December 7, 2008 (San Francisco, California) — Cancer patients receiving chemotherapy are known to be at high risk for thromboembolic events, but at present little is done about this. Now a large trial showing that prophylaxis with an anticoagulant can halve this risk, presented here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition, might encourage oncologists to think about taking some action.

“I really hope so,” commented Giancarlo Agnelli, MD, from the University of Perugia, Italy, who presented the new results at a plenary session. “We have shown a clear benefit from prophylaxis. There is a remarkable reduction in risk from thromboembolic events, and the price to pay in terms of side effects is extremely low.”

The results come from PROTECHT, a placebo-controlled study of nadroparin (Fraxiparine, Sanofi) for the prophylaxis of thromboembolic events in more than 1000 cancer patients receiving chemotherapy. The drug is a low-molecular-weight heparin derivative, and is a “traditionally used drug that has been available for many years,” Dr. Agnelli said.

“From a clinical point of view, the advantage is there, and so I hope this will lead to an increased use of prophylaxis,” Dr. Agnelli commented at an ASH press conference. Other experts present agreed with the sentiment, and moderator J. Evan Sadler, MD, from the Division of Hematology at Washington University, in St. Louis, Missouri, said the trial was potentially practice changing.

Currently, there is very little use of prophylaxis for thromboembolic events among cancer patients, they both acknowledged, and they noted that routine use of prophylaxis in cancer patients is not recommended in clinical guidelines.

It can be considered for immobilized patients and those undergoing surgery, but not for ambulatory cancer patients, Dr. Sadler commented. “There has been some resistance from clinicians,” he said, and also some concern about the use of an anticoagulant, because cancer patients are thought to be at increased risk for bleeding and thromboembolic events. Oncologists focus on treating the cancer, quite rightly, but “we have to look beyond that,” he said.

Currently, “oncologists are in the situation that orthopedic surgeons were in about 15 years ago,” said Alexander Turpie, MD, from McMaster University, in Hamilton, Ontario. At that time, they were focused on correcting the orthopedic problem and did not think about thrombosis; in fact, they were relatively unaware that this was a problem in their patients, he told Medscape Oncology. But several large trials and physician education efforts changed this stance, and prophylaxis is now commonly used in orthopedic surgery. A similar effort is need to increase awareness of the problem in cancer patients, Dr. Turpie said, especially as the risk for thromboembolic events “skyrockets” with some of the newer drugs, such as vascular endothelial growth-factor inhibitors like bevacizumb.

Risk for Clinical Thromboembolic Event Was Halved

PROTECHT was conducted in 1166 patients with metastatic or locally advanced cancer, and they were randomized 2:1 to receive nadroparin or placebo, both administered by subcutaneous injection.

The primary outcome of the study was a clinically overt thromboembolic event, either venous or arterial, which included deep vein thrombosis of the upper and lower limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infraction, ischemic stroke, acute peripheral thromboembolism, and unexplained deaths of possible thromboembolic origin.

The risk of having 1 of these events was nearly halved, from a rate of 3.9% in the placebo group (15 events in 381 patients) to a rate of 2.1% in the nadroparin group (16 events in 769 patients). The relative risk reduction was 49.6%, with an interim-adjusted P value of .024, Dr. Agnelli told the meeting.

The incidence of minor bleeding was similar in both groups — 7.4% with nadroparin and 7.9% with placebo — and the risk for a major bleed was increased only slightly in the nadroparin group (5 episodes in 769 patients; 0.7% vs 0% in the placebo group.).

I strongly believe that the clinical benefit is there.

For the overall patient population, the number needed to treat was 50, whereas the number needed to harm was 200 (i.e., 50 patients would need to be treated to prevent a thromboembolic event, and 200 to see a bleeding event). Because of these figures, “I strongly believe that the clinical benefit is there,” Dr. Agnelli commented.

The patients involved in the PROTECHT trial had a variety of solid tumors: 279 patients had lung cancer, 235 had colon cancer, 165 had breast cancer, 143 had ovarian cancer, 98 had stomach cancer, 87 had rectal cancer, 53 had pancreatic cancer, 36 had head and neck cancer, and 54 had other cancer. The largest groups were lung (25%) and gastrointestinal (35%) cancer.

Dr. Agnelli noted that patients with lung cancer and those with pancreatic cancer appear to be particularly at risk for thromboembolic events. Among pancreatic cancer patients, the overall risk was 7.3%; it was reduced from 8.3% with placebo (3 events in 36 patients) to 5.8% with nadroparin (1 event in 17 patients). In lung cancer patients, the risk was 8.8% with placebo and 4% with nadroparin. For this subgroup of lung cancer patients, the number needed to treat was 18 to prevent 1 event.

“These results provide proof of concept that thromboembolic events can be prevented in ambulatory cancer patients receiving chemotherapy,” Dr. Agnelli concluded. He suggested that future studies should focus on the patient populations identified as being at high risk (i.e., lung and pancreatic cancer patients).

Dr. Agnelli has disclosed no relevant financial relationships. One of the coauthors, Carlo Bianchini, MD, is an employee of Italfarmaco. Dr. Sadler reports consultancy work for Baxter Healthcare. Dr. Turpie reports consultancy and honoraria from Bayer and Johnson & Johnson.

American Society of Hematology meeting. Abstract 6. Presented December 7, 2008.


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