Ben Oshrine, MD
The Children's Hospital of Philadelphia
Last Modified: August 7, 2013
The term sarcoma generally describes a cancer of connective tissues, including bone, muscle, cartilage, and other tissue types. Ewing sarcoma is a specific type of sarcoma in which the cancer cells are primitive and described as small round blue cells. This is an aggressive cancer that is more common in children than adults and primarily affects the adolescent and young adult age group.
Ewing sarcoma most commonly originates from a bone, but can also arise outside the bone, when it is called "extraosseous." Unlike osteosarcoma (cancer of the bone), it tends to affect bones of the axial (central) skeleton (spinal column, pelvis, rib cage, etc.) about equally to the appendicular skeleton (long bones of the arms or legs). Ewing sarcoma is the second most common cause of bone cancer in children overall (next to osteosarcoma), but is the most common in children younger than 10 years old.
Most commonly, Ewing sarcoma is diagnosed after a child notices a mass arising from a bony area or experiences persistent bone pain. Sometimes the presence of Ewing sarcoma in a bone causes it to be particularly fragile, resulting in an easy (pathologic) fracture. Because the pain from an Ewing sarcoma is a non-specific symptom and is often first noticed after a child suffers minor trauma to the area, there is often a lag of several months between initial symptoms and reaching the diagnosis. Some children experience fevers, weight loss, and fatigue, but these are not typical.
Typically the first step in the diagnostic process is a plain X-ray of the area that is causing pain or where there is a bump or mass. If this is suggestive of a bone tumor, an MRI is performed to better characterize the lesion, and help determine whether a biopsy is needed. The imaging features of Ewing sarcoma (or other bone cancers like osteosarcoma) can lead doctors to suspect that a particular lesion is cancer, but imaging alone is not sufficient to arrive at a diagnosis.
In order to definitively diagnose a bone cancer of any type, a biopsy is required and is typically performed by an orthopedic surgeon. Once tissue has been obtained, the diagnosis can take several days to more than a week, as the pathologists perform special tests on the specimen to arrive at a specific diagnosis. Ewing sarcoma has special features that help to confirm the diagnosis, including the appearance of the cells under the microscope, and a specific genetic change in the tumor cells that is almost always seen.
Once the diagnosis is confirmed, tests will be performed to determine if the cancer has spread to other parts of the body (metastatic disease), which occurs in approximately 20-30% of children. The most common metastatic sites for Ewing sarcoma (in descending order of frequency) are: lungs, bone, bone marrow, or a combination of these sites. To assess for the presence of metastases, the following tests are typically performed:
While some characteristics of the primary tumor (e.g. location and size) influence prognosis, by far the most important information to accurately characterize stage is whether or not metastases (tumor has spread to other areas of the body) are present. Broadly, children with Ewing sarcoma are divided into two groups: those with and without metastases (called localized disease). Some forms of metastatic disease represent more of a treatment challenge, such as having multiple sites of metastases, particularly at bony sites (multiple spots in bones).
In children where the only identifiable site of Ewing sarcoma is the primary tumor, treatment is usually successful, but depends on two critical elements: (1) control of the primary tumor (local control) and (2) delivery of chemotherapy to eradicate so-called micro-metastases (adjuvant therapy). Micro-metastases are areas of microscopic disease that are spread throughout the body but cannot be visualized with available imaging studies. These are presumed to be present based on the fact that in the past when treatment was with surgery alone almost all children relapsed with metastatic disease, even if surgery was effective in removing the primary tumor.
Treatment begins with several cycles of multi-agent chemotherapy. Unlike many other childhood cancers where chemotherapy cycles are delivered every 3 weeks, administering chemotherapy every 2 weeks (called interval compression) is the standard of care in the treatment of children with Ewing sarcoma. This schedule is more effective without increasing toxicity. Exact regimens vary slightly, but the following agents are almost always included: vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Other medications will be administered with the chemotherapy to prevent or minimize side effects, particularly a growth factor to stimulate the bone marrow to make more white blood cells (filgrastim, pegfilgrastim) in an attempt to prevent a low white blood cell count (called neutropenia).
After several cycles of chemotherapy, a repeat assessment of the primary tumor will be performed (usually with an MRI) to assess the response to initial treatment and plan for local control. Both surgery and radiation (or a combination) can be used to successfully treat the primary tumor, but whenever possible, surgery is the preferred method (due to long-term risks of radiation therapy in children). The type of surgical procedure employed for primary tumor control depends entirely on the location. If local control with surgery is deemed impossible, or if surgery is unsuccessful at completely removing the tumor, radiation will be used. Radiation is effective in the treatment of Ewing sarcoma, but is associated with long-term risks – most significantly new cancers later in life and growth impairment of surrounding normal tissues – and so is avoided when possible.
After local control by whatever method, chemotherapy treatments will resume until the total treatment course is completed. Overall, treatment generally lasts 8-9 months.
Treatment of metastatic Ewing sarcoma is very challenging, and involves local control of the primary tumor, addressing all metastatic sites to attempt to eradicate all areas of disease, as well as chemotherapy to treat micrometastases. Micro-metastases are areas of microscopic disease that are spread throughout the body but cannot be visualized with available imaging studies.
Much like treatment of localized disease, treatment begins with several cycles of multi-agent chemotherapy. Unlike many other childhood cancers where chemotherapy cycles are delivered every 3 weeks, administering chemotherapy every 2 weeks (called interval compression) is the standard of care in the treatment of children with Ewing sarcoma. This schedule is more effective without increasing toxicity. Exact regimens vary slightly, but the following agents are often included: vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Other medications will be administered with the chemotherapy to prevent or minimize side effects, particularly a growth factor to stimulate the bone marrow to make more white blood cells (filgrastim, pegfilgrastim) in an attempt to prevent a low white blood cell count (called neutropenia). Because of the difficulty in curing metastatic Ewing sarcoma, newer or more intensive chemotherapy agents are being used in some ongoing clinical trials.
After a period of chemotherapy treatment, a repeat evaluation of all areas of disease will be performed to help guide the approach to both local and metastatic site control. Control of the primary tumor with surgery and/or radiation remains a mainstay of Ewing therapy. Sites of metastasis are dealt with on a site-by-site basis. If the initial cycles of chemotherapy successfully eliminate metastatic sites, no further site-specific treatment may be necessary. However, if there is persistent metastatic disease after the first several cycles of chemotherapy, treatment of these areas with radiation (and sometimes surgery) is attempted, sometimes including radiation therapy to the lung.
Using very high doses of chemotherapy with autologous stem cell rescue (autologous transplant) is sometimes used for children with metastatic (or recurrent) Ewing sarcoma, although its use is controversial and is usually limited to clinical trials.
The prognosis depends on a variety of factors, most importantly the presence of metastases.
In the event of a relapse of Ewing sarcoma, the approach to management depends on a variety of factors, most importantly time to relapse, location of relapse, initial treatment, and number of sites of relapse. While the prognosis for children with relapsed disease is often very poor, the chance of cure is higher if relapse occurs late and at fewer sites. Management of relapsed disease is highly specific to the patient and the pattern of disease, and may include a combination of chemotherapy (often with investigational agents), radiation, and surgery.
While intensive chemotherapy and aggressive local control with surgery/radiation results in an overall relatively good chance of cure for children with localized disease, there are both short-term and long-term consequences to this therapy. Survivors of Ewing sarcoma face some of the highest risk of late effects among all survivors of childhood cancer. This is related to both the chemotherapy agents used and radiation.
The chemotherapy agents used in Ewing sarcoma can result in long-term problems with heart function, kidney function, fertility, and second cancers such as leukemia. If radiation is used, this can cause cessation of growth to normal tissues that were in the radiation field, and second cancers such as leukemia, sarcomas, skin cancers, and others. All children who survive their disease are monitored for these potential side effects, based on the type of treatments they received. Learn more about late effects of treatment from CureSearch.
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Womer, RB et al. Chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. Journal of Clinical Oncology. 2013; 30: 4148-4154.