Neuroblastoma: Treatment

Pictured: Ester Dantis & Shakeel Modak Nurse practitioner Ester Dantis (left) and neuroblastoma specialist Shakeel Modak with a young patient and his family.

Neuroblastomas exhibit a variety of different behaviors. Some will go away without any treatment, and others can be cured by surgery alone. But approximately half of all neuroblastomas have already spread to the bone and bone marrow by the time they are found, and these tumors require more complex treatment. The best treatment for a particular child depends mainly on the child's age and the stage of the tumor. The location of the primary tumor and where it has spread will also be taken into consideration. Treatment will also vary depending on whether the patient is being treated for the first time or for relapse.

Treatment for neuroblastoma usually involves a variety of approaches (also called modalities). Some treatments, such as chemotherapy and radiation, are designed to kill neuroblastoma cells. Surgery involves the removal of neuroblastoma cells that have grown into a solid mass (i.e. tumor). Stem cell transplant is used to destroy the patient's neuroblastoma-infected bone marrow and replace it with stem cells that are relatively free of neuroblastoma. Immunotherapy arms and trains the body's own defense system to fight neuroblastoma. Finally, there are a number of other specialized treatments that may be used in appropriate cases. These include drugs that stop the growth of blood vessels that supply food to a tumor (“anti-angiogenesis”) and drugs such as isotretinoin (also known as cis-retinoic acid, or Accutane®) that encourage immature neuroblastoma cells to stop dividing or to die.

Our Risk-Based Treatments

The neuroblastoma treatment that an individual patient receives will vary based on several factors, including the age of the patient, the stage of the disease and its level of risk, as well as whether the treatment is for a newly diagnosed neuroblastoma or for a refractory or recurrent tumor.

Low-Risk and Intermediate-Risk Neuroblastoma

Low-risk neuroblastomas include all cases classified as stage 1 or stage 2 and most cases classified as stage 4S. Intermediate-risk groups include stage 3, stage 4 in babies (less than 18 months), stage 4S with large liver metastasis, and some patients with large tumors that have not spread. Between 80 to 95 percent of these tumors are curable, with the exception of 10 to 15 percent of stage 3 cases, which may not respond well to chemotherapy. Surgery for low- and intermediate-risk cases is usually performed if it will not damage important nearby organs. For neuroblastomas found in utero (usually discovered by chance during prenatal ultrasound) or in the first few months of life, close observation may be all that is needed. For patients with low-risk neuroblastoma, it has been our practice since the late 1980s to avoid both chemotherapy and radiation therapy. For patients with intermediate-risk neuroblastoma, chemotherapy and radiation are used cautiously and individualized as needed; babies (less than 18 months) with stage 4 are now generally treated with a short course of chemotherapy only.

High-Risk Neuroblastoma

Stage 4 metastatic neuroblastoma diagnosed after 18 months of age is considered high risk. In addition, tumors with the genetic characteristic known as MYCN amplification, irrespective of age or stage, are generally regarded as high risk. High-risk neuroblastoma is the most difficult stage of the disease to treat and requires the use of a combination of treatment approaches, including chemotherapy, radiation, surgery, and immunotherapy. These treatments are conducted in phases and usually take about two years to complete.

Given the difficulty of achieving long-term remission in cases of relapse, we put heavy emphasis on the prevention of relapse. The cause of relapse is usually from minimal residual disease (MRD). MRD refers to the presence of neuroblastoma cells too small and too dispersed throughout the body to be detected by the standard tests. MRD is typically assumed in patients who are declared to be in remission. We are developing highly sensitive methods to detect and monitor MRD, because when left unchecked MRD will progress to detectable relapse (i.e., there will be detectable gross disease). We believe that MRD is far easier to treat than gross disease. These monitoring methods are undergoing testing, and we hope to put them to clinical use in the near future.

When neuroblastoma does not respond to our general treatment regimens, we will try one or more specialized experimental treatments to achieve remission. These treatments may include drugs that stop the growth of blood vessels to a tumor in an attempt to prevent the tumor from growing and spreading (anti-angiogenesis), targeted radiation therapy (MIBG therapy or hot antibodies (the use of radioactive substances to destroy the neuroblastoma cells), monoclonal antibodies and vaccines designed to recognize and destroy neuroblastoma cells immunologically, and other novel chemotherapeutic agents.

Central Nervous System Relapse

Central nervous system (CNS) relapse (sometimes referred to as relapse in the brain or leptomeninges) has always been very hard to cure. One reason is that the type of radiation that is normally used to treat neuroblastoma is not sufficiently effective against CNS relapse. Over the past few years, however, we have started treating CNS relapse using monoclonal antibodies (either 3F8 or 8H9) to deliver liquid radiation directly to neuroblastoma cells in the CNS. When a certain form of radioactive iodine (131I) is attached to the antibodies, the antibodies can be safely injected into the cerebrospinal fluid, which bathes the CNS. This liquid radiation destroys neuroblastoma cells without damaging normal cells and is well tolerated with few side effects. When combined with surgery, radiation therapy, and chemotherapy, treatment with monocolonal antibodies has helped to make longer remissions possible. See Protocol 03-133 and Protocol 05-122 for details on our clinical trials related to CNS relapse. In addition, we are actively studying risk factors that may predict CNS relapse. Our hope is that by finding and understanding these markers we can identify patients who will need special treatment before relapse occurs.

Relapse Other than in the Central Nervous System

While we have made significant strides toward understanding and effectively treating neuroblastoma over the years, approximately 40 percent of our high-risk stage 4 patients (patients diagnosed after 18 months of age or those with MYCN amplification) relapse, usually within the first two to three years after diagnosis. Although some of these patients can be brought back to near remission, fewer than 20 percent of these patients are expected to survive for longer than five years. The treatment for relapsed neuroblastoma depends on what prior treatment the patient has received, but will usually include chemotherapy, radiation, immunotherapy, and possibly surgery.

Current Treatment Approach for High-Risk Neuroblastoma

Our current clinical trial protocol for treating high-risk neuroblastoma can be broken down into the following phases: induction, surgery, radiation, immunotherapy, and a process known as differentiation therapy. When a patient comes to us having started treatment elsewhere, we will review his or her case and discuss the structure of treatment with the parents.


Induction is the initial phase of treatment, and it usually consists of five rounds of chemotherapy. Chemotherapy refers to the use of chemicals to kill cancer cells. The drugs are given intravenously (injected through a vein into the bloodstream), usually on an outpatient basis. Chemotherapy is systemic; in other words, it is intended to kill all tumor cells that are reachable by blood vessels. Chemotherapy does cause damage to other cells in the body that are rapidly dividing, which is why most patients experience significant side effects.

The goal of the induction phase is to stop these rapidly growing cancers and to reduce the size of the primary (original site) tumor so that surgery can be safely performed. Historically, six or seven rounds of chemotherapy have been used, but our research has shown that the results are usually just as good with only five rounds and that eliminating the last one or two rounds greatly reduces the risk of chemotherapy-induced leukemia. Additional chemotherapy may be needed in rare cases in which significant disease remains after five rounds of chemotherapy.

Usually after three cycles of chemotherapy, we collect stem cells from the patient for future use for stem cell transplant if necessary.


Most patients with neuroblastoma will need surgery to remove the primary tumor or what is known as distant bulky soft tissue. Surgery is usually performed after three rounds of induction chemotherapy, when the maximal reduction in tumor size has been achieved, thereby making it easier to remove the cancer. In some cases surgery may be more appropriate at diagnosis or later in the chemotherapy cycle.


Radiation therapy uses large doses of x-rays to kill cancer cells. It is used after surgery on the primary tumor site and other sites at risk for relapse to prevent the cancer from regrowing. In some patients, radiation is given to boost the effect of chemotherapy at metastatic sites. If disease is advancing despite chemotherapy, radiation therapy may be used to treat cancer symptoms such as pain.

One of the limitations of radiation treatment is that it can damage nearby tissues and result in serious long-term side effects, especially in children. To minimize damage to healthy tissue, we use a technique originally pioneered at Memorial Sloan Kettering to treat prostate cancer, which is called intensity modulated radiation therapy (IMRT). This form of radiation targets tumors precisely, sparing healthy tissue, even when the tumor is wrapped around a vital organ, as is often the case with neuroblastoma.


Immunotherapy is used after tumors have been surgically removed, when the patient has only minimal disease left (in the bone marrow, for example) or when the patient has MRD. This treatment is designed to train the body's own immune system to detect and destroy neuroblastoma cells that have survived chemotherapy or radiation therapy. The treatment involves the injection of a substance called monoclonal antibody 3F8 into the bloodstream. The antibodies seek out and attach to neuroblastoma cells and signal the immune system to destroy them. We usually combine 3F8 with a protein called GM-CSF (granulocyte-macrophage colony stimulating factor), which stimulates myeloid white cells (neutrophils and macrophages) to make use of the antibodies.

The primary side effect of 3F8 treatment is a pain reaction requiring pain medications. Despite side effects that occur during 3F8 infusion, no long-term complications have been associated with these antibodies.

We are also using radioimmunotherapy to treat metastatic neuroblastoma, as well as central nervous system (CNS) relapse. For these treatments, antibodies are made to carry liquid radiation to the tumor cells. The results of these treatments have been particularly effective for CNS relapse.

Differentiation therapy

For patients who are in remission at the completion of or near the completion of immunotherapy, differentiation therapy is used to stop the growth and spread of any remaining neuroblastoma. Differentiation therapy, which generally involves a six-month course of an oral medication known as 13-cis-retinoic acid or isoretinoin (Accutane®), is a drug that works based on the fact that nerve cells that become neuroblastoma cells do so at a very early stage in development. When these immature nerve cells become neuroblastoma cells, they forget how to continue maturing into normal nerve cells and instead begin to divide non-stop. Differentiation therapy teaches neuroblastoma cells to mature again, i.e. to stop growing and turn into mature nerve-like cells that do not grow and divide. In this way, differentiation therapy may be able to stop any remaining neuroblastoma cells from growing and causing relapse.

Specialized Treatments

If at any point during treatment the disease gets worse, we may use one or more specialized treatments to try to stop the progression. These treatments may include targeted radiation therapies or new agents being developed to fight neuroblastoma. Targeted radiation therapies include hot antibodies and MIBG therapy, which both make use of substances that seek out and kill neuroblastoma cells. By attaching radioactive iodine to these substances, liquid radiation is selectively delivered to neuroblastoma cells.


Our ultimate goal is successfully treating patients with neuroblastoma and ensuring their quality of life after treatment. For patients who began their treatment at Memorial Sloan Kettering and achieved complete remission, most relapses have occurred within three years from diagnosis. Relapses can, however, occur five years after diagnosis, and unfortunately there is no time period after which we can say definitively that a patient will not relapse.

Nevertheless, by three years after diagnosis, our concern for our patients’ health shifts from relapse to the long-term effects of cancer treatment, and that is when the patients’ care is transitioned from the neuroblastoma program to the Long-Term Follow-Up Program. The team of doctors, nurse practitioners, social workers, and others who make up the Long-Term Follow-Up Program is expert in screening for, monitoring, treating, and coordinating the care for medical issues that may arise as a result of having been treated for neuroblastoma.

One question many parents have concerns immunizations. As of early 2008, we have a protocol for childhood inoculations that begins six to nine months after the end of chemotherapy treatments.