Seniors Can Find Standard Meds Hard to Swallow

Before a drug is approved for use in patients, researchers conduct large-scale trials to make sure it is safe and effective. But seniors are often underrepresented in these trials, an oversight that could mask age-related differences in how well the drug works and can be tolerated.

Cancer therapies experienced a tide-turning moment in late February when the U.S. Food and Drug Administration (FDA) approved an anticancer drug that works by stalling the growth of a tumor's blood supply--the first so-called angiogenesis inhibitor to get the federal green light. When administered with a traditional chemotherapy agent, the drug--called Avastin--can extend the life of people in advanced stages of colon cancer by 5 months. The finding has generated "a lot of excitement" in the clinical community, says oncologist William Li, president and medical director of the Angiogenesis Foundation in Cambridge, Massachusetts.

But blood-vessel growth naturally slows as people age, which leads researchers to wonder how well angiogenesis inhibitors will work in seniors. Although the clinical trials for Avastin included older patients, some scientists fear that the population that suffers most often from colon cancer--the 75-and-over set--was underrepresented. This failure to adequately enroll senior citizens in drug tests is a serious concern not just for cancer but for a range of disorders from heart disease to arthritis. Now some advocates are calling for legislation that will remedy this oversight, a step that would bring us closer to guaranteeing that the elderly receive treatments that are right for them.

Angiogenesis inhibitors such as Avastin slow cancer by obstructing the action of vascular endothelial growth factor (VEGF), a protein that tumors use to spark the growth of blood vessels that supply them with oxygen and nutrients. People over 60 produce up to 40% less VEGF in their muscle and other tissues than do those under 35, says physiologist Timothy Gavin of East Carolina University in Greenville, North Carolina. If their tumors also produce less VEGF--something that hasn't yet been determined--the difference could have implications for the action of drugs like Avastin. "The cell biologist side of me thinks that an equally matched tumor in an older person would be less responsive to the drug than the same tumor type in a younger person," says May Reed, a cell biologist and geriatrician at the University of Washington School of Medicine in Seattle. Then again, the opposite is also possible. "These drugs may also have a larger absolute benefit to older people because they have fewer blood vessels at the start," she says.

An ability to sprout new blood vessels is not the only age-related change that might affect the way seniors respond to therapeutics. Aging is accompanied by an increase in the relative amount of body fat. As a result, drugs that accumulate in fatty tissue, such as Valium, can be more potent in the elderly because the compounds take longer to clear from their system, Reed says. Conversely, the beta-blockers used to treat high blood pressure might not work as well in older patients because the cell-surface molecules to which the drugs bind become less effective with age, she says. And age-related changes in kidney and liver function influence how well all drugs are metabolized--and whether seniors experience adverse reactions.

But information about a drug's performance and safety for seniors is not always easy to find. Most clinical trials "woefully" underrepresent patients aged 65 and older, says gerontologist Robert Butler, president and CEO of the International Longevity Center--USA (ILC). Butler attributes skewed representation to a "widespread misperception" that older people do not want to participate in trials or are less likely to follow complex research protocols. Many are also excluded because of multiple, unrelated conditions that make it harder to interpret the effect of a drug. But this information about how well drugs work in the presence of other conditions and whether their side effects are tolerable is what's crucial for determining whether a drug is safe and effective for older patients, says cell biologist Jay Edelberg of Cornell University's Weill Medical College in New York City. Butler advocates enacting legislation that compels FDA to set regulatory standards for an appropriate proportion of older persons in clinical trials, similar to the recently passed Pediatric Research Equity Act of 2003. This law requires that drugs used by children include them in testing.

Participants in the decisive Avastin trial for colorectal cancer had a median age of 60, with 29% over the age of 65 and only 6% over the age of 75--a statistic that worries some researchers. "The average age of patients with colorectal cancer is 74," says oncologist Michele Basche of the University of Colorado Cancer Center in Denver, who is conducting a study on barriers that limit enrollment of elderly patients in clinical trials. So tests of Avastin for this cancer might warrant a specific effort to recruit from the affected age group.

The Avastin trials showed an improvement in survival in all patient subpopulations, including the elderly, says Dawn Kalmar, a spokesperson for Genentech, the South San Francisco company that produces the drug. But according to the information that FDA requires pharmaceutical manufacturers to provide to physicians and patients, there were too few participants over 65 to determine whether adverse side effects were more common or more severe in elderly patients. Researchers intend to fill this data gap by monitoring older patients who are currently receiving the drug and by continuing to enroll seniors in additional studies to determine whether adverse effects are more severe in this subpopulation, says oncologist Major David McCune of Madigan Army Medical Center in Tacoma, Washington, who led one of the pivotal Avastin trials.

Some researchers are even starting to organize drug trials in which all the participants are over 65. Such studies have become more common with last year's launching of the Integrating Cancer and Aging initiative, sponsored jointly by the National Institute on Aging and the National Cancer Institute. The program supports eight new centers that will try to identify the factors that interfere with older patients' participation in clinical trials and to determine how age-related differences in physiology affect the ways various chemotherapy drugs act and are tolerated.

The study of how the elderly respond to drugs will begin to take off as baby boomers hit their retirement years, projects ILC's Butler. "The sheer fact of the size and political power of the aging population will demand safe drugs for cancer, diabetes, and Alzheimer's dementia that have been specifically tested on older people," he says. Although boomers are not yet marching on Washington to demand inclusion in drug trials, Butler, for one, says it might just be a matter of time.

Erica Goldman is an almost-30-something freelance writer in Silver Spring, Maryland. She thanks the soon-retiring baby boomers in advance for paving the way to safer drugs and plans to reap the benefits in due course.