Breath test shows if chemo dose is correct for individual - works for Taxotere
Uses Antibiotic, FDA Puts on Fast Track

April 24, 2000 - Taking chemotherapy for cancer and coping with the typical side effects is a big enough challenge without having to worry that the treatment may make you acutely ill and even kill you.

Standard doses of chemotherapy for prostate cancer and other solid tumors have killed some patients whose livers did not clear the drug at the normal rate. Despite ordinary liver function tests, doctors had no way of telling beforehand which patients might have this trouble.

Now, a North Carolina physician has invented a simple test to distinguish between patients who metabolize docetaxel (brand name Taxotere) normally and those who need lower doses for safety.

Docetaxel is one chemotherapy being tested and used for advanced prostate cancer as well as for other cancers. Researchers say the acute toxicity test might work for other chemotherapy agents 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 at University of North Carolina's Chapel Hill 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."

At the other end of the "normal" response scale, patients whose livers clear a chemotherapy rapidly may not get a dose strong enough to be effective against their cancer, he said. This test will help the patient's oncologist adjust the dose without waste of precious time on ineffective dose levels while the disease progresses.

"Breathalyzer" Using Common Antibiotic

What Watkins has invented is a simple breath test using a non-toxic drug. Patients preparing to take the chemotherapy take a trace dose of the common antibiotic erythromycin. Doctors measure the amount of carbon dioxide they breath out.

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.

The liver uses the same enzyme system, or pathway, to clear docetaxel as it does to process erythromycin. The antibiotic test gives an accurate prediction of how the patient's liver will handle Taxotere.

To see if this really works, investigators took blood samples from 21 cancer patients several times over 24 hours to find out how fast their livers cleared the docetaxel (Taxotere) and compared those results with results from a measurement of the patients' breath. The breath test takes about twenty minutes.

"We didn't look at the data until the study was over," Watkins 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," he said, "where it looks like it will work."

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.

A report on the new study appears in the April 2000 issue of Clinical Cancer Research. Besides Watkins, authors include Drs. JoAnn Hirth, Myla Strawerman, Anne Schott and Laurence Baker of the University of Michigan.

Money for the study came from a General Clinical Research Center grant from the National Institutes of Health.

Dr. Watkins won The American College of Clinical Pharmacy 1998 Therapeutic Frontiers Award. The National Institutes of Health recently gave him a MERIT award.