Skip to main content
Current Oncology logoLink to Current Oncology
. 2008 Jan;15(Suppl 1):S58–S67. doi: 10.3747/co.2008.177

Cancer-associated thrombosis: prevention and treatment

KMJ Brose *, AYY Lee †,
PMCID: PMC2216419  PMID: 18231650

Abstract

Patients with cancer are at high risk to develop venous thromboembolism, and they are also more likely to develop complications from anticoagulant treatment. Because little research has focused on the oncology population to date, the optimal methods of prophylaxis and treatment remain uncertain in some clinical situations. Currently, low molecular weight heparin and warfarin are the most frequently used pharmacologic agents; however, they have their limitations. Other therapeutic options, such as inferior caval filters, are poorly studied and remain controversial. A summary of the most recent evidence on the prevention and treatment of venous thromboembolism in cancer patients is presented here.

Keywords: Neoplasm, deep vein thrombosis, thromboembolism, prophylaxis, low molecular weight heparin, heparin, warfarin

1. INTRODUCTION

It is well established that cancer patients are at an increased risk of venous thromboembolism (vte). In fact, the presence of malignancy increases the risk of vte by a factor of 4 to 6, and large population-based studies show that the incidence of vte is on the rise 1,2. Overall, cancer patients constitute 15%–20% of the patients diagnosed with vte, and depending on the type of tumour, extent of malignancy, type of cancer treatment, and presence of other risk factors, 1%–25% of patients with malignancy will develop thrombosis.

Furthermore, cancer-associated thrombosis is linked with poor prognosis, and it is the second leading cause of death in cancer patients 3. In one study of a population registry, the 1-year survival of cancer patients diagnosed with vte was one third that of cancer patients without vte (12% vs. 36%) matched for sex, age, tumour type, and duration of the cancer 4. In another population-based study, the in-hospital mortality for cancer patients who developed vte while in hospital was double that for patients who did not develop the complication 5. This increase in mortality is partly attributable to fatal pulmonary embolism, but it also reflects the advanced stages of cancer and underlying aggressive tumour biology in these patients.

Cancer patients are also prone to adverse effects and failure of anticoagulant therapy. In comparison with patients without cancer, patients with cancer who are receiving warfarin experience 2 to 6 times more major bleeding episodes and 2 to 3 times more vte recurrences 6,7. Based on prospective studies, the annual risk of recurrent vte is 21%–27% and the annual risk of major bleeding is 12%–13%.

Primary prevention is the most effective way to reduce the morbidity and mortality associated with cancer-associated thrombosis, but surveys and registries consistently report the failure of physicians to comply with established guidelines leading to underutilization of primary prophylaxis in oncology patients 8. Given the impact that vte has on this high-risk population, an increased focus on identifying optimal methods to prevent and treat vte in patients with malignancy is needed. Current management strategies, and the evidence supporting them, are presented here.

2. PRIMARY PREVENTION: SURGICAL SETTINGS

The risk of vte in cancer patients undergoing surgery has been estimated to be as high as 50% without prophylaxis 9. The exact risk varies with the type of surgery, but anticoagulants are generally effective in reducing the risk by 50%–80%. Tables I to iii summarize the results from randomized controlled trials evaluating the efficacy and safety of anticoagulant prophylaxis in various oncologic surgery settings 1023.

TABLE I.

Randomized controlled trials for primary prophylaxis in cancer-related major abdominal and pelvic surgery

Trial Surgical setting Cancer patients (n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study (%) Control (%) p Value Study (%) Control (%) p Value
Enoxacan Study Group, 1997 10 Abdominal and pelvic 631 Enoxapari 40 mg daily ufh 5000 IU 3 times daily 10 Days vte on bilateral venography or pulmonary scintigraphy 14.7 18.2 >0.05 4.1 2.9 >0.05
McLeod et al., 2001 11 Colorectal 324 Enoxaparin 40 mg daily ufh 5000 IU 3 times daily Up to 10 days pe, venographic dvt at postoperative days 5, 9 13.9 16.9 0.052 2.7a 1.5a 0.136a
Agnelli et al., 2005 12 Major abdominal 1941 Fondaparinux 2.5 mg daily Dalteparin 5000 IU daily 5–9 Days Venographic dvt or pe up to postoperative day 10 4.7 7.7 <0.05 3.4 2.5 0.355
Bergqvist et al., 2002 13 Abdominal and pelvic 332 Enoxaparin 40 mg daily Enoxaparin 40 mg daily 27–31 Days (study) 6–10 Days (control) Bilateral venography between days 25 and 31 4.8 12.0 0.02 0.4 0 >0.99
Rasmussen et al., 2006 14 Major abdominal 198 Dalteparin 5000 IU daily Dalteparin 5000 IU daily 28 Days (study) 7 Days (control) Venographic vte on postoperative days 7–28 8.8 19.6 0.03 0.5a 1.8a >0.05a
a

Results for the overall study population, including cancer and noncancer patients.

vte = venous thromboembolism; ufh = unfractionated heparin; pe = pulmonary embolism; dvt = deep vein thrombosis.

TABLE III.

Randomized controlled trials for primary prophylaxis in cancer-related gynecologic surgery

Trial Patients (n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study(%) Control (%) p Value Study (%) Control (%) p Value
Heilmann et al., 1989 19 300 lmwh 1500 IU daily ufh 5000 IU 3 times daily 7 Days pe, dvt by impedance plethysmography to day 7 1.3 4.0 >0.05 No significant difference in clinical and laboratory measures, specific incidence of major bleeding not cited
Clarke–Pearson et al., 1990 20 200 ufh 5000 IU every 8 hours pre- and postoperatively No prophylaxis Until discharge pe, dvt by 125I-labelled fibrinogen scan, impedance plethysmography to day 30 6.2 18.4 0.008 No significant difference in clinical and laboratory measures, specific incidence of major bleeding not cited
Fricker et al., 1988 21 80 Dalteparin 2500 IU 2 hours preoperatively and at 12 hours, then 5000 IU daily ufh 5000 IU 2 hours preoperatively, then 3 times daily 10 Days pe, dvt by 125I-labelled fibrinogen scan, venography to 4 weeks 0 2.5 >0.05 5.1 2.5 >0.05
Von Tempelhoff et al., 1997 22 60 lmwh 3000 IU daily ufh 5000 IU 3 times daily 7 Days pe on scintigraphy, by impedance dvt plethysmography, venography, up to day 30 6.7 0 >0.05 Not assessed
Heilmann et al., 1998 23 324 Certoparin 3000 IU daily ufh 5000 IU 3 times daily 7 Days dvt by impedance plethysmography, venography up to day 10 6.3 6.1 1.0 16.8 28.7 0.01

vte = venous thromboembolism; lmwh = low molecular weight heparin; ufh = unfractionated heparin; pe = pulmonary embolism; dvt = deep vein thrombosis.

2.1 Major Abdominal and Pelvic Surgery

After major abdominal or pelvic cancer surgery, pharmacologic intervention with anticoagulants for 7–14 days postoperatively can reduce the risk of vte to 1.3% for symptomatic deep vein thrombosis (dvt) and 0.4% for fatal pulmonary embolism. However, these numbers still represent a doubling or tripling of the risk as compared with patients without malignancy 24,25. Of the agents available for thromboprophylaxis, low molecular weight heparins (lmwhs) provide the most convenient, efficacious, and safe option (Table I) 1014,26. Compared with lmwhs, unfractionated heparin requires 3-times-daily injection and has a higher risk of heparin-induced thrombocytopenia. And although fondaparinux appears to be comparable to lmwh in efficacy and safety, limited data are available for it in the cancer setting, and a specific antidote for it is lacking. A post hoc subgroup analysis of cancer patients in a randomized trial found a lower risk of vte with fondaparinux than with dalteparin, but that finding requires confirmation in future studies 12.

However, as hospital stays have shortened, the duration of prophylaxis may be inadequate for some patients. Cancer patients are at particularly high risk, considering that many of them undergo extensive surgery and require prolonged periods of recovery. In a prospective cohort study in which 2373 cancer patients were followed for a minimum of 30 days after surgery, 40% of symptomatic VTE occurred more than 3 weeks postoperatively, and 46% of deaths were the result of fatal pulmonary embolism 27. Clinical factors found to be associated with a higher risk of vte were previous history of vte [odds ratio (or): 6.0], anaesthesia lasting 2 hours or longer (or: 4.5), bed rest for 4 days or longer (or: 4.4), an advanced stage of cancer (or: 2.7), and age 60 years or older (or: 2.6).

Randomized controlled trials have shown that continuing prophylaxis with a lmwh up to 30 days postoperatively can reduce the risk of vte by 60% without increasing the risk of bleeding (Table I) 13,14. Based on these and other supportive studies, it is reasonable to prescribe extended prophylaxis in patients with one or more risk factors for vte.

2.2 Neurosurgery

Neurosurgical patients present a challenging prophylaxis problem because of the underlying concern of intracerebral hemorrhage combined with a high incidence of vte. In fact, craniotomy for brain neoplasm carries a vte risk of 60% in the postoperative period and 23% at 1 year 28. This risk can be reduced by 40% with the use of lmwh prophylaxis starting 24 hours postoperatively (Table II) 1518. The risk of major bleeding, including intracranial hemorrhage, is less than 3%, but that risk is increased if lmwh prophylaxis is administered preoperatively 29. However, given the devastating consequences of an intracranial hemorrhage, most neurosurgeons prefer to use mechanical compression devices in the early operative period and to start pharmacologic prophylaxis when patients are more stable.

TABLE II.

Randomized controlled trials for primary prophylaxis in cancer-related neurosurgery

Trial Surgical setting Patients (n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study (%) Control (%) p Value Study (%) Control (%) p Value
Nurmohamed et al., 1996 15 Craniotomy or spinal surgery for tumour or injury 485 Nadroparin 7500 IU daily and gcs Placebo and gcs 10 Days or until discharge Venographic dvt at day 10 18.7 26.3 0.047 2.50 0.80 0.87
Agnelli et al., 1998 16 Elective cranial or spinal surgery for tumours 307 Enoxaparin 40 mg daily and gcs Placebo and gcs At least 7 days Venographic dvt at day 8, or pe 17 33 0.004 3 3 >0.05
Goldhaber et al., 2002 17 Craniotomy for brain tumour 150 Enoxaparin 40 mg daily and gcs and ipc ufh 5000 IU twice daily and gcs and ipc Until vte or discharge Ultrasonographic dvt at discharge 12 6.7 0.401 2.7 1.3 >0.05
Macdonald et al., 2003 18 Craniotomy 100 Dalteparin 2500 IU daily and ipc ufh 5000 IU twice daily and ipc 7 Days, or until ambulating pe, or ultrasonographic dvt at 1 month 4 0 >0.05 4 2 >0.05

vte = venous thromboembolism; gcs = graduated compression stockings; dvt = deep vein thrombosis; pe = pulmonary embolism; ipc = intermittent pneumatic compression; ufh = unfractionated heparin.

2.4 Gynecologic Surgery

Compared with the previous two groups, women undergoing gynecologic cancer surgery have a lower risk of vte—about 2%. But that level of risk represents an increase by a factor of 5 over the risk in women having surgery for benign gynecologic problems 9. As with abdominal and pelvic surgery, unfractionated heparin and lmwh are both equally effective and safe in preventing dvt in this setting ) (Table III 1923,30. Mechanical devices have also been shown to be effective.

2.5 Other Surgeries

There is a paucity of research on the risk of vte and on its prevention in other surgical settings. Based on limited data and extrapolation from other surgical groups, unfractionated heparin and lmwh both appear relatively safe and effective, but solid evidence is lacking.

2.6 Mechanical Prophylaxis in Surgical Settings

As shown in one meta-analysis 31, compression stockings are effective in reducing the risk of vte by two thirds in patients at moderate risk. Pneumatic compression devices are also effective, but they are cumbersome and interfere with mobilization. Also, they are more likely than pharmacologic prophylaxis to fail in high-risk groups 32. Compression devices are therefore currently reserved for situations in which anticoagulation is contraindicated. These devices are most effective when applied intraoperatively or immediately after surgery (Table IV)3335. Whether mechanical methods in combination with anticoagulants result in additional risk reduction is not clear.

TABLE IV.

Randomized controlled trials for primary prophylaxis using pneumatic compression stockings

Trial Surgical setting Patients(n) Regimen Duration of treatment Outcome Incidence of vte
Study Control Study (%) Control (%) p Value
Clarke–Pearson et al., 1993 33 Gynecologic malignancy 208 ufh 5000 IU 3 times daily pre- and postoperatively Intra- and postoperative ipc ufh: 7 days postoperatively, or until discharge ipc: 5 days postoperatively, or until discharge dvt by 125I-labelled fibrinogen scan, impedance plethysmography; pe on scintigraphy up to day 30 postoperatively 6.5 4.0 0.54
Clarke–Pearson et al., 1984 34 Gynecologic malignancy 194 Intra- and postoperative ipc No prophylaxis Maximum 24 hours postoperatively dvt by 125I-labelled fibrinogen scan, impedance plethysmography 18.6 12.4 >0.05
Clarke–Pearson et al., 1984 35 Gynecologic malignancy 107 Intra- and postoperative ipc No prophylaxis 5 Days dvt by 125I-labelled fibrinogen scan, impedance plethysmography 12.7 34.6 <0.005

vte = venous thromboembolism; ufh = unfractionated heparin; ipc = intermittent pneumatic compression; dvt = deep vein thrombosis; pe = pulmonary embolism.

2.7 Summary: Surgical Settings

Good evidence supports the routine use of postoperative thromboprophylaxis in patients undergoing surgery for cancer (Tables I to IV). That finding is endorsed by international and national consensus guidelines, including those from the American College of Chest Physicians (accp)9, the American Society of Clinical Oncology (asco)36, and the Italian Association of Medical Oncology (aiom)37. Unfractionated heparin and lmwh are equally effective in preventing vte and have a comparable risk for bleeding. Less experience and data are available for fondaparinux. Extended prophylaxis should be strongly considered in patients with additional risk factors for vte. In those patients who have a contraindication for anticoagulation, mechanical methods are reasonable substitutes.

3. PRIMARY PREVENTION: MEDICAL SETTINGS

3.1 Ambulatory Patients

The risk of symptomatic vte in the ambulatory outpatient setting is lower than that in the surgical setting, and little research had been done to investigate the role of anticoagulant prophylaxis. More recently, three separate randomized controlled trials have evaluated lmwh prophylaxis in patients with metastatic breast cancer, non-small-cell lung cancer, and grades and iii and iv malignant glioma (Table V) 3840. No significant difference in vte or major bleeding was observed between the groups receiving lmwh and placebo. Consequently, routine prophylaxis is not recommended in ambulatory patients. Notably, the risk of vte and major bleeding appear to vary considerably, depending on the type of tumour.

TABLE V.

Randomized controlled trials for primary prophylaxis in medical outpatients with cancer

Trial Medical setting Patients(n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study(%) Control (%) p Value Study (%) Control (%) p Value
Levine et al., 1994 38 Breast cancer stage iv 311 Warfarin 1 mg daily for 6 weeks, then adjusted for inr 1.3–1.9 Placebo 1 Week after completion of chemotherapy Symptomatic vte 0.7 4.4 0.031 5.30 3.10 0.4
Haas et al., 2005 39 Advanced breast cancer 353 Certoparin 3000 IU daily Placebo 6 Months Ultrasonographic dvt 4.0 3.9 >0.05 1.7 0 >0.05
Advanced non-small-cell lung cancer 547 Certoparin 3000 IU daily Placebo 6 Months Ultrasonographic dvt 4.5 8.3 0.07 3.7 2.2 >0.05
Perry et al., 2007 40 Glioma grade iii or iv 186 Dalteparin 5000 IU daily Placebo 6 Months pe, symptomatic dvt 11 17 0.3 5.1 1.2 0.2

vte = venous thromboembolism; dvt = deep vein thrombosis; pe = pulmonary embolism; inr = international normalized ratio.

On the other hand, as many as 20%–30% of patients receiving thalidomide in combination with chemotherapy or high-dose corticosteroids for treatment of multiple myeloma will develop symptomatic vte 41,42. Although many studies have reported the use of warfarin, aspirin, or lmwh, insufficient reliable data are available to support the efficacy and safety of these agents. Whether lenalidomide is also associated with a high risk of vte is uncertain. Patients receiving vascular endothelial growth factor inhibitors such as bevacizumab also have an increased risk of arterial and, possibly, venous thrombosis 43,44, but because of an increased bleeding tendency already associated with this treatment, anticoagulation prophylaxis is not recommended.

3.2 Hospitalized Patients

No study has been conducted in cancer patients to determine the effects of vte prophylaxis in the inpatient setting. Large randomized trials that included small numbers of cancer patients have shown that lmwh or fondaparinux can reduce the vte risk by 50% or more, but whether such results can apply to all hospitalized cancer patients is questionable, because of the higher risks for vte and major bleeding in those patients 4547.

3.3 Summary: Medical Settings

Based on limited data, routine prophylaxis in the outpatient setting is not recommended, but prophylaxis should be considered in patients receiving thalidomide- or lenalidomide-containing regimens. Anticoagulant prophylaxis for hospitalized patients is warranted based on studies in noncancer patients, but the risk–benefit ratio is uncertain, given the lack of randomized trial evidence.

4. PROPHYLAXIS FOR CENTRAL VENOUS CATHETERS

Central venous catheters are frequently placed in cancer patients, and those devices represent an ongoing thrombogenic focus 48. Many attempts have been made to reduce the incidence of thrombotic complications in this setting, but randomized placebo-controlled trials have failed to show a reduction in catheter-related thrombosis with thromboprophylaxis. In particular, low-dose warfarin 49, adjusted-dose warfarin 50, and prophylactic-dose lmwh 51,52 do not reduce the 4% risk of symptomatic catheter–related thrombosis (Table VI) 4952. For that reason and because of the possibility of increased risk of bleeding, the routine use of prophylaxis in this setting is not recommended 9.

TABLE VI.

Randomized controlled trials for primary prophylaxis in central venous catheters in cancer patients

Trial Patients (n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study (%) Control (%) p Value Study (%) Control (%) p Value
Couban et al., 2005 49 255 Warfarin 1 mg Placebo Until dvt, or until line removed cvc-associated thrombosis on ultrasound or venography 4.6 4.0 >0.05 0 2 0.5
Young et al., 2005 50 1589 Adjusted warfarin for inr 1.5–2.0 or warfarin 1 mg Placebo Until dvt, or until line removed cvc-associated thrombosis on ultrasound or venography 5 6 0.84 2 0.2 0.07
Verso et al., 2005 51 321 Enoxaparin 40 mg daily Placebo Until dvt, or until line removed Venographic dvt, or pe 14.1 18.0 0.35 0 0 >0.05
Karthaus et al., 2006 52 425 Dalteparin 5000 IU daily Placebo 12 Weeks pe, venographic or ultrasonographic dvt 3.7 3.4 0.88 0.004 0 >0.05

vte = venous thromboembolism; dvt = deep vein thrombosis; cvc = central venous catheter; inr = international normalized ratio; pe = pulmonary embolism.

5. SECONDARY PREVENTION

5.1 Treatment of VTE

Traditional therapy for acute vte has consisted of initial therapy with unfractionated heparin or lmwh, followed by long-term warfarin therapy. Unfortunately, many cancer patients tolerate warfarin poorly, especially when receiving chemotherapy, with its ensuing gastrointestinal and hematologic side effects. Also, despite maintenance of therapeutic levels of warfarin, one third of patients experience recurrent vte or treatment-related bleeding 6,7.

However, lmwh is clearly superior to warfarin with respect to convenience and efficacy. Given as a once-daily subcutaneous injection, lmwh does not require routine laboratory monitoring, has few drug interactions, and does not rely on gastrointestinal absorption. In the clot study, 676 cancer patients with acute dvt or pulmonary embolism were randomized to a 6-month course of traditional therapy with dalteparin followed by warfarin, or to dalteparin alone 53. To reduce the risk of bleeding in the dalteparin-only group, the dalteparin dose was reduced by 20%–25% after the first month of therapy. After 6 months of treatment, the long-term dalteparin group experienced a 52% reduction in symptomatic recurrent vte (17% vs. 9%, p = 0.002) as compared with the group continuing on warfarin. In other words, 1 episode of recurrent vte was prevented for every 13 patients treated. Furthermore, the groups showed no significant difference in bleeding (4% vs. 6% respectively) and no difference in overall mortality.

Based on those results and on supportive findings from other trials (Table VII) 5356, the 2004 accp guidelines 57, the asco vte guidelines 36, and aiom 37 recommend the use of lmwh alone for treatment of vte in most patients with cancer. Currently, only dalteparin has received regulatory approval for long-term treatment of symptomatic vte in patients with cancer.

TABLE VII.

Randomized controlled trials for treatment of cancer-related venous thromboembolism (vte)

Trial Patients (n) Regimen Duration of treatment Outcome Incidences
Study Control vte Major bleeding
Study (%) Control (%) p Value Study (%) Control (%) p Value
Meyer et al., 2002 54 146 Enoxaparin 1.5 mg/kg daily Enoxaparin 1.5 mg/kg daily for 5–7 days, then warfarin at inr 2–3 3 Months Combined recurrent vte and hemorrhage 10.5a 21.1a 0.09a 7.0 16.0 0.09
Lee et al., 2003 53 672 Dalteparin 200 IU/kg daily for 1 month, then 150 IU/kg daily for 5 months Dalteparin 200 IU/kg daily for 5–7 days, then warfarin at inr 2–3 As described in “Regimen” Recurrent vte 9.0 17.0 0.002 6 4 0.27
Deitcher et al., 2006 55 122 Enoxaparin 1 mg/kg twice daily, then 1.0 mg/kg daily or 1.5 mg/kg daily Enoxaparin 1 mg/kg twice daily, then warfarin at inr 2–3 5 Days at twice daily, then 6 months Recurrent vte 6.9 (1 mg), 6.3 (1.5 mg) 10.00 >0.05 6.5 (1 mg), 11.1 (1.5 mg) 2.90 >0.05
Hull et al., 2006 56 200 Tinzaparin 175 IU/kg daily ufh infusion then warfarin at inr 2–3 3 Months Recurrent vte 6.0b 10.0b >0.05b 7.0 7.0 >0.05
a

Combined 3-month incidence of patients with either recurrent venous thromboembolism or major bleeding.

b

3-Month incidence of patients with recurrent venous thromboembolism.

vte = venous thromboembolism; inr = international normalized ratio.

5.2 Recurrent VTE

As mentioned earlier, recurrence of vte is more common in the setting of warfarin therapy than of lmwh therapy. Unfortunately, the optimal treatment for such patients has yet to be determined. Inferior caval filters have frequently been used in cases of warfarin failure, but evidence from a large randomized trial primarily in patients without cancer showed that, although the risk of short-term pulmonary embolism is reduced by about three quarters, patients receiving a filter are about twice as likely to develop recurrent vte. Also, no difference in overall survival was seen 58. Furthermore, because of the increased risk of recurrent vte, cancer patients may be at higher risk for development of postphlebitic syndrome.

Based on the foregoing findings, using caval filters as treatment for recurrent vte cannot be recommended. Rather, changing a warfarin regimen to lmwh, or increasing the dose of lmwh would be appropriate.

5.3 Duration of Therapy

The optimum duration of anticoagulation in patients with cancer has not been investigated. Extrapolating from populations without cancer, most patients should receive a minimum of 3–6 months of therapy. However, given that cancer represents an ongoing risk factor in this population, the general recommendation is to continue anticoagulation for long as evidence of active malignancy continues. It is of foremost importance that patient care be tailored to suit the individual, with due consideration for quality of life and life expectancy.

5.4 Summary of Secondary Prevention

First-line treatment of vte in patients with cancer is lmwh for a minimum of 3–6 months. This approach is endorsed by the accp, asco, aiom, and the National Comprehensive Cancer Network. The optimum duration is not known, but treatment is usually continued for as long as evidence of malignancy continues.

6. FUTURE DIRECTIONS

The lmwhs have simplified and improved the prevention and treatment of vte in patients with cancer. Much work must still be done to help identify high-risk patients who would benefit from primary thromboprophylaxis for extended periods after cancer surgery, during medical hospitalization, for prevention of catheter-related thrombosis, and for prevention of vte associated with highly thrombogenic agents (thalidomide, for example). Also, optimal management in patients with established vte should be investigated, especially with regard to duration of therapy and the potential role, if any, of invasive strategies such as filter insertion. Lastly, education of physicians to improve the appropriate utilization of prophylaxis in various settings will go a long way toward reducing morbidity and mortality in this vulnerable population.

7. SUMMARY

Recommendations for managing risk of thrombotic events:

  • Cancer patients undergoing surgery require vte prophylaxis, and this prophylaxis can safely be extended in high-risk patients after discharge.

  • Medical inpatients with cancer should receive vte prophylaxis unless absolute contraindications—active bleeding, for instance—are present.

  • Prophylaxis for central venous catheters is not recommended.

  • Prophylaxis in ambulatory patients is not recommended, except in those who are receiving thalidomide- or lenalidomide-based combination chemotherapy.

  • Venous thromboembolism is best treated with lmwh for a minimum of 3–6 months, and treatment can be continued for as long as active cancer is present.

  • Inferior caval filters prevent pulmonary embolism in the short term, but they carry a long-term risk of increased vte and should therefore be avoided when anticoagulation can be administered.

8. REFERENCES

  • 1.Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ., 3rd Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809–15. doi: 10.1001/archinte.160.6.809. [DOI] [PubMed] [Google Scholar]
  • 2.Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006;119:60–8. doi: 10.1016/j.amjmed.2005.06.058. [DOI] [PubMed] [Google Scholar]
  • 3.Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–4. doi: 10.1111/j.1538-7836.2007.02374.x. [DOI] [PubMed] [Google Scholar]
  • 4.Sørensen HT, Mellemkjær L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343:1846–50. doi: 10.1056/NEJM200012213432504. [DOI] [PubMed] [Google Scholar]
  • 5.Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24:484–90. doi: 10.1200/JCO.2005.03.8877. [DOI] [PubMed] [Google Scholar]
  • 6.Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. 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. 2000;18:3078–83. doi: 10.1200/JCO.2000.18.17.3078. [DOI] [PubMed] [Google Scholar]
  • 7.Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–8. doi: 10.1182/blood-2002-01-0108. [DOI] [PubMed] [Google Scholar]
  • 8.Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in U.S. medical centers: success or failure? J Thromb Haemost. 2007;5:1610–16. doi: 10.1111/j.1538-7836.2007.02650.x. [DOI] [PubMed] [Google Scholar]
  • 9.Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: The Seventh accp Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):338S–400S. doi: 10.1378/chest.126.3_suppl.338S. [DOI] [PubMed] [Google Scholar]
  • 10.Enoxacan Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg. 1997;84:1099–103. [PubMed] [Google Scholar]
  • 11.McLeod RS, Geerts WH, Sniderman KW, et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the Canadian colorectal dvt prophylaxis trial: a randomized, double-blind trial. Ann Surg. 2001;233:438–44. doi: 10.1097/00000658-200103000-00020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M on behalf of the pegasus investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005;92:1212–20. doi: 10.1002/bjs.5154. [DOI] [PubMed] [Google Scholar]
  • 13.Bergqvist D, Agnelli G, Cohen AT, et al. on behalf of the enoxacan ii Investigators. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975–80. doi: 10.1056/NEJMoa012385. [DOI] [PubMed] [Google Scholar]
  • 14.Rasmussen MS, Wille–Jorgensen P, Jorgensen LN, et al. Prolonged thromboprophylaxis with low molecular weight heparin (dalteparin) following major abdominal surgery for malignancy [abstract 186] Blood. 2003;102:56a. [Google Scholar]
  • 15.Nurmohamed MT, van Riel AM, Henkens CM, et al. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost. 1996;75:233–8. [PubMed] [Google Scholar]
  • 16.Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med. 1998;339:80–5. doi: 10.1056/NEJM199807093390204. [DOI] [PubMed] [Google Scholar]
  • 17.Goldhaber SZ, Dunn K, Gerhard–Herman M, Park JK, Black PM. Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest. 2002;122:1933–7. doi: 10.1378/chest.122.6.1933. [DOI] [PubMed] [Google Scholar]
  • 18.Macdonald RL, Amidei C, Baron J, et al. Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy. Surg Neurol. 2003;59:362–71. doi: 10.1016/s0090-3019(03)00111-3. [DOI] [PubMed] [Google Scholar]
  • 19.Heilmann L, Kruck M, Schindler AE. Prevention of thrombosis in gynecology: double-blind comparison of low molecular weight heparin and unfractionated heparin [German] Geburtshilfe Frauenheilkd. 1989;49:803–7. doi: 10.1055/s-2008-1036089. [DOI] [PubMed] [Google Scholar]
  • 20.Clark–Pearson DL, DeLong E, Synan IS, Soper JT, Creasman WT, Coleman RE. A controlled trial of two low-dose heparin regimens for the prevention of postoperative deep vein thrombosis. Obstet Gynecol. 1990;75:684–9. [PubMed] [Google Scholar]
  • 21.Fricker JP, Vergnes Y, Schach R, et al. Low dose heparin versus low molecular weight heparin (Kabi 2165, Fragmin) in the prophylaxis of thromboembolic complications of abdominal oncological surgery. Eur J Clin Invest. 1988;18:561–7. doi: 10.1111/j.1365-2362.1988.tb01268.x. [DOI] [PubMed] [Google Scholar]
  • 22.von Tempelhoff GF, Dietrich M, Niemann F, Schneider D, Hommel G, Heilmann L. Blood coagulation and thrombosis in patients with ovarian malignancy. Thromb Haemost. 1997;77:456–61. [PubMed] [Google Scholar]
  • 23.Heilmann L, von Tempelhoff GF, Kirkpatrick C, Schneider DM, Hommel G, Pollow K. Comparison of unfractionated versus low molecular weight heparin for deep vein thrombosis prophylaxis during breast and pelvic cancer surgery: efficacy, safety, and follow-up. Clin Appl Thromb Hemost. 1998;4:268–73. [Google Scholar]
  • 24.Haas S, Wolf H, Kakkar AK, Fareed J, Encke A. Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized double-blind comparison of lmwh with unfractionated heparin. Thromb Haemost. 2005;94:814–19. doi: 10.1160/TH02-10-0189. [DOI] [PubMed] [Google Scholar]
  • 25.Kakkar AK, Haas S, Wolf H, Encke A. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the mc-4 cancer substudy. Thromb Haemost. 2005;94:867–71. doi: 10.1160/TH04-03-0189. [DOI] [PubMed] [Google Scholar]
  • 26.Mismetti P, Laporte S, Darmon JY, Buchmüller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg. 2001;88:913–30. doi: 10.1046/j.0007-1323.2001.01800.x. [DOI] [PubMed] [Google Scholar]
  • 27.Agnelli G, Bolis G, Capussotti L, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @ristos project. Ann Surg. 2006;243:89–95. doi: 10.1097/01.sla.0000193959.44677.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Marras LC, Geerts WH, Perry JR. The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer. 2000;89:640–6. doi: 10.1002/1097-0142(20000801)89:3<640::aid-cncr20>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  • 29.Dickinson LD, Miller LD, Patel CP, Gupta SK. Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery. 1998;43:1074–9. doi: 10.1097/00006123-199811000-00039. [DOI] [PubMed] [Google Scholar]
  • 30.Oates–Whitehead RM, D’Angelo A, Mol B. Anticoagulant and aspirin prophylaxis for preventing thromboembolism after major gynaecological surgery. Cochrane Database Syst Rev. 2003:CD003679. doi: 10.1002/14651858.CD003679. [DOI] [PubMed] [Google Scholar]
  • 31.Wells PS, Lensing AW, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis. Arch Intern Med. 1994;154:67–72. [PubMed] [Google Scholar]
  • 32.Clarke–Pearson DL, Dodge RK, Synan I, McClelland RC, Maxwell GL. Venous thromboembolism prophylaxis: patients at high risk to fail intermittent pneumatic compression. Obstet Gynecol. 2003;101:157–63. doi: 10.1016/s0029-7844(02)02444-4. [DOI] [PubMed] [Google Scholar]
  • 33.Clarke–Pearson DL, Synan IS, Dodge R, Soper JT, Berchuck A, Coleman RE. A randomized trial of low-dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis after gynecologic oncology surgery. Am J Obstet Gynecol. 1993;168:1146–53. doi: 10.1016/0002-9378(93)90360-u. [DOI] [PubMed] [Google Scholar]
  • 34.Clarke–Pearson DL, Creasman WT, Coleman RE, Synan IS, Hinshaw WM. Perioperative external pneumatic calf compression as thromboembolism prophylaxis in gynecologic oncology: report of a randomized controlled trial. Gynecol Oncol. 1984;18:226–32. doi: 10.1016/0090-8258(84)90030-1. [DOI] [PubMed] [Google Scholar]
  • 35.Clarke–Pearson DL, Synan IS, Hinshaw WM, Coleman RE, Creasman WT. Prevention of postoperative venous thromboembolism by external pneumatic calf compression in patients with gynecologic malignancy. Obstet Gynecol. 1984;63:92–8. [PubMed] [Google Scholar]
  • 36.Lyman GH, Khorana AA, Falanga A, et al. on behalf of the American Society of Clinical Oncology. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490–505. doi: 10.1200/JCO.2007.14.1283. [DOI] [PubMed] [Google Scholar]
  • 37.Mandalà M, Falanga A, Piccioli A, et al. for working group aiom. Venous thromboembolism and cancer: guidelines of the Italian Association of Medical Oncology (aiom) Crit Rev Oncol Hematol. 2006;59:194–204. doi: 10.1016/j.critrevonc.2006.05.001. [DOI] [PubMed] [Google Scholar]
  • 38.Levine M, Hirsh J, Gent M, et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage iv breast cancer. Lancet. 1994;343:886–9. doi: 10.1016/s0140-6736(94)90008-6. [DOI] [PubMed] [Google Scholar]
  • 39.Haas S, Kakkar A, Kemkes–Matthes B, et al. 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. 2005;3(suppl 1):OR059. [Google Scholar]
  • 40.Perry JR, Rogers L, Laperriere N, et al. prodige: A phase iii randomized placebo-controlled trial of thromboprophylaxis using dalteparin low molecular weight heparin (lmwh) in patients with newly diagnosed malignant glioma [abstract] Proc Am Soc Clin Oncol. 2007;25:2011. [Google Scholar]
  • 41.Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20:4319–23. doi: 10.1200/JCO.2002.02.116. [DOI] [PubMed] [Google Scholar]
  • 42.Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98:1614–15. doi: 10.1182/blood.v98.5.1614. [DOI] [PubMed] [Google Scholar]
  • 43.Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase ii, randomized trial comparing bevacizumab plus fluorouracil (fu)/leucovorin (lv) with fu/lv alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–5. doi: 10.1200/JCO.2003.10.066. [DOI] [PubMed] [Google Scholar]
  • 44.Marx GM, Steer CB, Harper P, Pavlakis N, Rixe O, Khayat D. Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock! J Clin Oncol. 2002;20:1446–8. doi: 10.1200/JCO.2002.20.6.1446. [DOI] [PubMed] [Google Scholar]
  • 45.Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332:325–9. doi: 10.1136/bmj.38733.466748.7C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ on behalf of the prevent Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110:874–9. doi: 10.1161/01.CIR.0000138928.83266.24. [DOI] [PubMed] [Google Scholar]
  • 47.Samama MM, Cohen AT, Darmon JY, et al. 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. 1999;341:793–800. doi: 10.1056/NEJM199909093411103. [DOI] [PubMed] [Google Scholar]
  • 48.Lee AY, Levine MN, Butler G, et al. Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer. J Clin Oncol. 2006;24:1404–8. doi: 10.1200/JCO.2005.03.5600. [DOI] [PubMed] [Google Scholar]
  • 49.Couban S, Goodyear M, Burnell M, et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol. 2005;23:4063–9. doi: 10.1200/JCO.2005.10.192. [DOI] [PubMed] [Google Scholar]
  • 50.Young AM, Begum G, Billingham LJ, et al. on behalf of the warp Collaborative Group. U.K. warp—a multicentre prospective randomised controlled trial (rct) of thrombosis prophylaxis with warfarin in cancer patients with central venous catheters (cvcs) [abstract] Proc Am Soc Clin Oncol. 2005;23:8004. [Google Scholar]
  • 51.Verso M, Agnelli G, Bertoglio S, et al. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients. J Clin Oncol. 2005;23:4057–62. doi: 10.1200/JCO.2005.06.084. [DOI] [PubMed] [Google Scholar]
  • 52.Karthaus M, Kretzschmar A, Kröning H, et al. Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase iii trial. Ann Oncol. 2006;17:289–96. doi: 10.1093/annonc/mdj059. [DOI] [PubMed] [Google Scholar]
  • 53.Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53. doi: 10.1056/NEJMoa025313. [DOI] [PubMed] [Google Scholar]
  • 54.Meyer G, Marjanovic Z, Valcke J, et al. 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. 2002;162:1729–35. doi: 10.1001/archinte.162.15.1729. [DOI] [PubMed] [Google Scholar]
  • 55.Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J on behalf of the oncenox Investigators. 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. 2006;12:389–96. doi: 10.1177/1076029606293692. [DOI] [PubMed] [Google Scholar]
  • 56.Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119:1062–72. doi: 10.1016/j.amjmed.2006.02.022. [DOI] [PubMed] [Google Scholar]
  • 57.Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh accp Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):401S–28S. doi: 10.1378/chest.126.3_suppl.401S. [DOI] [PubMed] [Google Scholar]
  • 58.Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338:409–16. doi: 10.1056/NEJM199802123380701. [DOI] [PubMed] [Google Scholar]

Articles from Current Oncology are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES