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On The Cutting Edge

Patients in clinical trials of new drugs must weigh risk vs. reward.

Posted October 13, 2009 by Ken Terry

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Dee Sparacio
Former schoolteacher Dee Sparacio, left, was undergoing treatment for stage three ovarian cancer when she agreed to take part in a clinical trial at the Cancer Institute of New Jersey.
Photo by Chris Crisman.

Dr. Lorna Rodriguez
Dr. Lorna Rodriguez chief of gynecologic oncology at CINJ, led the team of researchers in Sparacio’s study.
Photo by Chris Crisman.

Clinical Trials Image
All newly diagnosed adult cancer patients who come to CINJ are offered clinical trials if one exists for them. About 15 percent end up participating.
Photo by Chris Crisman.

Dee Sparacio, a 54-year-old former schoolteacher from Edison, is a cancer survivor. Four years ago, she was diagnosed with stage three ovarian cancer after being rushed to the emergency room at Robert Wood Johnson University Hospital in excruciating pain. Following a hysterectomy to remove the diseased organs, she recounts, “I was told that I needed chemotherapy ASAP, and then I was offered a clinical trial.”

Dr. Lorna Rodriguez, one of the researchers who treated Sparacio and recruited her for that study, explains that it was the first step toward finding out whether the mineral selenium could reduce the resistance of ovarian cancer cells to the chemotherapy agents—carboplatin and paclitaxel—that are used to kill them.

While these agents can cause tumors to shrink, the tumors often grow back because the cancer cells develop resistance to drugs. In mouse studies, when selenium was added to the chemo regimen, the tumors kept shrinking. So a team led by Rodriguez, chief of gynecologic oncology at the Cancer Institute of New Jersey in New Brunswick, mounted a trial to determine a safe dosage for selenium in humans when it is administered along with standard chemotherapy.

Although the doctors could not promise that it would benefit her treatment, Sparacio enrolled in the trial after thoroughly researching the topic. Trained as an engineer at Rutgers, she had worked in R&D at Colgate-Palmolive before becoming a middle school and high school math and science teacher. Because of her scientific background, she already knew what selenium was, and she understood how to read scientific papers. With the help of the CINJ librarian, she combed through the medical literature and dug up other cancer studies involving selenium.

After weighing what she had learned, along with her doctors’ explanations, Sparacio decided the trial was worthwhile: “There were side effects with selenium, but I thought I could get a benefit, and those benefits could outweigh any difficulties I might have. I knew it would take more time and that I wouldn’t be able to work while I was on chemotherapy. But I said, ‘Sure, I’ll give it a shot.’”

Sparacio went into remission after her treatment. Despite one cancer recurrence two years later—resolved with additional surgery and chemo—Sparacio is glad she enrolled in the study. For one thing, she says the selenium apparently reduced the side effects of her first round of chemotherapy. Also, while she does not know whether the treatment helped suppress her tumors, she believes that it might have kept the recurrence confined to the two organs—her spleen and her liver—that were later operated on. “If the cancer had recurred in a number of locations, surgery wouldn’t have been considered an option,” she says. For now, she’s back in remission and happy to be alive.

The kind of research to which Sparacio contributed is being done all the time at CINJ, a federally recognized center of excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. The only New Jersey facility designated as a comprehensive cancer center by the National Cancer Institute, CINJ is one of 40 such centers across the country that do cutting-edge research, collaborate on multicenter clinical trials, and treat adult and pediatric patients. CINJ focuses on translating lab discoveries into clinical studies that can help improve cancer care. CINJ scientists make some of these discoveries; other experimental drugs—some available nowhere else—come from pharmaceutical companies. CINJ, which has as many as 130 trials running at any time during the year, receives financial support from NCI and other federal agencies, the state of New Jersey, public and private companies as well as philanthropic support.

The drug studies done at CINJ are mostly phase 1 and phase 2 trials. (There are also studies of surgery and radiation therapy, as well as preventive care.) Phase 1 studies determine the safety of a medication. Increasing dosages of the drug are administered to different patients to find out at what level the agent becomes toxic to humans. In phase 2, a drug’s efficacy is tested. If it is shown to be safe and effective in these relatively small trials, the medication might become the subject of a national phase 3 trial. That has happened with nine of the agents CINJ has tested during the past five years.

All patients get the new drug in phase 1 studies and some phase 2 trials. But in other phase 2 and most phase 3 trials, patients are randomly assigned to either a study or a control group, and the new treatment is applied only in the study group. Rarely, the control group in one of these randomized controlled trials receives only a placebo. But in most cancer studies, patients receive the standard treatment for their disease, whichever arm of the study they are assigned to.

One exception to the standard treatment rule occurs in studies of melanoma, a skin cancer that has a very high mortality rate when it progresses beyond the early stages. Once the cancer has metastasized throughout the body, neither surgery nor the current drug treatments help most people, says Dr. James Goydos, associate professor of surgery in the division of surgical oncology at UMDNJ, who runs CINJ’s melanoma and soft tissue oncology center. “Once you get stage 4 melanoma, it’s almost imperative that you go on a clinical trial,” Goydos says.

Goydos and his team are now testing the effect on stage 4 melanoma of the drug Riluzole, which has been FDA approved for the treatment of Lou Gehrig’s disease (amyotrophic lateral sclerosis). The result of a decade of research on mice by Suzie Chen, a scientist at Rutgers University, the phase 2 clinical study is investigating whether Riluzole can halt the spread of the cancer by targeting the gene that is understood to make melanoma cells grow. In animals given Riluzole, Goydos says, “the tumors stop growing and in many cases start to shrink.”

Because the U.S. Food and Drug Administration does not want human subjects to take unnecessary risks, the agency had earlier authorized CINJ to do an unusual phase 0 trial to make sure that Riluzole actually targets the gene under study. Goydos enrolled patients who were scheduled to have their melanomas removed by surgery. They received Riluzole at full strength for two weeks, and the researchers did biopsies of their tumors before and after the drug treatment.

“We found that in a third of patients, we were affecting the signaling pathways in the melanoma cells as we expected,” says Goydos. “Unexpectedly, in the same patients, their tumors shrank—which is remarkable in only two weeks of treatment.”

One of the first patients to enroll in the current phase 2 Riluzole trial was Margaret Mount, a former administrative assistant who lives in Old Bridge. Mount, 57, has stage 4 melanoma, and has been in three other CINJ trials. Admitting her prognosis is “not good,” she says, “They’re trying to prolong my life through the different trials. This Riluzole trial sounds pretty promising. So I decided that I’d rather do that than the standard treatment.”

When her oncologist, Dr. Janice Mehnert, suggested she enroll in clinical trials, Mount recalls, she was hesitant because she did not know much about these studies. “I thought that maybe those treatments wouldn’t be that effective. I just wasn’t sure if it would help me, and I thought there would be another drug that would be more helpful.” But, after learning more about melanoma and visiting the Memorial Sloan-Kettering Cancer Institute in New York, she realized that her choices really boiled down to entering clinical trials at Sloan-Kettering or at CINJ. She decided to stay at CINJ, partly because it was closer to her home. Mount is hopeful because of what Goydos told her about the response of the patients in the earlier Riluzole study.

Her role in this trial, which required her to go to New Brunswick once a week for the first month, is to take the drug and have periodic tests and biopsies.

Sparacio had to do more in the phase 1 selenium trial. Every three weeks, she went to CINJ on a Monday and received an infusion of selenium, which took five hours. Then, on the following Wednesday, she returned for her chemotherapy. She went through nine cycles of this treatment, rather than the usual six, because a spot had appeared on her liver. In addition, she had to have her blood drawn regularly.

Sparacio didn’t mind, because she thought the trial was worthwhile and hoped that it would help her as well. Many study subjects have this hope, say researchers, even though they’re told in advance that there is little chance of therapeutic benefit in early-stage cancer trials. David Wendler, an ethicist at the National Institutes of Health, says that the opportunity for clinical benefit is present in less than 30 percent of these studies.

Nationally more than half of the patients who are invited to be in clinical trials decline, but fewer than 20 percent decline CINJ’s clinical trials. The biggest reason for their hesitancy, says Susan Goodin, associate director of clinical trials and therapeutics at the cancer institute, is that they fear being the first to try a new drug. “I assure patients that because of many regulations and the way we practice, we don’t study something—a new drug or some other kind of treatment—unless we think it’s as good as, if not better than, what’s currently available. That’s a strong point, but it’s a hard one for patients to understand.”

For people who have advanced cancer, an even greater fear is that they will receive a placebo instead of the new drug, Goodin says. However, she notes, there is little to be concerned about. “We use placebos frequently in the prevention setting. But in the treatment setting, where you have cancer and we’re trying to treat it, it’s infrequent that we’re using placebos. Some trials do use them, but patients are told up front of the potential.”

Dr. Roger Strair, who is researching a new treatment to decrease the resistance of acute myelogenous leukemia cells to chemotherapy and other forms of treatment, points out that most of the patients who come to him at CINJ have blood and immune system disorders. While he does not hold out the hope that being in the trial will benefit them, he observes, “Everything we know about treating patients, every standard therapy in 2009, derives in part from clinical trials done over the last several years and even decades. I tell patients that, just as the people in clinical trials in 1990 paved the way for the treatments of 2000, we’re trying to pave the way for the treatments of 2020.”

How people respond to his pitch depends on their personality and their outlook, Strair says. “Some people have a strong bias against it, because they feel like they’re being studied, and participation in the study will sacrifice the individualism or the individual nature of their care. Other people go into this saying, ‘This is what people in the ’90s did to help me, and I’ll do this for people who have my form of cancer five to ten years from now.’”

There are other factors that limit the number of patients in cancer trials. “Eighty percent of cancer care is delivered in the community, in practices that don’t have access to clinical trials,” Goodin says. “So we’re caring for about 15 to 20 percent of all new cancer diagnoses. Because most physicians don’t have access to clinical trials, they don’t present it as an option to their patients.”

A recent New York Times article noted more than 6,500 cancer trials across the country are seeking adult patients, and that many trials will be abandoned for lack of subjects. Twenty percent of trials sponsored by the NCI do not enroll anyone, and only half recruit enough people to yield a statistically significant sample. One reason for this poor track record, the Times suggested, is that many oncologists do not want to take part in trials—they can make more money by administering standard chemotherapy drugs—and they discourage patients from participating.

That has not been the case at CINJ. The oncologists who practice at the institute’s network of sixteen hospitals across the state help recruit patients for CINJ trials and often participate in them, says Goodin. Other kinds of physicians, including primary-care doctors, also refer patients to CINJ regularly. “Our network is vital to our ability to make new discoveries in cancer treatment,” Goodin says.

CINJ trial subjects are protected from harm in several ways. First, an internal scientific group ensures that the studies are scientifically sound before they are launched. An institutional review board attached to Robert Wood Johnson University Medical School makes sure that the proposed study is ethical. And an NCI-approved external review board monitors the institute’s clinical trials for safety.

“They make sure that if there’s even a signal that we’re causing harm, they’ll shut down our studies,” says Goodin. While phase 1 trials are always halted if the drugs begin to show signs of toxicity, she adds, no phase 2 trials at CINJ have needed to be stopped because of harm to patients since she joined the institute sixteen years ago.

Another safeguard for patients is the informed consent form that each must read and sign before he or she enrolls in a trial. The consent form includes information about the goals of the study, the potential side effects of a drug or a procedure, the sponsors of the trial, and the requirements for participation. Also, notes Nancy Berlinger, deputy director and a research scholar at the Hastings Center, a nonprofit bioethics institute in Garrison, New York, people must be told that they have the right not to participate and that they can withdraw from a trial whenever they choose to.

These forms are sometimes long—CINJ’s average 20 pages—and may be hard to understand. Ethicists from the Hastings Center and NIH recently published a template for a simpler, more logically structured form for phase 1 cancer trials.

While that template is not in general use yet, CINJ tries to ensure that every patient who is considering a trial fully understands all the implications. CINJ has a phone-based service that translates its consent forms into a number of languages, including Spanish. Shortened versions of the consent forms in other languages are also available for some trials. In addition, notes Rodriguez, a research nurse goes through the consent form thoroughly with each patient after the physician explains the big picture. Rodriguez herself stays out of the informed consent process, she adds, to avoid influencing her patients.

Despite the federal regulations that govern informed consent, plus strict IRB oversight, some observers still raise ethical questions about early-phase drug trials. The overriding concern in the case of cancer studies is whether it is right to subject sick patients to potential risks that are far greater than the potential therapeutic benefits from participating in the trials.

In the view of David Wendler, the NIH ethicist, the ethical issues are related to the reasons why a person volunteers for a study. If the patient has no other treatment option and realizes there is a low chance of benefiting from a trial but wants to do it anyway, that’s all right, in his opinion. And if an individual, whether sick or healthy, simply wants to make a contribution to science and future patients by participating, “it might be a perfectly fine thing to do,” he says. But in either case, the study must be important and socially valuable for patient participation to be ethical.

Berlinger says the biggest concern about early-phase drug trials is that some patients may not fully understand that the risks can be greater than the potential benefits. If researchers give patients the impression that an experimental drug might help them after approved treatments have failed, she says, “that would be encouraging a misconception. But in cancer treatment, especially when somebody has advanced disease, it is hard to draw a bright line between treatment and research.”

Sparacio agrees, but she also believes that clinical trials can serve both purposes. “A lot of people only think about clinical trials when there’s nothing else that they can do. I think people need to get past that. It should not be the last resort. It’s something they should consider in line with their regular treatment protocols. They should leave themselves open to take advantage of something that could be of benefit to them and to other people.”

One cancer patient who really wanted to help other people sticks in Rodriguez’s mind. She was a 40-year-old woman who had a little daughter. None of the drugs she had taken or the trials she had been in had helped her. Yet when an opportunity to participate in another study came up, Rodriguez recalls, she did not hesitate. “She said, ‘I feel that if I can help someone else in the future by being in the trial, even if the drug doesn’t help me, it would be worthwhile.’ That blew my mind. Because to be 40 with a little girl, so sick and yet to be able to think of others…I was very touched by her. I will never forget her.”

Click here to read a related story: 100 Miles For The Cure.

Ken Terry, a former editor of Medical Economics magazine, is the author of the book Rx for Health Care Reform.


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