For certain nonmalignant diseases, just the act of giving patients what they believe to be a drug can lead to improvements in their symptoms. This so-called placebo effect has been shown to relieve postoperative pain and to reduce anxiety and depression.
In cancer, some studies have found that patients taking a placebo sometimes experience a reduction in pain and other cancer-related symptoms. However, the question remains whether there is a true "placebo effect" in cancer patients, either for the symptoms of cancer or for the disease itself.
In a review article in this issue of the Journal (see p. 19), Giséle Chvetzoff, M.D., of the Centre Léon Bérard in Lyon, France, and Ian F. Tannock, M.D., Ph.D., of the Princess Margaret Hospital in Toronto, found that placebos were sometimes associated with improvement in symptoms such as pain and appetite but rarely associated with positive tumor response. After examining placebo responses in 37 randomized, placebo-controlled trials, they concluded that any substantial improvement is unlikely to be the result of the placebo effect.
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Tannock added that if they had found a big effect of placebos in oncology, it would have made the demands on clinical trial design even more rigorous. "Any trial really would need to have a placebo [control group]," he said in an interview.
Robert Temple, M.D., of the FDAs Center for Drug Evaluation and Research, pointed out in an accompanying editorial (see p. 2) that there were individual responses to placebos in symptoms such as pain and appetite and that these changes should not be overlooked. He said that as a general matter, the FDA has been extremely skeptical about accepting as evidence of a drug effect in single-arm trials anything other than tumor responses. The findings by Chvetzoff and Tannock are "consistent with what weve been thinking," he added in an interview.
In addition, Chvetzoff and Tannock said that they strongly support the use of a double-blind, placebo-controlled design for randomized trials whenever appropriate because such trials can ensure equal conditions in both arms and minimize investigator bias. "If you can use a placebo in your trial and youre not causing patients any substantial problems, its better to design your trial like that," Tannock said in an interview.
Clinical Trials
The topic of when placebos are appropriate in clinical trials is an area of growing interest. In March 2002, the Canadian Institutes of Health Research held a national conference to address just this issue. One topic up for discussion was the use of placebos in clinical trials of cancer.
Joseph Pater, M.D., director of the Clinical Trials Group at the National Cancer Institute of Canada pointed out in his talk at the conference that placebos can play a prominent role in trials evaluating time-to-disease progression as an endpoint.
But until recently, researchers have had a hard time blinding placebo-controlled studies because many cancer drugs have toxic side effects that placebos cannot mimic, Pater said in an interview. As a result, investigators quickly figure out who received the active drug and who did not.
With the development of new oral drugs that have fewer side effects, blinding may become easier. "My opinion is that there is and will be a growing use of placebos in cancer clinical trials," Pater said.
New cancer treatment drugs are tested against a placebo only when best supportive care is the standard treatment option. But placebos are particularly useful in trials of new chemopreventive agents, a rapidly growing area of drug development. In the Breast Cancer Prevention Trial, 13,000 women at increased risk of breast cancer were randomly assigned to take a placebo or tamoxifen every day for 5 years. When preliminary data revealed that women taking tamoxifen experienced almost a 50% decrease in breast cancer risk compared with women taking a placebo, the trial was halted and women in the placebo group were given the opportunity to take tamoxifen.
A recent study illustrated the importance of placebo control in prevention studies. In the November 21 issue of the New England Journal of Medicine, researchers randomly assigned 2,392 young women to receive either a vaccine for the human papillomavirus 16 (the virus that causes cervical cancer) or a placebo. By the end of the study, nine women had developed HPV-16-related cervical intraepithelial neoplasia; all nine had received a placebo. Had there been no placebo group, it would have been more difficult to know whether the vaccine actually prevented women from becoming infected with HPV or whether the investigators simply chose a low-risk population.
One concern with placebo-controlled trials is that patients are often reluctant to enroll in such trials for fear that they will receive the sham treatment. To get around that, Keegan urges physicians to educate patients about the purpose of placebo-controlled trials.
"I think its the job of the physician who runs the trial to explain to the patient why we think its important, why they shouldnt presume that the drug is doing something before we actually know the answer," she said.
Clinical Use
Outside of clinical trials, some physicians and nurses have admitted to using placebos to see if a patients pain is real. A 1979 survey of placebo use found that 47 of 60 physicians and 32 of 39 nurses who responded to the survey had either ordered or administered at least one placebo medication for relief of pain.
In an effort to end this deceitful practice, the Oncology Nursing Society in 1997 developed the first position statement saying that "placebos should not be used in the assessment and management of cancer pain." Since then, 27 other professional organizations have endorsed the statement and several institutions have policies against the use of placebos in clinical practice.
Despite the efforts, Margo McCaffery, R.N., a consultant in the care of patients with pain, said that she does not think that the situation has changed very much. While the prevalence of placebo use for this purpose today is unknown, McCaffery said that she believes that the practice continues.
In 1992, McCaffery and her colleagues conducted a survey, which found that of 150 U.S. nurses surveyed, 16% believed that placebos could be used for assessing cancer pain. In a separate survey of 601 nurses, 26% reported use of placebos in their workplaces and 18% reported administering placebos themselves.
The problem with pain and other cancer-related symptoms, such as fatigue and depression, is that they are subjective and no tools can effectively quantify these symptoms.
"What we need to do is to continue to educate professionals and make available the existing position statements, point people toward the guidelines and have greater professional awareness that placebos are unethical in clinical practice," said Betty Ferrell, Ph.D., an oncology nursing expert at the City of Hope Cancer Center in Duarte, Calif.
But there is evidence that placebos can produce measurable changes in a patients physiology and enhance response to treatment. In fact, Chvetzoff and Tannock found that patients in placebo groups sometimes experienced an improvement in their symptoms. In trials that looked at individual response to placebos, up to 21% of patients showed improvement in pain or decreased intake of pain medications, and up to 27% of patients showed an improvement in appetite.
But such effects do not need to come from placebos. They can come from simple actions like saying the right things to build a patients confidence in the treatment, noted Kristine Kwekkeboom, Ph.D., of the University of Iowa.
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Exactly how placebo effects are brought about remains a mystery. Researchers are examining several mechanisms, including the release of chemical endorphins in the brain. In November 2000, the National Institutes of Health hosted a conference on the Science of the Placebo; one of the topics explored was mechanisms for placebo effects. Conference participant Michael Stefanek, Ph.D., of the Behavioral Research Program at the National Cancer Institute, noted that are now new imaging technologies that may be able to track placebo effects in the brain. "Thats something weve never been able to do before and probably will also spur interest in the placebo effect," he said. "Theres a lot of fascinating work to be done and a lot to be learned."
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