Neuroblastoma is a type of cancer that develops in neuroblasts, which are early nerve cells found in an embryo or fetus. This form of cancer occurs most often in infants and children younger than 10 years old. Although rare overall, this cancer accounts for around 50% of all cancers in infants, making it the most common tumor found in patients younger than 1 year old. Survival rates for neuroblastoma have a relatively wide range, spanning from 95% survival in low-risk neuroblastoma patients to 50% survival in high-risk patients.
Neuroblastoma is a cancer of the sympathetic nervous system. The sympathetic nervous system is a division of the autonomic nervous system, which controls things such as heart rate, blood pressure, and other bodily functions that we are not always consciously aware of. The sympathetic nervous system is composed of nerve fibers that run along the spinal cord, ganglia, which are clusters of nerve cells at different points along the nerve fibers, and nerve-like cells that are found in the medulla of the adrenal glands, which sit on top of each kidney. These glands make various hormones, like epinephrine, for example. The ganglia are the site of origin for around 1/4 of all neuroblastoma cases and the adrenal glands account for 1/3 of all neuroblastoma cases. Neuroblastoma cells are often capable of releasing hormones themselves, which are related to the adrenal glands. These secreted hormones are usually responsible for some of the more common symptoms seen with this cancer, such as high blood pressure or rapid heartbeat.
If the patient has signs or symptoms that might be caused by a neuroblastoma the doctor will want to get a complete medical history to learn more about the symptoms. The doctor might also ask if there’s a family history of any type of cancer. The physician will examine the patient for possible signs of a neuroblastoma and other health problems. For example, the doctor may be able to see or feel an abnormal mass or swelling in the body or may find a child has lumps or bumps under the skin or high blood pressure. Neuroblastomas can sometimes grow close to the spinal cord, which can affect movement and strength in the child’s arms and legs, so the doctor will pay close attention to these specific signs.
Some signs that could be caused by neuroblastoma, such as fever and enlarged lymph nodes, are much more likely to be caused by an infection, so the doctor might look for other signs of infection at first.
If the history and exam suggest a child might have a neuroblastoma other tests will be done. These could include blood and urine tests, imaging tests, and biopsies. These tests are important because many of the symptoms and signs of neuroblastoma can also be caused by other diseases, such as infections, or even other types of cancer.
Sympathetic nerve cells normally release hormones called catecholamines, such as epinephrine (adrenaline) and norepinephrine, which enter the blood. Eventually the body breaks these down into metabolites, which then pass out of the body in the urine.
Neuroblastoma cells can also make these hormones themselves. In most cases, neuroblastoma cells make enough catecholamines to be detected by blood or urine tests. The two catecholamine metabolites most often measured in these tests are homovanillic acid (HVA) and vanillylmandelic acid (VMA).
If neuroblastoma is suspected or has been found, the patient’s physician will probably order blood tests to check blood cell counts, liver and kidney function, and the balance of salts in the body. A urinalysis may also be done to further check kidney function.
Imaging test use x-rays, magnetic fields, sound waves, or radioactive substances to create pictures of the inside of the body. Imaging tests can be done for a number of reasons, including to help find out if a suspicious area might be cancerous, to learn how far cancer has spread, and to help determine if treatment has been effective. Most children who have or might have neuroblastoma will have one or more of these tests in order to confirm their diagnosis. Children with neuroblastoma, however, are often very young, so it can be hard to do some of these tests.
Ultrasound is often one of the first tests done in small children if a tumor is suspected, because it is fairly quick and easy, it does not use radiation, and it can often give the physician a good view inside the body, especially in the abdomen. This test uses sound waves to create pictures of organs or masses inside the body. For this test, the patient lies on a table while a small wand called a transducer is placed on the skin over the belly. The wand gives off sound waves and picks up the echoes as they bounce off organs. The echoes are converted by a computer into a black and white image on a screen. The test is not usually painful, but it might cause some discomfort if the transducer is pressed down hard on the belly. Ultrasound is used most often to look for tumors in the abdomen. Ultrasound can detect if kidneys have become swollen because the outflow of urine has been blocked by enlarged lymph nodes or a mass. It can also be used to help guide a biopsy needle into a suspected tumor to get a sample for testing. It is particularly useful in checking to see if tumors in the abdomen are shrinking. The pictures from ultrasound aren’t as detailed as those from some other tests, so even if a tumor is found, CT or MRI scans might still be needed.
The physician may also order an x-ray of the chest or another part of the body as an early test if a child is having symptoms but it’s not clear what might be causing them. The images from an x-ray, however, might not always be detailed enough to spot tumors. If neuroblastoma has already been diagnosed, x-rays can be useful to see if cancer has spread to certain bones. An x-ray of the head may be done to see if cancer has spread to the skull bones. An MIBG scan or a bone scan is usually better for looking at the bones in the rest of the body, but x-rays may be used in infants, where these scans might not be possible. A standard chest x-ray may be done if doctors suspect that the tumor has invaded the lungs, but a CT or MRI scan of the chest can show the area in more detail.
CT scans are often used to look for neuroblastoma in the abdomen, pelvis, and chest. The CT scan is an x-ray test that produces detailed cross-sectional images of parts of the body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around the patient while he or she lies on a table. A computer then combines these pictures into images showing slices of the part of the body being studied. Unlike a regular x-ray, a CT scan creates detailed images of the soft tissues in the body. Before the test, the patient may be asked to drink a contrast solution and/or get an IV injection of a contrast dye. This helps better outline structures in the body. The contrast may cause some flushing, or a feeling of warmth, especially in the face. Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. CT scans take longer than regular x-rays. A CT scanner has been described as a large donut, with a narrow table in the middle opening. The patient will need to lie still on the table while the scans are being done. During the test, the table slides in and out of the scanner. Younger children may be sedated before the test to reduce movement and help make sure the imaging comes out well.
Magnetic resonance imaging, or MRI scans, provide detailed images of soft tissues in the body. These scans are very helpful in looking at the brain and spinal cord. They may be slightly better than CT scans for seeing the extent of a neuroblastoma tumor, especially around the spine, but this test can be harder to do in small children. MRI scans use radio waves and strong magnets to create the images ins
tead of x-rays, so there i
s no radiation. A contrast material called gadolinium may be injected into a vein before the scan to better see details, but this is needed less often than with a CT scan. It usually does not cause allergic reactions, but it can cause other problems in children with kidney disease, so doctors are careful when they use it. MRI scans take longer than CT scans, often up to an hour. For most MRI machines, the patient has to lie inside a narrow tube, which is confining and can be distressing. Newer, more open MRI machines may be an option in some cases, but they still require the child to stay still for long periods of time. The MRI machine also makes loud buzzing and clicking noises that may be disturbing. Younger children are often given a sedative to help keep them calm or even asleep during the test.
This scan uses a form of the chemical meta-iodobenzylguanidine (MIBG) that contains a small amount of radioactive iodine. MIBG is similar to norepinephrine, a hormone made by sympathetic nerve cells. It is injected into a vein and travels through the blood, and in most patients it will attach to neuroblastoma cells anywhere in the body. Several hours or days later, the body is scanned with a special camera to look for areas that picked up the radioactivity. This helps doctors tell where the neuroblastoma is and whether it has spread to the bones and/or other parts of the body.
The MIBG scan is preferred by many doctors as a standard test in children with neuroblastoma. It can be repeated after treatment to see if the treatment regimen has been effective. It is also good to know if the tumor takes up the MIBG because in some cases, this radioactive molecule can be used at higher doses to treat the neuroblastoma.
The signs and symptoms of neuroblastoma can vary widely depending on the size of the tumor in the patients, the location of the tumor, if the tumor has metastasized and spread to other areas in the body, and if the tumor cells are capable of secreting hormones or not. One of the most common symptoms associated with neuroblastoma is the development of tumors in the abdomen or pelvis. Tumor formation in this area may result in the patients not wanting to eat, which could lead to weight loss and stomach pain. Tumors in the abdomen may also cause swollen legs if the tumor is blocking any lymph vessels that would prevent the circulation of fluids in the body. Tumors can also form in the chest or neck. This may cause swelling in the face, neck or arms, headache, dizziness, and changes in consciousness if the cancer begins to affect the brain. After initial tumor formation, many patients also encounter the problem of metastasis. Typically in neuroblastoma patients, metastasis is to the lymph nodes and bones. If the cancer spreads to the lymph nodes, the patient may present with abnormal swollen lymph nodes across the body. If the tumor metastasizes into the bones, the child may complain of bone pain and may limp or refuse to walk altogether. If the cancer spreads into the bone marrow, hematopoiesis may be compromised and the child may be abnormally tired, weak, prone to frequent infections, or show excess bruising or bleeding. Neuroblastoma may also present in patients as a variety of hormone-related symptoms, including constant diarrhea, fever, high blood pressure, rapid heartbeat, and sweating. These symptoms are often referred to as paraneoplastic syndromes.
The stage of a cancer describes how far it has spread. A patient’s treatment and prognosis depend, to a large extent, on the cancer’s stage. The stage of the neuroblastoma is based on results of physical exams, imaging tests, and biopsies of the main tumor and other tissues. The results of surgery are sometimes used in staging as well. For neuroblastoma, several other factors also affect prognosis, including a child’s age and certain tests of blood and tumor specimens. These prognostic factors are not used to determine the stage of the cancer, but they are used along with the stage to determine which risk group a child falls into, which in turn affects treatment options.
A staging system is a standard way for the cancer care team to sum up the extent of the cancer. Since the mid-1990s, most cancer centers have used the International Neuroblastoma Staging System (INSS) to stage neuroblastoma. This system takes into account the results of surgery to remove the tumor. In simplified form, the stages are stage 1, stage 2A and 2B, stage 3, stage 4, and recurrent.
In stage 1, the cancer is still in the area where it started. It is on one side of the body (right or left). All visible tumor has been removed completely by surgery, although looking at the tumor’s edges under the microscope after surgery may show some cancer cells. Lymph nodes outside the tumor are free of cancer, although nodes enclosed within the tumor may contain neuroblastoma cells.
In stage 2A, cancer is still in the area where it started and on one side of the body, but not all of the visible tumor could be removed by surgery. Lymph nodes outside the tumor are free of cancer, although nodes enclosed within the tumor may contain neuroblastoma cells.
In stage 2B, the cancer is on one side of the body, and may or may not have been removed completely by surgery. Nearby lymph nodes outside the tumor contain neuroblastoma cells, but the cancer has not spread to lymph nodes on the other side of the body or elsewhere.
In stage 3, the cancer has not spread to distant parts of the body, but either the cancer cannot be removed completely by surgery and it has crossed the midline to the other side of the body. The cancer may or may not have spread to nearby lymph nodes, or the cancer is still in the area where it started and is on one side of the body. I has spread to the lymph nodes that are relatively nearby but on the other side of the body. This stage may also be characterized if the cancer is in the middle of the body and is growing toward both sides and cannot be removed completely by surgery.
In stage 4, the cancer has spread to distant sites such as distant lymph nodes, bone, liver, skin, bone marrow, or other organs.
While not formally part of the staging system, the term recurrent is used to describe cancer that has come back (recurred) after it has been treated. The cancer might come back in the area where it first started or in another part of the body.
Many of the treatment options used for neuroblastoma are common among other cancer treatment options. Typically, neuroblastoma is treated with surgery to debulk the tumor that is developing in the patient’s body, chemotherapy to destroy the malignant cells, and radiation therapy, which also targets malignant cells and works to destroy them. Retinoid therapy is also used in the treatment of neuroblastoma. This therapy option uses therapeutic agents that are related to vitamin A and are thought to help some cancerous cells develop into normal cells. The main idea behind using this therapy option in neuroblastoma cases is that since neuroblastoma is a cancer of early nerve cells, inducing the cells to mature would hopefully stop them from proliferating more cancer cells. Neuroblastoma is also treated with immunotherapy, which uses monoclonal antibodies to help the patient’s own immune system recognize and destroy the cancer cells more effectively. The final treatment option that is used in neuroblastoma patients is a stem cell transplant paired with high-dose chemotherapy or radiation.
Stem cell transplants are often only used in children with high-risk neuroblastoma who are unlikely to be responsive to any other common treatments. Typically, stem cell transplants are given after a regimen of high-dose chemotherapy, high-dose radiation, or a combination of both. High-dose regimens are often prescribed in these cases because the patients who are high-risk haven’t responded well to other treatments, and high-dose chemotherapy or radiation may be the only effective way t
o kill the cancer cells. T
ypically, treatments such as these are not prescribed at such high doses because it would cause too much damage to the bone marrow, and could result in life-threatening shortages of blood. Physicians are sometimes able to get around this problem by essentially replacing the patient’s bone marrow in a stem cell transplant after administering these high-dose treatments.
The process of a stem cell transplant occurs in essentially three separate stages. First, before a patient is scheduled for their high-dose treatment, their stem cells are collected, usually through apheresis. This process is similar to donating blood, but instead of collecting the blood, the stem cells are collected and the other blood components are returned to the patients. The stem cells are then frozen until they are needed. The next stage of this treatment is administering the high-dose chemotherapy or radiation. This destroys the cancer cells in the body, but also destroys normal cells in the bone marrow. After treatment, the frozen stem cells are thawed and given back to the patient in an autologous stem cell transplant. In an autologous transplant, such as the technique used for the treatment of neuroblastoma, the stem cells that are transplanted are from the patient who is receiving them. This is essential to avoid any unwanted rejections by the host immune system. The transplantation of stem cells into the patient essentially replaces the destroyed hematopoietic stem cells and allows for new stem cells, and eventually blood cells, to be produced. After a few weeks, the stem cells will begin to make new white blood cells, platelets, and red blood cells. Patients will typically stay in the hospital until their absolute neutrophil count is back up to safe levels. With normal absolute neutrophil counts, or ANC’s as they are sometimes referred to, ranging from 1500-1800 cells/mm3, safe levels were the patients are discharged form the hospital are considered to be anywhere over 500 cells/mm3.
One of the most recent advances in the treatment of neuroblastoma involves autologous stem cell transplants. In general, stem cells are undifferentiated cells in the body that can become differentiated into other cell types in the body. Mesenchymal Stem Cells, which are used in many of the clinical trials to treat neuroblastoma, can differentiate into a variety of stem cells such as bone cells (osteoblasts and osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and stromal cells. Mesenchymal Stem Cells, or MSCs, are sometimes referred to as “immunologically privileged” because they don’t express a lot of the histocompatibility complexes and molecules that some other cells might. This makes them a lot less likely to be rejected after being transplanted into a patient, and therefore, makes them a good candidate for a variety of stem cell transplants. In autologous stem cell transplants, a patient receives stem cells from themselves that were harvested prior to the transplant. Because high levels of stem cells are not normally found in the peripheral blood, patients are usually given shots of growth factors, specifically G-CSF, which stimulate the production of stem cells and cause them to move from the bone marrow into the peripheral blood for collection. This process is called mobilization and priming. Priming and mobilization usually lasts from 3-4 days prior to the donor having their stem cells collected, and will continue until the last day of collection. The actual collection of stem cells takes anywhere from 3-6 hours, depending on the donor and the volume of blood that can be processed through the apheresis machine at a time. Most transplants only require 1 or 2 donations per dose, which is about 5-10 million cells per kilogram of the recipient’s body weight for each dose. In some instances, the patient undergoing the transplant may be administered a dose of chemotherapy before receiving the actual transplant. After chemotherapy, stem cells are infused into the patient through a catheter that is placed into a blood vessel in the chest. The entire dose of transplanted cells can usually be done in one day, but if more than 10 bags of cells are required for a patient, the transplant can take up to 2 days to complete. On average, 10-14 days are needed for the patient to begin showing signs of engraftment with increase white blood cell counts, signifying a successful transplantation.
Hematopoietic stem cells (HSCs) or hemocytoblasts are the stem cells that give rise to all of the other blood cell types through the process of hematopoiesis. They are derived from the mesoderm and are located in the red bone marrow, which is contained in the core of most bones.
HSCs give rise to both the myeloid and lymphoid lineages of blood cells. The myeloid cell lineage gives rise to monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes, or platelets. The lymphoid cell lineage includes T cells, B cells, and natural killer cells. The definition of hematopoietic stem cells has evolved since HSCs were first discovered in 1961. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent progenitors.
HSC studies through much of the past half century have led to a much deeper understanding of how stem cells function in the body, and the therapeutic applications that they are capable of. More recent advances have resulted in the use of HSC transplants in the treatment of cancers, such as neuroblastoma, and other immune system disorders.
In order to develop more targeted treatments for neuroblastoma patients, clinical trials are being conducted to find new and effective combinations of therapy. One clinical trial, conducted by the Children’s Hospital of Los Angeles and the National Cancer Institute from 2005 to 2016, tested the effects of targeted combination chemotherapy and radiation therapy paired with autologous stem cell transplants in patients with relapsed or refractory neuroblastoma. This was a phase 2 clinical trial that studied how well giving
I-131 and MIBG with a combined regimen of chemotherapy could treat these high-risk patients. I-131 is a radioactive isotope of iodine. When introduced into the body, I-131 is capable of stopping the growth of tumor cells and causing oncogenic tissue damage if it can be targeted to those specific areas of the body. When paired with MIBG, or metaiodobenzylguanidine, the radioactive isotope is targeted directly towards the neuroblastoma cells specifically. MIBG is a radiopharmaceutical that binds with the radioactive iodine and localizes to adrenergic tissue, which is the specific tissue type that is affected by neuroblastoma. Because the radiation therapy can be targeted so well to this tissue type, the use of I-131 with MIBG is a fairly effective treatment for low-risk neuroblastoma patients.
In this clinical trial specifically, a regimen of Carboplatin, Etoposide, and Melphalan were used for chemotherapy in combination with the I-131 MIBG radiation therapy, as described. Prior to the treatment regimen, stem cells were collected from the patient through apheresis with the use of Filgrastim, which is the pharmaceutical name for G-CSF. This mobilized the stem cells into the peripheral blood and allowed for easier collection.
The design of this study was separated into 42 poor-risk patients and 8 good-risk patients. Poor-risk patients were identified as those who had shown minimal or no response to prior treatments for their relapsed neuroblastoma, and good-risk patients were identified as those that had shown a partial response to previous treatment regimens for their relapsed neuroblastoma. Neither of the patient groups showed a full response to any prior treatments, and thus, were seeking out the treatment option being studied in this clinical trial.
After the treatment stage of the trial was completed, the research team assessed the results 60 days post s
tem cell transplant
and then again after 3 years since the start of treatment. At 60 days post stem cell transplant, both primary and secondary responses were recorded and after 3 years, only secondary responses to the treatment were assessed.
Discussion
At 60 days post stem cell transplant, the investigators conducting the clinical trial at the Children’s Hospital of Los Angeles measured both primary and secondary responses to the treatments. The primary response that was measures what the tumor response to the actual treatment regimen. The patients were evaluated with various scans and tests to determine the response of the tumors to the chemotherapy and the radiation with I-131 MIBG. This would have been measured by any reduction in tumor size. It was found that 4 out of the 42 poor-risk patients exhibited a response to their treatment and 3 of the 8 goo-risk patients showed a response to the treatments. Although these seem like low values, these patients are high-risk, having relapsed neuroblastoma, and have not shown any other responses to treatment. Any increase in the treatment response was considered a positive result in the case of this study.
The first secondary response that was assessed at 60 days post stem cell treatment was the engraftment DLT of the patients. DLT stands for the dose limiting toxicity and refers to the stem cell engraftment. This assessment measured the amount of either delayed stem cell engraftment in patients or failed stem cell engraftment. To measure this, blood cell counts were collected to see if there was an increase, decrease, or no change in the white blood cell, or WBC, and platelet productions from the newly introduced stem cells. This was quantitatively measured by obtaining a sample of the patient’s peripheral blood and getting blood cell counts of the white blood cells and platelets in the sample. It was found that only 2 of the total poor-risk patients and 1 of the total good-risk patients showed failed engraftment. This means that only 3 patients in the total clinical trial had a stem cell transplant that was ineffective.
The second secondary response that was measured 60 days post stem cell transplant was the diagnosis of veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS). These disease presentations can be characterized by an enlargement of the liver, also referred to as hepatomegaly, increased bilirubin levels, and other related conditions post treatment. Most often, these symptoms develop as a result of hematopoiesis occurring in the liver and spleen, also known as extramedullary hematopoiesis. After assessing the patients, it was found that 6 of the poor-risk patients developed either veno-occlusive disease or sinusoidal obstruction syndrome, and 0 of the good-risk patients developed either veno-occusive disease or sinusoidal obstruction syndrome after receiving the high-dose chemotherapy and radiation therapy.
After 3 years since the start of treatment for the patients, the investigators conducting the clinical trial measured another secondary response. This secondary response measured the event-free survival in the patients in the 3 years following the treatment regimen that was given to them. The event-free survival was described as the probably of the individual patients having no recurrence or increase in the disease presentation in the 3 consecutive years following the high-dose chemotherapy and radiation treatment regimen. For this clinical trial, it was calculated that the poor-risk patients would have a 20% chance of being event-free after 3 years post treatment and the good-risk patients would have a 38% chance of being event-free after 3 years post treatment.
Summary and Conclusions
Overall, the clinical trial conducted at the Children’s Hospital of Los Angeles met the initial goal of treating high-risk neuroblastoma patients that that otherwise not responded to previous treatments, such chemotherapy or radiation. After assessing the data that was collected during the study, up to 3 years after the start of treatment, it was found that the rates of increased survival in these patients were not significant. When compared to the success rates of other established treatment options, the results of this study and the specific combination therapy that was used for it were very similar. This may have been because they study was completed with a relatively small sample size, so the true results may not have been as obvious. Having a small sample size would make one or two outlier patients seem as though they were a larger percentage of the population than is actually representative of what the real population of patients with relapsed neuroblastoma would be.
Although the results of this trial were not statistically significant when compared to more commonly used treatment regimens, the clinical trial did not present a bad or failed treatment option to the patients enrolled in it. Rather, the treatment used in this clinical trial just didn’t increase the patient’s chance of survival any more than another treatment regimen would have.
It is also important to consider that the patients that were enrolled in this study all had relapsed neuroblastoma. Having a relapse in this disease specifically, makes treatment much more difficult. The tumors often show a much lower response to typical treatment regimens, and therefore, the patient’s chance of survival is drastically lowered compared to the chances of survival after being first diagnosed with neuroblastoma. The fact that the patients showed some positive response to the newly investigated treatment regimen is a great improvement and advance.
Unlike what most people think about when they hear about stem cells being used as a therapeutic treatment option, there are no real controversies associated with the use of stem cells for the treatment of neuroblastoma. The stem cells used in this trial, as well as other treatment options that have been well established to treat neuroblastoma, are not embryonically derived, which is where most of the controversy concerning stem cells typically comes from. Since this treatment also uses an autologous transplant, there are no real complications with rejections of the stem cells after receiving the transplant. In allogeneic transplants, even though donors are matched to the stem cell recipient, there is always the possibility that the recipient’s immune system will recognize the stem cells as foreign and attack them in an immune response. This immune response in reaction to rejecting the newly transplanted stem cells could cause various complications for the patient and may even cause death if the immune response becomes systemic and puts the patient in a state of shock.
Overall, the treatment regimen investigated in the clinical trial conducted by the Children’s Hospital of Los Angeles and the National Cancer Institute provides some hope for the targeted treatment of recurrent neuroblastoma patients.