CHAPEL HILL, NC -- April 24, 2000 -- Battling
cancer is traumatic enough without worrying about whether chemotherapy will
prove toxic, but that's the added risk facing a minority of cancer patients.
Standard doses of chemotherapy -- often effective in treating various solid tumors -- sometimes kill people whose livers cannot clear the drug at the normal rate. Doctors can't tell beforehand which patients might have trouble with the treatment.
Now, a new study shows a relatively simple technique pioneered by a University of North Carolina at Chapel Hill, physicians can distinguish between patients who metabolize one anti-cancer drug normally and those who need to receive lower doses for safety. Researchers say the approach might work for other chemotherapy agents and perhaps other non-cancer drug treatments as well.
"When you take a drug like aspirin or Tylenol, the reason you need to take it again in four to six hours is that your body has chewed it up and gotten rid of it through a certain chemical pathway in the liver," said Dr. Paul B. Watkins, professor of medicine and director of the Verne S. Caviness General Clinical Research Center at the UNC-CH School of Medicine. "Because of diet, genetics and other factors, some people just metabolize drugs a lot more slowly. As a result, the recommended dose of many chemotherapies will predictably make about 10 percent of patients very ill, and 1 or 2 percent of patients may die as a direct result of the treatment."
Conversely, patients whose livers clear a given chemotherapy rapidly may not get a dose strong enough to be effective against their cancer, he said.
A report on the new study appears in the April issue of Clinical Cancer Research, a medical journal that has just been released. Besides Dr. Watkins, authors include Drs. JoAnn Hirth, Myla Strawerman, Anne Schott and Laurence Baker of the University of Michigan.
Investigators took blood samples from 21 cancer patients several times over 24 hours to determine how fast their livers cleared the drug docetaxel and compared those results with results from a measurement of the patients' breath. In the latter 20-minute test, which Watkins developed and patented, doctors give patients a trace dose of the common antibiotic erythromycin and measure the amount of carbon dioxide they exhale.
Higher concentrations of exhaled carbon dioxide mean that patients are metabolizing erythromycin more quickly, and lower concentrations mean they are metabolizing it slower, Watkins said. That's important because the liver uses the same enzyme system, or pathway, to clear docetaxel as it does to process erythromycin.
"We didn't look at the data until the study was over," the physician said. "Among other things, we found that the two patients who got very ill and had to be hospitalized showed the lowest test results and the lowest enzyme activity."
In an accompanying editorial, Dr. Jerry M. Collins, director of the Laboratory of Clinical Pharmacology at the U.S. Food and Drug Administration, said the new test, which builds on a tradition of using breath tests as indicators of liver function, has multiple promising advantages.
"It is rapid, relatively noninvasive, requires only a single time point and can be used prospectively before dosing," he said. "Because of the narrow therapeutic range of anticancer drugs, lowering the likelihood of toxicity in the patients at greatest risk is a useful contribution."
Watkins said that while it is not proven yet, some other forms of chemotherapy likely employ the same pathway measured by his breath test. Even if they do not, comparable simple tests probably can be developed that will help protect patients treated with drugs metabolized via different enzymes.
"This is exciting because it is the first example in cancer where it looks like it will work," he said.
A General Clinical Research Center grant from the National Institutes of Health supported the study of docetaxel, commercially known as Taxotere.
A larger study is now underway at the University of Michigan to confirm the results of the new erythromycin breath test, or ERMBT. UNC-CH physicians already have begun using the technique in studies. The latter also have been investigating it for its usefulness in dosing drugs used to treat malaria.
The American College of Clinical Pharmacy presented its 1998 Therapeutic Frontiers Award to Watkins for his original research, and the National Institutes of Health recently gave him a MERIT award.