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Cancer Medicine :: Neuroblastoma Treatment


How is neuroblastoma treated?

Children with neuroblastoma and their families have special needs. These needs can be met best by cancer centers for children, working closely with the child’s primary care doctor. Treatment in these centers gives you the advantage of having teams of specialists who understand the differences between cancers in adults and those in children, as well as the unique needs of younger people with cancer.
Treating neuroblastoma is complex and often requires the expertise of many different doctors, nurses, and other health professionals. The doctors on this team often include:
A pediatric cancer surgeon
A pediatric oncologist (doctor who uses chemotherapy and other medicines to treat childhood cancers)
A pediatric radiation oncologist (doctor who uses radiation therapy to treat cancer in children)
Many other specialists may be involved in your child’s care as well, including nurse practitioners, nurses, psychologists, social workers, rehabilitation specialists, and other health professionals.
The approach to treatment of neuroblastoma depends on the stage of the cancer, the child's age, and other factors such as the prognostic markers mentioned previously. The types of treatment used may include:
Retinoid therapy
Radiation therapy
High-dose chemotherapy/radiation therapy and stem cell transplant
In many cases, more than one type of treatment is needed.
Neuroblastoma surgery
Surgery can be used both to help diagnose neuroblastoma and to treat it. For smaller tumors that have not spread, surgery is often the only treatment that is needed.
Surgical (open) biopsy
In many cases, doctors need to get a sample of the tumor to be sure it is a neuroblastoma before deciding on treatment options. Tumor samples are removed during a surgical biopsy to be looked at under a microscope and for other lab tests.
If the tumor is in the abdomen, the surgeon may do the biopsy with the aid of a laparoscope. This is a long, thin tube with a tiny video camera on the end. It is inserted into the abdomen through a small incision to allow the surgeon to see inside. The surgeon then makes a second small incision to reach inside the abdomen with long, thin instruments and remove pieces of tumor.
Surgery as treatment
After neuroblastoma is diagnosed, surgery is often used to try to remove as much of the tumor as possible. In some cases, surgery can remove the entire tumor and bring about a cure.
During the operation, the surgeon looks carefully for signs of tumor spread to other organs. Nearby lymph nodes (small collections of immune system cells to which cancers often spread first) are removed and looked at under a microscope for cancer cells.
If possible, the surgeon will remove the entire tumor. This is less likely if the tumor is near vital structures or wrapped around large blood vessels. Even if some the tumor is left behind, treatment with chemotherapy (and sometimes radiation therapy) after surgery may still result in a cure. Sometimes surgery is repeated after other treatments (chemotherapy and/or radiation therapy) to check the results of therapy and to remove any remaining cancer if possible.
If the tumor is very large, chemotherapy may be used before surgery. This can shrink the tumor and make it easier to remove.
Possible risks and side effects of surgery
Like all forms of treatment, surgery poses some risk of complications. These depend on the location and extent of the operation and the child’s health beforehand. Serious complications, although rare, can include problems with anesthesia, excess bleeding, infections, and damage to blood vessels, kidneys, other organs, or nerves. Complications are more likely if the tumor is large and growing into blood vessels or nerves. Most children will have some pain for a while after the operation, but this can usually be helped with medicines if needed.
Chemotherapy for neuroblastoma
Chemotherapy (chemo) uses anti-cancer drugs, which are usually given into a vein. The drugs enter the bloodstream and travel throughout the body to reach and destroy cancer cells. This makes chemo useful for treating neuroblastoma that has spread to the lymph nodes, bone marrow, liver, lungs, or other organs.
Some children with neuroblastoma are treated with chemotherapy either before surgery (neoadjuvant chemotherapy) or after surgery (adjuvant chemotherapy). In other cases, especially when the cancer has spread too far to be completely removed by surgery, chemotherapy is the main treatment.
Most children with neuroblastoma will need to have chemotherapy with a combination of drugs. The main drugs used to treat neuroblastoma include:
Cyclophosphamide or ifosfamide
Cisplatin or carboplatin
Doxorubicin (Adriamycin)
Busulfan and melphalan (sometimes used during stem cell transplant)
The most common combination of drugs to treat neuroblastoma includes carboplatin (or cisplatin), cyclophosphamide, doxorubicin, and etoposide, but others may be used. For children in the high-risk group, larger combinations are used, and the drugs are given at higher doses, which may be followed by a stem cell transplant (described further on).
Doctors give chemo in cycles, which consist of treatment on a few days in a row, followed by time off to allow the body time to recover. The cycles are typically repeated every 3 or 4 weeks. The total length of treatment depends on which risk group the child is in – higher risk groups usually require longer treatment.
Possible side effects of chemotherapy
Chemo drugs attack cells that are dividing quickly, which is why they work against cancer cells. But other cells in the body, such as those in the bone marrow, the lining of the mouth and intestines, and the hair follicles, also divide quickly. These cells are also likely to be affected by chemotherapy, which can lead to side effects.
The side effects of chemotherapy depend on the type and dose of drugs given and the length of time they are taken. General side effects of chemotherapy drugs can include:
Hair loss
Mouth sores
Loss of appetite
Nausea and vomiting
Increased chance of infections (due to low white blood cell counts)
Easy bruising or bleeding (due to low blood platelet counts)
Fatigue (due to low red blood cell counts)
Most of these side effects are short-term and tend to go away after treatment is finished. There are often ways to lessen these side effects. For example, drugs can be given to help prevent or reduce nausea and vomiting. Be sure to ask your child’s doctor or nurse about medicines to help reduce side effects, and let him or her know if your child has side effects so they can be managed.
Along with the effects listed above, some drugs can have specific side effects. For example:
Cyclophosphamide and ifosfamide can damage the bladder, which can cause blood in the urine. The chance of this happening can be lowered by giving the drugs with plenty of fluids and with a drug called mesna, which helps protect the bladder. These drugs can also damage the ovaries or testicles and may affect fertility (the ability to have children).
Doxorubicin can cause heart damage. Doctors try to reduce this risk as much as possible by not giving more than the recommended doses of doxorubicin and by checking the heart with a test called an echocardiogram (an ultrasound of the heart) during treatment. This drug can also cause skin damage if it should leak out of the vein while it is being given.
Cisplatin and carboplatin can affect the kidneys. Giving plenty of fluids can help reduce this risk. These drugs can also affect hearing. Your child’s doctor may order hearing tests (audiograms) during or after treatment.
Vincristine can damage nerves. Some patients may notice weakness, tingling, numbness, or pain, particularly in the hands and feet.
Chemotherapy may also have longer-term side effects in some cases. For example, some drugs used to treat neuroblastoma can increase the risk of later developing a cancer of white blood cells known as acute myeloid leukemia (AML). While this is a serious risk, it is not common, and the small increase in risk has to be weighed against the importance of chemotherapy in treating neuroblastoma.
Retinoid therapy for neuroblastoma
Retinoids are chemicals that are related to vitamin A. They are known as differentiating agents because they are thought to help some cancer cells to mature (differentiate) into normal cells.
In children with high-risk neuroblastoma, treatment with a retinoid called 13-cis-retinoic acid (isotretinoin) reduces the risk of recurrence after high-dose chemotherapy and stem cell transplant. Most doctors now recommend 6 months of 13-cis-retinoic acid once a transplant is completed. It is taken as a capsule, twice a day for 2 weeks, followed by 2 weeks off.
Researchers are now trying to develop more effective retinoids and to define the exact role of this approach in the treatment of neuroblastoma.
Radiation therapy for neuroblastoma
Radiation therapy uses high-energy rays or particles to kill cancer cells. Radiation is sometimes a necessary part of treatment, but because of the possible long-term side effects in children, it is avoided when possible. Two types of radiation therapy can be used to treat children with neuroblastoma.
External beam radiation therapy
External radiation therapy focuses the radiation on the cancer from a source outside the body. This type of treatment might be used:
To destroy neuroblastoma cells that remain behind after surgery and chemotherapy
To try to shrink tumors before surgery, making them easier to remove at the time of surgery
To treat larger tumors that are causing serious problems (such as trouble breathing) and do not respond quickly to chemotherapy
As part of the treatment regimen (along with high-dose chemotherapy) before a stem cell transplant in children with high-risk neuroblastoma
To help relieve pain caused by advanced neuroblastoma
Most often, the radiation is aimed at the tumor itself, but in some cases it may also target other parts of the body to reduce the risk of cancer spread. When radiation is aimed at the whole body, it is known as total body irradiation (TBI).
Before treatments start, the radiation team takes careful measurements with imaging tests such as MRI scans to determine the correct angles for aiming the radiation beams and the proper dose of radiation.
Radiation therapy is much like getting an x-ray, but the dose of radiation is much higher. Your child may be fitted with a plastic mold resembling a body cast to keep him or her in the same position each time so that the radiation can be aimed more accurately. For each session, your child will lie on a special table while a machine delivers the radiation from a precise angle. The treatment is not painful.
Each actual treatment lasts only a few minutes, but the setup time – getting your child into place for treatment – usually takes longer. Young children may be given medicine to make them sleep so they will not move during the treatment. The number of radiation treatments given will depend on the situation.
Possible side effects: Radiation is sometimes an important part of treatment, but young children’s bodies are very sensitive to it, so doctors try to use as little radiation as possible to help avoid or limit any problems. Radiation therapy can cause both short-term and long-term side effects, which depend on the dose of radiation and where it is aimed.
Possible short-term effects: Effects on skin areas that receive radiation can range from mild sunburn-like changes and hair loss to more severe skin reactions.
Radiation to the abdomen (belly) can cause nausea or diarrhea.
Radiation therapy can make a child tired, especially toward the end of treatment.
Radiation may also make the side effects of chemotherapy worse. Talk with your child's doctor about the possible side effects because there are ways to relieve some of them.
Possible long-term effects:Radiation therapy can slow the growth of normal body tissues (such as bones) that get radiation, especially in younger children. In the past this led to problems such as short bones or a curving of the spine, but this is less likely with the lower doses of radiation used today.
Radiation that reaches the chest area can affect the heart and lungs. This does not usually cause problems right away, but in some children it may eventually lead to heart or lung problems as they get older.
Radiation to the abdomen in girls may damage the ovaries. This might lead to abnormal menstrual cycles or problems getting pregnant or having children later on.
Radiation can damage DNA. As a result, radiation therapy slightly increases the risk of developing a second cancer in the areas that get radiation, usually many years after the radiation is given.
Close follow-up with doctors is important as children grow older so that any problems can be found and treated as soon as possible. For more on the possible long-term effects of treatment, see the section “Long-term effects of neuroblastoma and its treatment.”
MIBG radiotherapy
As described in the section “How is neuroblastoma diagnosed?,” MIBG is a chemical similar to norepinephrine, which is made by sympathetic nerve cells. A slightly radioactive form of MIBG is sometimes injected into the bloodstream as part of an imaging test to look for neuroblastoma cells in the body.
A more highly radioactive form of MIBG is also used to treat some children with advanced neuroblastoma, often along with other treatments. Once injected into the bloodstream, the MIBG goes to the sites of tumors anywhere in the body, where it delivers its radiation. The child will need to stay in a special room for a few days after the injection until most of the radiation has left the body.
Possible side effects: MIBG therapy can sometimes cause nausea and vomiting. It can also lower blood cell counts because of its effects on the bone marrow. In rare cases it may cause high blood pressure for a short period of time. Because it contains iodine, MIBG may build up in the thyroid gland, which can sometimes lower the levels of thyroid hormone in the body.
High-dose chemotherapy/radiation therapy and stem cell transplant for neuroblastoma
This type of treatment is often used in children with high-risk neuroblastoma who are unlikely to be cured with other treatments.
Giving higher doses of chemotherapy (and sometimes radiation) might be more effective in treating these cancers, but normally this can’t be done because it would cause severe damage to the bone marrow, where new blood cells are made. This could lead to life-threatening shortages of blood cells.
Doctors can sometimes get around this problem by giving the high-dose treatments, then replacing the patient’s bone marrow cells by giving them new blood-making cells (called stem cells). This is known as a stem cell transplant (SCT).
In the past, the stem cells were often collected from the child’s own bone marrow before treatment, which required drilling small holes in certain bones. The treatment was commonly referred to as a bone marrow transplant.
But doctors have found that stem cells can be collected from the bloodstream during a procedure known as apheresis. This is similar to donating blood, but instead of going into a collecting bag, the blood goes into a special machine that filters out the stem cells and returns the other parts of the blood back to the person’s body. This process may be repeated over a few days. The stem cells are then frozen until the transplant.
How the transplant is done
The child will typically be admitted to the stem cell transplant unit of the hospital on the day before the high-dose chemo begins. He or she will usually stay in the hospital until after the chemo and the stem cells have been given, and until the stem cells have started making new blood cells again.
The child gets high-dose chemotherapy, often along with radiation. This destroys the cancer cells in the body, as well as the normal cells in the bone marrow. After treatment, the frozen stem cells are thawed and given as a blood transfusion. The stem cells travel through the bloodstream and settle in the child’s bone marrow.
Usually within a couple of weeks, the stem cells begin making new white blood cells. This is later followed by new platelet production and new red blood cell production. Until this happens, the child is at high risk of infection because of a low white blood cell count, as well as bleeding because of a low platelet count. To help lower the risk of infection, the child stays in a special hospital room, and visitors must wear protective clothing. Blood and platelet transfusions and treatment with IV antibiotics may also be used to help prevent or treat infections or bleeding problems.
Children usually stay in the hospital room until part of their white blood cell count (known as the absolute neutrophil count, or ANC) rises above 500. They may be able to leave the hospital when their ANC is near 1,000. The child is then seen in an outpatient clinic almost every day for several weeks. Because platelet counts often take longer to return to a safe level, the child may get platelet transfusions as an outpatient. Patients may need to make regular visits to the outpatient clinic for about 6 months, after which time their care may be continued by their regular doctors.
Practical points
A stem cell transplant is a complex treatment that can cause life-threatening side effects. If the doctors think your child may benefit from a transplant, the best place to have this done is at a nationally recognized cancer center where the staff has experience with the procedure and managing the recovery period.
A stem cell transplant often requires a long hospital stay and can be very expensive (costing well over $100,000). Be sure to get a written approval from your insurer if the procedure is recommended for your child. Even if the transplant is covered by your insurance, co-pays or other costs could easily amount to tens of thousands of dollars. Find out what your insurer will cover before the transplant so you will have an idea of what you might have to pay.
Possible side effects
The possible side effects from SCT are generally divided into early and long-term effects.
Early or short-term side effects
Possible early complications and side effects are basically the same as those caused by high-dose chemotherapy or radiation therapy and can be severe. They are caused by damage to the bone marrow and other quickly growing tissues of the body, and can include:
Low blood cell counts (with fatigue and increased risk of infection and bleeding)
Nausea and vomiting
Loss of appetite
Mouth sores
Hair loss
One of the most common and serious short-term effects is an increased risk for infection. Antibiotics are often given to try to prevent this. Other side effects, like low red blood cell and platelet counts, may require blood product transfusions or other treatments.
Late or long-term side effects
Some complications and side effects can persist for a long time or may not occur until years after the transplant. These can include:
Radiation damage to the heart or lungs
Problems with the thyroid or other hormone-making glands
Problems with fertility
Damage to bones or problems with bone growth
Development of another cancer (including leukemia) years later.
Immunotherapy for neuroblastoma
Monoclonal antibodies are man-made versions of immune system proteins that can be made to attack a very specific target. These molecules can be injected into the body to seek out and attach to cancer cells to help treat some cancers.
A monoclonal antibody called ch14.18 attaches to the ganglioside GD2, a substance found on the surface of many neuroblastoma cells. This antibody can be given together with cytokines (immune system hormones) such as GM-CSF and interleukin-2 (IL-2) to help the child’s immune system to recognize and destroy neuroblastoma cells. This antibody is now part of the routine treatment for many children with high-risk neuroblastoma, often after a stem cell transplant.
Possible side effects
Side effects of ch.14.18 may include nerve pain (which can be severe), leaking of fluid in the body (which can lead to low blood pressure, fast heart rate, shortness of breath, and swelling), and allergic reactions.
What happens after treatment for neuroblastoma?
Many children with neuroblastoma have a good chance of long-term survival following treatment.
After treatment for neuroblastoma, the main concerns for most families are the short- and long-term effects of the tumor and its treatment, and concerns about the tumor coming back.
It is certainly normal to want to put the tumor and its treatment behind you and to get back to a life that doesn't revolve around cancer. But it's important to realize that follow-up care is a central part of this process that offers your child the best chance for recovery and long-term survival.
Follow-up exams
After treatment, the doctor will likely order follow-up tests, which may include lab tests and imaging tests (MIBG scans, PET scans, ultrasound, CT scans, and/or MRI scans) to see if there is any tumor remaining. The tests done will depend on the risk group, the size and location of the tumor, and other factors.
Because there is a chance that the cancer may return after treatment, it is very important to keep all follow-up appointments and to report any new symptoms to your child's doctor right away. The health care team will discuss a follow-up schedule with you, including which tests should be done and how often. Doctor visits, lab tests, and imaging tests to look for signs of recurrence are done more often at first. If nothing abnormal is found, the time between tests can then be extended.
A benefit of follow-up care is that it gives you a chance to discuss any questions and concerns that arise during and after your child’s recovery. For example, almost any cancer treatment can have side effects. Some may last for a few weeks to several months, but others can be permanent. It is important to report any new symptoms to the doctor right away so that the cause can be found and treated, if needed.
It is also important to keep health insurance. Even though no one wants to think of the cancer coming back, it is a possibility. If it happens, the last thing you want is to have to worry about paying for treatment.
What’s new in neuroblastoma research and treatment?
Important research into neuroblastoma is under way right now in many university hospitals, medical centers, and other institutions around the world. Each year, scientists find out more about what causes the disease and how to improve treatment.
Genetics of neuroblastomas
Researchers now have better lab tests to look for changes in the genes of neuroblastoma cells. They have made a great deal of progress in recent years in figuring out which neuroblastomas are likely to be cured with standard treatment, and which will need more aggressive treatment.
For example, using newer lab tests, researchers have found that certain DNA changes on the short arm of chromosome 6 (6p22) are more likely to be seen in neuroblastomas that grow more aggressively. More recently, researchers have found that neuroblastoma cells in older children are more likely to have changes in the ATRX tumor suppressor gene. Tumors with this gene change tend to grow more slowly, but they are also harder to cure. This may help explain why younger children with neuroblastoma tend to do better in the long term than children who are older when they are diagnosed.
Doctors are now looking to use these and other findings to help aid in choosing the best treatments. Newer staging systems and risk group classifications, which take advantage of some of these findings, should be in use within the next few years.
Survival rates for neuroblastoma have gotten better as doctors have found ways to improve on current treatments.
Doctors continue to search for the best combinations of chemotherapy drugs to treat neuroblastoma.
Several chemotherapy drugs that are already used to treat other cancers, such as topotecan, irinotecan, and temozolomide, are now being studied for use against neuroblastoma. Some newer drugs that work in different ways from standard chemotherapy drugs are being studied against neuroblastoma as well. Examples include bortezomib, vorinostat, nifurtimox, and lestaurtinib.
Other studies are looking to see if children with low or intermediate risk neuroblastoma can be treated with less chemotherapy. The goal is to still have the same good results, but with fewer side effects from treatment.
Stem cell transplants
Doctors are also trying to improve the success rate with high-dose chemotherapy and stem cell transplants, using different combinations of chemotherapy, radiation therapy, retinoids, and other treatments. Some clinical trials are studying the use of more than one stem cell transplant in the same patient (known as a tandem transplant). Others are looking to see if using stem cells donated from another person (an allogeneic transplant) might help some children with hard-to-treat tumors.
Retinoids such as 13-cis-retinoic acid (isotretinoin) have reduced the risk of recurrence after treatment in children with high-risk neuroblastoma. Newer, potentially more effective retinoids, such as fenretinide.
Newer forms of treatment
Knowledge about what makes neuroblastoma cells different from normal cells may lead to new approaches to treating this disease. Newer forms of therapy that target neuroblastoma cells more specifically than standard treatments are now being studied in clinical trials. For example, doctors are now studying medicines that specifically target the machinery of neuroblastoma cells, such as drugs that inhibit the ALK pathway or aurora A pathway.
One example is crizotinib (Xalkori), a drug that targets cells with changes in the ALK gene. Up to 15% of neuroblastomas have changes in this gene. In an early study, crizotinib was found to cause some neuroblastomas to shrink, although it’s not clear how long this might last. Researchers are now looking to see if adding second type of drug, called an mTOR inhibitor, might help make this drug more effective.
The monoclonal antibody ch14.18, which targets GD2 on neuroblastoma cells, is now used routinely for children with high-risk neuroblastoma, to help immune system cells find and destroy the cancer cells. Clinical trials are now testing the effectiveness of several other antibodies that target GD2. One example is hu14.18-IL2, an antibody that is linked to interleukin-2 (an immune-boosting cytokine). Early results have found that this antibody/cytokine combination may help some children in whom other treatments are no longer working.
Several cancer vaccines are also being studied for use against neuroblastoma. For these vaccines, modified neuroblastoma cells or other substances are injected into the body to try to get the child's own immune system to attack cancer cells.

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