By Rafat Abonour, MD

2008-12-08

We heard yesterday in the Plenary Session about the Prophylaxis of Thromboembolic Events in Cancer Patients Receiving Chemotherapy (PROTECHT) trial, which is the first randomized controlled trial to show that a low-molecular-weight heparin (LMWH) is effective at reducing the risk of symptomatic thrombotic events in patients receiving chemotherapy for selected groups of solid tumors. It is fitting to have Dr. Giancarlo Agnelli, of the University of Perugia in Umbria, Italy, present his work that has spanned more than three decades. The work presented in the Plenary abstract (#6) was successful, unlike several other studies that have asked the same question but have reported negative results. Moreover, it is important to note that these previous studies only looked at reduction of venous thromboembolic events, whereas PROTECHT used a combination endpoint of arterial and venous events.

PROTECHT was designed to evaluate the efficacy of the LMWH nadroparin for prophylaxis of thromboembolic events in cancer patients receiving chemotherapy. Patients with metastatic or locally advanced lung, breast, gastrointestinal, ovarian, or head and neck cancer with an ECOG performance status ≤ 2 were included in the study. Patients on adjuvant or neo-adjuvant therapy were excluded from the study. Eligible patients were randomized in a 2:1 ratio to receive subcutaneous injections of nadroparin (3,800 anti-Xa IU) once daily, or they received a placebo. Treatment was started on the day of initiation of the first cycle or a new course of chemotherapy and planned for the overall duration of chemotherapy or up to a maximum of four months. The primary study endpoint was the composite of clinically overt venous or arterial thromboembolic events. The average study treatment duration was about three months in both groups. One thousand one hundred and fifty (1,150) patients received at least one dose of the study treatment. Sixteen of the 769 patients treated with nadroparin (2.0%) and 15 of the 381 patients treated with placebo (3.9%) had a thromboembolic event with a relative risk reduction of 47.2 percent. Venous thromboembolism accounted for 11 events in both the nadroparin and placebo patients. Fifteen of the thromboembolic events occurred in patients with lung cancer (3.5% and 8.8% in nadroparin and placebo patients, respectively). Pancreatic cancer was associated with an overall rate of thromboembolic events of 7.5 percent. Five patients in the nadroparin group (0.7%) and none in the placebo group suffered major bleeding. The incidence of minor bleeding was similar in the two treatment groups.

Dr. Agnes Y. Y. Lee, of the University of British Columbia in Vancouver, who introduced the abstract, noted that the PROTECHT trial comes 14 years after the first and only randomized trial that showed adjusted dose warfarin provided protection against symptomatic venous thromboembolic events in women receiving chemotherapy for metastatic breast cancer (Levine, et al. Lancet. 1994;343:886-9). Despite the positive results from the Levine trial, primary prevention with warfarin has never been incorporated into standard practice. This is partly due to the difficulty with warfarin usage, including the need for laboratory monitoring and frequent dose adjustment, difficulty with rapid reversal of the anticoagulant effect in patients receiving chemotherapy, and questionable benefit in patients with other tumors, since the study was limited to patients with breast cancer.

Because PROTECHT studied a LMWH, which requires daily subcutaneous injections (not attractive to patients) and is costly in North America, it also has a number of obstacles in achieving practice-changing status. Dr. Lee added that the lack of consistent benefit across all tumor types studied and a slightly higher incidence of bleeding in the LMWH group may also dampen enthusiasm to adopt this as standard practice.

Regardless, the PROTECT study is an important step in the right direction. The study may raise more questions than it answers. But, one of the best things about scientific advancement is that there is always more to learn!

Dr. Abonour indicated no relevant conflicts of interest.

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