ASCO Issues Update on VTE in Cancer: Tell Patients of Risk

Zosia Chustecka

May 15, 2013

Telling cancer patients that they are at increased risk for venous thromboembolism (VTE) is "crucial," according to a panel of experts who updated clinical practice guidelines on the issue. At the very least, oncologists and other professionals on the oncology team should ensure that patients "have a basic recognition of VTE warning signs."

"Patients are woefully unaware of that risk and of warning signs and symptoms," the panel notes. Two recent patient surveys found that fewer than 50% of patients are aware of the increased risk for VTE with malignancy (Cancer Invest. 2010;28:44-45 and J Clin Oncol. 29;2011 [suppl:abstr 9101]).

This is one of the 2 new recommendations that appear in an update to the American Society of Clinical Oncology clinical practice guidelines on VTE prophylaxis and treatment in patients with cancer, published online May 13 in the Journal of Clinical Oncology.

The other new recommendation is that patients with cancer be assessed for VTE risk at the time if chemotherapy initiation, and periodically thereafter.

Slight changes were made to the remaining recommendations after the panel considered all evidence published since the guidelines were issued in 2007.

"We added a few cautionary notes," said panel chair Gary H. Lyman, MD, professor of medicine and director of comparative effectiveness and outcomes research at the Duke University School of Medicine and the Duke Cancer Institute in Durham, North Carolina. "But the main point is that the treating physician, usually an oncologist, needs to assess and then reassess the risk periodically. In patients who are thought to be at higher risk, then certainly a discussion should take place...so that the patient knows what to look for — swelling in the leg, shortness of breath, those sorts of things," Dr. Lyman told Medscape Medical News.

"In patients who are at highest risk, a discussion needs to take place, on a case-by-case basis, about trying to prevent a blood clot with anticoagulation," he said. However, this comes with the downside of an increased risk of bleeding, and cancer patients are already at increased risk of bleeding because of the malignancy and/or cancer surgery. "There is a constant balancing act between the benefit from anticoagulation and the risk of doing more harm than good," Dr. Lyman said.

This was a major consideration when the recommendation against the routine use of thromboprophylaxis for most ambulatory patients with cancer was made, he said.

Routine Use Not Recommended

That recommendation remains unchanged, despite the fact that since 2007, 2 large clinical trials have shown a benefit from such prophylaxis.

In 2008, the PROTECHT trial showed that the low-molecular-weight heparin (LMWH) nadroparin halved the rate of the composite end point of symptomatic VTEs and arterial thromboembolic events, compared with placebo (20% vs 3.9%), with a number needed to treat (NNT) of 53.

In 2012, the largest trial to date, the SAVE-ONCO trial, showed that the LMWH semuloparin significantly decreased the rate of symptomatic VTEs, compared with placebo (1.2% vs 3.4%), with an NNT of 45.

When the SAVE-ONCO trial was published, Alok Khorana, MD, associate professor and vice chief of hematology/oncology at the University of Rochester in New York, who is a member of the panel that updated the guidelines, said that even the results from these 2 large studies cannot lead to a recommendation for prophylaxis for all cancer patients.

Also, when the SAVE-ONCO trial was discussed at an FDA Oncologic Drug Advisory meeting last year, the experts voted overwhelmingly against the use of semuloparin thromboprophylaxis, citing a lack of evidence for a sufficient demonstration of a positive benefit/risk assessment. The manufacturer of semuloparin (sanofi-aventis) subsequently withdrew its approval application, and has since withdrawn the drug from sale worldwide.

Dr. Lyman told Medscape Medical News that both trials clearly show that routine thromboprophylaxis does reduce the risk, "but the problem has been that, in unselected patients, basically all patients with cancer, the risk is relatively low, so you take a low risk and make it even lower, but you have to treat everybody to make that incremental reduction."

The recommendation against routine prophylaxis is not "because it doesn't work — it does — but the risk is reduced from about 2.5% to 3.0% to about 1.0% to 1.5%, and you had to treat essentially 50 patients to derive benefit. Plus, these drugs have not been shown to improve survival," Dr. Lyman explained.

The panel therefore decided that a better strategy at the moment is to identify high-risk patients and then for the clinician to have a discussion with these patients on a case-by-case basis, Dr. Lyman noted.

One exception to the recommendation against routine prophylaxis is patients with multiple myeloma who are receiving thalidomide or lenalidomide along with chemotherapy and/or dexamethasone. For these patients, routine thromboprophylaxis with a LMWH for higher-risk patients and with a LMWH or aspirin for lower-risk patients is recommended.

Patients with multiple myeloma are an exception because they are at particularly a high risk for VTE — from 10% to 30% in different cohorts, explained Dr. Lyman. In addition, drugs such as thalidomide and lenalidomide are antiangiogenic agents, and "they put these patients at even further risk, we believe," he said. "The risk is very high and we have no reason to doubt that prophylaxis would be any less effective in these patients.... In fact, you would expect an even bigger gain, but we have to be honest here — there have not been any large randomized trials," although trials ongoing, he added.

Routine Prophylaxis Recommended in Some Patients

The updated document reiterates the previous recommendation for the use of routine thromboprophylaxis in certain patients with cancer — particularly those who are hospitalized and those who are undergoing major surgery.

For prophylaxis in hospitalized medical patients and for surgical patients, the panel recommends unfractionated heparin, one of the LMWHs, such as dalteparin or enoxaparin, or the factor Xa inhibitor fondaparinux.

The same drugs are recommended for the initial treatment of established VTE, but another is added to the list — tinzaparin (which is not available in the United States). For the long-term treatment of established VTE, the panel recommends dalteparin, enoxaparin, tinzaparin, or warfarin.

Novel oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and edoxaban, are now approved for VTE prevention and treatment in selected patients, but very few patients with cancer have been included in clinical trials of these agents.

"The use of these novel oral anticoagulants for either prevention or treatment of VTE in patients with cancer is not recommended at this time," the panel concludes.

J Clin Oncol. Published online May 13, 2013. Abstract

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