Neuroblastoma Recurrent

When neuroblastoma returns after treatment or doesn’t respond to initial therapy, families face difficult challenges, but treatments and support are available.

Table of contents

• What is Recurrent or Refractory Neuroblastoma?
• Signs and Symptoms
• What Causes Recurrence
• How is Recurrence Diagnosed
• Risk of Relapse
• Treatment Options
• Research and Clinical Trials

What is Recurrent or Refractory Neuroblastoma?

Relapsed neuroblastoma refers to cancer that has returned after a child has already undergone treatment for the disease^[1]. This is different from refractory neuroblastoma, which describes cancer that does not respond to initial treatment^[1].

Approximately half of children who are treated for high-risk neuroblastoma and achieve an initial remission (when cancer cannot be detected) will have the disease come back^[1]. In about 15 percent of children with high-risk neuroblastoma, the tumor does not respond to initial treatment at all^[1]. The treatment approach for children with refractory neuroblastoma is similar to that for children with relapsed neuroblastoma^[1].

For children with high-risk neuroblastoma, about 10 percent will have disease that does not respond to chemotherapy, while another 40 to 50 percent will see the disease go away at some point but eventually relapse during or after treatment^[2]. While low-risk and intermediate-risk forms of neuroblastoma may also relapse after surgery or chemotherapy, these children are usually cured with standard techniques^[2].

It is important to understand that recurrent or relapsed disease is always considered progressive disease at discovery, because it has increased from “no evidence of disease”^[7]. Nearly 50 percent of children with high-risk disease will be refractory to therapy or suffer a relapse, and both situations are extremely serious challenges^[4].

Signs and Symptoms

Just like newly diagnosed neuroblastoma, signs and symptoms of a relapse will vary greatly depending on the size and location of the tumor and how much it has spread to other parts of the body^[1]. While neuroblastoma usually begins in the abdomen, especially in the tissues of the adrenal glands (organs that sit on top of the kidneys and produce important hormones), it may also begin in nerve tissues in the neck, chest, or pelvis^[1].

Relapse is often detected on imaging scans when there are no symptoms at all^[2]. Pain is the most common sign of relapse, but there are many potential symptoms, ranging from fatigue to new areas of swelling^[2].

The symptoms of relapsed neuroblastoma can include:

• An abdominal mass
• Enlarged lymph nodes in the neck
• Swelling and bruising of the area around the eyes
• Unexplained fevers, bone pain, or limping
• Weakness or paralysis
• Weight loss or poor appetite
• Uncontrolled eye or leg movements

These tumors often spread to other areas of the body, including the lymph nodes, liver, bones, and bone marrow^[1].

What Causes Recurrence

No one has determined exactly what causes neuroblastoma relapse after the cancer appeared to be gone^[7]. It is important to understand that tumors often emerge with no known cause. Many may result from the combined effects of genetic and environmental factors^[1].

Theories for the cause of recurrence include:

• Re-introduction of neuroblastoma cells in contaminated stem cells (special cells collected from the patient and given back after high-dose treatment) during rescue
• Neuroblastoma cells “hiding” in sanctuary sites such as the brain or testes
• Neuroblastoma cells becoming resistant to treatment

These are theories, and the exact cause remains unknown^[7].

How is Recurrence Diagnosed

Children who have completed treatment for neuroblastoma will have regularly scheduled scans for about 3 years after initial treatment^[2]. These scans will alert your child’s medical team of a potential relapse very quickly. If a relapse is suspected, your child will undergo a series of tests to show the extent of the relapse^[2].

To make a diagnosis of relapsed neuroblastoma, your doctor may order a variety of tests, including:

• Computerized tomography (CT or CAT) scan – an imaging test that uses X-rays to create detailed pictures of the inside of the body
• Magnetic resonance imaging (MRI) scan – an imaging test that uses magnets and radio waves to create detailed images
• Bone scan
• Metaiodobenzylguanidine (MIBG) scan – a special scan that uses a small amount of radioactive material that neuroblastoma cells pick up, making them visible on the scan
• Bone marrow biopsy and/or aspiration – a procedure to remove a small sample of bone marrow to check for cancer cells
• Urine tests
• Blood tests

In some cases, your doctor may also order a tumor biopsy, in which surgeons or specialists remove either a piece of the tumor or the whole tumor, depending on tumor location and size. Specialists will analyze the tumor, and other important tests will be done to determine the tumor biology, such as genetic studies^[1].

Risk of Relapse

High-risk neuroblastoma has a greater chance of recurring than low- or intermediate-risk neuroblastoma^[9]. In children with low-risk or intermediate-risk neuroblastoma, relapses occur in only 5 to 15 percent of cases. However, it is estimated that as many as 50 to 60 percent of children with high-risk neuroblastoma will eventually suffer a relapse^[14].

The risk of relapse decreases every year after successful treatment, since most relapses occur within two years after stem cell transplant or completing chemotherapy^[7]. If neuroblastoma is going to relapse at all, it usually does so within the first two years after the end of treatment. Relapses occurring more than five years after the completion of therapy are rare^[14].

In general, when the disease comes back in only one area, the outlook is better than when it recurs in many locations, such as bone and bone marrow^[9]. The length of time in remission, the location and nature of the disease, the prior treatment, and many other factors must be considered to determine how to treat recurrent disease^[7].

Treatment Options

The treatment approach for children with recurrent or refractory neuroblastoma depends on several factors, including where the cancer has come back, the original risk group the child was in, the treatment they have had before, and the seriousness of any side effects they have had^[5].

Treatment for Low-Risk Disease That Recurs

Children first treated for low-risk neuroblastoma who have a recurrence that is found in one place may be treated with surgery or chemotherapy or both^[9]. If the recurrent neuroblastoma has spread to other parts of the body, it is often treated with chemotherapy. Surgery may be done to remove as much of the recurrent tumor as possible^[9].

Chemotherapy combinations used to treat recurrent neuroblastoma include:

• Carboplatin, cyclophosphamide, doxorubicin and etoposide
• Cyclophosphamide and topotecan
• Irinotecan and temozolomide

Treatment for Intermediate-Risk Disease That Recurs

Children first treated for intermediate-risk neuroblastoma who have a recurrence found in one place may be treated with surgery, and chemotherapy may also be given^[9]. Radiation therapy may be used if the cancer keeps growing or spreads after chemotherapy and surgery.

If the recurrent neuroblastoma has spread to other parts of the body, treatment often needs to be more aggressive. A combination of therapies are used, including chemotherapy, surgery, radiation therapy, stem cell rescue, retinoids (substances related to vitamin A), and immunotherapy (treatment that helps the immune system fight cancer)^[9].

Treatment for High-Risk Disease That Recurs

For children with high-risk neuroblastoma, treatment is usually more intense and is likely to include a combination of treatments^[5]. The type of chemotherapy your child will have is likely to be different from their first treatment^[5].

One of the most effective treatment plans is chemotherapy combined with immunotherapy^[9]. Chemotherapy combinations that may be used include:

• Temozolomide and irinotecan (sometimes with dinutuximab, an immunotherapy drug)
• Topotecan and cyclophosphamide

Targeted radiotherapy is another treatment your child’s doctor might suggest^[5]. Targeted radiotherapy, called MIBG therapy, is similar to the MIBG scan used to diagnose neuroblastoma. As a treatment, your child will have a higher dose of radioactive material than they did with the scan. The cancer cells pick up the MIBG and die^[5].

Sometimes radioisotope therapy with MIBG may be used to treat high-risk neuroblastoma that recurs. This treatment is only available in a few centers and is often given within a clinical trial. Stem cell rescue may be needed after treatment to help the bone marrow recover^[9].

Some children might go on to have other treatments such as:

• An immunotherapy drug such as dinutuximab beta
• 13-cis-retinoic acid (isotretinoin) – a substance related to vitamin A

ALK inhibitors (such as crizotinib) are drugs that target neuroblastoma cells that have an abnormal ALK gene. ALK inhibitors may be used to treat neuroblastoma that is no longer responding to other treatments if there is evidence that the tumor has an abnormal ALK gene^[9].

Research and Clinical Trials

Researchers are looking into different ways of treating relapsed or refractory neuroblastoma^[5]. Your doctor might suggest your child has treatment as part of a clinical trial, which is a research study testing new treatments^[5].

Targeted Cancer Drugs and Immunotherapy

Targeted cancer drugs work by targeting the differences in cancer cells that help them to grow and survive. Immunotherapy drugs help the immune system to attack the cancer^[5].

Bevacizumab is a type of targeted cancer drug called a monoclonal antibody. It targets the tumor’s blood supply. By cutting off the tumor’s blood supply, the cancer cells will die. Researchers have been looking at this drug alongside chemotherapy drugs. They recommend that children with relapsed or refractory neuroblastoma have bevacizumab alongside irinotecan and temozolomide, or other combinations^[5].

Doctors are also looking into other targeted cancer drugs, either on their own or with chemotherapy. Some of these drugs include venetoclax, lorlatinib, idasanutlin, and entrectinib^[5].

Other Research

There is no standard treatment for children whose cancer continues to grow and does not respond to their first treatment. Doctors would like to know which treatment or treatment combinations work best in these situations. Research projects are comparing different types of intensive treatment^[5].

The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma. Additional clinical trials using genetic tumor profiling to target tumor-specific changes are ongoing. Combinations of these new treatments with current treatment plans will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma^[11].

Future improvements in high-risk neuroblastoma outcomes will require the identification of disease and patient-specific weaknesses that can be used in treatment. Rational development of novel approaches to neuroblastoma therapy requires forward-thinking strategies to prove activity in the relapse setting, and ultimately effectiveness in curing patients when integrated into frontline treatment plans^[4].