancer patients [16]. In patients in whom anticoagulation is contraindicated (i.e. patients with very high risk of bleeding or recent clinically relevant bleeding), alternative approaches are represented by surgical pulmonary embolectomy and percutaneous catheter embolectomy [92].

Only one retrospective multicentre cohort study on the use of thrombolytic drugs in patients with VTE and cancer was published (including patients from five randomised studies) [93]. This study included 57 cancer patients with pulmonary embolism, who were treated with r-tPA or urokinase followed by intravenous UFH. Pulmonary angiography and scan revealed a reduction in clot burden of 77% and 72%, respectively. There was a 6% rate of recurrent VTE within 14 days after treatment administration. Major haemorrhages within 72 h after treatment administration were reported in 12% of patients. Although these data are insufficient to conclude on the value of thrombolytic drugs in patients with VTE and cancer, they suggest that the presence of cancer per se does not represent a contraindication to thrombolytic therapy for the treatment of pulmonary embolism.

Brain metastases or primary cancer of central nervous system

Patients with primitive or metastatic intracranial malignancies present an increased risk of both VTE and bleeding. The rate of symptomatic DVT in patients with malignant glioma is 20–30% [94,95]. The new antiangiogenic agent bevacizumab, used in recurrent glioblastoma, is associated with a further increased risk of VTE [96]. The risk of intracranial bleeding is reported to be up to 7% and this is the main cause of the reluctance of physicians to use anticoagulants in this setting [97]. The risk of intratumoral haemorrhage on therapeutic anticoagulation is estimated to be 2% [98,99].

Historically, physicians have often favoured the insertion of inferior vena cava filters over anticoagulation in patients with malignant glioma and VTE but, more recently, it has been reported a high rate of VTE recurrence with inferior vena cava filters, without improved overall survival or reduced intracranial haemorrhage.

Limited data are available regarding the safety and efficacy of antithrombotic therapy in patients with primary or metastatic tumours of the brain who develop concurrent VTE [84,100–103]. However, the presence of an intracranial tumour or brain metastases without evidence of active bleeding is not an absolute contraindication to anticoagulation. Careful monitoring is necessary to limit the risk of haemorrhagic complications. Anticoagulation should be avoided in the presence of active intracranial bleeding, recent surgery, bleeding diathesis such as thrombocytopenia (platelet count < 50 000 L−1) or coagulopathy [17].

References

  1. Top of page
  2. Abstract
  3. The clinical burden of venous thromboembolism in patients with cancer
  4. Prophylaxis of VTE in cancer patients
  5. Diagnosis of VTE in cancer patients
  6. Treatment of VTE and its optimal duration
  7. Treatment of specific situation
  8. Disclosure of Conflict of Interests
  9. References
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