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Introduction. Neuroblastoma is a solid tumor of childhood that arises in the nervous system outside of the brain. Children who have aggressive neuroblastomas are at high-risk for having the tumor recur and or grow out of control ("progress") if given standard (low-dose) chemotherapy. These patients are classified as having "high-risk neuroblastoma".

This portion of the NANT web site briefly reviews the initial treatment options available for children with high-risk neuroblastoma. We also present some of the new approaches to treating patients with high-risk neuroblastoma whose tumors have progressed or recurred.

What is high-risk neuroblastoma? The clinical behavior of neuroblastoma is highly variable, with some tumors being easily treatable, but approximately 50% of the tumors are very aggressive. This brief summary only addresses therapy of high-risk neuroblastoma. The treatment of low or intermediate risk tumors is very different from treating high-risk disease.

International Neuroblastoma Staging System (INSS)
(Please click on the diagram thumbnail to load a larger version)

The staging system (by degree of tumor spread) for neuroblastoma is shown above. All patients with stage 4 disease diagnosed after 18 months of age are in the high-risk category. In stage 4 disease, the neuroblastoma tumor cells have already spread (metastasized) to other sites in the body such as the bone or bone marrow. Additionally, essentially all patients who have tumors with many copies ("gene amplification") of the MYCN cancer gene also have high-risk disease, even if they do not have evidence of the tumor having spread.

It is accepted practice to treat high-risk neuroblastoma patients with intensive therapy (including stem cell transplant) because these patients are at high risk of not surviving their disease unless they receive very aggressive treatment.

Most pediatric oncologists agree that even with optimal current intensive therapy, the survival rate of such patients warrants entering as many of these children as possible on clinical trials that may identify improved forms of treatment for this aggressive tumor.

Initial Therapy of High-Risk Neuroblastoma.

During the last 15 years, clinical trials have shown that patients with high-risk neuroblastoma should receive induction chemotherapy over about five months followed by "consolidation" with very high dose chemotherapy + stem cell transplant.

The patient's own stem cells are obtained during "induction" from either the bone marrow or peripheral blood (PBSC) to give back after the high-dose chemotherapy. Patients also receive local radiation to sites of tumor. Two months after stem cell transplant, when recovery from "consolidation" has occurred, patients begin the last phase of treatment, which uses 13-cis-retinoic acid (Accutane) for six months in an attempt to eliminate any remaining tumor cells. These established principles apply to "up-front" therapy of high-risk neuroblastoma.

To date, only a single large clinical study with long-term survival data (the Childrens Cancer Group CCG-3891 study which was completed in 1996) has employed all of these therapeutic principles uniformly in a large group of patients beginning at diagnosis. Based on the CCG data, when treated with the above approaches, a child diagnosed with high-risk neuroblastoma has an estimated 40% chance of surviving at 4 years from diagnosis without any disease. Potential improvements in all phases of therapy (induction chemotherapy, intensive consolidation with stem cell transplant, and post-transplant therapy) have occurred since the CCG-3891 study. Thus, it is reasonable to expect a somewhat greater disease-free survival for high-risk neuroblastoma in ongoing and future clinical trials.

For patients whose tumor grows during or after the above therapy, the chance of survival is greatly reduced. Because there are no established effective treatments for such patients, experimental therapies, such as those being developed and studied by investigators of the NANT consortium may be appropriate.

Recurrent or Progressive Neuroblastoma. High-risk neuroblastomas that grow during therapy or return after apparently having gone away almost always are resistant to the "standard" induction, consolidation, or post-consolidation therapy discussed above. Patients in this condition are encouraged to enroll in phase I or II clinical trials that test new therapeutic strategies. A variety of phase I and II studies are carried out by the NANT, the Children's Oncology Group and other organizations.

These studies almost always are limited to patients with recurrent or progressive neuroblastoma because their side effects and ability to improve survival are not well-defined.

Brief descriptions of the clinical trials being conducted by the NANT are available on this web site under "Clinical Trials". Web sites for the National Cancer Institute and the Children's Oncology Group also provide information on other clinical trials that are available for patients with neuroblastoma.