Incorporating Platelet Growth Factors Into Guidelines

FORT LAUDERDALE, Fla--Recently, the FDA approved recombinant interleukin-11 (rIL-11 or oprelvekin, Neumega) for the prevention of severe thrombocytopenia in cancer patients with solid tumors or lymphoma. The availability of platelet growth factors represents a significant breakthrough in oncology, and methods are needed to help incorporate these agents into clinical practice guidelines.

Linda Elting, DrPH, and Edward B. Rubenstein, MD, of the University of Texas M.D. Anderson Cancer Center, addressed this issue at the third annual conference of the the National Comprehensive Cancer Network (NCCN), a coalition of 16 leading US cancer centers.

The first step toward writing guidelines for platelet factors is the development of predictive models to identify patients at risk of thrombocytopenia who would most benefit from their use. Drs. Rubenstein and Elting have been working on such a model.

Dr. Elting said that approximately one-quarter of patients with solid tumors undergoing chemotherapy develop throm-bocytopenia, defined as a platelet count less than 50 × 109/L; about 10% to 15% experience platelet counts below 20 × 109/L. Half of all patients whose platelet levels fall below 20 × 109/L experience bleeding, she added.

"In our study," Dr. Elting said, "serious clinical events occurred in 15% of patients who developed chemotherapy-induced thrombocytopenia, including 43 cases of major hemorrhage."

The depth and duration of throm-bocytopenia correlated to the development of serious clinical events, she said. Patients experiencing fewer than 7 days of thrombocytopenia had a 10% risk of any event, while patients whose throm-bocytopenia persisted more than 2 weeks had a 60% risk.

Logistic regression was used to identify patients at high risk for serious clinical outcomes related to thrombocytopenia. Significant risk factors include a previous history of bleeding, a baseline platelet count less than 75 × 109/L, the presence of bone marrow metastases or a necrotic tumor site, a baseline Zubrod score greater than 2 (a measure of performance status), and chemotherapy regimens highly toxic to the bone marrow.

"Because of their high risk," Dr. Elting said, "patients who fit this clinical profile may derive great benefit from platelet growth factors, and these findings may be useful in targeting guidelines to those patients who are most likely to benefit."

Reduces Platelet Transfusions

Several thrombopoietic growth factors are undergoing clinical investigations, but oprelvekin is the only one currently approved for managing chemotherapy-

induced platelet depletion. Dr. Rubenstein reported that oprelvekin has been shown to be safe and effective in reducing the need for platelet transfusions in placebo-controlled trials of patients with solid tumors receiving dose-intensive chemotherapy; 68% of oprelvekin recipients avoided transfusion altogether, compared with 41% of those who received placebo.

Adverse effects associated with oprelvekin, which included peripheral edema, dyspnea, tachycardia, and conjunctival redness, were mild to moderate in severity. Edema appears to be a clinical problem, Dr. Rubenstein noted, but it tends to be mild and self-limited. Due to fluid retention, some patients taking oprelvekin will require diuretic therapy. In addition, pleural effusions have been known to develop, and some shortness of breath may occur.

Approximately 10% of patients were noted to develop tachycardia. "This is thought potentially to be due to fluid retention leading to atrial tachyarrhyth-mias," Dr. Rubenstein said.

The philosophy behind the NCCN’s practice guidelines is logical and straightforward. "In guideline development," Dr. Rubenstein explained, "we would like to identify the therapeutic alternatives and the costs and outcomes associated with them."

The options for managing chemotherapy-induced thrombocytopenia prior to the introduction of platelet growth factors, he stated, were to transfuse platelets after a patient with thrombocytopenia started bleeding or after the platelet count fell below a certain threshold.

The availability of oprelvekin offers clinicians another alternative. When considering its use, however, the question arises of whether to (1) administer growth factors as primary prophylaxis in patients likely to develop significant thrombocyto-penia or (2) administer them as secondary prophylaxis in patients who have already experienced severe platelet depletion in a previous cycle of myelosup-pressive therapy.

"We need to model these different strategies as we develop our guidelines and work out the costs of each," he said.

Finally, Dr. Rubenstein reminded the audience not to forget the patient. "Patients have preferences for outcomes, and clearly there are quality-of-life issues in evaluating new technology," he said.

Patients with thrombocytopenia often fear physical contact and physical activity, which can affect productivity and their ability to work and conduct the activities of daily living. Further, delays in chemotherapy or dose reductions in subsequent cycles due to thrombocyto-penia may significantly hamper a patient’s ability to receive optimum treatment.

Dr. Rubenstein pointed out that much work lies ahead in the development of guidelines for the use of platelet growth factors, and that "more research is needed before we’re ready to have a fully robust guideline. The first thing to do is gain experience using new products and consider using them in patients who are likely to benefit."