• What are clinical trials?
  
• Why use clinical trials?
  
• Won't I be just a guinea pig?
  
• Placebos
  
• How are clinical trials run?
  
• Where are clinical trials run?
  
• How can I find trials for colorectal cancer?
  
• Why research trials on your own?
  

The National Cancer Institute recommends that if you have stage II or higher colorectal cancer, or colorectal cancer that has not responded to standard treatment or that has relapsed, examination of clinical trials may be very much worth your while.

Nonetheless, all colorectal cancer survivors should become familiar with methods for finding 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.

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.

There are many kinds of clinical trials. The ones that usually interest most colorectal cancer survivors are the ones that focus on treatment, but trials also exist to improve cancer support, detection, and prevention. A clinical trial can test either a new substance, a new combination of substances, a new surgical technique, or a new method for administering treatment.

Clinical trials are designed and structured such 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 are 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 who 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 each individual is unique.
• In a blinded trial, not only are patients randomized, they also are unaware of which treatment they're being given. 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 it's truly measurable, while others believe 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 being given to 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 being given. The doctor writing orders as outlined by the trial's protocol is aware, though, as he or she must be prepared to deal with side effects that arise. Double-blinding is used to eliminate the possibility that subtle factors, such as motivation and mood on the part of the nursing staff, might be sensed by the patient. 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 previous 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 trials both randomized and double-blinded currently in NCI's clinical trials database:

• Phase II randomized, double-blind, placebo-controlled study of high-dose folic acid for the prevention of colorectal cancer in patients with resected adenomatous polyps
• 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 Dronavinol versus both in patients with cancer-related anorexia and cachexia
• Phase III randomized double-blind study of intratumoral CDDP/Epinephrine injectable gel for recurrent or refractory squamous cell carcinoma of the head and neck

In these respects, clinical trials differ from less rigorous tests designed and administered by doctors and researchers working independently on new substances in for-profit 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--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 may or 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. For example, a monoclonal antibody treatment for colorectal cancer, Panorex, has been available for several years to those with colorectal cancer who were willing to enroll in clinical trials testing this substance. Intron-A, a manmade version of interferon-alfa, a human body product that fights infection and cancer, was approved by the FDA in December 1997, but was used by patients in clinical trials for years beforehand.

Steve Dunn is a nine-year survivor of metastasized kidney cancer. In CancerGuide, he tells of his difficult experience with this cancer, which, prior to the availability of interleukin-2 therapy developed at NCI, had five-year survival statistics in the 2 to 3 percent range. Like most of us, 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, 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 on 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 when, and what action will be taken if certain undesirable effects occur. You should always ask for a copy of the full protocol, and read it thoroughly.

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 there still remain cases of patients being 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 colorectal cancers progress fast enough to require a same-day, or even a same-week, decision.

• Always ask that the consent forms and the protocol be sent to you well in advance of your scheduled visits.
• 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 being treated in a for-profit hospital that receives no government support, it's 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 NCI, 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 it 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--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 purged using an experimental technique.

How are clinical trials run?

Clinical trials are organized into three stages: phase I, phase II, and phase III. Each phase attempts to address different and increasingly complex issues concerning the success of the new treatment. Some drugs are tested in trials that are a combination of two phases, such as phase I/II or phase II/III. Usually this is done if some knowledge of the new treatment's effect in humans is already known so that its development and testing can be expedited.

There may be clinical trials in which you can participate locally on an outpatient basis, but many require travel and in-patient stays.

Phase I clinical trials

The primary purpose of a phase I clinical trial is to measure the safety and toxicity of different doses of a new substance in the human body. Some phase I studies may also assess tumor response, therapeutic effectiveness, the amount of drug that accumulates in the body, and a substance's general behavior (pharmacokinetics) in the body.

Phase I trials are preceded by animal studies that measure toxicity, so an estimated safe human dose is already known. Rigorous controls are enforced to be sure that no patient suffers adverse effects. For example, blood or urine values of certain body substances may be measured several times a day to ensure that the liver and kidneys are not compromised. Doses that are found to be unacceptably toxic are lowered.

Phase I trials usually enroll just a few patients, perhaps ten to thirty. Often these patients have a variety of different cancers. Sometimes one cohort of patients will receive only a low dose of the drug, and a different group will receive higher doses, but in other studies, the same patients who initially receive a low dose may be given a higher dose later if toxicity is not too profound.

The advantages of a phase I trial are:

• You may receive a treatment that may be better than anything else currently approved by the FDA years before it becomes available to the general public.
• If this drug is already in use for other illnesses, its toxic effects might not be completely unknown.
• Candidate substances for cancer treatment are not approved for phase I trials unless the substance has shown reasonably acceptable toxicity, and activity against cancer, in cultured tumor cell lines and in animal studies. Of every 5,000 substances tested in animals, only 5 enter phase I trials.
• Doses found to cause unacceptable toxicity are lowered.

The disadvantages of a phase I trial are:

• For every 100 drugs tested in phase I trials, only 70 will prove successful or safe enough to carry forward into phase II trials.
• Because phase I trials are chiefly concerned with discovering dose-limiting toxicity, they are brief compared to phase II and III trials. You may receive too few doses of the test substance to destroy all of your cancerous cells.
• Phase I trials usually test one substance alone, yet experience has shown that, at least for the chemotherapeutic agents commonly used today, combined drug regimens are more effective against most cancers than single-drug regimens.
• The substance, although it may be an approved drug for other illnesses or even for other cancers, most likely has never before been used in humans for your illness. Although it has been tested in cultured tumor cell lines, and in animals implanted with tumors, it may not be effective against your tumor, or it may be no better than existing treatments.
• The substance, although it may be an approved drug for other illnesses or even for other cancers, may be administered to you at a much higher, more toxic dose.
• The dosage will be varied among those enrolled, thus its effects on your tumor may not be directly comparable to the effects on the tumors of others enrolled in the trial ... and patients do talk among themselves.
• The use of patients with different tumor types makes it difficult for you to compare your progress to that of other patients.
• Toxicity may cause substantial discomfort, illness, or permanent damage, in spite of the safeguards designed to prevent damage.
• Often phase I trials are run by one principal investigator at one institution. You may have to travel to participate in a phase I trial.

Here are the titles of a few phase I trials for colorectal cancer selected from the NCI clinical trials database. Note that the titles state the phase number, and at this phase make no reference to randomization or blinding. Don't be distracted by the overly technical verbiage in these titles. You'll become more familiar with the terminology as you read more about your illness:

• Phase I Pilot Study of Flt3 Ligand Prior to Resection of Hepatic Metastases of Colon Cancer
• Phase I/II Study of Irinotecan and Radiotherapy in Patients with Unresectable or Locally Recurrent Large Bowel Cancer
• Phase I Study of Iodine I 131 Humanized Monoclonal Antibody A33 in Patients with Advanced Colorectal Carcinoma
• Phase I Study of Sequential ICI D1694 and Fluorouracil in Advanced Colorectal Carcinoma
• Phase I Study of Oral Capecitabine as a Radiation Enhancer in Patients with Locally Unresectable, Residual, or Recurrent Colorectal Cancer Localized in the Pelvis

Phase II clinical trials

Phase II trials measure the effectiveness of new treatments against cancer after phase I trials have demonstrated the maximum safe dose. Some phase II trials also attempt to measure how best to deliver the drug to the tumor--orally, by infusion, and so on--and how often the dose should be given.

Phase II trials enroll many more patients than phase I trials, perhaps 15 to 80, so that the substance will receive a more thorough test and the statistics collected will be more meaningful.

Sometimes, but not always, phase II clinical trials are divided into arms, with one arm getting one version of the experimental treatment and a second arm getting another--perhaps the same experimental agent combined with an established, FDA-approved cancer-killing drug, or delivered by another route, or on a different dose schedule.

Because some phase I trials seek preliminary evidence of efficacy against disease, a clearer idea might exist regarding what cancers will benefit most from this treatment when it's used in a phase II trial.2 Nonetheless, the types of cancers that will be addressed in a phase II trial usually are determined by the researchers designing the trial. Sometimes parallel phase II trials for different cancers will be designed and funded.

Phase II trials take more time than phase I trials because, unlike phase I trials, more of the new agent is administered for a longer time in an attempt to cause tumor regression.

The advantages of a phase II trial are:

• Candidate substances for cancer treatment are not approved for phase II trials unless phase I trials have shown that the substance is safe at a given dose and, in some trials, that the substance has some activity against cancer in humans.
• You'll be receiving a treatment that may be better than anything else currently approved by the FDA several years before it becomes available to the general public.
• Only doses of acceptable toxicity, determined during phase I testing, are utilized.
• Randomizing and blinding usually are not used in phase II trials. Therefore, you are assured of receiving the experimental treatment.

The disadvantages of a phase II trial are:

• More than half of the drugs used in phase II trials will be found ineffective against cancer or too problematic for use. Of the original 100 drugs that entered phase I trials, of which 70 survived to pass to phase II, only 33 will survive phase II testing.
• The substance, although it may be an approved drug for other illnesses or even for other cancers, may not prove to be better than existing treatments for your illness.
• Although its toxicity was determined in the phase I trial of this substance, the substance is still an evolving treatment with the potential for unexpected side effects.
• More of your time will be needed for a phase II trial than for a phase I trial.
• You may have to travel to participate in a phase II trial.

Here are a few examples of phase II trials for colorectal cancer selected from the NCI clinical trial database. Note the occasional use of randomization, and the trend toward fewer cancer types being eligible, as opposed to phase I trials:

• Phase II Study of Flavopiridol in Patients with Metastatic or Recurrent Colorectal Cancer
• Phase I/II Study of Amifostine as a Protective Agent for Irinotecan Toxicities in Patients with Metastatic Colorectal Cancer
• Phase II Study of MOAB 17-1A/GM-CSF for 5-FU-Resistant Metastatic Colorectal Cancer
• Phase I/II Study of Active Immunotherapy with Carcinoembryonic Antigen RNA Pulsed Dendritic Cells in Patients with Resected Hepatic Metastases from Adenocarcinoma of the Colon

Phase III clinical trials

Phase III clinical trials test a new substance's efficacy compared to existing standard treatments.

Phase III trials are much larger than phase II trials, and are almost always multi-center trials--that is, trials run in many sites simultaneously. They run for years, including perpetual follow-up of the patient's cancer status and overall health.

The large number of patients in a phase III trial tends to flatten any aberrant statistics that result from patient differences that lessen the usefulness of statistical data collected in a smaller trial. For this reason, patients in a phase III randomized trial can be of various ages and both sexes, for example, as long as they're all colorectal cancer patients, or all lymphoma patients, and so on.

Phase III trials are almost always randomized (case-control studies are not), but are rarely blinded or double-blinded. When blinding is used, patients might discover which treatment they're receiving based on side effects, comparison in conversations with other patients, or other overt or subtle phenomena.

The advantages of a phase III trial are:

• A substance that has survived the scrutiny of phases I and II is very likely to be better than current treatments: either more efficacious, or equally effective but less toxic.
• You'll be receiving a treatment that may be better than anything else currently approved by the FDA a year or two before it becomes available to the general public.
• If, during the trial, a new treatment shows itself to be profoundly superior to existing treatment, those receiving the existing treatment are switched to the arm of the study utilizing the new substance.
• If a new treatment shows itself to be clearly or dangerously inferior to existing treatment, those receiving the new treatment are switched to the standard treatment regimen.

The disadvantages of a phase III trial are:

• Of the 33 drugs that survived phase II testing, only about 25 will be found effective in phase III trials.
• Randomizing and blinding may not appeal to those who are determined to receive only the new treatment, not the contrasting current treatment.
• The new substance may prove to be just as effective as, but no better than, the existing treatment.

Here are a few examples of phase III trials for colorectal cancer selected from the NCI clinical trials database:

• Phase III Postsurgical Maintenance Immunotherapy with Corynebacterium granulosum P40 for Patients with Colon and Breast Cancer and Melanoma Residual Following Surgery
• Phase III Randomized Study Comparing Two Adjuvant Chemotherapy Regimens with Fluorouracil and Leucovorin Calcium in Patients with Stage II or III Colon Cancer
• Phase III Randomized Study of Conventional Versus Laparoscopic-Assisted Surgery for Colorectal Cancer
• Phase III Randomized Study of Leucovorin Calcium Plus Fluorouracil with Either Irinotecan or Oxaliplatin in Patients with Recurrent Metastatic Colorectal Cancer
• Phase III Postsurgical Maintenance Immunotherapy with Corynebacterium granulosum P40 for Patients with Colon and Breast Cancer and Melanoma Residual Following Surgery

Which phase is best?

This article cannot offer you absolute advice about which type of clinical trial is best for you. This decision should be made only by you and your treatment team. Several aspects can be considered, though:

• A phase III trial that offers randomization to either standard therapy or a new therapy might be the choice that's right for you. The relative safety of receiving a known regimen might be reassuring to those who discover that they have not been randomized to the new treatment arm.
• A phase III trial in which all patients receive the new drug and only an ancillary feature of treatment (such as one antibiotic against another to control infection) is randomized might be as good a choice as a phase II trial of a less well-known substance.
• A phase II trial of a very promising substance might appeal to patients who find phase I trials too risky and phase III trials too controlled.
• A phase I trial of a drug with a long, safe history of use for another illness might be a reasonable choice for you if animal studies have shown that the agent is active against colorectal cancer and if you have tried several other treatments without success.

Where are clinical trials run?

Clinical trials are found most often at the NCI-designated Comprehensive Cancer Centers and Clinical Cancer Centers, and at other university medical hospitals that receive federal funding and cooperate with NCI on clinical trials. Your community oncologist may participate through association with NCI's community clinical oncology programs.

How can I find trials for colorectal cancer?

If you're an adult with colorectal cancer, you must take an active role in finding the best care for your disease. Adults with cancer are seldom asked to join a trial unless they are being treated in a regional cancer care center. The approach is different from that used for children with cancer, whose families are commonly approached regarding enrollment in clinical trials, and 75 percent of whom eventually are enrolled in clinical trials. The NCI estimates that less than 5 percent of adults eligible for clinical trials enroll, and that minorities are underrepresented in the clinical trial process.

You can use several methods to find clinical trials:

• You can ask your oncologist which trials would suit your medical circumstances. This has its advantages and disadvantages, one advantage being that you need do very little except trust. The disadvantages are described later in the section called "Why research trials on your own?"
• You can call the National Cancer Institute at (800) 4-CANCER and ask about trials for your subtype of colorectal cancer, being sure to specify whether you're willing to travel--otherwise they'll send you local trials only. Be sure to ask for the full document, not the summary. Be warned that if you call often with this request, which is not an unreasonable thing to do, because new trials are added every month, eventually they may decline to send you any more listings. This has been the experience of some cancer survivors who've used this service, which is provided by various regional cancer care centers under the auspices of NCI.
• You can research US and international clinical trials on your own at the NCI's web site. This, in conjunction with learning to use Medline, is by far the most comprehensive way to check on new treatments being tested. This service alone may be worth the cost of a personal computer and the time spent learning to use it. Once available only to those who subscribed to the NCI's Information Associates' program for $100 per year, now the NCI provides this tool free of charge on the Internet.

We strongly suggest that you examine all trials available for colorectal cancer, not just those in your area. At the time of this writing, the URL for the protocol search geared to physicians (another, less edifying tool is available for patients) is: http://cnetdb.nci.nih.gov/trialsrch.shtml.

• You can use CenterWatch on the Internet to track new cancer treatment trials. CenterWatch has improved their service greatly in the last few months, adding new information showing what agent is being tested and at what center the trial is being held, instead of only a general trial title and city. (This additional information is imperative if you're searching for trials at a top-notch cancer center in a large urban area.) The listings are still by state, however, forcing you to review some of the same information over and over for each state if you're willing to travel and want to be familiar with all trials available. The web address for CenterWatch is: www.centerwatch.com.
• You can use the services of commercial Internet service providers such as America Online (AOL) to receive email press releases from pharmaceutical companies concerning new products in development. Be aware, though, that press releases often will simply echo in less detail the medical information you may already have found elsewhere. Furthermore, press releases typically are written to attract or reassure investors, rather than impart information to cancer survivors.
• To find trials specifically for children, you can search the National Childhood Cancer Foundation site in addition to the NCI site listed earlier.

Why research trials on your own?

Some people who have depended only on their oncologists for comprehensive and up-to-date information on clinical trials have been disappointed. In many cases, oncologists in clinical practice--and that means most oncologists--are aware only of the high-priority trials that receive emphasis in publications such as Oncology Times, or those that are offered nearby. Some still do not use a computer to search the NCI's database for all applicable trials. Perhaps they haven't the time to do so: remember that most oncologists in the trenches must track information on every cancer known, whereas you have the opportunity to focus intensely on your own cancer, subtype, and stage.

At the other end of the colorectal cancer oncologist spectrum is the oncologist associated with a university medical school or cancer research center. You can usually expect very good to excellent treatment from such a specialist, but often when consideration of clinical trials is appropriate, they may be biased toward their own research, or toward trials run by colleagues at their own institution.

The following story is an all-too-common example of our need to educate ourselves about clinical trials:

Several months ago I had a phone call from a friend who now has a second cancer, a lymphoma, following treatment as a child for bone cancer. She thanked me for sending her information on the FDA's approval of a new monoclonal antibody treatment for lymphoma.

She was originally enrolled in an antiviral trial at a prestigious East Coast cancer center, but the trial was halted following concerns about safety. When she showed her doctors the information on the new monoclonal antibody, they immediately put her on it. "They had never heard of it," she said. Today, ten months later, she continues in remission.

The ideal oncologist is one somewhere in the middle: educated about all trials and aware of what's a good fit for you, but not biased toward her own work or that of colleagues.

Life doesn't often approach the ideal, so it's a good idea to learn to search for clinical trials on your own, and to repeat your search every month, because new trials are constantly opening. Once you have found a trial for which you believe you qualify, you should bring it to your doctor's attention. Suppose you find several trials that seem to admit patients with your profile? How can you tell which trial would be best for you? Clearly this is one of the most important questions that will arise in your experience with colorectal cancer.

At this point, you need to acquire skills for searching Medline and reading the studies that result from your searches. The substances used in each clinical trial may have results published regarding their previous use in animals or in humans. These studies should be found, evaluated, and compared, by you and your doctor, to single out the substance most likely to benefit you. Detailed techniques for searching Medline are discussed in Chapter 24, Researching Your Illness.

If your oncologist is unwilling to help you, is negative, or is at best ho-hum about your proactive attitude toward searching for trials, find a new doctor, because you'll need a doctor's recommendation to get admitted to a trial.