Neuroblastoma Relapse and Secondary Cancer

Dealing with Relapse
The focus of this chapter is on relapse after treatment for high-risk neuroblastoma. As always in the case of NB, the guidance of an experienced doctor you trust is absolutely crucial, especially in the complex decisions involved in relapse treatment. However, your knowledge can be a valuable ally. The more you know, the easier it is to understand the issues presented by relapse, have a meaningful dialogue with your child’s doctor, and make informed decisions about the many treatment options.

This chapter draws extensively from “Treatment of Relapsed and Refractory Neuroblastoma,” authored by Drs. K. Matthay and B. Kushner, in the 2005 pediatric oncology text Neuroblastoma (Cheung & Cohn, eds). There is some overlap with the previous chapter in this Handbook on treating refractory disease, because both are “resistant disease” -- standard frontline therapy has failed and new treatments options are needed. However, whereas refractory disease is considered “progressive” only if NB spreads to new sites or the size of a lesion is increased, relapsed disease (also referred to as “recurrent” disease) is always progressive disease at discovery, because it has increased from “no evidence of disease.” The length of the time of remission, the location and nature of the disease, the prior treatment, and many other factors must be considered to determine how to treat this new, recurrent disease.

Background Information
A Note on Low-Risk and Intermediate-Risk Cases. The treatment strategies discussed here do not apply to relapse after low- or intermediate-risk NB. Risk of relapse is small after successful treatment for low- or intermediate-risk NB. Localized relapse in low- and intermediate-risk cases can often be successfully treated by surgery. In the case of metastatic relapse after low- or intermediate-risk treatment, the child’s relapse treatment is usually very similar to high-risk frontline therapy. However, some of the general observations that follow may be relevant as well for low- and intermediate-risk relapse cases.

Risk of Relapse for High-Risk NB. Phase III and pilot studies from the past 15 years have revealed long-term survival after high-risk treatment ranging from 25 percent to over 50 percent. For example, follow-up of children with high-risk disease treated in 1991-1996 on clinical trial “CCG-3891” revealed nearly 60 percent long-term survival for the 50 children who reached remission and completed both transplant and six months of Accutane (13-cis-retinoic acid). In other words, about 40 percent relapsed after successful treatment. Since then, the dose of induction chemo has been intensified, transplant regimens have changed, and additional treatments for minimal residual disease such as antibodies have often been used, so it may be that the risk of relapse after successful treatment is now lower. It is also encouraging to know that the risk of relapse decreases every year after successful frontline therapy since most relapses occur within two years after stem cell transplant or completing chemotherapy.

What causes relapse? No one has determined what causes neuroblastoma relapse after clinical remission. Theories for its cause include:
  • Re-introduction of neuroblastoma cells in contaminated stem cells at rescue;
  • Neuroblastoma cells “hiding” in sanctuary sites such as brain or testes; and
  • Neuroblastoma cells becoming resistant during frontline therapy.
The recent results of a clinical trial (“C0G-A3973”) comparing randomized patients receiving purged stem cells after transplant versus un-purged showed no difference in survival between the two groups, so contaminated stem cells are probably not the cause of most relapses. Many researchers believe developing more effective treatments for minimal residual disease (MRD) will reduce the incidence of relapse in high-risk cases.

By far the most common sites for relapse are bone and bone marrow, and sites not involved at first diagnosis (such as brain and lungs) are seen in up to 8% of relapsed children.

Monitoring after Frontline Treatment

For about two years after finishing neuroblastoma treatment, a child does follow-up tests and scans every three months, then every six months and eventually none; the schedule varies according to the institution and the particular case. It is certainly hard not to worry however far from treatment a child may be, because the symptoms of relapse can be similar to those of a host of childhood illnesses and conditions. Parents must continue to be vigilant -- but without being alarmist.

If your child has a complaint that persists over a few hours or days, depending on the symptom and its severity, naturally you should follow up with your pediatrician or your oncologist. Some parents recommend keeping a log of the child’s complaints (discreetly, without upsetting the child), because it is important to be able to describe the precise symptoms and their duration to the doctors. It may take time, but ideally you will develop a good working routine for dealing with your professional team (which should include a pediatrician informed about your child’s history) when you are troubled by your child’s symptoms. You are the person most familiar with your child, and your invaluable instincts should be given careful consideration by your medical team.

Establishing Conclusive Evidence of Relapse

Just as with first diagnosis, relapse is not always obvious. Some neuroblastoma relapses have no symptoms and are discovered by routine follow-up tests and scans; others present with similar symptoms as seen at first diagnosis (pain, fever, fatigue, anemia, etc.) or with new symptoms not present before (as with headaches in brain relapses).

Worrisome symptoms may require an oncology clinic visit for a physical exam, often followed by a CBC and urine HVA/VMA tests, and possibly even scans. Neuroblastoma relapse must be absolutely proven before treatment can commence, because some secondary cancers can resemble NB, and correct treatment must be given. Tests that evidenced the child’s first diagnosis may no longer be reliable. One large German study found a relatively low incidence (54 percent) of abnormal HVA/VMA results at relapse; occasionally relapsed NBs are MIBG-negative although previously MIBG-avid. Hence, other scans may be necessary, such as PET. See “Getting through Tests and Scans.” Biopsy of bone marrow or suspicious spots on scans is often done in cases where a bone scan or PET is positive but catecholamines are normal. The possibility of residual matured (harmless) tumor can further complicate the determination of whether relapse treatment is needed, so rescanning may be required after a few weeks to determine if the disease is growing and active.

If relapse is confirmed, many of the same staging, pathology and genetic tests done at first diagnosis are performed, as well as baseline tests for heart, hearing, and other organ function. Since most treatment begins with some type of chemotherapy, a central venous access will be required. A port is often chosen rather than a Hickman or Broviac, depending on impending treatment choices. See “Broviacs, Hickmans, Ports, etc.”

Beginning Relapse Treatment

After the whirlwind of scans, tests, and line placement, most often “retrieval” chemotherapy is begun. Depending on the relapse scenario, children very often respond to chemo again, especially if relapse occurs after more than one year of remission.

However, relapse after high-risk treatment is a different scenario from first diagnosis. Whereas at first diagnosis a well-defined road map of the frontline protocol is provided, there is generally no set treatment path for a relapsed child. The NB team will often present several optional treatments to parents and discuss the various benefits and disadvantages of each. Some doctors even list “no treatment” as one of the options. Doctors may discuss the possible timing of various subsequent treatments that will depend on the child’s response to the initial relapse chemo and on various personal considerations. In other words, relapse treatment is usually very individualized – and parents are generally expected to participate in the process of determining the particular treatment plan for their child.

Although perhaps less obvious, the considerations and analyses underlying relapse treatment are also different from those at first diagnosis. As Drs. K. Matthay and B. Kushner note in “Treatment of Relapsed and Refractory Neuroblastoma”:

“The appropriate approach to the patient with recurrent or resistant neuroblastoma depends on the goals of the therapy. Although in previous studies the median survival for patients who relapsed after myeloablative therapy and bone marrow transplantation was only 3 months, with current multimodality approaches and judicious use of established as well as investigational agents, the survival can be prolonged for years, and cure may be a possibility in some settings. Whether the goal is symptom palliation, prolongation of life, or complete remission depends on the timing and nature of the relapse, the prior therapy, and the tumor biology.”

To participate fully in such difficult treatment decisions, parents of a relapsed child must have a basic understanding of the underlying rationales for the various treatment paths, and the benefits and detriments of these treatments for their child’s specific case, both from a medical and a personal perspective. The following section will provide some general information on the various considerations to be weighed in determining relapse treatment – keeping in mind, of course, that the guidance of an experienced and trusted oncologist in these complex and difficult decisions is absolutely crucial.