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Why would anyone choose an experimental therapy over standard lung cancer treatments that have well-known risks? Aren't clinical trials of new treatments dangerous? Aren't these experimental treatments just for people who have no other choices left? And why are they called clinical trials?
Lung cancer is the subject of a great deal of very promising research. These new and possibly better treatments are available to lung cancer survivors in carefully controlled settings called clinical trials.
Many of the treatments now in the pipeline are of very low toxicity, unlike some traditional, standard chemotherapeutic agents. Many experimental treatments, such as monoclonal antibodies, use natural cancer-fighting body products that are amplified outside the body and then reinserted. Others, such as idiotype vaccines, use your own white blood cells that are retrained to attack tumors. Other treatments aim for and destroy the parts of the cancer cells chromosomes that make cancer cells immortal.

In this chapter, we discuss the structure of clinical trials, how they're run, their advantages and disadvantages, safeguards for the patient, and your rights as a patient. We show you why its often to your advantage to do your own searching, instead of relying on trials your doctor may recommend, and how to evaluate different trials. We explain what to expect and what to do when you're finally enrolled in a trial.
This chapter focuses on finding and evaluating clinical trials for treatment, not for support, prevention, or detection. For the sake of readability, we will use the word "substance" throughout this chapter, with the understanding that either new substances or new methods can be the objects of testing.
For more information on clinical trials, see Robert Finns book, Cancer Clinical Trials (O'Reilly, 1999).

Who should examine clinical trials?
The National Cancer Institute recommends that if you have any stage of small cell lung cancer, or non-small cell lung cancer at a stage beyond IA, examination of clinical trials may be very much worth your while. The factors that contribute to this statement are discussed at length in Chapter 6, Prognosis.
All lung cancer survivors should become familiar with methods for finding clinical trials and with the general structure and function of trials. If you wait until you need a trial to attempt to learn these things, you may run out of time.
Geri Capasso, whose brother Anthony participated in a clinical trial, reinforces this need for preparedness:
No matter which treatment you're on, find out how they are measuring the results and, as soon as it’s not working, be ready with a second line of treatment. We sent my brother's tumor cells to the Weisenthallab in California for chemosensitivity testing, and he is now on weekly Taxol with daily thalidomide. There have been a few articles about some work with low-dose, more frequent chemo, which seems to lessen the adverse side effects and seems more effective. Don't hesitate to speak to the oncologist about symptoms.

What are clinical trials?
Clinical trials are the tests by which new treatments are evaluated to see if they offer more benefit than existing treatments. Success of a new treatment in the highly structured, controlled environment of a clinical trial is required by the US Food and Drug Administration (FDA) before treatment can be approved for wider use by doctors and patients in less controlled settings. When clinical trials show that a new treatment is better than older, standard care and these results are verified by objective third parties, the treatment that was used in the clinical trial becomes the new standard for care.
Clinical trials are tests run in the clinic, or, more clearly stated, on humans. The word "clinical" distinguishes these trials from tests done on tumor samples or on animals. Clinical trials are not started on humans until a substance has shown promise when tested first on human tumor samples and then on animals, usually mice.
Clinical trials are designed and structured so that the results can withstand the minute and critical scientific scrutiny necessary to determine if a new treatment is effective. Three study designs that aid in ensuring that the results of treatment are attributable to the new agent and not to chance or confounding factors include randomization, blinding, and double-blinding. Blinded and double-blinded trials are rare in the testing of new cancer therapies, but an explanation of these concepts is included here so that you will be well informed should you be asked to participate in a blinded trial:
• A randomized trial is one in which a large number of patients with the same disease are assigned via computer to receive either the new treatment or existing, standard treatment. This means that you might not receive the new substance at all. Randomization is used to demonstrate as clearly as possible that a group of similar patients did either better or worse, and that only the treatment given explains the difference in outcome. The ideal randomized clinical trial would treat only patients that are alike in every respect except for the treatment given. This would ensure that the only difference that accounted for success or failure is the treatment used. In reality, this regimentation is not possible because patients are human beings who might differ in many respects.
• In a blinded trial, not only are patients randomized, they also are unaware of which treatment they're receiving. This is considered necessary to rule out the placebo effect, defined as the ability of the human body to respond differently to treatment in measurable, physical ways, based on complex psychological and motivational factors experienced by the patient. Some patients might respond better to a treatment, for example, simply if they know they're getting a new treatment as opposed to an older one. Passive, compliant patients might report responses that they think will please the doctor and staff. The placebo effect is the subject of some controversy, with some researchers maintaining its truly measurable, and others believing that its supposed effects can be attributed to other phenomena, such as inaccurate metrics or patient subjectivity
• A double-blinded trial is one in which the patients and some of the medical staff are unaware which substance is received by whom. For example, the patient, the nurse who measures vital signs, and the pathologist who examines tissue samples might be unaware of which substance is received. The doctor writing orders as outlined by the trial's protocol is aware, though, because she must be prepared to deal with side effects that arise. Double-blinding is used to eliminate the possibility that the patient might sense subtle factors, such as motivation and mood on the part of the nursing staff. These could account for differences seen in the progress of the group receiving the new treatment compared to those receiving the old-see the placebo effect, described in the preceding paragraph.
• A case-control study is one in which patients are matched on as many characteristics as possible, then one group is given a particular treatment and the other group is not. For cancer clinical trials, the characteristics on which patients are matched are disease characteristics. Very few case-control studies are designed for cancer treatment, although they are for cancer prevention.
Here are examples of cancer trials both randomized and double-blinded currently in the NCIs clinical trials database:
• Phase III randomized, double-blind study of warfarin versus placebo for chemoprevention of thrombosis in central venous access catheters in cancer patients
• Phase III randomized, double-blind study of megestrol versus dronabinol versus both drugs in patients with cancer-related anorexia and cachexia

Because of their trilevel structure, peer-reviewed design, and enforced controls, clinical trials differ from less rigorous tests designed and administered by doctors and researchers working independently on new substances in for-profit cancer clinics. These researchers-some of whom are well respected by the broader medical community, some of whom are not-often lack complete records and consistent evidence that can be verified by impartial observers. Often, their patients are not subjected to the necessary long-term evaluation of five years or more that determines whether the new treatment truly made a sustained difference in patient survival.
In general, if trials are run by a university, an NCI-designated regional cancer center, or a pharmaceutical company adhering to NCI and FDA guidelines, the chances are very good that safeguards for the patient are part of the design and that the substance being tested has been reviewed and approved for use by a committee of responsible and knowledgeable researchers. Therapies offered by independent researchers in their own for-profit clinics, especially those that involve ingesting or injecting an untested substance, should be avoided or, at the very least, approached with extreme caution.

Why use clinical trials?
Aside from the altruistic aspect of participating in a trial in order to benefit others an aspect that mayor may not motivate you-clinical trials offer you a good chance to receive more effective treatment, and perhaps a cure, years before it's available to the general public.

Steve Dunn is a nine-year survivor of metastasized kidney cancer. In Cancer Guide, he tells of his difficult experience with this cancer, which, prior to the availability of interleukin-2 therapy developed at the NCl, had five-year survival statistics in the 2 to 3 percent range. Like most people facing cancer treatment decisions, Steve started at ground zero with no medical background or insider information to assist his search.
Steve's story is available at the CancerGuide web site, http://www.cancerguide.org, one of the best cancer sites on the Internet. His personal story alone is probably enough to convince most people of the benefits of finding the best clinical trial for their circumstances. Moreover, his advice to patients for locating, examining, and choosing a clinical trial is unparalleled in the scientific and lay literature.

Won't I be just a guinea pig?
In the US, the long and not altogether honorable history of the clinical trial process has resulted in laws, procedures, and methods that safeguard the patient. For example, each clinical trial has a lengthy plan, called a protocol, that will be given to you if you ask for it. The protocol describes what will be done and when, and what action will be taken if certain undesirable effects occur. You should always ask for, and read thoroughly, a copy of the full protocol.
Informing the prospective patient and obtaining consent from the patient are time consuming and repetitive processes done to ensure that all risks and benefits are made clear. For example, the patient should be made aware that she can drop out of the study at any time and that care cannot be denied her if she does so.

Unfortunately, sometimes patients are pressured to sign clinical trial consent forms without full information, or at the last minute, without time to consider other options. Remember that very few lung cancers progress fast enough to require a same-day decision.
• Always ask that the consent forms and the protocol be sent to you well in advance of your scheduled visit.
• Do not sign a consent form until you have received and read a copy of the full protocol and have considered all other clinical trials for which you might be eligible.
Only institutions funded by the federal government or governed by pertinent local laws are required to abide by consent guidelines. If you're in a for-profit hospital that receives no government support, its possible for you to be treated in a study without your knowledge or consent, thinking that you're getting standard treatment. Ask your doctor if your treatment represents state-of-the-art treatment as defined by the Ncr or if you're being treated in a study. In addition, phone your state health department to determine if your state has its own laws regarding consent issues.

Placebos
For cancer clinical trials, true placebos are almost never used. A true placebo is a drug or treatment that has been made to look exactly like the active substance or the effective procedure, but has no effect. In clinical trials of antihistamines, for instance, the placebo used most often is a sugar pill.

For randomized cancer treatment trials-usually phase III trials, of which more is said later in the chapter-the new treatment is compared to existing, accepted treatment, not to a placebo. Exceptions to this ethical policy are new treatments for which no corresponding previous treatment exists, such as trials of the earliest efforts to purge bone marrow of cancerous cells prior to bone marrow transplantation. In that instance, standard care was represented by reinfusion of unpurged marrow, and the test treatment involved reinfusion of marrow that was purged using an experimental technique.