Chronotherapy: Cancer

by Food and Drug Administration (FDA)

(Page 2 of 2)

Animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully selected times.

"The data in animals are very compelling," says Gerald Sokol, M.D., an oncologist with the division of oncology in FDA's Center for Drug Evaluation and Research. However, he says, additional studies in humans are needed.

"There really aren't any controlled trials demonstrating that chronotherapy for cancer is important," says Robert Justice, M.D., deputy director of the division. "I'm not saying it can't be. I just don't think it's been demonstrated."

The studies so far suggest that there may be different chronobiological cycles for normal cells and tumor cells. If this is true, the goal would be to time the administration of cancer drugs to the chronobiological cycles of tumor cells, making them more effective against the cancer and less toxic to normal tissues, Sokol explains.

Before chronotherapy could become part of standard cancer treatment, Sokol adds, it would have to be determined whether there is an optimal time to give a drug.

Also to be determined would be how to handle the logistics of giving drugs at scattered times throughout the day and night. "Chronotherapy means we can't bring in all our cancer patients in the morning to receive their drug therapies," says Sokol, who also has a hospital practice in Tampa, Fla. "Some patients may be better served by getting their drugs late in the afternoon or even at night."

Portable infusion pumps may hold the answer. "The patient can be sent home with an implantable pump that will automatically distribute the drug at the appropriate time," he explains.

Cancer Surgery

The optimal timing of cancer surgery, particularly breast cancer, has also come under study. Some researchers believe that in premenopausal women, surgical cure of breast cancer is more likely if surgery is performed in the middle of a woman's menstrual cycle in the week or so following ovulation.

At the May 1996 International Conference on Breast Diseases in Houston, Umberto Veronesi, M.D., of the European Institute of Oncology in Milan, Italy, presented 20 years of follow-up data on nearly 1,200 premenopausal women who underwent surgery for breast cancer. Of patients who had surgery in the week following ovulation, 76 percent were tumor-free after five years, compared with 63 percent in patients who had surgery earlier in their menstrual cycle.

Many experts believe that any improved outcome is hormone-related. In the first half of the menstrual cycle, estrogen levels are high, and progesterone is not produced. In the second half, progesterone rises and estrogen falls. It is believed that progesterone may inhibit the production of some enzymes that help cancer spread.

However, some experts dispute the need to time breast cancer surgery according to the menstrual cycle. G.M. Clark, M.D., of the University of Texas Health Science Center at San Antonio, reported at the conference that retrospective analyses from at least 23 studies involving more than 6,000 patients failed to find any significant impact of the menstrual cycle division on breast cancer prognosis.

Regulatory Implications

Chronotherapeutics present new challenges to regulators and scientists alike. For example, according to FDA's Sokol, chronotherapeutic clinical studies need to consider additional parameters not usually required of other clinical trials. Among additional factors that must be considered, he says, are:

• time of day a drug is administered
• time-related biological factors, such as seasonal disorders (for example, seasonal affective disorder)
• patients' normal routines (for example, eating times and sleep patterns).

Making chronotherapy the focus of more clinical trials would be welcome news to many in the medical community, according to a 1996 American Medical Association survey. The study found that about 75 percent of the doctors surveyed said they would like more treatment options to match a patient's circadian, or daily, rhythms.

But chronotherapy has a way to go, considering that only 5 percent of the doctors surveyed said they were "very familiar" with the subject.

"Chronotherapy is not well recognized in the medical community," Sokol says, "but awareness is increasing. The implications are broad in every area of medicine."

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.