If a clinical trial is open for your child’s particular type and risk level of leukemia, within days of diagnosis you will be asked to consider enrolling your child in it. You then must choose between standard treatment and the clinical trial.

Clinical trials are carefully controlled research experiments that use human volunteers to develop better ways to prevent or cure diseases. Pediatric clinical trials attempt to improve existing treatments. A clinical trial can involve a totally new approach that seems promising, or it may fine-tune existing treatments by reducing their toxicity or developing new ways to assess responses to treatment. Many children are needed in each clinical trial for the results to be statistically meaningful.

Sometimes, parents choose to enroll their child in a clinical trial because they want to contribute to better treatments in the future. Other parents may be wary of participating in an experimental program and may opt for standard treatment. There is no right choice. Obtain all the information you can, weigh the pros and cons, and make a decision based on your values and comfort level.

The study that our institution was participating in at the time of my daughter’s diagnosis was attempting to lessen the treatment to reduce toxicity yet still cure the disease. My family began a massive research effort on the issue, and we had several family friends who were physicians discuss the case with the heads of pediatric oncology at their institutions. The consensus was that since my daughter was at the high end of the high-risk description, it was advisable to choose the standard treatment, which was more aggressive than one of the parts of the proposed clinical trial.

Your treatment team may also tell you about studies that are sponsored by pharmaceutical companies, especially those designed to help with the side effects of treatment. Such supportive care trials evaluate antibiotics, antinausea drugs, and new agents to raise blood counts, minimize pain, or control other symptoms. The oversight and control of these trials is entirely different than the oncology treatment studies discussed in this chapter. Ask your doctor or nurse to discuss these studies with you if your child is invited to participate in one.

Types of clinical trials

The three main types of clinical trials for children with leukemia are described below.

Phase I. If laboratory evidence suggests a drug might work in humans, it is first tested in a Phase I study. These studies:

• Examine how the body processes (metabolizes) the drug
• Establish the highest dose that can safely be given (the maximum tolerated dose, or MTD)
• Evaluate side effects

In pediatric Phase I trials, the dose of a new drug is gradually increased in small groups of children until it becomes too toxic; essentially, one small group of children gets a low dose, the next small group gets a slightly higher dose, and so on, until an unacceptable number of children experience unacceptable side effects.

Phase I studies are experiments, and their purpose is not to cure the participants. The true beneficiaries of Phase I studies are future patients. In most cases, parents are not asked to enroll their child in a Phase I study unless all other treatment options have failed. Parents often enroll their children in these trials in the hope that a new and untried drug will be effective against their child’s disease, but they need to recognize that the chances of that are low.

Phase II. Phase II trials test new drugs to see whether they are effective for specific diseases. This is the stage at which many drugs fail—meaning they are not as effective as originally predicted or they have unexpected or serious side effects.

Phase III. These clinical trials determine whether a new treatment is better or worse than the standard therapy. Some Phase III trials are designed solely to improve survival; others are done to try to maintain survival rates while lowering the toxicity of treatment. In pediatric Phase III studies, some children will receive the standard therapy, while others receive the experimental treatment. Some children will derive direct benefit if a new treatment is superior to the standard therapy; other children might be on an experimental therapy that is later learned to not be as effective as the standard therapy.

To ensure the results are accurate, Phase III studies require hundreds to thousands of participants and take several years to complete.

The National Cancer Institute (NCI) offers several resources to help parents understand the clinical trial process. You can call the NCI at (800) 422-6237 or visit its clinical trials website at www.cancer.gov/clinical_trials.

The information in the rest of this chapter pertains to Phase III trials that are reviewed and funded by the NCI. Enrolling in Phase I and Phase II trials is very different, as is enrolling in trials sponsored by pharmaceutical companies.

Design of clinical trials

In 2000, four pediatric cancer research groups merged to form a single pediatric cancer research organization called the Children’s Oncology Group (COG), which is supported by the NCI. Approximately 230 institutions that treat children with cancer are members of COG (www.childrensoncologygroup.org). Researchers from these institutions contribute to the design of new clinical trials for children with cancer. In addition, the NCI and some large children’s hospitals design their own clinical trials for children. When designing pediatric clinical trials, the first priority is to protect the children from harm. Researchers are ethically bound to offer treatments they think will be at least as safe and effective as the standard treatment.

Study arms

Phase III clinical trials sort participants into different groups that receive different treatments (called arms). Every Phase III trial has one arm that is the current standard treatment, called the standard arm. Each of the other arms contains one or more experimental components, such as the following:

• New drugs
• Old drugs used in a new way (e.g., different dose or new combinations of old drugs)
• Duration of treatment that is shorter or longer than standard treatment
• The addition, deletion, or change in dose or timing of certain treatments (e.g., radiation therapy)
• The use of new supportive care interventions (e.g., preventative antibiotics or new drugs to control nausea)

Once the trial is complete, the effectiveness of each experimental arm is compared to the standard arm.

Randomization

Phase III trials require a process called randomization, meaning that after parents agree to enroll their child in a clinical trial, a computer randomly assigns the child to one arm of the study. The parents (and the doctors) will not know which treatment their child will receive until the computer assigns one. The purpose of computer assignment is to ensure that children are evenly assigned to each arm without bias from doctors or families. One group of children (the control group) always receives the standard treatment to provide a basis for comparison to the experimental arms. At the time the clinical trial is designed, there is no conclusive evidence to indicate which arm will be superior. As a result, it is impossible to predict whether your child will benefit from participating in the study.

We had a hard time deciding whether to go with the standard treatment or to participate in the study. The “B” arm of the study seemed, on intuition, to be too harsh for her because she was so weak at the time. We finally did opt for the study, hoping we wouldn’t be randomized to “B.” We chose the study basically so that the computer could choose and we wouldn’t ever have to think “we should have gone with the study.” As it turned out, we were randomized to the standard arm, so we got what we wanted while still participating in the study.

• • • • •

We decided not to participate in a study for several reasons. One arm would require extra spinal taps, and our son was just so little that we couldn’t bear the thought of any more treatments than were required in the standard arm. Another arm contained a second induction, and since we were on Medicaid, we just didn’t feel it was right for the taxpayers to pay for anything extra. We felt we were only entitled to basic healthcare.

Researchers closely monitor each ongoing clinical trial and modify it if one arm is identified as superior during the course of the trial or if an arm has unacceptable side effects.

Supervision of clinical trials

The ethical and legal codes governing medical practice also apply to clinical trials. In addition, most research is federally funded or regulated and has rules that protect patients. For example, all COG trials are federally funded and have review boards that meet at prearranged dates for the duration of each trial to ensure the risks of the trial are acceptable relative to the benefits.

The treating institution is required to report all adverse side effects to COG, which reports them to the U.S. Food and Drug Administration. If concerns are raised, the study may be put on hold while an independent Data Safety and Monitoring Board and the study committee review the situation. If one arm of the trial is causing unacceptable side effects, that arm is stopped, and the children enrolled are given the better treatment.

All institutions that conduct clinical trials have an Institutional Review Board (IRB)—made up of scientists, doctors, nurses, and citizens from the community—that reviews and approves all research taking place there. The purpose of the IRB is to protect patients. Funding agencies (e.g., National Cancer Institute) also review and approve trials before children are enrolled.

Questions to ask about clinical trials

To fully understand the clinical trial proposed for your child, here are some important questions to ask the oncologist:

• What is the purpose of the study?
• Who is sponsoring the study? Who monitors patient safety?
• What tests and treatments will be done during the study? How do these differ from standard treatment?
• What are the possible benefits?
• What are the possible disadvantages?
• What are the possible side effects of the study compared to those of standard treatment?
• What are the possible long-term impacts of the study compared with the standard treatment?
• Will the study require more hospitalizations than standard treatment?
• Does the study include long-term follow-up?
• Will you compare the study versus standard treatment in terms of possible outcomes, side effects, time involved, costs, and quality of life?
• Will our insurance cover the costs of the clinical trial?

After discussing the clinical trial with the team, you will need a copy of the information to review later. Many parents record the conversations or bring a friend to take notes; others write down all the doctor’s answers for later reference.

A clinical trial involving very high-dose chemotherapy followed by stem cell transplant was proposed for our 2-year-old daughter. We asked numerous questions, and I wrote down all the answers in my notebook. The two primary questions were: How many kids die during and after this treatment? Are her chances of long-term survival worth the pain we were going to put her through? We struggled with the concept of hurting her if it wasn’t going to do any good. We also asked about the specific drugs, their side effects, and what to expect from each treatment. It was a very difficult process and decision.

Things to consider about clinical trials

Deciding whether to enroll your child in a clinical trial is often difficult. The following lists describe why some families choose to enroll and why others choose not to enroll. These lists may help clarify your feelings about this important decision.

Why some families choose to enroll:

• Children receive either state-of-the-art investigational therapy or the standard therapy.
• Clinical trials can provide the chance to benefit from a new therapy before it is widely available.
• Children enrolled in clinical trials may be monitored more frequently throughout treatment.
• Review boards of scientists oversee clinical trials.
• Participating in a clinical trial often makes parents feel they did everything medically possible for their child.
• Information gained from clinical trials will benefit children with cancer in the future.

Reasons why families choose not to enroll:

• The experimental arm may not provide treatment that is as effective as the standard therapy, or it may cause additional side effects or risks.
• Some families do not like the feeling of not having control over choosing the child’s treatment.
• Some clinical trials require more hospitalizations, treatments, clinic visits, or tests that may be more painful than the standard treatment.
• Some families feel additional stress about which arm is the best treatment for their child.
• Insurance may not cover investigational studies. Parents need to carefully explore this issue prior to signing the consent form.