Clinical Trials - Today's Cutting Edge -- John S. Link, MD -- 10/02/02

Last Editorial Review: 10/23/2003

By Milton Lakin
WebMD Live Events Transcript

Tomorrow's perfect weapon against breast cancer may be in development today -- in a clinical trial. These studies of prevention, treatment, and even quality of life issues help shape the future of medicine. We discussed joining a clinical trial, what's involved, and how trials work when oncologist John S. Link, MD, was our guest.

The opinions expressed in this transcript are those of the health professional and have not been reviewed by a WebMD physician. If you have questions about your health, you should consult your personal physician. This event is meant for informational purposes only.

Moderator: Welcome to WebMD University: "Alive & Well: Taking Charge of Your Breast Cancer Treatments." Our instructor today is John Link, MD, and author of The Breast Cancer Survival Manual: A Step-by-Step Guide for the Woman With Newly Diagnosed Breast Cancer.

Member: What's in it for a participant who joins a trial?

Link: A clinical trial in breast cancer treatment varies from prevention to what we call adjuvant therapy, which is systemic treatment after primary surgery or treatment of women with advanced disease with new drugs. The benefits to a women going on any of these trials is that the woman will hopefully get the state of the art therapy and in some cases will get a new drug to see if it improves outcome.

An example would be the following: Women who are at high risk of developing breast cancer can enroll in a trial testing two different SERM drugs, which stands for selective estrogen receptor modulator. This trial tests Tamoxifen, the standard, against a new drug called Raloxifene.

An example of an adjuvant trial would be a woman with a newly diagnosed breast cancer that's been removed surgically and the cancer over-expresses an oncogene called the HER-2 oncogene. There are three trials in the world that woman with this particular type of breast cancer can go on that tests state of the art therapy versus a regimen of the same plus a new drug called Herceptin.

A third example would be woman with advanced disease to her lungs or liver or bone who would enter onto a new trial testing a new type of agent -- for example, an anti-angiogenesis agent or a new molecule such as Irresa. In all three of these examples a woman will get hopefully state of the art treatment and in some cases may have access to a drug that is not able to be given in the clinic and is not yet approved by the FDA.

The other major benefit is that woman can contribute to the progress that we're making in the eradication of this disease. Because if we're not able to test these new agents in some type of objective fashion then progress will be extremely slow and difficult. One of the major things that we have learned about breast cancer that is sometimes obscured by not only the press but even the scientific community, is that breast cancer is a very heterogeneous disease and that many of the treatment and research protocols are based on selecting certain sub-types of breast cancer in which we have found ways to treat.

Member: Are clinical trials proven to be more effective than the standard chemo/radiation treatments? When should one chose to go into a clinical trial?

Link: Somewhat related to the last question, the purpose of a clinical trial is to test a new method or drug to see if it does improve outcome. Approximately two-thirds of clinical trials have been positive showing that the arm containing the new treatment proves to be better than the standard. One-third of the time however, this is not the case, and the new treatment is either toxic or harmful. And that is the very reason that the trial needs to be conducted. Most of the modern clinical trials involve standard therapy as the basis so that no woman would be denied standard care.

Member: I am not able to find many trials for metastatic BC to the brain. Any update?

Link: The problem with trials for women with disease in the brain is that the standard drugs often times don't penetrate what we call the blood-brain barrier. There are a few new agents that seem to perhaps get in the brain and there are some agents being looked at that may break down this barrier. And there are some new techniques using radio-surgery that may prove to be some benefit. My advice would be to contact the National Cancer Institute either by phone or through the Internet for possible sources for these new trials.

Member: Is NCI the best organization to contact for info on joining a clinical trial? Are there others you recommend?

Link: No, I think that's probably the best source. They have an agency there that really directs most consumers to appropriate clinical trials. They also have listings for not only all NCI registered trials but I believe that they also have access to a majority of primary clinical investigator trials working with the pharmaceutical industry and independently.

Member: How risky is it to participate in a clinical trial? How much is known about the safety of the drug or protocol before it is tried on humans? What safety measures are in place?

Link: Before a new procedure or drug can be tested in a widespread manner, i.e., a clinical trial, it must go through some preliminary procedure. The drug or procedure must have some theoretical basis for being effective. It then goes through animal testing for both toxicity and for efficacy. This is done in a dose step-wise manner in which usually rats are given increasing doses of the drug and then liver, bone, and kidney function are monitored carefully, which are the standard areas in which we first see toxicity. Many of these new drugs today are proteins, antibodies, and enzymes and so allergic reactions are also monitored for.

The actual efficacy for killing breast cancer is monitored by implanting different sub-types of breast cancer underneath the skin of a type of mouse that has an impaired immune system that allows to grow. This model allows for the growth of a human breast cancer underneath the skin of this mouse so that response can be very easily observed.

Once a drug has been proven in animal models to be relatively safe and efficacious, then a license is requested for human testing from the FDA.

The first human testing is called phase one testing and this is usually looking for toxicity. So small increments of the drug are administered and the amounts then are doubled with each successive administration. These are usually in patients with advanced cancer. Also, tumor response is monitored but at this point that is slightly secondary to the toxicity monitoring. The info from this preliminary trial is dose seeking, determining the appropriate dose that does not lead to toxicity.

The next phase is called a phase two trial in which a clinical response is looked for, i.e., tumor shrinkage. If the new agent passes the first two phases, then comparison trials begin comparing it to other agents that are known to be worthwhile. If the agent continues to be successful in the testing, it would then be advanced to being added to the standard regimen in the treatment of an early cancer to prevent cells from spreading into the system or eradicating cells that have done this.

Member: I heard that there are waiting lists for certain clinical trials. True?

Link: In the past when a new drug has been tested that is extremely promising and receives a large degree of publicity there have been waiting lists to get on such trials. I'm not aware of this happening recently with any of the new agents being tested but was the case several years with the drug Herceptin.

Moderator: Seems the problem is much more with not enough people signing up, than the other way around. Is that true?

Link: I'm not really aware of that. It turns out that, for example, with breast cancer in this country, less than five percent of women with newly diagnosed breast cancer enroll in a clinical trial. The problem comes I think with more advanced disease when people run out of the traditional treatments and are looking for some drug to give them hope and extra time. What we call the phase one, phase two trials for these new agents sometimes have limited enrollment and this becomes a problem. But in general terms, if a woman wants to go on a trial there are a number that are available and often the impediment is that she is not eligible because of physicians not planning ahead or the woman not having the proper requirements which often requires immeasurable disease.

Member: Are all clinical trials double-blind?

Link: No. But the term double-blind means that there are two arms of the trial, two different treatments and the investigator and the patient do not know which of the two treatments the patient is receiving. This is done to eliminate bias in interpretation. Many of the trials we do in breast cancer are open-labeled or even can be single arms looking at a new drug and comparing it to a historical group with a similar type of situation.

Member: How long does it take for a successful clinical study to become standard treatment?

Link: That's good question. The process has been fast track and to prove a new treatment has utility and is efficacious is a statistical problem at times. The early phases of testing a new drug look at tumor response and that takes days, weeks, and months. So one can find a new agent and know that it works fairly rapidly, but ultimately, one needs to prove that an agent prolongs life and hopefully eradicates the disease. This endpoint takes longer to prove. Part of the problem here is financial -- enough money to finance a clinical trial with adequate power to show meaningful results. So one needs a number of factors, including adequate women enrolling onto a trial and the machinery in place to conduct a trial with a large enough group of women to give statistical, accurate results.

Fifteen years ago, such a trial going from the animal model to human testing and then being FDA approved as a treatment drug could take 10 or more years. This has been greatly accelerated and a new agent can reach the pharmacy or the doctor's office or the cancer ward in as short as three years. The case in point would be the drug Herceptin and the whole history of Herceptin in breast cancer is laid out in a book called Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer by Robert Bazell, who is a writer for the New York Times.

Member: I am interested in finding out more about the difference between Taxotere and Taxol in the treatment of advanced breast cancer.

Link: Taxol and Taxotere are two drugs that are synthesized from products of the yew tree. Both are very potent anti-cancer drugs. Originally, we as clinicians thought they had very similar activity and range of activity. It turns out that they appear to be very different and as a generalization, Taxotere appears to be a much better breast cancer drug than Taxol. This may not be the case, for example, in ovarian cancer, however. The evidence for this is in the results in a number of large trials testing Taxol and Taxotere against standard therapy. Some of these trials are what we call neo-adjuvant trials in which woman with larger breast cancers are treated with these drugs before surgery and their actual response can be measured fairly quickly.

In two large trials testing Taxol added to the standard adriamycin cytoxin, the so -called CALGB, the 93-44 trial, and the NSABP, B28 both showed only a modest benefit from Taxol. Whereas, two recent trials using Taxotere, the B27 trial and the so-called Aberdeen trial show a much larger and promising response by adding Taxotere to the standard AC. Albeit, these last two trials were neo-adjuvant trials. There are a few trials testing Taxol against Taxotere but the results of these are pending.

Member: Who is a good candidate for Herceptin? How positive does the her2neu have to be before Herceptin is an appropriate treatment?

Link: The mechanism of action of Herceptin is the attachment of the antibody to the cell surface of the cancer cell. This depends upon the presence of the Her-2 receptor on the surface, which is a result of the over-production of a gene fragment in the cell nucleus called the Her-2 oncogene. The screening test to see if a cell is making or over-producing this oncogene is an immunohisto chemical stain measuring the amount of gene fragments.

The results of this test are quantified by 0 to 3. The 0 and 1s statistically will not benefit by receiving Herceptin. The 3s are 90% of the time very positive and potentially will have positive results. It's the 2-pluses that give us problems. And it's with the 2-pluses that we use a second test that has the acronym FISH. This test then predicts whether Herceptin will work or not in the 2-pluses. We feel that it's extremely important to go through this testing in that the drug itself is extremely expensive, has some cardiac toxicity, and should only be given when it has a chance to work.

Member: I am afraid to go into a clinical trial because I might get the placebo instead of the medicine. On the other hand, I can't get the medicine unless I go into the trial. How would you decide whether or not to participate in a clinical trial?

Member: Placebo-based trials are rare today and when we see them they are usually in advanced disease. And the only way to get a new agent would be to enter the trial. Usually trials have as their basic standard care the best agents known at the time so that receiving the new drug or not would not deny someone treatment. However, in the rare trials that randomize the woman to no treatment, i.e., placebo versus the new agent, the only way to have access to the new agent is to take one's chances. So my advice is to go for it.

Moderator: Thanks for joining us, members, and thanks to John Link, MD, for being our guest. For more information, read The Breast Cancer Survival Manual: A Step-by-Step Guide for the Woman With Newly Diagnosed Breast Cancer and Take Charge of Your Breast Cancer: How to Get the Best Possible Treatment, both by John Link, MD.

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