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What are "Clinical Trials" and Why do we need research?
As any of us who has lost a loved one to cancer knows, for most cancers, especially in the later stages, we simply do not have a "cure".
We got to the moon, so why don't we have a cure for cancer by now?
Simple and obvious question. The answer is not so simple. "Cancer" is over a hundred different diseases. In some cases, we understand these
diseases very well and have developed cures. For example, most young men who develop cancer of the testicles (also called "testes" or "gonads")
or little children younger than 2 years who develop leukemia can now expect to be cured of their disease. However, the most common cancers that
affect patients-- breast cancer, colon cancer, lung cancer, prostate cancer-are still not curable when the disease is advanced. We still don't have
enough information about these tumors-for example, how they get started, what makes them escape the body's immune defense system and keep
growing-to develop weapons powerful enough to prevent or kill them.
Because cancer is the second leading cause of death in the United States, the US government began a "war on cancer" some 27 years ago.
President Richard Nixon signed the Cancer Act on December 23, 1971. While it may sound trite (need 6th grade word), our study of cancer is
very similar to a war. Think about our recent "Desert Storm" war. Remember those detailed interviews with the military experts who told us how
a war is fought and about the different "fronts" on which a war is fought? The war on cancer is fought on many "fronts" at the same time.
The "fronts" on the War on Cancer
First, we need information (the military folks call it "intelligence") about the enemy. This is the part of cancer research called "Tumor Biology".
Often this involves scientists working with pieces of tumor tissue in laboratories. However, some aspects of "tumor biology" are familiar to all of
us. Can you recall all the excitement when TV and radio journalists reported on the discovery of the chemicals that stopped tumors from growing
blood vessels to feed them? David Letterman joked that the entire population of mice in the United States had a celebration when these reports of
Dr Judah Folkman's "angiostatin" showed that large tumors in mice could be shrunk to the size of a sesame seed and not kill the mouse. Many
research trials involve getting pieces of tumor tissue and studying it for the presence of certain chemicals. Treatments can be developed from this
information. For example, if a certain chemical or gene (a part of the chromosomes-see the dictionary at the end) is present, then another chemical
can be given to inactivate it. This is part of what we learned from the studies about the "HER-2" gene. With the addition of the US government
funded project to "decode" all the chromosomes in humans (this is "HUGO", the "HUman Genome PrOject"), we are learning in minute detail
about how we are made and how we can be vulnerable to changes in our chromosomes that can cause cancer. This project is producing incredible
amounts of information. However, imagine being in a room with 10 TV sets all ON and all tuned to different stations. You can't absorb all of the
information at once. It will take our scientists time to figure out how all of this fits together so it can be used to prevent and fight cancer.
The second "front" for the war on cancer is testing new weapons. Like Desert Storm, this usually involves "chemical warfare". Many of the best
weapons we currently have are chemicals that affect growing cells, usually called "chemotherapy". However, information from the first type of
research studies about the biology of the tumor, have given us new weapons recently that are not chemotherapy. For example, we have antibodies
for lymphoma ("Rituxan®"-generic "rituximab") and a "bone protecting drug" ("Aredia®"-generic "pamidronate") for multiple myeloma and
breast cancer.
How are new treatments or medications tested to prove they are safe and will work?
Preclinical testing: The "pre" means "before". "Pre-clinical testing" means testing BEFORE humans are treated. There are 2 parts to this:
- In Vitro Before any medications are EVER given to patients, they are tested in test tubes against cancer cells. We call this part the "in vitro"
tests. "Vitro" is the Latin word for "glass" which refers to the glass test tubes. If these cancer cells die, then the drug "passes" and the next
phase, In Vivo, testing begins.
- In Vivo In this phase, the drug is tested against tumors that are present in mice or rats or other animals. We call this part the "in vivo" tests.
"Vivo" is the Latin word for "living". The drug is tested against tumors living or growing on animals.
The In Vivo tests also have 2 purposes.
- First, to determine how powerful the medication is against tumors that are growing on the animals.
- Second, to determine what side effects the medicine will cause. In this part, the medication is almost always given to dogs. For some reason,
dogs are very sensitive to any medication that causes vomiting. If the dog can tolerate the medicine without vomiting, then it is very likely the
medication will not cause vomiting in people.
Testing in Humans: The Phase I, II, and III Trials
There are three "phases" of testing new drugs or treatments. Each of them has a different purpose.
Phase I The purpose of the phase I trial is to figure out what is the highest dose of medication that can be safely given to humans. We call this the
Maximum Tolerated Dose. Researchers look at the amount of medicine that could be safely given to dogs and mice. There is a formula
converting the dose from mice to men. Then, usually only 10% of the dose that causes serious side effects is given to the human patient.
Generally, 3 patients are treated at the same dose and then the doctors wait to see what effects the medication has on them. If there are no effects,
then the next group of 3 patients get double the dose, and so on.
Side effects are measured by a very detailed scale developed by cancer researchers. This scale is available on-line at www.nih.National Cancer Institute.gov. Basically,
it classifies or "grades" the side effects as NONE (grade 0), MILD (grade 1), MODERATE (grade 2), SEVERE (grade 3), or LIFE-THREATENING (grade 4).
When the patients begin to have side effects that are moderate (grade 2), then the next group of patients will get a smaller increase, and so on, until
severe or life-threatening side effects (grades 3 and 4) are seen.
When grades 3 or 4 side effects are seen, the records are reviewed carefully to assure that they are caused by the drug and not by some unusual
reason related to the patient. For example, if the doctors noticed that the only patients who had severe lowering of the blood counts were the ones
who had received radiation treatments previously, then they would only test that dose-level in patients who had NOT received radiation treatments.
Most studies have a rule that if 2 or more patients treated at a certain dose-level develop grade 3 side effects, then that dose is too high for safe
administration. We call those effects DOSE-LIMITING TOXICITY ("DLT" for short). The dose-level just below that is declared to be the
MAXIMUM TOLERATED DOSE and the phase I part is declared "Done".
Phase II The purpose of the phase II trial is to administer the medication at the Maximum Tolerated Dose (MTD) to a certain group of patients to
see how many have tumor killed or shrunk. We call this "determining the objective response rate".
Most phase II trials will start with a small number of patients, like 14. If 1 or more of the 14 patients has tumor shrinkage, then another 14 to 20
patients are treated so that the doctors can get a more accurate picture of how effectively the drug kills tumors.
The types of patients treated in the phase II trials are usually patients with only one kind of cancer and the number of types or previous treatments
the patients may have received is also specified. For example, in the first phase II trial of Taxol (paclitaxel) that was done at M. D. Anderson
Cancer Center, I treated patients who had metastatic (spread) breast cancer who had only received 1 previous chemotherapy treatment and only
small amounts of radiation.
Again, the side effects are "graded" to see if anything new turns up that wasn't seen in the phase I trials.
Generally, the medication is tested in many different phase II trials. Often the timing of drug administration or retreatment is changed in different
studies. This allows doctors to figure out if certain "schedules" as they call them are better than others. For example, when I first gave Taxol, we
gave it by a slow drip over 24-hours. Other researchers have shown that it can also be given over 1-hour or 3-hours and still be effective.
Phase III The aim of this trial is to compare the anti-cancer effectiveness of the new drug to that of standard treatments. For example, in breast
cancer, the new drug Xeloda® (generic is "Capecitabine") was compared to a standard combination of three drugs that is routinely given to patients
with breast cancer. The "acronym" or abbreviation for that drug combination is "CMF" which stands for Cyclophosphamide, Methotrexate, and
Fluorouracil (You can see why we use the "CMF" abbreviation!).
The only proper way to compare 2 treatments is to do a "randomized" trial. A "randomized" trial means that the patient is assigned to take either
the NEW treatment or the STANDARD treatment "at random". Generally this is done by a computer program. The purpose of this is to avoid
"bias" which could cause a false result.
 For example. Say that your doctor tells you about a phase III trial of preventive chemotherapy for
breast cancer after lumpectomy or mastectomy. This trial compares a standard treatment like
"CMF" to a new drug called "Tumorex". From the phase I and II trials, you know that "Tumorex"
is a very good tumor killer, but that it has LOTS of side effects. Since your tumor did not spread
to any lymph glands and was less than 1 inch in size, you figure that you could probably do just as
well with the standard treatment, "CMF" and not mess with all the possible side effects of
"Tumorex". Well, if every patient who was offered that trial did that, then only patients with very
aggressive tumors would get "Tumorex" and only patients with "wimpy" tumors would get "CMF".
That means that the trial would not be a FAIR comparison because trial was "biased". That is, the
group of patients who got "Tumorex" had much worse tumor and were not at all similar to those
who got "CMF". It would be like comparing apples and oranges-we wouldn't learn whether or not
"Tumorex" was better or worse than "CMF".
Who can perform clinical trials? I mean-are they safe? Who checks to make sure that patients don't receive dangerous treatments?
In the past, almost anyone could decide to perform a clinical trial. Unfortunately, many abuses occurred in this situation. Most of these abuses,
fortunately, were not serious. However, some very serious abuses DID occur. The most famous example was the Tuskagee Syphilis Experiment
for which our President recently apologized to the survivors and relatives.
In the Tuskagee Syphilis Experiment, researchers wanted to see what would happen to patients who did not get treatment for syphilis. At that time,
there were effective treatments available-penicillin. At a state-sponsored clinic for patients who received free medical care because they were poor
("indigent"), a group of patients were diagnosed with syphilis. Syphilis is a disease caused by an unusual type of germ called "Treponema
pallidum". This germ lives in the body for long periods of time. It can be passed by sexual contact and from mothers to babies in the womb. It
can causes effects in ALL parts of the body. The most common parts are: skin, lymph nodes, bones, teeth, nerves, brain. However, it can cause
inflammation reactions anywhere (called "gummas"). If a "gumma" occurs in a serious area, like the pacemaker part of the heart, for example,
patients can develop heart block. This is definitely NOT a germ to let wander around in ANYONE's body without treatment.
Anyway, these researchers never told these patients that they had this disease. Even though they treated them for all of the other disease they got,
like diabetes, high blood pressure, and so on, they never treated them for the syphilis. Most of the patients died. However, many of them passed
the syphilis to their wives or husbands or children causing injury or sickness in them.
THIS WAS WRONG! No patient should ever be denied standard treatment without being advised of the consequences of it in language he or she
can easily understand. Similarly, it is a "standard of care" that no patient should ever be given a treatment-- even a standard treatment-without
their permission. Nowadays, the LAW requires that a patient sign an INFORMED CONSENT document before any procedure.
 What an "Informed Consent" document should explain
- the reason for the treatment
- the risks of getting the treatment
- the risks of not getting the treatment
- the expected benefits of the treatment
- possible bad effects of the treatment
Institutional Review Boards "IRBs"
The LAW requires that all organized bodies that perform clinical research (test new treatments or devices in human subjects), have a committee to
review all possible research trials. This committee is called an Institutional Review Board or "IRB". The IRB must have people who understand
medicine (doctors, nurses or pharmacists) as well as people who represent the interests of patients (social workers or psychiatrists or lawyers or
ministers, and so forth). None of the people on this board are allowed to have a finaNational Cancer Instituteal connection with the research trial in question. In fact, the
LAW requires a full resume on each member of the IRB. Each member is required to declare if he or she has a finaNational Cancer Instituteal interest in any of the trials
being reviewed.
The job of the IRB is to review any trial that is proposed for the patients it supports. For example, every hospital that does clinical research, like
Memorial City, has an IRB. What the IRB evaluates:
- Is the trial medically reasonable? Is there a good scientific reason to use this new treatment or to compare it to an older treatment?
- Is the trial safe? Will patients be taking a big risk if they receive this new treatment? If the treatment is risky, is it still a reasonable trial
because either there is no effective treatment available or because the available treatments don't work very well. An example of this situation is
some of the early trials of the medications for AIDS.
- Does the trial have an Informed Consent document that the patient must sign? Is this document understandable to the average lay person?
Should I be treated on a clinical trial?
The short answer is, "Yes" but with much explanation.
At the present time, only about 2 out of every 100 patients who are diagnosed with cancer are treated on a clinical trial. Most patients who require
treatment for their cancer get "standard treatment". However, we know that the current "standard treatment" programs are not 100% curative for
most patients. The only way we will get more effective treatments is to test them in phase I, II, or III clinical trials.
Why don't more patients participate on clinical research trials?
Patients list many reasons. Here are some:
"I don't want to be a Guinea pig."
Many patients don't understand the purpose of clinical trials and especially the different "phases" of testing. Also, in previous years, the
safeguards for patients were not as effective. Today, most clinical trials have very strict guidelines and supervision. However, voluntary consent
is critical to clinical trials. If a patient does not wish to be treated on a clinical trial, he or she SHOULD NOT be badgered into it.
"There aren't any experimental drugs for my condition."
This may well be true for a number of patients. As mentioned above, each trial has certain requirements for the patient. For example, the number
and types of previous chemotherapy or radiation treatments. Also, the "stage" of the tumor is usually specified. For information on "tumor
staging", see...
"You have to go to a Cancer Center to get experimental drugs. I don't want to travel anywhere."
That USED TO BE TRUE. Not anymore. Many doctors right here at Memorial City Memorial Hospital are members of research groups which
are testing new treatments that they can give to patients right in their offices.
"I don't know what drugs are being tested for my condition. How do I find out about investigational studies?"
It is difficult for every doctor to be aware of all the research trials that may be suited to your situation. For this reason, you may wish to refer to
registries of clinical trials. The US government has extensive resources through the National Cancer Institute. You can access these national lists
of protocol studies through a number of sources: the web, by telephone, by fax. The following is a list of the US goverment resources:
National Cancer Institute Clinical Trials Resource Web site: http://cancerTrials.nci.nih.gov
National Cancer Institute Cancer Information Service:
Web: http://www.nic.nih.gov
Phone: 1-800-4-CANCER will answer with a recorded message with these options by pressing number
1 Recorded information about news items and other cancer topics
2 Order publications
3 Locate an FDA-certified mammography facility
4 Speak with cancer information specialist Monday thru Fri 9A to 430 pm local time
National Cancer Institute CancerFax:
Automated fax service that provides cancer info from National Cancer Institute including PDQ (Patient Data Query). This service is available 7 days a week and in English AND Spanish.
Phone: 1-301-402-5874
Call from a telephone on a fax machine and the fax machine must be set to touch tone dialing. If you do not have a phone/fax, call 1 800
422 6237
Clinical Trials in the United States:
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This government sponsored web site lists clinical trials throughout the
United States.
http://www.cancer.gov/clinicaltrials
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This government sponsored web site lists the clinical trials available at
the National Cancer Institute in Bethesda, MD
http://bethesdatrials.cancer.gov
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