If a clinical trial is open for your child’s particular type and stage of tumor, you will be asked to consider enrolling your child in it within days of diagnosis. You then must choose between the 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 upon existing treatments. A clinical trial can involve a totally new approach that is thought to be promising, or it may entail fine-tuning existing treatments, reducing the toxicity of known treatments, or developing new ways to assess responses to treatments. Many children are needed in each clinical trial for the results to be statistically meaningful.
In some cases, such as with average-risk medulloblastoma, the standard treatment has a high likelihood of resulting in complete and lasting remission. For other types of tumors, the prognosis is poor on the standard treatment, and parents may be more motivated to choose a clinical trial. Occasionally, 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 with the choice.
Your treatment team may tell you about studies that are sponsored by pharmaceutical companies, especially those designed to support patients through the effects of treatment. Such supportive care trials evaluate antibiotics, anti-nausea drugs, and new agents to raise blood counts, minimize pain, or control other symptoms. The oversight and control of these trials involves an entirely different mechanism 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.
You also may be asked for permission to allow biological studies of your child’s tumor. These studies involve performing specific tests on pieces of your child’s tumor to better understand how the cancer works with the hope that knowledge will lead to the development of better treatments. The neurosurgeon or pediatric oncologist may ask your permission to send any tumor left over after diagnosis to a tumor bank for research. Because brain tumors can have subtle differences (called subtypes), biological studies help researchers better identify and understand the subtypes. The categorization of different types of medulloblastoma has come from this type of research. Scientists are also using banked tumor cells to test response to new medications and immunotherapy.
Types of clinical trials
There are three main types of clinical trials offered to children with brain or spinal cord tumors.
Phase I. Drug studies begin in laboratories, where the drugs are evaluated using chemical or biological models, tissue samples, and other methods to see if there is a chance the drug might be effective at treating disease. If laboratory evidence suggests a drug may 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 to a patient (the maximum tolerated dose, or MTD), and evaluate the 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 toxicities. Phase I studies are true 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 achieving remission are low. Because they require careful monitoring, Phase I studies are only conducted in a select few hospitals.
Phase II. Phase II trials refine the safety parameters and evaluate new drugs’ effects on specific tumors. 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 in many patients. Sometimes patients are enrolled when their tumors have regrown after treatment. Occasionally, Phase II trials are designed to test an exceptionally promising agent against a tumor for which other effective therapies exist.
Phase III trials. These clinical trials determine if a new treatment is better than the usual or standard therapy. Some Phase III trials are designed solely to improve survival; others try to maintain survival rates while lowering toxicity of treatment. In pediatric Phase III studies, some children will receive the standard therapy, while others receive some modification, such as higher or lower doses of medication or radiation, different combinations of drugs, or shorter or longer treatments. Some children will derive direct benefit if a new treatment proves superior to standard therapy. Others will receive the same therapy they would have received if not enrolled on the study (the standard arm). To ensure the results are accurate, Phase III studies require thousands of participants and several years to complete.
The 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. Issues for enrolling in Phase I and Phase II trials are very different, as are concerns when enrolling in trials sponsored by private 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 (www.childrensoncologygroup.org). Approximately 200 institutions that treat children with cancer are members of COG. The NCI also sponsors a consortium called The Pediatric Brain Tumor Consortium (PBTC) that consists of 11 institutions in the United States (all of which are members of COG):
- Children’s Hospital Los Angeles (California)
- Children’s National Medical Center (Washington, DC)
- Children’s Memorial Hospital (Chicago, Illinois)
- Cincinnati Children’s Hospital Medical Center (Ohio)
- The Brain Tumor Center at Duke (Durham, North Carolina)
- Lucile Packard Children’s Hospital (Palo Alto, California)
- Memorial Sloan Kettering Cancer Center (New York)
- National Cancer Institute (Bethesda, Maryland)
- St. Jude Children’s Research Hospital (Memphis, Tennessee)
- Texas Children’s Cancer Center (Houston)
- University of Pittsburgh (Pennsylvania)
The purpose of the PBTC is to test new agents and therapies for pediatric brain tumors and to evaluate cutting-edge diagnostic technology (Phase 1 and Phase II trials). All members of PBTC have well-established, multidisciplinary brain tumor programs and are capable of performing technically challenging studies. You can learn more about this group at its website www.pbtc.org.
Phase III studies have multiple arms, which means participants are sorted into different groups (called arms) that receive different treatments. Every Phase III trial has one arm that is the current standard of care. Each of the other arms contains one or more experimental components, such as:
- 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 care
- The addition, deletion, or change in dose of certain treatments (such as radiation therapy)
- The use of new supportive care interventions, such as preventative antibiotics or new drugs to control nausea
When the trial is completed and all the data is analyzed, the effectiveness of each experimental arm is compared to the “standard of care” arm. 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 of care.
Sean missed the deadline for enrolling in a clinical trial when he was diagnosed. However, when his tumor regrew we did enroll him on a trial. The particular trial he was in was a randomized computer trial that decided if he was getting one or two chemotherapy agents. We felt if we enrolled him in the trial, maybe the results would help other children.
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 will not know which treatment their child will receive until the computer assigns one. The purpose of computer assignment is to ensure patients are evenly assigned to each treatment plan without bias from physicians 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 is superior. Thus, 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.
Researchers closely monitor ongoing studies and modify the study if one arm is clearly 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 ruling medical practice also apply to clinical trials. In addition, most research is federally funded or regulated (all COG trials are), with rules that protect patients. COG and PBCT also have review boards that meet at prearranged dates for the duration of a clinical trial to ensure the risks of all parts 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 temporarily halted while an independent Data Safety and Monitoring Board and the study committee review the situation. If one arm of the trial is causing unexpected or unacceptable side effects, that portion is stopped, and the children enrolled are given the better treatment.
All institutions that conduct clinical trials also have an Institutional Review Board (IRB) that reviews and approves all research taking place there. The purpose of such boards and committees—made up of scientists, doctors, nurses, and citizens from the community—is to protect patients. Funding agencies (e.g., NCI) review and approve trials before children are enrolled.
Questions to ask about clinical trials
To fully understand the clinical trial that has been proposed, here are some important questions to ask the oncologist:
- What is the purpose of the study?
- Who is sponsoring the study? Who reviews it? How often is it reviewed? Who monitors patient safety?
- What tests and treatments will be done during the study? How do these differ from standard treatment?
- Why is it thought that the treatment being studied may be better than standard treatment?
- What are the possible benefits?
- What are all possible disadvantages?
- What are the possible side effects or risks of the study? What are the side effects of the study compared to those of standard treatment?
- How will the study affect my child’s daily life?
- What are the possible long-term impacts of the study compared with the standard treatment?
- How long will the study last? Is this shorter or longer than standard treatment?
- Will the study require more hospitalization than standard treatment?
- Does the study include long-term follow-up care?
- What happens if my child is harmed as a result of the research?
- Will you compare for me the study versus standard treatment in terms of possible outcomes, side effects, time involved, costs, and quality of life?
- Have insurers been reimbursing for care on this protocol?
After discussing the clinical trial with the oncologist, you will need a copy of the information to review later. Many parents record the conversation or bring a friend to take notes; others write down all the doctor’s answers for later reference.
Pros and cons of clinical trials
Our 18-year-old daughter Morgan was diagnosed with a medulloblastoma in her cerebellum when she was 2 years old. A clinical trial involving very high-dose chemotherapy followed by stem cell transplant was proposed. 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.
Making the decision whether to have your child participate in a clinical trial is often difficult. The following list of reasons why some families chose whether or not to enroll 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 best standard therapy available.
- Clinical trials can provide an opportunity to benefit from a new therapy before it is generally available.
- Children enrolled in clinical trials may be monitored more frequently throughout treatment.
- Review boards of scientists oversee the operation of 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 as effective as the standard, or it may generate 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.
When my son was diagnosed with an optic glioma, we were told we had two options: a clinical trial or standard treatment. We decided to get a second opinion before making our decision. Our pediatrician, my husband, and I met in the doctor’s office for a telephone conference with a pediatric oncologist from a major brain tumor center. We each presented our concerns, including our pediatrician, who thought of some issues we hadn’t considered. I think we all came away better informed of our options.
True informed consent is a process—not merely an explanation and signing of documents. Informed consent requires that:
- All treatments available to the child have been explained—not just the treatment available at your hospital or through your doctor, but all the treatments that could be beneficial, wherever they are given.
- The parents and, to the extent possible, the child, have discussed these options and decided they want to consider one of them.
- The option selected is thoroughly discussed, with all its benefits and risks clearly explained.
- Those aspects of the study that are considered experimental and those that are standard are clearly described.
A fully informed medical decision is one that weighs the relative merits of a therapy after full disclosure of benefits, risks, and alternatives. During the discussions between the doctor(s) and family, all questions should be answered in language that is clearly understood by the parents and child, and there should be no pressure on parents to enroll their child in a study. The objective of the informed consent process is that all family members are comfortable with their choice and can comply with it. Studies show that the more questions parents ask during the informed consent process, the better they understand what they are agreeing to.
We had many discussions with the staff prior to signing the informed consent to participate in the clinical trial. We asked innumerable questions, all of which were answered in a frank and honest manner. We felt that participating gave our child the best chance for a cure, and we felt good about increasing the knowledge that would help other children later.
Informed consent is a process that occurs over several meetings during which the physician provides information and the parents ask questions (and get answers). Sometimes the informed consent process does not work as it should because of several factors, including the state of mind of the parents, the communication style of the doctor, and the system (if any) in place to discuss treatment options. Usually, this situation is the result of miscommunication arising from some combination of the following:
- No formal meeting times were established in advance to discuss treatment options, so parents do not understand the importance of the discussion they are having with the doctor and the treatment team.
- Parents, who are tired, confused, and mentally numb, may appear to understand things they are barely hearing.
- The doctor does not recognize that the parents are not following what he is saying and that they need more guidance and time to absorb the choices.
- The doctor is unconsciously promoting the choice she believes is the best one and she interprets the lack of questions as agreement.
- There is no one in the room except the doctor and the parents; therefore, there is no one to intervene if communication breaks down.
It is a good idea to ask the treatment team immediately after diagnosis when and how the treatment decision will be made and to ask for specific meeting dates and times to discuss treatment, even if it means a slight delay before starting treatment. Parents may also want to invite a trusted friend or their child’s pediatrician to attend this meeting to ensure they understand their options.
Studies have shown that when treatment team members who are not doctors are present during the informed consent meetings, parents have a better understanding of their choices. You may want to ask that a nurse or a social worker be present for the meetings.
Two days after my child was diagnosed, the oncologist told me it was time to begin treatment. I do remember him talking a lot, but I swear it actually sounded like “Wah, wah, wah, protocol, wah, wah, wah, very successful, wah, wah, wah, sign here.” And I did. It was several days before it sank in that I had authorized an experimental treatment protocol and not the standard of care. The irony is that I worked in clinical research. I knew how this was supposed to go. But I was alone and tired and frightened and went along like a sheep. Did he railroad me? Maybe; but I don’t think he meant to and in the end it was my responsibility to hold it together and ask what needed to be asked. But it just wasn’t in me at the time. Later, I told the doctor this and he was astonished to learn that I hadn’t heard a word he said. My child is doing well now, so I am happy, but if I had it to do again, I might not have made the choice I did.
The form parents sign will have language similar to the following: “The study described above has been explained to me, and I voluntarily agree to have my child participate in this study. I have had all of my questions answered, and understand that all future questions that I have about this research will be answered by the investigators listed above.”
By the time a study is published in the literature, doctors on the cutting edge of treatment are 2 to 4 years into improving that treatment or learning of its shortcomings. For this reason, it is best to make decisions in partnership with knowledgeable medical caregivers, rather than on your own.
No matter how comfortable you are with your child’s treating oncologist, it may be helpful to have another medical caregiver help sort out your options. Often, that person will be the family’s pediatrician or family doctor. Second opinions can be obtained from physicians at other COG institutions or one of the members of PBTC. They will arrange to review the information (e.g., scans, pathology, biological and molecular tumor cell characteristics) and then will provide a second opinion. It is most useful to get a second opinion from a center that treats significant numbers of patients with your child’s diagnosis. Most pediatric oncologists are willing to facilitate this process for you.
Assent means that children and adolescents are involved in decisions about their treatment. Children younger than age 18 do not have the right to refuse standard treatment for their cancer. They do, however, have the right to accept or reject experimental treatments. All clinical trials are considered to be experimental treatments. Regardless of whether children will receive the standard treatment or an experimental treatment, they have rights to have the disease, treatment, and procedures explained to them at an age-appropriate level.
Doctors and parents are required to allow children to provide input to the extent of the child’s abilities. According to the American Academy of Pediatrics (AAP), assent means that the child:
- Is aware of the nature of his or her disease
- Understands what to expect from tests and treatments
- Has had his or her understanding assessed
- Has had an opportunity to accept or reject the proposed treatment
Parents can read or download a copy of the AAP policy statement (“Informed Consent, Parental Permission, and Assent in Pediatric Practice”) at http://pediatrics.aappublications.org/content/95/2/314.full.pdf+html. This policy was reaffirmed by the AAP in 2011. In part, the policy states, “In situations in which the patient will have to receive medical care despite his or her objection, the patient should be told that fact and should not be deceived.” This policy applies to standard treatment.
Clinical trials, however, are research. An added layer of protection is added for research trials, and IRBs decide whether assent of the child is needed. If parents and the child disagree, usually several discussions are held with mediators (for example, a social worker or pediatric psychologist) to try to reach an agreement. If parents and their child still disagree, an advocate for the child is appointed and a decision about treatment is made by the hospital ethics committee.
In short, parents can legally make decisions about standard care, but both parents and children have decision-making rights about whether or not to participate in research.
Saying no to a clinical trial
Parents, older children, and teens have the legal right to decide whether or not to participate in a clinical trial. If the family chooses for the child not to participate in the proposed clinical trial, the child is given the best-known treatment (standard treatment) for his type of tumor.
The entire clinical trial document
We just were not comfortable with the concept of a clinical trial. It seemed like gambling to us. We also felt totally overwhelmed about making decisions on important subjects that we didn’t understand. Even though we asked many, many questions, we just couldn’t come to grips with the whole idea in the 2 days after our daughter was diagnosed. So, we declined the trial and had the best-known treatment. We were happy with our decision.
If your child is enrolled in a clinical trial, the roadmap described earlier is actually a very small portion of a lengthy document describing all aspects of the study. The entire document usually exceeds 100 pages and covers the following topics: study hypothesis, experimental design, scientific background and rationale with relevant references from the scientific literature, patient eligibility and randomization, therapy for each arm of the study, required observations, pathology guidelines, radiation therapy guidelines (if applicable), supportive care guidelines, specific information about each drug, relapse therapy guidelines, statistical considerations, study committee members, record-keeping requirements, reporting of adverse drug reactions, and a consent form.
However, some parents are medical professionals or people who want to better understand their child’s illness and treatment. These parents may want to have a copy of the study document for several reasons. First, it provides a description of some of the clinical trials that preceded the present one and explains the reasons the investigators designed this particular study. Second, it provides detailed descriptions of drug reactions, which comfort many parents who worry that their child is the only one exhibiting extreme responses to some drugs. Third, motivated parents who have only one protocol to keep track of occasionally prevent errors in treatment. Finally, for parents who are adrift in the world of cancer treatment, it can return to them a bit of control over their child’s life.
Since knowledge is comfort for me, I really wanted to have the entire clinical trial document, despite its technical language. Whereas the brief protocol that I had listed day, drug, and dose, the expanded version listed the potential side effects for each drug, and what actions should be taken should any occur. I learned the parameters.
Other parents find that reading hundreds of pages of technical information is overwhelming or just not helpful. As with almost every topic discussed in this book, families need to make individual choices based on what works best for their unique needs.
If your child is enrolled in a clinical trial and you would like a copy of the entire document, ask your child’s neuro-oncologist for one. If the neuro-oncologist will not provide it, call COG (626-447-0064) and ask for a copy. Informed consent documents for COG trials specifically state that families will receive a copy of the full protocol upon request. After reading the protocol, it may be helpful to schedule an appointment with your physician, nurse practitioner, or research nurse to discuss any questions or concerns.
The protocol is not for general distribution, because it is unethical to use these protocols outside a controlled research setting. Parents who obtain a copy should not circulate it.
Removing a child from a clinical trial
Parents have the legal right to withdraw their child from a clinical trial at any time, for any reason. But before doing so, it’s a good idea to discuss questions or concerns with your child’s doctor. The decision to withdraw from a trial should not be held against the parent, and the child will still receive the best available care for her type of cancer. On the consent form signed by the parent, there will be language similar to this: “You are free not to have your child participate in this research or to withdraw your child at any time without penalty or jeopardizing future care.”
Jesse was enrolled in a clinical trial to assess long-term neuropsychological consequences of cranial radiation. The testing was free, and we were glad to participate. Unfortunately, the billing department of the hospital continually billed us in error. We tried to correct the problem, but it became such a hassle that we withdrew from the study.
Table of ContentsAll Guides
- 1. Diagnosis
- 2. The Brain and Spinal Cord
- 3. Types of Tumors
- 4. Telling Your Child and Others
- 5. Choosing a Treatment
- 6. Coping with Procedures
- 7. Forming a Partnership with the Treatment Team
- 8. Hospitalization
- 9. Venous Catheters
- 10. Surgery
- 11. Chemotherapy
- 12. Common Side Effects of Chemotherapy
- 13. Radiation Therapy
- 14. Peripheral Blood Stem Cell Transplantation
- 15. Siblings
- 16. Family and Friends
- 17. Communication and Behavior
- 18. School
- 19. Sources of Support
- 20. Nutrition
- 21. Medical and Financial Record-keeping
- 22. End of Treatment and Beyond
- 23. Recurrence
- 24. Death and Bereavement
- 25. Looking Forward
- Appendix A. Blood Tests and What They Mean
- Appendix C. Books and Websites