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Journal Of Experimental And Clinical Cancer Research

Many people believe that the therapies on the cutting edge of cancer research offer the last vestige of hope only for terminally ill patients. In fact, participation in a clinical trial that examines promising but as-yet-unproven treatments can benefit people who have just been diagnosed as well as those with more advanced disease. And for all of them, volunteering for a study is one way to leave a legacy of better medicine to those who follow.

Today in the United States, about 52% of all patients with potentially life-threatening cancers are being cured. Boarder participation in clinical trials could hike that to 75% by the year 2000, according to the American Cancer Society. Yet not even 2% of Americans with cancer are now in such trials.

Experimental therapy should not be a last-ditch effort. "People need to think about clinical trials when they first learn that they have a very high likelihood of dying from their disease," says cancer specialist Karen Antman, an associate professor of medicine at Harvard Medical School and clinical director of the Solid Tumor Autologous Marrow Program at the Dana Farber Cancer Institute in Boston. "Waiting until you have used every conventional treatment available" gives cancer time to develop resistance to drugs, get bulky, and spread, says Dr. Antman. By then, "a new treatment is unlikely to be appropriate."

Good clinical trials are carefully designed to answer specific questions about drugs, radiation therapy, or other procedures while scrupulously protecting the rights and safety of those in the study. Because precise answers are the goal, only patients who meet specific criteria can be enrolled, and sometimes more applicants are turned down than are admitted. The protocol (plan for treatment) is reviewed by ethics boards at hospitals or clinics where the study is being done, and often by federal agencies as well. Reviewers won't approve a trial unless there is good reason to believe that the new treatment is at least as good as the old.

"We can't offer something inferior," says Michael A. Friedman, associate director of the Cancer Therapy Evaluation Program at the NCI in Bethesda, Maryland. If a clinical trial uncovers what turns out to be a breakthrough treatment, then participants have received what comes to be recognized as superior therapy, he notes. But if patients have doubts along the way, they can withdraw from the study at any time. Doing so may jeopardize study results, however, so researchers will urge them to stay.

Proper clinical trials are not the same as "unconventional" therapies that claim miraculous results from bizarre diets and procedures. When University of Pennsylvania researchers compared terminally ill patients receiving standard care at an academic center with those having unconventional treatments at an "unorthodox cancer clinic" in addition to standard care, they found no difference in the survival times for the two groups, but a lower quality of life for people on unconventional therapy.

"Unconventional" is being used as a code word for quackery, John R. Durant suggested in an editorial that appeared in the journal Cancer. "As long as there are desperate people seeking solutions to profound human miseries, such as cancer, there will be unscrupulous people (often supported by groups of true believers) who will exploit the weak and miserable," wrote Dr. Durant, director of the University of Alabama Medical Center.

Clinical trials are sponsored not only by the government, but by organizations including drug companies, clinics, hospitals, and even individual physicians. Studies run by federal agencies and major universities automatically receive intensive evaluation. The quality of scrutiny may vary from one institution to the next, Dr. Friedman said. Before signing up for a study, a person should make sure that the protocol has been reviewed by independent experts and that the physicians conducting the study are not biased by having a financial stake in its outcome.

The NCI is the premier sponsor of cancer research, with hundreds of trials under way at any one time. People with adult acute nonlymphocytic leukemia, melanoma, or cancer of the breast, stomach, colon, rectum, lung, prostate, or bladder may be able to enroll quickly in an NCI "high-priority" trial (see box, "Actively Seeking Volunteers").

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Anyone considering participation in an experimental trial "needs a guide who is willing and able to take the time to help translate" the protocol and distinguish good clinical options from "well-intentioned, fringy" ones, said Robert J. Mayer, associate professor of medicine at Harvard Medical School and oncologist at the Dana Farber. "The old concept of finding a physician in whom you have confidence" is what is needed. This physician-guide does not necessarily have to be at "a highfalutin academic cancer center," Dr. Mayer added. In fact, about half of all NCI trial participants sign up through community physicians, and most get their experimental care only a short drive from home.

Unfortunately, many community physicians are "not very cooperative" when it comes to helping patients gain access to experimental treatments, notes patient advocate Elenore Pred, president of Breast Cancer Action. One reason may be that the extra paperwork or monitoring required by study protocols consumes a great deal of time for busy private practitioners and is poorly (if at all) compensated, Dr. Durant said.

Grounds for discontent

According to Ms. Pred, a "huge groundswell" of discontent with the whole system is building among cancer patients. They hope to equal the AIDS activists' success in forcing researchers to let trial participants have more say in how the studies are conducted.

Another critic of the status quo is Robert Oldham, former associate director of cancer treatment at the NCI, who jumped ship to head the nonprofit Biological Therapy Institute in Franklin, Tennessee. He is one of many who complain that the cancer-research establishment is "not patient-centered enough. The research is for the researchers, not the patients." His advice to people who have exhausted conventional treatment options is to resist signing up for the first promising new therapy they hear about and instead "make a lot of phone calls before coming to a decision." Not surprisingly, "really pushy, aggressive individuals tend to get more right answers" to questions about experimental care, he says.

Dr. Oldham treats cancer patients with investigational agents such as interferon and interleukin-2, following protocols registered with the Food and Drug Administration but without funding from any government agency. Drug companies, insurance carriers, and patients foot the bill for studies carried out by his group, which collaborates with about 15 hospitals around the country.

Dr. Oldham, Ms. Pred, and other critics fault the NCI for taking too long to enroll people in clinical trials, and for testing what often seems like "the same old stuff" over and over. Instead, Ms. Pred would like to see the NCI push for faster Food and Drug Administration approval for tests of new agents such as antiangiogenics (see the Harvard Health Letter, May 1991), which slow tumor growth by interfering with growth of new blood vessels. One of these drugs, pentasan, is now in Phase I studies (see box, "One Two Three").

Realistically, it's important to note that antiangiogenics are the latest in a long list of compounds that have looked good in the laboratory, said Dr. Mayer. Unfortunately, very few of these agents actually live up to their promise when tested in humans.

Passing the buck

Most medical ethicists believe it is wrong for patients who have volunteered for these clinical trials to have to pay for the privilege of being studied. But when research grants do not cover all costs, the institution where the study is conducted bills the individual participants' insurance carriers.

"Sometimes study costs are reimbursed by insurers, sometimes they are not, sometimes only partially, sometimes completely. It differs from trial to trial and insurer to insurer," says American Cancer Society spokesperson Joann Schellenbach. The insurers balk because the responsibility belongs to the companies that make the studied drugs, argues John L. Cova, director of medical-technology assessment at the Health Insurance Association of America (HIAA), whose 300 member companies cover 95 million people.

HIAA's nonbinding policy is that patients with terminal disease who are being treated with experimental agents in a study approved by the FDA should not automatically be ineligible for coverage solely because the treatment involved is unproven. Instead, member companies are urged to evaluate each experimental protocol on its own merits. People who want to find out whether their policy will cover a specific trial should ask their employer's personnel or benefits manager for an appropriate insurance-company contact.

"Many, many patients get turned down the first time" they ask their carrier to pay for experimental care, warns Dr. Antman. When that happens, it is well worth the effort to ask for a review because many claims are approved the second time around. Sometimes intervention from the patient's congressman, clergyperson, and employer can help to effect payment. Clinical researchers can also assist by providing insurance companies with data needed to understand the experimental treatment and its chances for success, says Dr. Antman. That is crucial, according to HIAA's Dr. Cova. Companies will stonewall if they see any indication that the treatment is dangerous or ineffective, but "if they have good reason to believe it will provide benefit, they will pay."

Whispering the "E" word

Payment is complicated in part because there is no one definition for "experimental" treatment, Dr. Cova said. Many dotors avoid using "the 'E' word" because it means different things to different people; they find that substituting the term "protocol treatment" may reduce snags in reimbursement.

Courts and legislatures have begun responding to the plight of people who find themselves both extremely ill and despondent over rejected claims. In several court cases judges have ordered insurers to cover autologous bone-marrow transplants because the companies' rules against paying for "experimental" care did not realistically define the term. This month, the Office of Technology Assessment is holding a conference in Washington, D.C., to grapple with issues surrounding payment for experimental therapies.

In Congress a bill introduced by Rep. Tom Campbell (R-California) would "expedite approval" for drugs aimed at treating "life-threatening or seriously debilitating diseases," as long as there is evidence that the agent is reasonably safe in humans and effective in laboratory tests. This "Access to Life-Saving Therapies Act" would allow compounds being investigated to be sold outside of clinical trials while testing is under way and would require insurers to reimburse for their use.

Making experimental drugs more accessible outside the structure of well-designed clinical trials may lengthen life, but it probably will not do much to advance scientific knowledge. (However, some valuable data on the safety of ddI, an experimental drug that is nearing FDA approval, were gathered through the "expanded-access" program set up to study potential treatments for AIDS.)

Participation in clinical trials, on the other hand, provides state-of-the-art treatment and enables patients to contribute to society, says Dr. Mayer. Everyone benefits -- both today's patients and tomorrow's -- when people volunteer to improve the odds of curing cancer by enrolling in such investigations.

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