Chapter 2 Literature Review
2.2 Venous Thromboembolism in Patients with Cancer
2.2.6 Treatment of Venous Thromboembolism in Cancer Patients
In response to the increasing concern regarding VTE in cancer patients, several
international cancer organizations have recently issued guidelines regarding its
treatment and prevention. These include the Italian Association of Medical Oncology
(AIOM),68 the National Comprehensive Cancer Network (NCCN),69 the American
Society of Clinical Oncology (ASCO),1 the European Society of Medical Oncology
(ESMO),70 and the French National Federation of the League of Centers Against Cancer
(FNCLCC).71,72 Anticoagulant therapy remains the cornerstone of VTE treatment.
Anticoagulant therapy is divided into two phases: initial treatment to minimize the risk
of thrombus extension and subsequent fatal PE, and long-term treatment to prevent
recurrent VTE, thereby reducing the risk of post-phlebitic syndrome.73
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2.2.6.1 Initial Treatment of Venous Thromboembolism
When VTE is objectively confirmed, parenteral anticoagulants should be initiated.
Treatment is started with unfractionated heparin (UFH), low molecular weight heparin
(LMWH) or fondaparinux. Agent selection should be individualized according to
characteristics of the individual agents (ease of administration, reversibility, half-life,
and cost) and patient’s clinical situation (inpatient or outpatient status, renal function,
medical or surgical patient). In most circumstances, LMWH is preferred because it is
recommended for the long-term treatment of VTE in patients with cancer and facilitates
the transition to outpatient management. 1,44,69-71
Furthermore, LMWH and fondaparinux
provide additional advantages over UFH, including better bioavailability after
subcutaneous administration, longer half-life, more predictable anticoagulant response
and lower incidence of heparin-induced thrombocytopenia.74 LMWH should be used
cautiously in patients with creatinine clearance (CCr) < 30 mL/min and fondaparinux is
contraindicated in these patients.1,69,70
2.2.6.2 Long-term Treatment of Venous Thromboembolism
After initial treatment for 5 to 10 days, LMWH is the preferable approach for
long-term treatment lasting at least 3 to 6 months for patients with VTE. Vitamin K
antagonists (VKA) with a target international normalized ratio (INR) of 2 to 3 are
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considerable choice for long-term treatment when LMWH is not available or in patients
with severe renal insufficiency. Indefinite therapy may be required for patients with
active cancer, such as those with metastatic disease and those receiving chemotherapy
or hormonal therapy. 1,69,70,75 Although enoxaparin and tinzaparin also have been studied
in open-label randomized controlled trials in cancer patients, the efficacy of dalteparin
is supported by the highest quality evidence and it is the only LMWH approved by the
FDA for long-term treatment of VTE in cancer patients.69 Randomized controlled trials
indicate that LMWH is more effective than VKA in long-term treatment for preventing
VTE recurrence with similar bleeding risk.76-79 The CLOT (Randomized Comparison of
LMWH versus Oral Anticoagulant for The Prevention of Recurrent VTE in Patients
with Cancer) study demonstrated a relative risk reduction of 49% with LMWH versus a
VKA.77 In patients with contraindications to anticoagulation, inferior vena cava filter is
an alternative but anticoagulant therapy should be resumed once the bleeding risk is
resolved. Dosage regimens and recommendations for treatment of VTE in patients with
cancer are provided in Table 2.6 and 2.7.1,69,70,75
On the other hand, cancer patients are more likely to have thrombosis in
uncommon sites such as the veins of upper extremities, vena cava, visceral, portal, or
cerebral circulation.80 There are no specific guidelines and randomized controlled trials
focus on the treatment of abdominal DVT in cancer patients or non-cancer patients.
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Recently, the 9th American College of Chest Physicians (ACCP) guidelines published in
2012 recommend anticoagulation over no anticoagulation in patients with symptomatic
splanchnic vein thrombosis.75
Treatment of VTE in cancer patients is more challenging than general population.
Compared with those without malignancy, VTE recurs 3-folds more frequently in
cancer patients and they are more prone to bleeding complications during long-term
treatment of VKA therapy despite a stable INR between 2 to 3. Interactions between
VKA and chemotherapeutic agents may cause elevation of INR and clinically relevant
bleeding. Tendencies toward thrombocytopenia, osteopenia, malnutrition, brain
metastasis and hepatic metastasis all further complicate thrombosis care in cancer
patients.3,55
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Table 2.6 Regimens for prophylaxis/treatment of VTE in patients with cancer
Management Drug Regimen
Prophylaxis Treatment of established VTE
Initial
100 U/kg every 12 hours 200 U/kg daily
then 150 U/kg daily 5-10 mg PO daily; adjust dose to INR 2-3
Adapted from Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-505.
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Table 2.7 Recommendations for treatment of VTE in cancer patients
ASCO1 NCCN69 ESMO70 ACCP75
Initial treatment of VTE
LMWH is the preferred approach for the initial 5-10 days
LMWH, UFH or fondaparinux according to patient’s
characteristics and clinical situation
Weight-adjusted dose LMWH.
If Ccr < 25-30 mL/min, either UFH or LMWH with anti-Xa monitoring
Suggest LMWH or
fondaparinux over UFH for minimum of 5 days
Long-term treatment of VTE
LMWH for at least 6 months is preferred; VKA are
acceptable when LMWH is not available. Indefinite anticoagulation in patients with active cancer
LMWH is preferred; 3-6 months for DVT and 6-12 months for PE. Indefinite anticoagulation in patients with active cancer or persistent risk factors
LMWH is preferred for 6 months with 75-80% of the initial dose. Long-term LMWH for patients with active cancer
Suggest extended
anticoagulant therapy (~3 months to indefinite);
LMWH is preferred over VKA therapy
Thrombolytic therapy in the initial
treatment
Restricted to patients with life- or limb-threatening thrombotic events
Patients with massive PE or submassive PE with moderate or severe RV enlargement or dysfunction
Restricted to patients with PE presenting with severe RV dysfunction, or limb-
threatening thrombotic events
Restricted to patients with massive PE and impending venous gangrene
Inferior vena cava filters
Restricted to patients with contraindications to
anticoagulation or recurrent VTE despite adequate long- term LMWH
Contraindications to failure of anticoagulation; cardiac or pulmonary dysfunction severe enough to make any new PE life-threatening or multiple PE with chronic pulmonary hypertension
Contraindications to
anticoagulation or recurrent PE despite adequate long- term LMWH. Resume
anticoagulation on the risk of bleeding is reduced
Contraindications to
anticoagulation or recurrent PE despite adequate long- term LMWH. Start
anticoagulation if the risk of bleeding is resolved
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Table 2.7 Recommendations for treatment of VTE in cancer patients (continued)
ASCO1 NCCN69 ESMO70 ACCP75
Treatment of catheter- related thrombosis
NA Anticoagulation for as long
as catheter is in place and for at least 3 months after catheter removal
NA 3 months of anticoagulation
if the catheter is removed;
continue anticoagulation as long as the CVC remains Abbreviations: VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network; ESMO, European Society of Medical Oncology; UFH, unfractionated heparin;
LMWH, low molecular weight heparin; VKA, vitamin K antagonist; RV, right ventricular; Ccr, creatinine clearance; NA, not addressed.
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