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Current Management of Neuroblastoma
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Submitted By: James Geiger, M.D.
Article by Craig A McKinney, M.D, and James D Geiger, M.D.
Department of Pediatric Surgery, University of Michigan
Definition and Diagnosis
Mainly affecting children, neuroblastoma is a rare tumor of the sympathetic nervous system (a specialized nerve network). Approximately 600 usually young children will be diagnosed each year with neuroblastoma, which is the most common solid childhood cancer other than brain tumors. It represents 10% of all childhood cancers, but nearly half of all cancer in infants(1,2). These tumors may begin as a growth or mass in the nerve tissue of the neck, chest, abdomen, or pelvis, but most commonly start in the adrenal glands (40%) which are located above each kidney.
The cause of neuroblastoma is unknown, but a number of genetic and other factors are being investigated. This tumor has been diagnosed on fetal ultrasounds during pregnancy and through screening programs. Neuroblastoma identified by such screening methods in general has a favorable prognosis. Some neuroblastomas may change back into benign tissue and are then called ganglioneuroma. Despite screening, nearly 50% of children unfortunately present with tumors that can not be initially removed and/or have disease that has spread (metastatic disease) usually to bone, bone marrow, lymph nodes, or the liver(3). Such screening tests in children in their first year of life have not reduced deaths from neuroblastoma or the number of patients that present with advanced cases. Until these tests are improved, they are not routinely recommended(2).
The symptoms of neuroblastoma are often vague and may include fatigue and weight loss. About half of all patients with neuroblastoma present with an abdominal mass or swollen belly. There are, however, many other symptoms that can be present, depending on the tumors location. In some cases the child may experience weakness in the legs or difficulty walking, caused by the tumor pressing against the spinal cord.
Over 90% of these tumors secrete excess adrenaline and related hormones, which can at times lead to the development of high blood pressure. The production of these hormones can aid in the diagnosis, as their broken-down products are excreted in the urine.
Other tests used to diagnose neuroblastoma include radiographic (CT scan or MRI) and Nuclear Medicine studies (bone scan and a special test using MIBG, which is similar to adrenaline and is taking up by the tumor cells.) Additionally, examination of the cellular components of aspirated bone marrow is also used to evaluate the extent of disease.
Cross-section of adrenal neuroblastoma prior to therapy
Staging and Treatment
After all the test results are known, the extent of the disease will be determined. This is called staging and is critical in determining the type of therapy needed for a particular neuroblastoma. The staging system takes into account the location of the main tumor, whether it is completely resectable, and whether it has spread to other organs, including lymph nodes and bone marrow. The stages are numbered from I to IV and have been developed in part to predict a patient's outcome or prognosis. There are a number of other factors which have been shown to be associated with prognosis, including the appearance under a microscope, the presence of certain cell-surface markers, the age of the patient at diagnosis, and the expression of a characteristic gene named N-myc(1).
The treatment of neuroblastoma in a particular patient is chosen based on their relative risk group (low, intermediate, and high), which is determined by their stage and the presence or absence of poor prognostic factors. Generally, patients considered low risk do not require treatment beyond surgery to excise the primary tumor, as these patients tend not to have metastatic disease and will be expected to do very well. Patients who fall into the intermediate risk group require chemotherapy with a number of drugs in addition to surgery, and some of them will have radiation. The patients in this group have tumors that may not have been completely removed and may have spread to nearby lymph nodes.
High risk patients (most stage III and IV patients) also undergo chemotherapy, but the therapy is more aggressive and often toxic to normal bone marrow as well as cancer cells. For this reason most will undergo a bone marrow or stem cell transplant. If possible, the primary tumor is also removed, but more often than not surgery initially consists of a tumor sampling and placement of a special venous catheter for chemotherapy.1 A second operation and radiation is usually used later in the treatment. A drug related to vitamin A, called 13-cis-retinoic acid, has been shown to benefit advanced stage patients and while the prognosis for these patients has improved, it is still quite poor with long-term survival of less than 30%(4).
Because of the toxicity of chemotherapy and the poor prognosis for patients with high risk tumors, other treatment methods are actively being developed in the hope of finding better treatments that also have fewer side effects. Antibody therapy, employing structures of the immune system that attach to the surface the neuroblastoma cells and then use the body's own immune system to attack the tumor, are currently being studied in the current Children's Oncology Group trials(3). Another form of immune therapy is the use of a cancer vaccine to acitivate the immune system to kill the tumor. Some treatments attempt to target therapy directly to the neuroblastoma cells. An example of this type of therapy is the use of MIBG that targets radiation to the malignant tissue. This therapy still is usually followed by a transplant due to toxicity to the bone marrow(5). Many other new therapies including less toxic chemotherapy are currently being developed.
Conclusion
Similar to many difficult cancers, it is anticipated that over the next decade significant improvements will be made in the treatment of children with neuroblastoma. There has already been quite a bit of success in the treatment of lower stage patients, and alternative treatment methods are being refined every day for those children who have to this point not seen the same kind of success. These new therapies should provide hope for ultimately impacting on the survival of this disease.
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Additional Authors: |
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Works Cited: |
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1. Grosfeld JL. Risk-Based Management of Solid Tumors in Children. Am J Surg 2000 Nov; 180: 322-7
2. Berthold F, Hero B. Neuroblastoma: Current Drug Therapy Recommendations as Part of the Total Treatment Approach. Drugs 2000 Jun; 59 (6): 1261-77
3. Cheung NV, Kushner BH, Kramer K. Monoclonal Antibody-Based Therapy of Neuroblastoma. Hematol Oncol Clin North Am 2001 Oct; 15 (5): 853-66
4. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-Cis-Retinoic Acid. N Engl J Med 1999 Oct 14; 341 (16): 1165-73
5. Hoefnagel CA. Nuclear Medicine Therapy of Neuroblastoma. Q J Nucl Med 1999 Dec; 43: 336-43
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