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58. My doctor
told me that I'm “a perfect candidate for a clinical trial,” but I'm not sure
what he means by this. What is a clinical trial?
A clinical trial is a
study of patients with similar characteristics designed to answer a specific
question or set of questions. Ideally, clinical trials study small populations,
but they are intended to yield answers that may be applied to a larger
population of similar patients. A clinical trial may study people who have not
had a disease but are at risk for developing it. A clinical trial may test the
effectiveness of a new drug or study a different way to give an older drug. A
clinical trial may ask patients to give blood samples or tissue samples for
testing after receiving different doses of a drug. A clinical trial may compare
two different types of therapy in two sets of patients to determine which
treatment is better tolerated or more effective. There are at least two
components common to all clinical trials: a written research plan, or
protocol, written for the investigators conducting the study; and the
informed consent, which tells the patient what the clinical trial
is designed to do and what he or she is expected to do as part of the study.
As in the examples above,
not all clinical trials are designed to test new therapies. Although many new
drugs or treatment strategies have been studied in a clinical trial, there are
many questions unanswered because no clinical trial has yet studied that
question.
If your doctor has
encouraged you to find out more about clinical trials, and said that you are a
"perfect candidate," he is not only paying you a compliment; he's telling you
something about your medical condition. A patient who enters a clinical trial
must be able to understand the principles of the trial he is considering. This
does not mean that the patient needs a college degree, but it does mean that the
patient should not have unrealistic expectations about the purpose of the trial
and what the clinical trial will do for him as an individual. Clinical trials
are not written for the benefit of individual patients; they are written to
further the development of new treatments for a future population of patients.
Also, patients who have severe medical problems that may interfere with the
treatment on the trial are not eligible to participate in the study.
59. I'm
interested in finding a clinical trial of a new treatment for glioblastoma
multiforme. What do I need to know before I enroll in a study? Are clinical
trials only conducted at universities and research centers?
Patients who are
interested in enrolling in a clinical trial should be commended! Participation
in a clinical trial can be time-consuming, inconvenient, and expensive, and
patients are not paid for their participation. Some clinical trials may require
frequent visits to a clinic or research center. Some trials may require more
frequent testing than traditional therapy outside of a clinical trial. Some
trials may require surgery or other invasive procedures. However, the only
accurate way to answer questions about the side effects and effectiveness of new
therapies is with a carefully conducted clinical trial.
There are several
different types of clinical trials. A pilot or feasibility
study is a small study of a new therapy or technology that may be very
complicated or expensive. This type of study involves a small group of patients.
It allows investigators to determine whether a larger trial should be performed.
In some cases, the sponsor of a study (the organization that funds the research)
will require that the new therapy show promise before allowing a large number of
patients to receive it. An example of a pilot study is a trial that studies a
group of brain tumor patients who are on the same therapy at two month intervals
using MRI, PET, and a new imaging modality. The purpose of the study is to
determine whether the new imaging technique provides additional information that
may help predict the patient's response to therapy.
Preclinical
studies are studies that use live animals to
determine if a particular treatment affects the heart, lungs, kidneys, and other
organs. Animal models (animals with implanted tumors) are given the treatment to
determine whether the treatment kills tumors without harming the animals. Other
animal studies are conducted in normal animals to determine the effects of large
doses of a drug. This type of study reveals the likely side effects that a human
will experience after several months of taking the drug.
A Sample Clinical
Trial: The Preclinical Study
A new drug, YZ-1234 is
discovered to kill human brain tumor cells in cell cultures. When administered
to laboratory mice that have been implanted with human brain tumors, the tumors
appear to shrink. YZ-1234 is then administered in larger doses to normal animals
to determine its side effects. If any of the animals die after receiving the
large doses of YZ-1234, their organs are studied to determine why they died.
A phase I
trial usually studies a small group of patients to determine if a new treatment
is safe. Patients participating in a phase I study may not have the same type of
tumor. In some cases, phase I studies are researching drugs that have not yet
been studied in humans and the investigators begin the trial using a fraction of
the dose found to be toxic in animals. As patients enter the trial, the doses of
the drug are gradually escalated, with a careful review of side effects and
laboratory tests. When side effects of the drug are noted more frequently or
become more severe, the trial is stopped. Blood and urine tests are obtained
during treatment to determine how the dose of the drug given correlates with the
level of the drug in the blood and how rapidly the body excretes it. These
studies, called pharmacokinetics, are very important in determining the
how toxic the drug may be in different patients and whether the drug can be used
in patients who are taking other drugs. Remember that phase I trials rarely
result in successful control of the patient's tumor. Even when the drug has been
very effective in animal studies, the dose that can be tolerated in humans may
not kill the tumor.
A Sample Clinical
Trial: Phase I
Patients entering a phase
I clinical trial of the drug YZ-1234 receive one-tenth of the dose found to be
toxic in mice. A small number of patients receiving YZ-1234 at the initial dose
have no side effects, so the next group of patients receiving YZ-1234 receives a
slightly higher dose. The trial continues until the patients receiving YZ-1234
show abnormalities in their blood tests or side effects that the investigators
determine to be toxic but reversible. The YZ-1234 dose that the investigators
find to be tolerable is 200 mg per day.
A phase II trial
studies a small group of patients, sometimes as few as 14, to determine whether
there is a statistical likelihood that a new treatment will be effective against
a specific tumor. If the study involves a drug, the dose that was determined to
be safe for humans from the phase I trial will be used in all of the patients
participating in the phase II trial. To determine whether the treatment is
effective, it is important that all of the patients entered on a phase II trial
are similar. Most phase II studies require that the patient have measurable
disease because there must be a reference for determining whether the tumor is
growing, shrinking, or remaining stable. The investigators may also choose to
set exclusion criteria, which may limit the patient's number of
previous treatments before entering the study. If the new treatment appears
promising in a proportion of the initial patients, the study may be expanded to
allow more patients to receive the drug.
A Sample Clinical
Trial: Phase II
In a phase II trial of
YZ-1234, 14 glioblastoma patients who have previously had surgery and radiation
therapy, and have evidence of tumor recurrence after radiation therapy receive
200 mg of YZ-1234 per day. After 2 months of treatment, 3 patients have evidence
of tumor response (shrinkage), 7 have no change, and 4 have evidence of tumor
growth.
A phase III trial
compares two or more kinds of treatment in two or more similar groups of
patients. Some phase III trials compare a new treatment that appeared promising
in a phase II trial with the more standard therapy. Most phase III studies are
randomized trials, meaning that the patients entering the trial
are not given a choice of therapy. Instead, they are asked to accept a random
chance of receiving either therapy. It is not known by either the investigators
or the patients which arm of the trial contains the most effective therapy,
although one arm may be less convenient, less toxic, or less expensive.
Therefore, it is very important to determine whether there is a definite
survival benefit in one arm over the other.
Some phase III trials are
placebo-controlled, which would appear to be unfair to patients who are
randomized to this group. A placebo often has the same appearance as the
"real drug": the placebo may be a "sugar pill" of the same size and color or an
intravenous solution of sugar water. However, some placebo-controlled trials
offer the same effective therapy in both arms of the trial, with the new drug or
placebo added to detect whether there is any additional benefit. This also
allows investigators to determine whether there are subtle side effects of the
new therapy. One recent example of a placebo-controlled trial used the Gliadel
wafer, which contains the chemotherapy drug carmustine, in one-half of the
patients having surgery for glioblastoma. The other glioblastoma patients also
had surgery and had a placebo wafer implanted that was identical in appearance
to Gliadel. Neither the patients nor their surgeons knew which patients were
receiving which wafers because all treatment was coded. At the end of the study,
the investigators matched the patients with the treatment they received and
determined that, on average, the patients who received Gliadel lived longer.
This finding was very important to determine with a placebo-controlled study
because all patients had some benefit just by removing the tumor.
Phase III studies are the
largest, most time-consuming, and most expensive clinical trials to conduct.
They often require hundreds of patients to detect statistical benefit. Many
phase III studies involve multiple research centers and take several years to
complete. Phase III studies may have an interim analysis stage, which is
designed to detect differences in the two groups before the study has been
completed. An interim analysis may suggest such a striking difference in the
expected outcome of the patients in the two arms that the investigators decide
to stop the study to avoid continuing to treat patients in the least effective
way.
A Sample Clinical
Trial: Phase III
The new drug YZ-1234
appears to be less toxic and at least as effective as some of the older
treatments that have been used in glioblastoma. Therefore, a phase III study of
500 glioblastoma patients is planned. In this study, 250 of the patients will be
randomized to receive radiation therapy followed by YZ-1234. The other 250
patients will receive radiation therapy followed by Temodar, which was chosen
because it is also an oral drug. It is estimated that the study will take 2 to 3
years to complete.
Patients who are
considering enrollment in a clinical trial should understand that clinical
trials involve an element of risk. These risks are explained in the informed
consent document. The patient should never sign an informed consent if he or she
does not understand the question being posed in the clinical trial.
Often the study title
contains the phase of the trial and the names of any drugs or treatments being
used. For example, the title for the sample clinical trial discussed above would
be: "A Phase I Study of YZ-1234 in Patients with Advanced Cancer." The known
side effects of the therapy proposed in the clinical trial must be carefully
stated in the informed consent. The informed consent usually states that unusual
or unforeseen side effects may also occur. The treatment alternatives, including
the standard treatments for the disease, must be stated. The investigators must
also disclose whether enrollment in the clinical trial would affect the
patient's enrollment in future clinical trials. Most clinical trials state that
effective contraception must be practiced during treatment in a clinical trial
because of a possible risk to an unborn child.
Enrollment in a clinical
trial may be restricted to patients who are "minimally pretreated" because
certain drugs may be more toxic to patients who have already had different types
of chemotherapy. For this reason, if you are considering participation in a
clinical trial, it is important to consider this early in treatment.
Many universities,
regional cancer centers, and community cancer programs participate in clinical
trials. Pharmaceutical companies sponsor some clinical trials, private
foundations sponsor some, and some are sponsored by the National Cancer
Institute (NCI). The NCI provides financial support to cancer centers around the
United States that participate in clinical research organizations, such as New
Approaches to Brain Tumor Therapy (NABTT), Southwest Oncology Group (SWOG), and
Eastern Cooperative Oncology Group (ECOG). In addition, the NCI conducts
clinical trials at the National Institutes of Health Clinical Center in
Bethesda, Maryland. Clinical trials that are supported by the NCI can be located
on the Web at www.cancer.gov/clinical_trials. In addition, many individual
cancer centers have Web sites that list their current clinical trials (see
Question 100). Finally, Dr. Al Musella's Web portal www.virtualtrials.com
contains a very comprehensive listing of clinical trials for brain tumor
patients.
60. What is the
difference between an investigational therapy, an "off-label" drug, a
complementary therapy, and an alternative therapy?
Investigational
therapies or
investigational drugs are treatments that are considered experimental or under
development in a clinical trial setting. Some investigational drugs have not yet
been approved for the treatment of any disease and cannot be obtained outside a
clinical trial. Drugs that have been approved by the Food and Drug
Administration (FDA) for the treatment of one type of cancer may be considered
investigational for the treatment of another type of cancer. Also, drugs that
may be approved for intravenous use may be considered investigational when used
by another route such as intra-arterially (injected directly into the artery
supplying the tumor) or intrathecally (injected into the spinal
fluid). Patients receiving investigational drugs on a clinical trial are
allowed to continue taking the drug only if the treatment appears to be
effective, as assessed by physical examination and scans. An investigational
drug may be supplied free of charge to a patient who is enrolled in a clinical
trial, but it is not always free, and the informed consent will specify this.
An off-label drug is
approved by the FDA for one type of treatment but may be prescribed for other
conditions. Some drugs may be both investigational and off-label. Because of the
time required and the expense of performing clinical trials, only a small
fraction of research studies are performed solely to obtain FDA approval for a
drug. Some drugs that are widely accepted in brain tumor therapy, such as
procarbazine and vincristine, have not been FDA-approved for this use. However,
when clinical trials are published demonstrating that a treatment is effective
and well-tolerated, doctors are more likely to prescribe the drug off-label. In
some cases, insurance coverage does not reimburse for off-label use of the drug,
even when the patient's doctor determines that the drug is likely to be
beneficial. You should always check with your doctor if you are concerned about
whether the drug will be covered by your insurance.
Complementary
therapies and alternative therapies encompass a wide
variety of treatments, including herbal preparations, vitamin- or
nutritional-based regimens, and therapeutic touch. Complementary
therapies are used in conjunction with conventional therapy such as
surgery, radiation therapy, and chemotherapy. Alternative therapies are
used in place of conventional therapy. Some alternative therapies are
based on the traditional medicines of other cultures, and others were developed
by individual practitioners. A few alternative therapies have been studied in
clinical trials. If you are interested in an alternative therapy, ask your
doctor whether the treatment has been studied. It is also important to ask how
long the treatment is expected to last because some alternative regimens cost
hundreds or thousands of dollars a month. It has been estimated that up to 75%
of all cancer patients use complementary or alternative therapy at some point
during their illness.
Although investigational
therapy and alternative therapy are both options for the patient who does not
want conventional therapy, there are many differences between the two
approaches. Doctors who offer the patient investigational therapy judge the
patient's response to treatment by conventional means such as neurological
examination and MRI. Patients enrolled in a clinical trial for an
investigational therapy may be asked to forego all other treatments (including
alternative therapies) that may interfere with the therapy being studied.
Alternative therapies may
be prescribed by naturopaths or herbalists who are not licensed to practice
medicine and therefore they cannot order radiographic studies to determine
response to treatment. Some naturopathic practitioners follow the principle of
complementary therapy. They allow chemotherapy or radiation treatment at the
same time as the alternative therapy. Many insurance plans do not cover the
costs of alternative therapy, even when it has been prescribed by a licensed
physician.
61. I am
interested in a clinical trial at a research center in another state, but my
doctor is opposed to this. He wants me to enter a trial at the medical school in
my city, or take standard chemotherapy. What should I do?
There are many reasons why
doctors do not refer their patients to clinical trials. If you have a good
relationship with your local doctor, and that doctor does not want you to
participate in a particular clinical trial, make sure you ask why. If you are
not happy with your doctor's answer, it is certainly possible to change doctors
to find one who is more accepting of the clinical trial you want. Although it is
possible to enter a clinical trial in another state without a referral from your
doctor, you still need to have a local doctor in case of an emergency.
Some doctors feel that
their patients assume that a clinical trial is better than standard therapy, but
they know that the trial may not be successful. By definition, a new drug is
being studied in a clinical trial because it has not proven superior to
standard therapy. Moreover, less is known about a new drug than one that has
already been studied and FDA-approved. This is especially true when the clinical
trial is a phase I study.
Some research centers have
well-known doctors on staff or new treatments that have received national media
attention. However, in most clinical trials, only a few patients have the degree
of success that is featured in the media. Your local doctor may be concerned
that you are choosing a research center based on its reputation rather than its
ability to offer you an appropriate treatment.
Some research centers
manage the patient's care with close communication with the local physician, and
some do not. If the clinical trial investigators do not provide information
about the investigational drug's side effects to a patient's local doctor, the
local doctor is left "out of the loop." This may cause problems if the patient
develops life-threatening complications related to the investigational drug and
the local physician has not been given any information about the side effects
expected. If the patient comes to his hometown emergency room, the local doctor,
not the research center doctor, will be called to see the patient. It is hardly
surprising that the local physician will be unlikely to refer patients to that
center in the future!
Some doctors feel that
nearby medical schools should be supported in their research programs, and they
may be more familiar with the investigators and the clinical trials offered at
the local medical school. Your local doctor may also feel that frequent travel
out of state will be more physically taxing on you than you realize.
It is best to schedule an
appointment with your doctor to discuss your concerns. If you are considering
conventional therapy after completion of the clinical trial, it is important to
keep in touch with your local physician.
62. I have
received three separate chemotherapy drugs, and each seemed to work for several
months. I now have an area of new tumor on my MRI scan. I'm interested in a
clinical trial, but several of the clinical trials I have seen don't allow
patients who have had previous chemotherapy to participate. Why is this?
Clinical trials enroll
patients who are very similar -- to level the playing field, so to speak. In a
phase II clinical trial, in which the objective of the trial is to test the
effectiveness of a new drug, patients who have had no chemotherapy at all often
respond better than patients who have had multiple types of chemotherapy.
Investigators have a better chance of evaluating the promise of a new drug if
patients who are "heavily pre-treated" are not enrolled.
Often an objective of the
clinical trial is to determine the potential side effects of a new treatment.
When selecting participants for this type of trial, a patient's bone marrow
reserve is an important factor. Bone marrow reserve is the term oncologists
use to describe the expected recovery of the bone marrow cells -- the cells that
develop into the white blood cells, red blood cells, and platelets. This reserve
is depleted when patients have had multiple treatment cycles of some
chemotherapy drugs (particularly BCNU and CCNU). A patient whose bone marrow has
been depleted by previous chemotherapy may require platelet transfusions or
growth factors such as Neupogen after every subsequent chemotherapy cycle to
help the blood counts return to a normal level. If that patient is included in a
clinical trial designed to study the side effects of a new treatment, the new
drug may decrease blood cell counts to very low levels. The patient may require
dose reductions of the new drug to continue chemotherapy, which may then lessen
the chances that the new drug will be effective.
Very healthy patients with
good bone marrow reserve are the favored subjects for clinical trial
investigators who are hoping that a highly successful drug can be rapidly
approved for general use. Again, it is important to remember that clinical
trials are not written to benefit individual patients. They are written to
develop new therapeutic strategies.
63. I have heard
about a new treatment that's only available at a clinic overseas. It sounds
promising, but how can I find out if it's safe?
There are clinical trials
in other countries that follow many of the same rules used for human research in
the United States. Laws for the protection of human subjects guarantee that
patients will be informed of the potential risks and benefits of participating
in a clinical trial. Before considering a clinical trial that takes place in
another country, you need to determine whether the treatment offered is funded
by a research organization because private insurance probably will not cover the
cost.
Clinical trials offered at
research institutions in Europe may have reported their results at the Congress
of the European Association for Neuro-Oncology. These abstracts can be
reviewed by your local oncologist. If you are interested in participating (and
you can afford it), your oncologist may be able to contact the principal
investigator of the study to determine your eligibility. In some cases, a drug
approved for cancer treatment overseas may be legally brought into the United
States for treatment of an individual patient.
There are some drugs and
therapies available in other countries that are not yet approved in the
United States,
but you should be careful to distinguish between investigational therapy and
"unproven" therapy. "Unproven" therapy in other countries may be offered through
"research clinics" that are little more than expensive resorts.
64. I have heard
a lot about herbal remedies, shark cartilage, and other non-toxic treatments,
but I was told that these treatments haven't been studied in a clinical trial.
Is this true? If it is true, why haven't these treatments been studied?
There has been an
explosion of interest in so-called "non-toxic" therapies. Patients interested in
such therapy can now investigate them and participate in clinical trials at a
number of sites. The National Institutes of Health's National Center for
Complementary and Alternative Medicine (NCCAM) reports that an estimated $27
billion is spent on alternative and complementary therapies, such as herbal
supplements, vitamins, plant extracts, shark cartilage, and hundreds of others.
Some, but not all, supplements have been studied. Reviews of the results of
these trials are now available.
Dr. Stephen Tomasovic,
professor of molecular and cellular oncology, has compiled a list of
complementary and alternative therapies and reviews of the scientific data,
including the results of animal studies and clinical trials. This information is
available on the Web at www.mdanderson.org/departments/CIMER. The list includes
traditional Chinese medicine, herbal and plant therapies, biologic agents,
special diets, and energy therapies. In addition, the site contains information
regarding drug interactions, a glossary of terms, and a "Frequently Asked
Questions" section.
In the past, researchers
who were interested in studying herbal supplements or non-traditional therapy
had difficulty attracting funding for animal studies and clinical trials. There
are now a number of sources of funding for such trials, including research
grants through the National Institutes of Health. Patients who are interested in
clinical trials for complementary and alternative therapies must be willing to
forego other treatments while on the clinical trial to avoid confusing the
results of the study.
M.L.'s comment:
Early on, my husband read
about clinical trials on the Internet. Further research has indicated to us that
clinical trials are a very good thing. Participation in a clinical trial was
never offered to me, but I understand that my tumor, anaplastic
oligodendroglioma, isn't as common, and there were no clinical trials in my area
for newly diagnosed tumors. Because the majority of my tumor had been resected
through surgery, I wouldn't have been eligible for phase II clinical trials.
These trials require visible disease to be present on a patient's MRI. My tumor
responded so well to radiation therapy and chemotherapy that I still don't have
enough visible disease to quality for a clinical trial... but this is fine by
me!
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