However knowledgeable your oncologist may be, you may decide yourself to investigate the available relapse treatments, in order to enhance your own understanding and comfort level. As noted, treatment options for a child with relapsed disease are numerous and varied, and there is much to investigate. The process is virtually identical to researching treatments for refractory neuroblastoma, especially if the child has relapsed while still on treatment.
For starters, there is a wealth of information on the internet—but it can be daunting to sort through. Relapse neuroblastoma trials can be found on these websites (using search mechanisms for recurrent neuroblastoma):
Institutional websites also list trials available only at their locations, so be sure to search websites of institutions of interest. Notable examples are Memorial Sloan-Kettering (www.mskcc.org
) and St Jude (www.stjude.org
); also, some NANT institutions have their own trials that are NOT listed on the NANT website.
By contacting institutions of interest and principal investigators, you will learn pertinent information not only about current clinical trials, but may also learn about trials that are expected to open soon or treatments available “off-trial.”
It is common for children to see one or more of the following treatment categories during the battle against relapse:
- Enrollment on phase I or II clinical trials. These may be specific to NB or for unspecified solid tumors. Phase III studies are rare for relapsed pediatric tumors including NB.
- Treatment “per” a clinical trial protocol although not enrolled, if not eligible and drugs are already FDA approved.
- Treatment with “off the shelf” agents that are FDA approved.
- Treatment on a “compassionate use” basis with drugs not yet FDA approved.
You will find on-line information about clinical trials organized in different ways, but key items to note are:
- whether trial is active/enrolling;
- any age limit;
- rationale for treatment on such trial;
- any requirement for disease sites/measurable disease;
- any organ function criteria; and
- any prior treatment limitations.
Becoming familiar with eligibility criteria of trials is a good idea, so you know what items are generally listed. Often the “consent forms” for the protocols can be read or downloaded from the internet.
Phase I and Phase II Distinctions
There is an important difference between phase I and phase II clinical trials. Drugs being administered in phase II studies have possible response results in children in a prior phase I study, and toxicities and maximum tolerated dose are known. Drugs in phase I studies do not have such information available— the purpose of a phase 1 study is to determine toxicities and maximum tolerated dose of a drug based on promising laboratory data from cell lines in glass dishes (in vitro) or activity in mice. Some agents look promising in vitro or in mice, but responses in children may be disappointing.
For further discussion of the distinctions between phase I, II, and III clinical trials, and background information about enrolling in a clinical trial, see “Clinical Trials.”
Timing of Entry
Another issue in considering enrollment in phase I studies has to do with timing. Many phase I studies enroll a small number of children (usually 3-6, called a cohort) at a certain dose level, observe for toxicities, and then the next cohort is enrolled at a higher dosage. Speaking with your child’s oncologist and the principal investigator about the timing of enrollment is important, to determine if your child would be one of the first to receive the drug, or would be enrolling at a higher dose level. Trials also sometimes open and close and then open again, depending on drug availability, toxicities and other factors. The principal investigator will be able to give you the up-to-date status of enrollment and may give an indication of how the earlier cohorts have fared.
Interpreting “Response” from Study Reports
As parents investigate available trials and try to discern what is most promising, they should be aware of the range of possibilities when studies report a “response” rate. Let’s say you are considering a phase II study of drug X. You uncover the phase I drug X results reporting a “30% response rate.” What does this mean? Does it mean 30 percent of the children on the study were cured? Unfortunately no, it does not. The 30% response rate may indicate that 30 percent of the children in the trial had some shrinkage or reduction in their NB, but often the duration of the response is unclear. Did some of the children have a complete response -- i.e., reach NED again? How long did the children respond before the disease progressed again? Did some of the children have shrinkage or reduction in their disease, and then experience stable disease for a while? How long? Asking such questions and getting all relevant information is advisable before committing to a trial. Unfortunately, some promising drugs that have a “high response rates” actually produce responses that are very short-lived, and you are entitled to know that. Answers to these questions are usually not available until a phase I study ends.
It helps to know the terminology used to report “response” in studies. Clinical trial protocols include a plan for closely monitoring the disease response so that if the treatment is not working, the child can quickly move onto something else. The International Neuroblastoma Response Criteria (INRC) was established in 1993 and uses the following terms:
- “complete response” (CR) is no evidence of disease;
- “very good partial response” (VGPR) is primary mass reduced by 90–99 percent, no evidence of distant disease except for skeletal residua, and catecholamines normal;
- “partial response” (PR) is greater than 50 percent decrease in measurable disease and 1 or no positive BM site;
- “mixed response” is greater than 50 percent decrease of any lesion with less than 50 percent decrease in any other;
- “no response” is less than 50 percent decrease but less than 25 percent increase in any lesion; and
- “progressive disease” (PD) is new lesion or greater than 25 percent increase in an existing lesion.
Risks and Benefits of Relapse Neuroblastoma Treatment
In evaluating any treatment, you must ask whether the potential for beneficial results outweighs the potential for further harm, either from progressive disease or side-effects. Your child’s prior treatment for neuroblastoma may have resulted in certain physical impairments such as hearing loss, kidney or heart damage. These effects are important to consider as you determine the next course of treatment. Any viable option almost surely will have some favorable factors as well as the potential for both short and long-term harm. See discussion on “maximizing your options,” above.
It is advisable to contact the principal investigator or those most experienced with the treatment strategy in order to get answers to your specific questions about any clinical trial or new treatment.
Realistic Expectations of Neuroblastoma Relapse
The rigors of relapse treatment cannot be minimized. You may be consulting with new and different doctors, traveling far from home for your child’s treatment on various clinical trials, weighing difficult quality of life issues for your family, and at times making treatment decisions based on a leap of faith. An oncologist with experience in treating relapsed neuroblastoma, and equally importantly, someone you feel comfortable with and can communicate with effectively, is the key resource in making your treatment decisions. However, the more informed you are, the more comfortable you will feel that you have made the best possible choices for your child.
There are successes in relapse situations. Unfortunately, because the relapse population involves such variation in relapse sites, in amount of disease, types of treatments tried, multiple treatment centers, and many other variables, it is virtually impossible to report long-term survival statistics. Even so, the reports of long-term survivors in some studies, the increasing numbers and approaches of available treatments, and the anecdotal evidence -- all suggest that the prospect for long survivorship after relapse is improving. There is increasing hope for relapsed children, and having an neuroblastoma team who expresses and shares your hope is also essential to this stage of the battle.