An advisory committee to the Food and Drug Administration (FDA) has recommended that the agency consider adding new restrictions on the use of antianemia drugs in cancer patients with chemotherapy-induced anemia. The advisory committee's May 10 meeting was the most recent stage for debate about what has become a matter of significant concern: whether use of a blockbuster class of drugs that reduces the need for blood transfusions in the estimated 450,000 cancer patients who receive them annually could be putting them at a greater risk of death.

None of the recommendations offered by the agency's Oncologic Drugs Advisory Committee (ODAC) were highly specific. The committee did, however, advise FDA to evaluate all available and forthcoming data to determine if the use of these drugs, often called erythropoiesis-stimulating agents (ESAs), should be limited in patients with certain tumor types; whether a specific hemoglobin level to trigger the drugs' use in asymptomatic patients should be established; and whether limits should be placed on their use within a certain time frame after chemotherapy is completed.

ODAC Chair Dr. S. Gail Eckhardt, from the University of Colorado Health Sciences Center, stressed that the committee should not be looking to return to the "dark ages" when transfusions of red blood cells were the primary supportive care options for anemic cancer patients. Rather, she said, the goal was to determine how to "move forward" given the safety concerns about ESAs prompted by several clinical trials completed over the last 4 years.

The results of one of those trials were presented just 3 weeks ago at the American Association of Cancer Research (AACR) annual meeting. The nearly 1,000-patient phase III, double-blind, randomized, placebo-controlled clinical trial - called the "103 study" - showed an increased mortality risk in cancer patients with a variety of tumor types who were given the ESA darbepoetin alfa (Aranesp), one of two FDA-approved ESAs manufactured by Amgen.

In early March, based largely on the 103 study results and some preliminary data from a Danish trial called DAHANCA 10 that suggested safety concerns, the FDA, among other measures, issued a public health advisory and added a new "black-box" warning to the ESAs marketed in the United States.

Of the clinical trials that have shown an increased mortality risk, only the 103 study's protocol called for using ESAs to achieve the hemoglobin level called for on the drugs' labels, 12 g/dl, explains the trial's lead investigator, Dr. John Glaspy from the UCLA Jonsson Comprehensive Cancer Center. The other ESA clinical trials that have shown a mortality risk were all designed to achieve hemoglobin levels in the 13 to 15 g/dl range - what Amgen representatives referred to as "beyond anemia correction" studies; in two of the trials, patients did not even have to be anemic to enroll.

The 103 study, which did not have survival as its primary endpoint, was also different from the other trials because it involved patients whose anemia was associated with their underlying cancer, for which no benefit of an ESA has been established.

"It's very appropriate to be cautious and do the additional work to run this down, because it's a patient safety issue," says Dr. Glaspy, who also spoke during the meeting on Amgen's behalf. "But I believe that at the end of the day, when used the way we've been using these drugs in oncology, they will be safe."

Amgen representatives also presented preliminary data from the recently completed, 600-patient "145 study," a randomized, double-blind trial in which patients with small-cell lung cancer were treated to a hemoglobin target of 13 g/dl. Patients treated with darbepoetin alfa had equivalent overall and progression-free survival compared with those given placebo.

Although the design and conduct of most of the trials that have exhibited a safety concern have come under intense criticism, says Dr. David P. Steensma from the Division of Hematology at the Mayo Clinic, "I think we have enough evidence now to suggest there is a problem."

During the meeting, ODAC members expressed dismay at the lack of simple trials involving ESAs with a progression-free or overall survival endpoint and the lack of data on ESAs' effects on tumors. They also criticized the direct-to-consumer TV ads for ESAs that suggest they improve problems like fatigue and quality of life, which are unapproved indications in the United States.

By Carmen Phillips