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43rd Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2007

Control of malignancy is the priority in cancer care, but failure to address its complications can adversely affect important outcomes, including survival. Patients with cancer have a four- to sixfold increased risk for venous thromboembolism (VTE) when compared to non-cancer patients and a threefold risk for recurrence. Surgery doubles the risk for VTE in cancer patients vs. those without cancer, while the death rate from cancer is four times higher in patients who develop a concurrent VTE. It is up to 90% higher within six months of hospital discharge in patients who develop a deep venous thrombosis (DVT) or pulmonary embolism (PE). The particular risks posed by cancer are not solely due to prolonged bed rest common to all acute diseases but to the hypercoagulability introduced by both cancer and its treatments.

“There is not a cancer drug that you can inject into your patients that doesn’t involve activation of clotting,” stated Dr. Frederick R. Rickles, Professor of Medicine, Pharmacology, and Physiology, George Washington University, Washington, DC. He cited data demonstrating that the risk of VTE is increased by more than 20-fold for hematological and solid tumour malignancies at many sites, including the lung and gastrointestinal systems. Within three months of a cancer diagnosis, the risk of VTE can be as much as 50-fold higher than in a non-cancer patient, and modest increases in risk persist for 10 years or more. These data are alarming because the risk of VTE cannot be eliminated but it can be greatly modified with appropriate prophylaxis. The issue is particularly pressing in the cancer patient undergoing surgery.

“Even among surgical patients who receive prophylaxis, cancer is associated with a more than threefold increase in the risk of fatal PE,” reported Dr. Craig Kessler, Director, Division of Coagulation, Lombardi Comprehensive Cancer Center, Washington, DC. He emphasized that these risks have been reflected in American College of Chest Physicians (ACCP) guidelines since 2004. While these guidelines provide daily low-dose unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) with a Grade 1A recommendation for patients hospitalized for cancer and a Grade 2A recommendation for continued LMWH prophylaxis after discharge in cancer surgery patients, far longer prophylaxis is now recommended for secondary VTE prevention.

CLOT Trial Findings

“There is a new development for secondary prevention of VTE and that is therapeutic doses of LMWH for a minimum of three to six months. This is a new standard of care and a Grade 1A recommendation from the ACCP,” Dr. Kessler told delegates. He credited the change to a series of trials comparing extended regimens of LMWH to oral anticoagulation, usually warfarin. The largest of those trials was called CLOT (Comparison of LMWH to Oral Anticoagulation Therapy for Prevention of Recurrent Thromboembolism in Patients with Cancer). In that six-month study which randomized 672 patients, the LMWH dalteparin (200 IU/kg for the first month and then 150 IU/kg for subsequent five months) was compared to warfarin (titrated to achieve a target international normalized ratio [INR] of 2.5). The risk of recurrent VTE was reduced by 52% (P=0.002) on dalteparin vs. the oral anticoagulant.

Characterizing CLOT as a “landmark” trial, Dr. Kessler observed, “As of last month, dalteparin became the only LMWH approved for both the treatment and secondary prevention of VTE in cancer.” He noted that although its efficacy as an anticoagulant is well established, one of the most important results of the CLOT study was the absence of a significant difference in bleeding. Indeed, the rate of overall bleeds trended in its favour (13.6% vs. 18.5%; P=0.09), while the rate of major bleeds did not differ (5.6% vs. 3.6%; P=0.27).

In cancer, both severity and extent of malignancy contribute the VTE risk. While there are data to demonstrate that VTE imposes a negative effect on quality of life, the largest concern is DVT or PE leading to a fatal event. In CLOT, the slight reduction in 12-month mortality for dalteparin relative to warfarin was not significant, but there was a 50% reduction (P=0.03) in deaths among those receiving dalteparin when the comparison was limited to those with metastases.

Corroborative Study Findings

Smaller studies with other LMWHs have provided relatively consistent findings for extended prophylaxis against cancer-associated VTE. These include a 138-patient trial with enoxaparin conducted over three months, a 167-patient trial with tinzaparin conducted over three months and a 102-patient study conducted with high and low doses of enoxaparin over six months. In all of these trials there was a non-significant difference in the risk for major bleeding when the LMWH arm was compared to the oral anticoagulant arm. The protection against recurrent VTE was significant in the tinzaparin trial (P=0.03), trended for an advantage in the three-month trial of enoxaparin (P=0.09) but was non-significant in the six-month enoxaparin trial. However, the three-month enoxaparin trial did associate the LMWH with a significant reduction in mortality (P=0.03). These LMWH agents, which have different molecular weights and pharmacokinetics and potentially different molecular activities, are not interchangeable, and neither enoxaparin nor tinzaparin is approved for secondary prevention of VTE in cancer.

Given the scale of evidence that anticoagulation can prevent VTE and its complications, there is increasing interest in identifying the obstacles to heparin compliance, particularly after discharge when risk of VTE remains high. According to one analysis of medical records, about 75% of VTE occurs in the outpatient setting. While the ACCP’s Grade 1A recommendation for the initial phase of anticoagulation is five to seven days of LMWH or UFH, covering the period of hospitalization in a large proportion of patients, the College recommends continuing anticoagulation with LMWH for three to six months in patients with recurrent VTE. If the malignancy has not resolved, the ACCP suggests considering LMWH or oral anticoagulation indefinitely.

John Fanikos, Assistant Director of Pharmacy, Brigham and Women’s Hospital, Boston, Massachusetts, provided evidence that the threat of malignancy to VTE and the complications of DVT and PE remain underappreciated. He cited a recently published Canadian study that found that patients with malignancy had a 40% chance of receiving thromboprophylaxis relative to other patients with an indication for anticoagulation (Kahn et al. Thromb Res 2007;119:145-55). This was particularly alarming because the study, which was based on chart audits of 29 Canadian hospitals, found that only 23% of the total candidates received any form of prophylaxis.

According to Fanikos, in hospital, the key to improving thromboprophylaxis is developing systems which provide an automatic evaluation of VTE risk in order to prompt orders for therapy. He also suggested that employing regimens that offer the best efficacy and opportunity for compliance might also be helpful. On both accounts, he indicated that LMWH appears to be preferable to low-dose UFH. He cited a soon-to-be-published meta-analysis of 36 randomized controlled trials with 23,000 hospitalized patients that found LMWH 33% more effective than UFH in preventing DVT. He also indicated that once-daily dosing without INR monitoring is also a considerable advantage of LMWH over UFH. However, he suggested that offering any effective method of VTE prophylaxis is better than none at all.

This perspective is supported by guidelines which, in addition to the ACCP recommendations, include those from the National Comprehensive Care Network. They recommend VTE prophylaxis in all patients with a diagnosis of cancer or a clinical suspicion of cancer. In those without such relative contraindications to pharmacologic anticoagulation such as recent active bleeding or thrombocytopenia, they recommend a LMWH, a pentasaccharide anticoagulant or UFH. Again, they indicated that duration of anticoagulation would depend on patient factors, including disease severity and past VTE history.

Summary

Inadequate use of anticoagulation in cancer patients is widespread despite a high risk of symptomatic VTE and fatal events due to PE in this population. While LMWH, UFH and pentasaccharide-type anticoagulants should be initiated immediately in patients with a diagnosis of cancer who do not have contraindications, LMWH at therapeutic doses for a minimum of three months has been identified as a standard of care for secondary VTE prevention. This Grade 1A recommendation from the ACCP is based largely on the CLOT trial with dalteparin, the only compound approved for both DVT treatment and secondary prevention of VTE in cancer. Based on risk of VTE in cancer, prophylaxis offers a significant opportunity to improve outcome.