Clinical Trials and the "Therapeutic Misconception"

Faced with a dire prognosis, some cancer patients turn to clinical trials. But how well do they, or their doctors, understand the purpose of such trials? Not very, according to a recent survey {Lancet 2001;358:1772-77}. Oncologists questioned 240 participants in treatment-related clinical trials. Half had either relapsed or progressive disease, and two-thirds had been told they had less than a ten percent chance of surviving five years. Most patients felt that they had read the informed consent form carefully and had received adequate explanations. Yet this survey found that patients enrolled in clinical trials at Boston's top cancer hospitals generally misunderstood the purpose and potential benefit of such trials.

Seventy percent did not realize that the treatment being researched had not been proven to be the best treatment for their cancer. Half did not understand that the trial used non-standard treatments or procedures or that participation might carry incremental risks (63 percent). Many did not understand that they might not receive any direct medical benefit from their participation or that the purpose of a clinical trial was to benefit future patients, not themselves. They suffered from what the authors call the "therapeutic misconception," i.e., that clinical trials are designed to benefit those who enroll in them.

Such misconceptions were shared by many of their physicians, more than half of whom did not realize that the goal of trials was to benefit future patients. Other studies show a widespread pattern of misunderstanding among patients taking part in clinical trials and the doctors who refer them. Institutional Review Boards (IRBs) are supposed to protect patients from unethical practices. But in one Midwestern survey, only a third of principal investigators provided a detailed description of proposed studies to review boards, and a meaningful discussion of risks, benefits, and alternatives, was virtually non-existent {J Clin Ethics 1996;7:60-68}.

In a survey of cancer consultations, 83 percent of patients were never questioned to make sure that they understood what had been told to them. Before enrolling, patients have to sign "informed consent" forms. But, in one survey, the average time spent explaining the new treatment and getting consent was 10 minutes {Eur J Cancer 1999;35:1187-93}.

Where do these widespread misconceptions come from? I think they originate with health authorities who vigorously promote clinical trials. Most of what I read about the alleged benefits of clinical trials is misleading. For example, the National Cancer Institute lists various reasons to participate in clinical trials. Here is one of their top reasons: "Access to new drugs and interventions before they are widely available." This implies a therapeutic benefit to the current patient. They also state that "if the approach being studied is found to be helpful, you may be among the first to benefit." The very last thing mentioned is "an opportunity to make a valuable contribution to cancer research."

Yet, medical ethicists tell us that an altruistic desire to help future generations of patients is the primary reason to participate in a clinical trial. Deriving personal benefit, much less a cure, is so remote that you could sooner win the Powerball lottery. There is a strong temptation to talk about personal benefit, since the number of self-sacrificing martyrs to science has always been rather small.

Patients who are confronting advanced cancer should first of all learn what are the best state-of-the-art treatments. They should not enroll in clinical trials to please a favorite physician, since she herself may not understand the low probability of benefit. Sometimes, more promising treatments are available in specialized treatment centers than in hometown facilities. Second, patients should explore all viable alternative treatments, including those that are only available abroad. Finally, they should always cast a cold eye at clinical trials. Phase I trials are dose-escalation trials, which deal with unproven agents at unknown doses.

Conversely, phase III trials deal with better understood agents, but are by their nature randomized. Patients only have a coin-toss chance of receiving the desired treatment. Phase II trials are more promising since at least a reasonably safe and effective dose is known. There is no randomization and there may be some preliminary evidence of benefit. But patients should not enter any clinical trial that precludes them from taking other promising alternative treatments, as well. Their doctors should help them avoid the "therapeutic misconception" that is so rampant.

Adjuvant Radiation for Patients with Rectal Cancer?

A recent systematic overview of randomized trials of adjuvant radiotherapy for rectal cancer has yielded important insights {Lancet 2001;358:1291-1304}. It clearly shows that neither preoperative nor postoperative radiation therapy has any appreciable effect on overall survival in patients with this disease. Patients who received postoperative radiation therapy did have a 9 percent lower risk of death from rectal cancer than did the controls. But this survival advantage was all but wiped out by the more frequent deaths from other causes in the radiation therapy group. Overall, the risk of death from causes other than rectal cancer was 15 percent higher in those who received radiation therapy than in those who did not. This was statistically significant.

The authors state that "there was no clear benefit of radiotherapy in respect of overall survival." Yet B. D. Minsky, in his accompanying editorial, believes that these results "give support to adjuvant radiotherapy for rectal cancer" {Lancet 2001;358:1285-86}. That is because preoperative radiation therapy did decrease the chance of a recurrence at five years by 7 percent. The article's authors also believe that since "uncontrolled local recurrence can have a devastating effect on a patient's quality of life improved local control with radiotherapy might be a sufficient benefit to justify its use."

Yes, uncontrolled local recurrences are devastating. But so too are excess deaths caused by radiation therapy, such as through cardiovascular disease, infections and mysterious "unknown causes." Neither article nor editorial mentions that the side effects to the bowel of radiation therapy can devastate one's quality of life. Patients receiving radiation therapy for rectal cancer have more chronic bowel dysfunction compared to those who undergo surgical resection alone {Annals of Surgery 1994;220:676-82}. Diarrhea, bleeding, tenesmus (painful spasm of the anal sphincter), and pain on defecation are frequent during therapy.

These symptoms commonly subside when treatment stops. But six months to a year or more later, delayed post-radiation symptoms may develop. Here is a description of these late effects from a recent textbook: "There may be two to four or even eight or more bowel movements a day, and the urgency may be compelling. Blood is also often seen. Tenesmus is frequent, and cramping pain is often associated with defecation. Radiation proctitis frequently is associated with pain and bleeding; the latter may be severe and persistent, occasionally requiring transfusions. Severe or complete obstruction may develop."

Any evaluation of radiation therapy must take into account not just the statistical effect of treatment on recurrences, but what patients actually experience as a result of the therapy. What patients and their families need is the complete picture, of costs as well as benefits, without which it is impossible for them to make educated treatment decisions. But how many rectal cancer patients, we wonder, are told that adjuvant radiation therapy has not been proven to extend life but may in fact cause serious short and long-term adverse effects? How many are told that adjuvant radiation may in fact lead to their untimely deaths?

A Bowl of Cherries...and Antioxidants

Singer Rudy Vallee used to croon: "Life is just a bowl of cherries." I always wondered, "Why cherries? Why not plums, pears, or persimmons?" No longer. Scientists are now proving that the cherry (particularly the tart cherry, Prunus cerasus) contains a host of marvelous compounds that fight diseases, including cancer.

The cherry is of course a harbinger of spring, its deep-colored fruit among the best of summertime treats. The tart cherry is a hardy and attractive planting. Despite its name (sometimes also called "sour cherry"), it is a delightfully pungent fruit to eat. My neighbor, Jan W., has a magnificent tart cherry tree in her front yard. The soil is not rich yet in good years she feasts off that tree, about 7,000 cherries in a good season! Tart cherries are only "sour" in comparison to sugary sweet cherries. The top tart cherry species in the US is the Montmorency, but recently, Dr. Amy Iezzoni of Michigan State University discovered another variety, called the Balaton, named for Hungary's largest lake. Balaton cherries are sweeter, larger and firmer that the Montmorency. Its juice is more highly colored, making it great for preserves.

For centuries, the cherry, either as bark, root or fruit, has been a source of medicine for indigenous peoples. Native Americans prized cherries as pain relievers, especially for sore throats. The Cherokees used an infusion of sour cherry bark to treat laryngitis. The Ojibwa used the crushed root for stomach pain. The Forest Potawatomi employed an infusion of the inner bark to alleviate internal pains while the MicMac used black cherry fruit as a health tonic. I suspect that the cherry flavoring of most cough medicines is a faint memory of this ancient Native American usage. (Use great caution in applying these folk remedies, since some wild cherry leaves, kernels or bark may be poisonous.)

In 1999, Michigan State University scientists discovered that cherries' dark coloring material is an outstanding source of anthocyanins. This makes them similar to the food supplement Pycnogenol. In fact, the antioxidant activity of tart black cherries is greater than of vitamin E, the benchmark antioxidant. Dark-colored Balaton cherries are particularly rich, with a total of 37.5 mg of anthocyanins in every 100 grams of fruit.

Second, cherries contain pain-relieving compounds. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, Vioxx, and Celebrex work by inhibiting cyclooxygenase I and II, popularly known as cox 1 and cox 2. Cherries also deliver a dose of cox inhibitors comparable to, say, Advil. Cox inhibitors are also being investigated for anticancer activity. Finally, cherries contain surprisingly high levels of melatonin, a hormone previously thought to be produced only by the pineal gland in the brain. Melatonin is part of the body's natural way of regulating sleep.

It also may have anticancer properties. "Consuming cherries could be an important source of dietary melatonin," said Texas scientists recently. For reasons such as these, last year, the National Center for Complementary and Alternative Medicine (NCCAM) gave a grant to Johns Hopkins University in Baltimore to study the use of sour cherries in alleviating the pain of cancer. How many cherries do you need to provide these benefits? "Cherries can prevent and treat many kinds of pain," said Muraleedharan Nair, the lead researcher of the Michigan State University project. "Twenty cherries provide 25 milligrams of anthocyanins, which help to shut down the enzymes that cause tissue inflammation in the first place."

Michigan produces 80 percent of America's tart cherries. Depending on the variety, two teaspoons to two tablespoons per day of concentrated cherry juice is a reasonable dose. I am unaware of any adverse effects, such as occur with aspirin or other NSAIDs.

At least one Michigan company is thinking of bringing out a cherry supplement pill. More power to them. For now, it is easy to find and take concentrated cherry juice. Or better yet, do as I have done, and plant a few tart cherry trees in your front yard and then help yourself to Nature's bounty.

Jefferson Course a Big Success

Our day-and-a-half course on Integrative Cancer Treatments at Thomas Jefferson Medical University in Philadelphia was a great success. We had about 80 participants: half were medical doctors; the rest health care practitioners and researchers. All had come to learn about the emerging academic medical discipline of integrative cancer care. To my knowledge, this was the first course on CAM cancer treatments ever hosted by a major American medical institution or approved for continuing medical education (CME) credits by the American Medical Association.

I was proud to share the podium with distinguished participants from Jefferson University, its Center for Integrative Medicine, and the affiliated Kimmel Cancer Center. I owe a great debt of gratitude to the staff of Jefferson University and the attendees, who braved many travel difficulties to attend this event. I hope we will have a chance to teach this course again and possibly to extend it to other medical schools and universities. If you are interested in hosting such a course at your institution please contact me at ralph@cancerdecisions.com.

Also, I offer a free weekly emailed newsletter on the latest developments in cancer. Just go to www.cancerdecisions.com to sign up.

--Ralph W. Moss, Ph.D.

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