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33rd Congress of the European Society for Medical Oncology

Stockholm, Sweden / September 12-16, 2008

Cancer is a prothrombotic condition. Within the first three months, the risk of a venous thromboembolism (VTE) has been calculated to be more than 50 times greater than in a healthy population. After adjusting for risk factors such as age, the overall risk of VTE in population studies is increased by six- to sevenfold. All patients hospitalized for an acute condition face an increased risk of VTE, but the relationship between cancer and thrombosis is not dependent on immobilization. Although anticoagulation is not currently recommended in ambulatory cancer patients without special risks for VTE, such as ongoing treatment with prothrombotic chemotherapies, secondary prevention is considered essential based on controlled trials.

Support from the CLOT Study

“The American Society of Clinical Oncology (ASCO) guidelines identify low molecular-weight heparin (LMWH) as the preferred choice for initial therapy and that it be given for at least six months. The vitamin K inhibitors are acceptable when LMWH is not available,” reported Dr. Mark Levine, Director, Ontario Clinical Oncology Group and Chair and Professor, Department of Oncology Research and Clinical Epidemiology/Biostatistics, McMaster University, Hamilton, Ontario. “The ESMO guidelines are very similar although they are more specific about doses.”

Both guidelines are anchored by results of the landmark CLOT (Randomized Comparison of Low Molecular Weight Heparin vs. Oral Anticoagulant Therapy) trial (Lee et al. N Engl J Med 2003;349:146-53). In CLOT, 672 cancer patients with acute, symptomatic deep-vein thrombosis (DVT), pulmonary embolism (PE) or both were randomized to a long-term strategy of LMWH dalteparin or an oral coumarin derivative (warfarin in most of the 48 centres but acenocoumarol was used in two of the eight participating countries). The risk reduction over the six months for the LMWH-based strategy was 52% (P=0.0017). Bleeding rates did not differ significantly.

In addition to the clinical advantage in regard to VTE in CLOT, LMWH was characterized by Dr. Levine as simplifying treatment. “In the group randomized to the oral anticoagulant, the average number of blood tests to check INR [international normalization ratio] was 23. The maximum was 83. That is a lot of bloodletting,” Dr. Levine observed.

In this study, all patients received an initial five to seven days of dalteparin 200 IU/kg body weight administered subcutaneously once daily. Those in the LMWH group remained on this dose for another month before a dose reduction to 150 IU/kg body weight that was maintained for the remainder of the study. Those switched to the oral anticoagulant after the initial dalteparin regimen had a target 2.5 INR. The primary end point was recurrent VTE.

At six months, 17% of those on the oral anticoagulant vs. 9% of those on LMWH had a recurrent VTE (hazard ratio 0.48). The rate of major bleeding events in both groups was low and not significantly different (6% for dalteparin and 4% for the oral anticoagulant). The rate of all bleeds (14% for dalteparin and 19% for the oral anticoagulant) also did not reach statistical significance.

“These were relatively sick patients. The majority of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 1 or 2 and more than two-thirds had metastatic disease,” reported Dr. Levine, who was a co-author of the study. He noted that both the ASCO and the ESMO guidelines specifically reference the CLOT study in recommending prolonged LMWH prophylaxis for secondary VTE prevention.

Hospitalized Cancer Patients

In primary prophylaxis for hospitalized cancer patients, LMWH may still have practical advantages over other options, including oral anticoagulants and unfractionated heparin (UFH) because it permits treatment without monitoring. In addition, LMWH is associated with a lower risk of heparin-induced thrombocytopenia relative to UFH and fewer drug-drug interactions or altered activity due to impaired organ function relative to warfarin. In a meta-analysis of 11 studies comparing LMWH to UFH for treatment of VTE, the odds ratio for a recurrent VTE (0.85; P=0.28) and bleeding event (0.71; P=0.25) both moved in a favourable direction for LMWH. Although neither was statistically significant, the meta-analysis suggested that the advantages of LMWH were not attained at the cost of reduced safety or efficacy.

The data supporting primary prophylaxis in patients hospitalized with cancer were generated by large trials in acutely hospitalized patients. In most studies, the cancer patients represented the minority of patients. However, these studies indicate that LMWH is as safe and effective as UFH, making the practical differences and costs of administration important for selection. The same appears to be true for VTE prophylaxis in cancer patients undergoing surgery. According to the ASCO and ESMO guidelines, perioperative thromboprophylaxis with LMWH or UFH is appropriate in all surgical patients, including those undergoing laparotomy, laparoscopy or thoracotomy lasting more than 30 minutes. At least seven to 10 days of anticoagulation therapy is recommended.

Potential Primary Prophylaxis for High-risk Patients

“One important reason to provide anticoagulation is that cancer surgical patients are at a higher risk of PE than non-surgical cancer patients,” stated Dr. Ajay K. Kakkar, Thrombosis Research Institute, Barts and the London School of Medicine and Dentistry, London, UK. Citing a retrospective study he conducted several years ago that included data on more than 20,000 surgical patients, Dr. Kakkar declared that the incidence of PE was more than four times greater (P<0.0001) in those with cancer and the death rate from PE was more than three times higher (3.1 vs. 0.7; P<0.0001).

The potential for LMWH agents to be used in primary prophylaxis for high-risk patients is being evaluated closely. Although some completed studies, such as one conducted with certoparin in breast cancer patients, have not associated prophylaxis with meaningful risk reductions, newer studies are evaluating these agents in very high-risk patients. For example, one study has randomized patients taking chemotherapy regimens that include gemcitabine, which is associated with prothrombotic effects, to VTE prophylaxis with dalteparin or no dalteparin. Such studies are considered feasible because of the advantages of LMWH.

“We now have data from several large studies, including CLOT, that LMWH does have an acceptable safety profile when administered in oncologic patients for extended periods. With a predictable clinical effect, once-daily dosing, and a low risk of such toxicities as thrombocytopenia, these therapies are attractive if they can be shown to reduce the increased risk of VTE,” indicated Dr. Anna Falanga, Department of Haematology/Oncology, Ospedali Riuniti di Bergamo, Italy.

As the most serious complication of VTE, PE is a measurable cause of death in patients with cancer. In all hospitalized patients, PE accounts for 5% to 10% of all mortalities, making it one of the most common causes of preventable in-hospital deaths. However, thrombosis formation and cancer may even share mechanisms. Data suggest that individuals with idiopathic VTE have a 10% risk of eventually being diagnosed with cancer. Just as cancer patients have a higher risk of VTE recurrence than other patients with VTE, the increased risk of cancer remains elevated in VTE patients relative to those patients without VTE for at least 10 years.

“Although the factors that increase the risk of VTE in cancer patients include prolonged immobilization, surgical procedures, adjuvant hormonal therapy, central venous catheters, administration of erythropoietin, and prothrombotic effects from some cancer treatments, there also appears to be a strong independent relationship between cancer and VTE,” reported Dr. Paolo Prandoni, Department of Medical and Surgical Sciences, University of Padua, Italy. “Prophylaxis along current guidelines is clearly an important part of cancer management.”

Summary

Data from the CLOT study, which associated the LMWH dalteparin with a 50% reduction in the risk of VTE, is the basis for current recommendations from both ASCO and ESMO to provide prophylaxis for at least six months in cancer patients with VTE. Due to the strong relationship between cancer and VTE, anticoagulation is recommended in several other groups, including those cancer patients undergoing surgery or who are taking prothrombotic chemotherapies. Other indications, including prophylaxis against primary VTE in high-risk groups, are being evaluated. Adherence to current ASCO and ESMO guidelines are considered an important opportunity to improve cancer outcomes.