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A Patient's Guide to
Managing Hormone-Refractory Prostate Cancer
Chapter 18.
Clinical trials and experimental treatments
Introduction
This chapter will not tell you which trials and experiments you should undergo.
It will tell you where to find FDA sanctioned trials. It will tell you how to
evaluate a trial, an experimental treatment, or an alternative treatment. And we
will suggest that you join support groups to participate in discussions about
these trials.
The subject of trials and experimental treatments is so fluid—and, often, so
emotional—that it is better dealt with in the forums found on the Internet and
in support groups around the country. Your medical expert can help guide you to
worthwhile trials and may even work with you on safe, experimental treatments.
The best possible input you can get is to talk with someone who is already on a
particular trial. Ask them if they are being helped. What are the side effects
of the trial? What about the conditions of trial admission? What do they think
of the personnel managing the trial?
What kind of trials are being done that relate to HRPCa?
There is a rather clear set of areas that is being investigated through trials.
Some of these include
1. Anti-angiogenesis. Finding an agent that will prevent the growth of new blood
vessels (neovascularization) to support the proliferation of cancer tumors.
2. Matrix metalloproteinase inhibitors. Finding an agent to stop these enzymes
that enable cancer cells to invade new tissue.
3. Immune system stimulation. Developing antibodies that will stimulate the
immune system to recognize and attack cancer cells.
4. Vaccines. Using altered cells to stimulate an immune system attack on the
cancer.
5. New combinations of chemotherapy. These are perennial trials that search for
new combinations and doses of chemotherapy agents to attack cancer cells.
Occasionally there are new agents, but most of these trials are done with
existing agents.
6. Apoptosis induction. Finding agents that will selectively initiate the
process of “cell suicide” in cancer cells, but not in normal cells.
These are some of the types of clinical trials underway. At the present there
have been no significant breakthroughs in any of the areas under research.
However—to be candid—we all watch these intently with the hope that one or more
can be made to work.
Backing up these trials is a universe of biological research at the molecular
level. These studies are proceeding by the thousands around the world. The goal
is to understand how cancer is initiated, not just identification of
carcinogens, but what is the sequence of molecular change. Once this process is
accomplished, the search for drugs to disrupt the carcinogenic process can surge
forward.
It may be obvious to say that this is a difficult search. Only in the mid-80’s
did medical science achieve the capabilities to carry research to this level.
Remember that the DNA structural identification done by Watson and Crick in the
50’s was theoretical. Up till today, medicine has often relied on stumbling
through the forest of possible treatments, hoping to find a Chinese or Indian
cure that will be the answer to cancer. It is unrealistic, because of the
astounding complexity of human biology, to believe that chronic disease will be
discovered by chance. The scientific process that will produce a cure is
underway. But there is no way to predict how many years lie between us and the
end of cancer.
Should I enter a clinical trial, undergo an experimental treatment?
We have strong, but mixed, feelings about clinical trials and experimental
treatments. The most intense debates on the support list are usually about these
treatments and their representatives. But we all agree on the importance of
evaluating the treatments with extraordinary care before you commit. We also
believe that your first obligation in life is to those you love and to those who
love you. We don’t think you should feel obliged to save mankind by sacrificing
your own life in a trial in which you don’t believe.
That said, we use several criteria to evaluate clinical trials and experimental
treatments:
1. Has it been demonstrated—preferably in a published trial—
that this treatment will help control HRPCa? If we are evaluating an alternative
treatment being marketed commercially, we always ask for the name and phone
numbers of 20 men with HRPCa who have been helped by this treatment. Then, we
call those 20 individuals and ask for the details of their PSA and treatment
data. In the case of experimental treatments, published reports of previous
experiments are the best information.
2. Has it been demonstrated—preferably in a published trial—
that this treatment will not kill you or harm you to the point that you can no
longer fight the disease? (If the treatment destroys, say, your kidneys or
liver, you lose the battle.) Don’t assume that an over-the-counter or herbal
remedy will have no side effects. Research these as well. You don’t want to be
first in line to see if an alternative treatment works.
3. Is the treatment available today, and as long as you will need it, under
reasonable conditions? Too many experimental treatments are available under
conditions you can’t meet or following the proverbial “five years till it’s on
the market.” On the other hand, many experimental treatments are run with drugs
that have already been licensed for another use. So long as a drug has been
licensed for use in the U.S. it is available for any other experimental use by a
physician.
4. Does the trial want you “bare,” that is, using no other treatments? If these
treatments are presently controlling the PSA, then stopping them to prepare
yourself for a trial—that may or may not work—can be a lethal mistake. Look at
your PSADT and decide how long you can safely go without your present treatment.
5. Do you know and trust the doctor who is running the trial? Is he being
reimbursed for recruiting patients for this trial? What is his motivation for
participating in the trial—a publication, a financial bonus, or the opportunity
to save your life?
Our strategy in this group is to find treatments that allow us to extend
survival, while staying healthy enough to fight another day, after the present
treatment fails.
We approach alternative treatments with at least as much skepticism as we apply
to medical studies. We require upfront proof, prior to payment. We see no reason
to buy a product that has no hard evidence of safety or efficaciousness. We
discourage anyone from serving as a paying participant in someone’s toxicity or
efficacy trial.
By diligently researching the medical literature we try to find those trials and
experiments that meet our criteria. We believe in actively seeking out trials
that may be successful for us.
Selecting a clinical trial
You can see the range of clinical trials by searching the Internet. The
following two addresses will open the field of trials that might be available to
you:
CapCure (Cancer of the Prostate Cure) Clinical
Trials -
CapCure
is now named Prostate Cancer
Foundation.
National Institutes of Health: www.clinicaltrials.gov (includes a
search capability to find locations and diseases)
Even though you identify a trial that seems suitable for you, you will still
need to do your own research into the probable success rates and the risks
associated with this trial. The trial sponsors should be able to supply you with
full-text articles supporting this trial and defining the drug toxicity. Make
use of the CancerLit database to see what literature has been published. Make
use of support lists and support groups to learn the experience of others with
this regimen and the participating medical organization.
Phase I trials - toxicity
These FDA-sanctioned studies are called toxicity trials, dose-escalation trials,
safety trials. The purpose is to take the findings from the laboratory (in vitro
and murine, or mouse) and determine if they are safe to administer to humans.
They are usually done with a small number of patients, who are given increasing
doses, until they experience bad reactions to the drug. People do sometimes die
in these trials. There is little hope of a beneficial therapeutic outcome for
the participants. Saving lives is not the purpose of these trials.
Phase I trials suffer from the same drawbacks of all FDA-approved trials. They
require that the participants meet certain disease criteria, which may exclude
HPRCa patients. They usually also require that the participant stop all other
therapies so that the data obtained will be “clean.” Unfortunately, HRPCa
patients are usually fighting a continuing battle to control PSA; if they stop
any treatment that is controlling the PSA, then the cancer may run out of
control, beyond recovery.
You should ask on every trial what the researchers consider to be the endpoint.
In many trials of treatments for advanced cancer, the main criterion is that the
participant have at least a certain number of months to live. Of course, the
researchers hope that their treatment saves the lives of the participants. But,
realistically, they expect to achieve only a longer duration of survival as the
benefit. In those cases the endpoint is the death of the patient. The
researchers use the duration of the test as their data. If your hope is to live
for many years, then a trial with death as the endpoint may not be a good
choice.
Phase II trials – efficacy
Phase II trials intend to determine if the drug is effective against the disease
it was designed to fight. Since toxicity has already been established, these
trials should be safer than Phase I. Usually the drug is given at different
levels to a small number of patients to assess (1) whether the drug works on the
disease in question and (2) what dosing conditions are optimal for the
treatment.
Phase III trials – licensing, comparison
Phase III trials are run to earn an FDA license, which requires proof that the
new drug is better than whatever else is already available on the market for
this disease. Additionally, there is also a comparison against a placebo, or
dummy treatment—to see whether the new drug is better than nothing. These trials
usually have three “arms:”
(1) the drug being tested;
(2) the already licensed comparison drug; and
(3) a placebo.
Phase III trials are notoriously expensive and slow. If you should choose to
participate in one of these trials, be sure that there is an arrangement to
watch for disease progression. In that case, the researchers determine if you
are on placebo, in which case, you are changed over to the drug under test. If
your disease progresses while you are on the new drug, you should be ready to
leave the trial. It would be dangerous to stay with a treatment that allows your
PSA to run free.
You should also ask about drug availability in case the trial is successful.
Will you be able to get a continuing supply of the drug even after the trial is
complete and before it is licensed for commercial distribution?
Experimental Therapies
Because there are no cures for HRPCa, and because we have a finite number of
treatments, we constantly scan the medical literature horizon for potential new
therapies. We rely heavily on human studies that are not FDA-sanctioned trials.
Such a study may be done if there is a licensed drug on the market that may—in
addition to its designed purpose—help fight HRPCa. An example is ketoconazole (Nizoral),
which was developed to fight fungi but which also is effective against HRPCa.
The methodology for finding these experimental treatments is to start with the
biological mechanism of the normal cell and that of the cancerous cell. The
purpose is to identify processes and chemicals that distinguish the cancerous
cell from the normal cell. If that can be done, then existing drugs can be
screened for possible application in inhibiting the cancerous processes with the
hope of suppressing the cancer.
Many drugs on the market today have uses other than what they were intended for.
The above example of ketoconazole is apropos.
The key to achieving a success in this area is a thorough understanding of the
biological processes involved. This understanding is difficult to reach due to
the sheer complexity of human biology. Nonetheless, it is the direction of
medical science today. The drugs that solve the problem of cancer and other
chronic diseases will be found through molecular cell biology.
Experimental treatments that are being tried in HRPCa
The following treatments have been identified by the above approach. They may or
may not be effective. In general, however, they carry a low risk of harm, so
they can be tried without serious risk. You should work with your medical expert
to incorporate drugs such as these into your battle strategy. There may be drug
interactions and issues of timing, so you should not take them without the full
understanding of your medical expert.
This list shows only a few of many possible drugs that may—or may not—be helpful
in your fight to suppress HRPCa. Each drug usually has a number of effects in
the body. Once again, the key to finding helpful treatments is a thorough
understanding of the biology of HRPCa.
Celebrex, originally developed as an arthritis pain reliever, has also been
found to inhibit the enzyme cyclooxygenase 2 (COX-2). COX-2 has been shown to
enable the production of cancer-stimulating hormones from fat. Celebrex also
helps shut down the angiogenesis that provides nutrients to the cancer tumor.
Celebrex also reduces the levels of matrix metalloproteinase, a chemical that is
used by cancer cells to invade new tissue. Doses as high as 400 mg b.i.d. are
recommended so long as there is not undue GI distress.
Dostinex suppresses prolactin, a hormone that has been associated with elevated
levels of PSA. You can get a blood test for prolactin; the value should be near
the lower end of normal. If not, then Dostinex will lower the value. The
recommended dose is 0.5 microgram on Mondays and Thursdays.
Periostat blocks matrix metalloproteinase and is synergistic with the
bisphosphonates. This is a tetracycline, so watch for sunburn due to increased
skin sensitivity. The recommended dose is 20 mg b.i.d., 1 hour before meals.
This is an area of considerable interest for all of us. Research is steadily
turning up possible cancer therapies based on drugs licensed for other purposes.
The medical literature searches in the on-line support group focus heavily in
this area.
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