Preventing VTE in Cancer Outpatients: Are We There Yet?

Alok A. Khorana, MD
Published: Friday, Mar 04, 2011
Cancer-associated thrombosis occurs commonly in patients with cancer, particularly during treatment with anticancer therapies. Recent reports suggest a steep increase in the incidence of cancer-related thrombotic events starting in the late 1990s.1,2 Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), has important consequences for patients with cancer: a requirement for long-term anticoagulation, a 12% annual risk of bleeding complications, a 21% annual risk of recurrent VTE,3 and the potential to affect chemotherapy delivery and quality of life. Most importantly, thrombotic events are the second leading cause of death in patients with cancer (after cancer itself) and are associated with decreased short-term and long-term survival.4-6 Thus, it is crucial to reduce the occurrence of VTE, especially considering that there are multiple available agents for thromboprophylaxis, including low-molecular-weight heparins (LMWHs) and warfarin.


The focus of thromboprophylaxis studies in the past has largely been in the hospital inpatient and postsurgical settings. Although these continue to be important settings, an increasing proportion of VTE events occur in the outpatient setting.7 Recent studies of thromboprophylaxis conducted primarily in the outpatient setting have implications for clinical practice.


PROTECHT (Prophylaxis of Thromboembolism During Chemotherapy Trial) was a multicenter, randomized, placebo-controlled, double-blind study in which prophylaxis was studied in patients with high-risk sites of cancer, including locally advanced or metastatic lung, gastrointestinal, pancreatic, breast, ovarian, and head/neck cancers, who were actively receiving chemotherapy.8 Patients receiving adjuvant or neoadjuvant chemotherapy, patients actively receiving antithrombotic treatment, and those with contraindications to anticoagulation were excluded.

Patients received either injections of nadroparin (an LMWH approved in Europe) or placebo in a 2:1 randomization ratio for the duration of chemotherapy or for a maximum of 4 months. The primary outcome in the trial was a combined endpoint of symptomatic VTE of the extremities, peripheral arterial thromboembolism, PE, cerebral or visceral venous thrombosis, myocardial infarction, ischemic stroke, and death secondary to a thromboembolic event. The study did not screen for asymptomatic events.

Overall, 2% of patients in the treatment group and 3.9% (n = 15) in the placebo group developed a thromboembolic event (one-sided; 95% CI, 0.303%; P = .02). DVTs comprised the majority of events in both arms, followed by PE, visceral venous thrombosis, and stroke/peripheral thrombosis (Table 1). No survival benefit was observed. Patients in the treatment arm were more likely than patients in the control arm to experience major bleeding (0.17% vs 0%, respectively; P = .18).8

This is the largest study of thromboprophylaxis conducted in outpatients with cancer to date, and it represents a significant advance in the prevention of VTE in this population. Although the study met its primary endpoint, the overall low event rate has not led to recommendations for the use of prophylaxis in outpatients. It is quite possible that the event rate is higher in specific subgroups of patients with cancer and that the risk-benefit ratio would have been more optimal for prophylaxis if higher-risk patients had been selected using either biomarkers or risk-assessment tools, which will be discussed later in this article.


It has been well established that patients with pancreatic cancer are at particularly high risk for VTE.9 The PROSPECTCONKO 004 (Prospective Randomized Trial of Simultaneous Pancreatic Cancer Treatment With Enoxaparin and Chemotherapy) study was a prospective, open, randomized multicenter phase III trial that evaluated thromboprophylaxis in patients with pancreatic cancer receiving gemcitabine (Gemzar)-based chemotherapy. The study was designed after an initial pilot study determined that adding enoxaparin to a chemotherapy regimen of gemcitabine, 5-fluorouracil, folinic acid, and cisplatin (GFFC) was safe and efficacious in advanced pancreatic cancer.10

Individuals with confirmed advanced pancreatic cancer and no prior chemotherapy or recent VTE events were eligible for enrollment. Patients were stratified according to Karnofsky performance status and renal function. Those with normal renal function and good performance status (>80%) received GFFC chemotherapy, whereas patients with elevated plasma levels of creatinine and worse performance status received gemcitabine alone. Patients were randomized to observation or prophylactic enoxaparin, receiving 1 mg/kg per day for 3 months, then 40 mg daily. The primary endpoint was reduction of symptomatic VTE. Time to progression (TTP) and overall survival (OS) were secondary outcomes.

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