Sarcoma, Ewing

  • Dana-Farber/Brigham and Women's Cancer Care

    Ewing sarcoma is a type of cancer that forms in bone or soft tissue. It is also called peripheral primitive neuroectodermal tumor (pPNET). Learn about Ewing sarcoma and find information on how we support and care for people with Ewing sarcoma before, during, and after treatment.

Treatment                                    

When you come to the Center for Sarcoma and Bone Oncology, you'll meet with members of our team who have expertise in caring for patients with sarcoma.

Patients with sarcoma often require a combination of surgery, chemotherapy, and radiation therapy. We recognize that a team approach is the best way to manage these complicated cases.

This means pathologists, medical oncologists, radiologists, surgeons and other health care professionals who specialize in sarcoma may be involved in decisions about your care.

Our group is also dedicated to clinical research to develop innovative treatment strategies for soft tissue and bone malignancies.

We will work with you to find other support services within Dana-Farber, including nutrition, complementary therapies, spiritual support, financial help, survivorship, and resources for families and young adults.

Our specialists see patients with all sarcomas and a variety of mesenchymal tumors, including: 

  • Alveolar soft part sarcoma
  • Angiosarcoma
  • Chondrosarcoma
  • Desmoid tumor
  • Desmoplastic small cell tumor
  • Epithelioid sarcoma
  • Ewings sarcoma
  • Extraskeletal mesenchymal chondrosarcoma
  • Extraskeletal osteosarcoma
  • Fibrous histiocytoma of bone
  • Fibrosarcoma
  • Gastrointestinal stromal tumor (GIST)
  • Kaposi's sarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Malignant fibrous histiocytoma (MFH)
  • Malignant mesenchymoma
  • Malignant primative neuroectodermal tumor (PNET)
  • Myofibroblastic sarcoma
  • Myxofibrosarcoma
  • Neurofibrosarcoma
  • Osteoganic sarcoma
  • Osteosarcoma
  • PEComa
  • Rhabdomyosarcoma
  • Malignant schwannoma
  • Spindle cell sarcoma
  • Synovial sarcoma

Contact us 

If you have never been seen before at Dana-Farber/Brigham and Women's Cancer Center, please call 877-442-3324 or use this online form to make an appointment.

If you need to schedule a follow-up appointment or for other questions, you’ll find your clinician’s contact information here  

Learn more about the Center for Sarcoma and Bone Oncology 

Information for: Patients | Healthcare Professionals

General Information About Ewing Sarcoma Family of Tumors

Ewing sarcoma family of tumors is a group of cancers of the bone and of soft tissue.

Ewing sarcoma family of tumors is a group of tumors that form from a certain kind of cell in bone or soft tissue. This family of tumors includes the following:

  • Ewing tumor of bone. This type of tumor is found in the bones of the legs, arms, chest, trunk, back, or head. There are three types of Ewing tumor of bone:
    • Classic Ewing sarcoma.
    • Primitive neuroectodermal tumor (PNET).
    • Askin tumor (PNET of the chest wall).
  • Extraosseous Ewing sarcoma (tumor growing in tissue other than bone). This type of soft tissue tumor is found in the trunk, arms, legs, head, and neck.

In some patients, the tumor may have spread by the time it is diagnosed.

Ewing tumors usually occur in teenagers and are more common in boys and Caucasians.

Possible signs of Ewing sarcoma family of tumors include swelling and pain near the tumor.

These and other symptoms may be caused by Ewing sarcoma family of tumors. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:

  • Pain and/or swelling, most commonly in the arms, legs, chest, back, or pelvis (area between the hips).
  • A lump (which may feel warm) in the arms, legs, chest, or pelvis.
  • Fever for no known reason.
  • A bone that breaks for no known reason.

Tests that examine the bone and soft tissue are used to diagnose and stage Ewing sarcoma family of tumors.

The following tests and procedures may be used to diagnose or stage Ewing sarcoma family of tumors:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells, white blood cells, and platelets.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as lactate dehydrogenase (LDH), released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Sedimentation rate: A procedure in which a sample of blood is drawn and checked for the rate at which the red blood cells settle to the bottom of the test tube.
  • X-ray: An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone. Samples are removed from both hipbones. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer.
  • Bone scan: A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones and is detected by a scanner.
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.

A biopsy is done to diagnose Ewing sarcoma family of tumors.

Cells and tissues are removed during a biopsy so they can be viewed under a microscope by a pathologist to check for signs of cancer. The specialists (pathologist, radiation oncologist, and surgeon) who will treat the patient usually work together to plan the biopsy. This is done so that the biopsy incision doesn't affect later treatment with surgery to remove the tumor and radiation therapy. It is helpful if the biopsy is done at the same center where treatment will be given.

The following tests may be done on the tissue that is removed:

  • Light and electron microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.
  • Cytogenetic analysis: A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Reverse-transcriptionpolymerase chain reaction test (RT-PCR): A laboratory test in which cells in a sample of tissue are studied using chemicals to look for certain changes in the genes.
  • Immunohistochemistry study: A laboratory test in which a substance such as an antibody, dye, or radioisotope is added to a sample of tissue to test for certain antigens. This type of study is used to tell the difference between different types of cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) depends on certain factors before and after treatment.

Before treatment, prognosis depends on:

  • Whether the tumor has spread to distant parts of the body.
  • Where in the body the tumor started.
  • How large the tumor is at diagnosis.
  • Whether the tumor has certain genetic changes.
  • The patient's age. Infants and patients aged younger than 15 years have a better prognosis than adolescents aged 15 years and older, young adults, or adults.
  • The patient's gender. Girls have a better prognosis than boys.
  • Whether the tumor has just been diagnosed or has recurred (come back).

After treatment, prognosis is affected by:

  • Whether the tumor was completely removed by surgery.
  • Whether the cancer came back more than two years after the initial treatment.

Treatment options depend on the following:

  • Where the tumor is found in the body and how large the tumor is.
  • The patient's age and general health.
  • The effect the treatment will have on the patient's appearance and important body functions.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Decisions about surgery may depend on how well the initial treatment with chemotherapy or radiation therapy works.

Stages of Ewing Sarcoma Family of Tumors

The results of diagnostic and staging tests are used to find out if cancer cells have spread.

The process used to find out if cancer has spread from where it began to other parts of the body is called staging. There is no standard staging system for Ewing sarcoma family of tumors. The results of the tests and procedures done to diagnose Ewing sarcoma family of tumors are used to group the tumors into localized or metastatic.

Ewing sarcoma family of tumors are grouped based on whether the cancer has spread from the bone or soft tissue in which the cancer began.

Ewing sarcoma family of tumors are described as either localized or metastatic.

Localized Ewing sarcoma family of tumors

The cancer is found in the bone or soft tissue in which the cancer began and may have spread to nearby tissue, including lymph nodes.

Metastatic Ewing sarcoma family of tumors

The cancer has spread from the bone or soft tissue in which the cancer began to other parts of the body. In Ewing tumor of bone, the cancer most often spreads to the lung, other bones, and bone marrow.

There are three ways that cancer spreads in the body.

The three ways that cancer spreads in the body are:

  • Through tissue. Cancer invades the surrounding normal tissue.
  • Through the lymph system. Cancer invades the lymph system and travels through the lymph vessels to other places in the body.
  • Through the blood. Cancer invades the veins and capillaries and travels through the blood to other places in the body.

When cancer cells break away from the primary (original) tumor and travel through the lymph or blood to other places in the body, another (secondary) tumor may form. This process is called metastasis. The secondary (metastatic) tumor is the same type of cancer as the primary tumor. For example, if bone cancer spreads to the lung, the cancer cells in the lung are actually bone cancer cells. The disease is metastatic bone cancer, not lung cancer.

Recurrent Ewing Sarcoma Family of Tumors

RecurrentEwing sarcoma family of tumors is cancer that has recurred (come back) after it has been treated. The cancer may come back in the tissues where it first started or in another part of the body.

Treatment Option Overview

There are different types of treatment for children with Ewing sarcoma family of tumors.

Different types of treatments are available for children with Ewing sarcoma family of tumors. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.

Children with Ewing sarcoma family of tumors should have their treatment planned by a team of health care providers who are experts in treating cancer in children.

Treatment will be overseen by a pediatriconcologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other health care providers who are experts in treating children with Ewing sarcoma family of tumors and who specialize in certain areas of medicine. These may include the following specialists:

  • Surgical oncologist or orthopedic oncologist.
  • Radiation oncologist.
  • Pediatric nurse specialist.
  • Social worker.
  • Rehabilitation specialist.
  • Psychologist.

Some cancer treatments cause side effects months or years after treatment has ended.

Side effects from cancer treatment that begin during or after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include the following:

  • Physical problems.
  • Changes in mood, feelings, thinking, learning, or memory.
  • Second cancers (new types of cancer). Patients treated for Ewing sarcoma family of tumors have an increased risk of developing acute myeloid leukemia, myelodysplastic syndrome, and sarcomas in the area treated with radiation therapy.

Some late effects may be treated or controlled. It is important to talk with your child's doctors about the effects cancer treatment can have on your child. (See the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Three types of standard treatment are used:

Chemotherapy

Chemotherapy is part of the treatment for all patients with Ewing tumors. It is usually given first, to shrink the tumor before treatment with surgery or radiation therapy. It may also be given to kill any tumor cells that have spread to other parts of the body.

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the type of the cancer being treated and whether it is found at the place it first formed only or whether it has spread to other parts of the body.

Surgery

Surgery is usually done to remove cancer that is left after chemotherapy or radiation therapy. When possible, the entire tumor is removed by surgery. Tissue and bone that are removed may be replaced with a graft using tissue and bone taken from another part of the patient's body or a donor, or with an implant such as artificial bone.

Radiation therapy

Radiation therapy may be used to shrink the tumor before surgery so less tissue needs to be removed. It may also be used to kill tumor cells that are left after surgery or chemotherapy. Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type of the cancer being treated and whether it is found at the place it first formed only or whether it has spread to other parts of the body.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.

Chemotherapy with stem cell transplant

Stem cell transplant is a way of replacing blood-forming cells destroyed by chemotherapy. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Angiogenesis inhibitors and monoclonal antibodies are two types of targeted therapies being studied in the treatment of Ewing sarcoma family of tumors.

Angiogenesis inhibitors are substances that block the growth of new blood vessels. In cancer treatment, angiogenesis inhibitors prevent the growth of new blood vessels needed for tumors to grow.

Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's clinical trials database.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options for Ewing Sarcoma Family of Tumors

A link to a list of current clinical trials is included for each treatment section. For some types or stages of cancer, there may not be any trials listed. Check with your doctor for clinical trials that are not listed here but may be right for you.

Localized Ewing Sarcoma Family of Tumors

Treatment of localizedEwing sarcoma family of tumors may include combination chemotherapy followed by surgery and/or radiation therapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized Ewing sarcoma/peripheral primitive neuroectodermal tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Metastatic Ewing Sarcoma Family of Tumors

Treatment of metastaticEwing sarcoma family of tumors may include the following:

  • Combination chemotherapy followed by radiation therapy to the area where the tumor first formed and the places where the tumor has spread.
  • A clinical trial of chemotherapy with either stem cell transplant or radiation therapy, for tumors that have spread to the lungs.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

Recurrent Ewing Sarcoma Family of Tumors

Treatment of recurrentEwing sarcoma family of tumors may include the following:

  • Surgery followed by combination chemotherapy.
  • Combination chemotherapy.
  • High-dose chemotherapy and sometimes a stem cell transplant using the patient's stem cells.
  • Radiation therapy or surgery to remove bone tumors, as palliative therapy to reduce symptoms and improve the quality of life.
  • Radiation therapy followed by surgery to remove tumors that have spread to the lungs.
  • A clinical trial of a monoclonal antibody (a cancer treatment that uses antibodies made from a single type of immune system cell) .

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.

To Learn More About the Ewing Sarcoma Family of Tumors

For more information from the National Cancer Institute about the Ewing sarcoma family of tumors, see the following:

For more childhood cancer information and other general cancer resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on December 8, 2009.


Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of the Ewing sarcoma family of tumors (ESFT). This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

In this summary, the ESFT includes:

  • Ewing tumor of bone (ETB) — tumor that begins in the bone including:
    • Classic Ewing sarcoma.
    • Primitive neuroectodermal tumor.
    • Askin tumor of the chest wall.
     
  • Ewing sarcoma — tumor that begins at a site other than the bone; referred to as extraosseous Ewing sarcoma (EOE).

Information about the following is included in this summary:

  • Cellular classification.
  • Stage information.
  • Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Origin and Incidence of Ewing Sarcoma Family of Tumors

Studies using immunohistochemical markers,[2] cytogenetics,[3][4] molecular genetics, and tissue culture [5] indicate that classic Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor (chest wall), as well as extraosseous Ewing sarcoma (EOE) are all derived from the same primordial bone marrow-derived mesenchymal stem cell.[6][7] The incidence of Ewing sarcoma family of tumors (ESFTs) is approximately three per 1,000,000 per year and remained unchanged for 30 years.[8] Data from the Surveillance, Epidemiology, and End Results (SEER) registries reports an overall incidence of ESFT of one per 1,000,000 in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten per 1,000,000. The same analysis suggests that the incidence of Ewing sarcoma is nine times greater in U.S. Caucasians than African Americans.[9]

The median age of patients with ESFT is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of ESFT in neonates and infants have been described.[10][11] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS), 59% of patients are male and 41% are female. Primary sites of bone disease include:

  • lower extremity (41%).
  • pelvis (26%).
  • chest wall (16%).
  • upper extremity (9%).
  • spine (6%).
  • skull (2%).[12]

For EOE, the most common primary sites of disease are:

  • trunk (32%).
  • extremity (26%).
  • head and neck (18%).
  • retroperitoneum (16%).
  • other sites (9%).[12]

Approximately 25% of patients will have metastatic disease at diagnosis.[8]

Prognostic Factors for Ewing Sarcoma

There are two major types of prognostic factors for patients with Ewing sarcoma: pretreatment factors and treatment response factors.

Pretreatment factors

  • Site: Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[13][14][15]
  • Size: Tumor volume has been shown to be an important prognostic factor in most studies. Cutoffs of either 100 mL or 200 mL are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[15][16]
  • Age: Infants and younger patients (<15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults.[11][13][14][15]
  • Gender: Girls with Ewing sarcoma have a better prognosis than boys.[9][14]
  • Serum lactate dehydrogenase: Increased serum lactate dehydrogenase (LDH) levels prior to treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.[14]
  • Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites.[13][15][17] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.[18] Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung.[19] Positron emission tomography (PET) scans using fluorine-18-fluorodeoxyglucose (FDG) are under investigation as a staging tool that may provide additional information and alter therapy planning.[20] Whole body MRI may provide additional information which could potentially alter therapy planning.[21]
  • Standard cytogenetics: Complex karyotype (defined as the presence of 5 or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[22]
  • Molecular pathology: The EWS-FL1 translocation associated with ESFT can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Some variants of the novel gene created by the translocation have been associated with a more favorable prognosis.[23]
  • Detectable fusion transcripts in morphologically normal marrow: Reverse transcription polymerase chain reaction can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow was associated with an increased risk of relapse.[24]
  • Other biological factors: Overexpression of the p53 protein [25] and loss of 16q [26] may be adverse prognostic factors. High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[27]

The following are not considered to be adverse prognostic factors for ESFT:

  • Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor for ETB.[28]
  • Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[29][30]

Treatment response factors to preoperative therapy

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival compared with patients with larger amounts of viable tumor.[18][31][32][33] Female gender and younger age predict a good histologic response to preoperative therapy.[34] Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[35] For patients who receive preinduction and postinduction chemotherapy PET scans, decreased PET uptake following chemotherapy correlated with good histologic response.[36]

References:

  1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  

  2. Olsen SH, Thomas DG, Lucas DR: Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol 19 (5): 659-68, 2006.  

  3. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.  

  4. Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001.  

  5. Llombart-Bosch A, Carda C, Peydro-Olaya A, et al.: Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype. Cancer 66 (12): 2589-601, 1990.  

  6. Suvà ML, Riggi N, Stehle JC, et al.: Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69 (5): 1776-81, 2009.  

  7. Tirode F, Laud-Duval K, Prieur A, et al.: Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11 (5): 421-9, 2007.  

  8. Esiashvili N, Goodman M, Marcus RB Jr: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30 (6): 425-30, 2008.  

  9. Jawad MU, Cheung MC, Min ES, et al.: Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer 115 (15): 3526-36, 2009.  

  10. Kim SY, Tsokos M, Helman LJ: Dilemmas associated with congenital ewing sarcoma family tumors. J Pediatr Hematol Oncol 30 (1): 4-7, 2008.  

  11. van den Berg H, Dirksen U, Ranft A, et al.: Ewing tumors in infants. Pediatr Blood Cancer 50 (4): 761-4, 2008.  

  12. Raney RB, Asmar L, Newton WA Jr, et al.: Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15 (2): 574-82, 1997.  

  13. Cotterill SJ, Ahrens S, Paulussen M, et al.: Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 18 (17): 3108-14, 2000.  

  14. Bacci G, Longhi A, Ferrari S, et al.: Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol 45 (4): 469-75, 2006.  

  15. Rodríguez-Galindo C, Liu T, Krasin MJ, et al.: Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer 110 (2): 375-84, 2007.  

  16. Ahrens S, Hoffmann C, Jabar S, et al.: Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 32 (3): 186-95, 1999.  

  17. Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004.  

  18. Paulussen M, Ahrens S, Dunst J, et al.: Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 19 (6): 1818-29, 2001.  

  19. Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998.  

  20. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007.  

  21. Mentzel HJ, Kentouche K, Sauner D, et al.: Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. Eur Radiol 14 (12): 2297-302, 2004.  

  22. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008.  

  23. de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16 (4): 1248-55, 1998.  

  24. Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003.  

  25. Abudu A, Mangham DC, Reynolds GM, et al.: Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer 79 (7-8): 1185-9, 1999.  

  26. Ozaki T, Paulussen M, Poremba C, et al.: Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer 32 (2): 164-71, 2001.  

  27. Scotlandi K, Remondini D, Castellani G, et al.: Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol 27 (13): 2209-16, 2009.  

  28. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007.  

  29. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999.  

  30. Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr.  

  31. Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999.  

  32. Wunder JS, Paulian G, Huvos AG, et al.: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80 (7): 1020-33, 1998.  

  33. Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001.  

  34. Ferrari S, Bertoni F, Palmerini E, et al.: Predictive factors of histologic response to primary chemotherapy in patients with Ewing sarcoma. J Pediatr Hematol Oncol 29 (6): 364-8, 2007.  

  35. Lin PP, Jaffe N, Herzog CE, et al.: Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 109 (3): 603-11, 2007.  

  36. Hawkins DS, Schuetze SM, Butrynski JE, et al.: [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 23 (34): 8828-34, 2005.  

Cellular Classification

Ewing sarcoma family of tumors (ESFT) belong to the group of neoplasms commonly referred to as small, round, blue-cell tumors of childhood. The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of ESFT and is useful in suggesting diagnosis of these tumors when the results are interpreted in the context of clinical and pathologic parameters.[1]MIC2 positivity is not unique to ESFT, and positivity by immunochemistry is found in several other tumors including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors. Concurrent positivity for membrane CD99 and FL-1 strongly suggest the diagnosis of ESFT.[1] The detection of a translocation involving the EWS gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of ESFT.[2]

The individual cells of ESFT contain round-to-oval nuclei with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.

Cytogenetic Changes in the Ewing Sarcoma Family of Tumors

Cytogenetic studies of the ESFT have identified a consistent alteration of the EWS locus on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21.[3] Characteristically, the amino terminus of the EWS gene is juxtaposed with the carboxy terminus of another gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the Ets family of transcription factor genes located on chromosome 11 band q24. Other Ets family members that may combine with the EWS gene in order of frequency are ERG, located on chromosome 21; ETV1, located on chromosome 7; and E1AF, located on chromosome 17; these result in the following translocations: t(21;22),[4] t(7;22), and t(17;22), respectively. Besides these consistent aberrations involving the EWS gene at 22q12, additional numerical and structural aberrations have been observed in ESFTs, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma tumors.[5] A molecular test (i.e., reverse transcription polymerase chain reaction [RT-PCR] and restriction analysis of PCR products), currently available on a research basis only, now offers the opportunity of markedly simplifying the definition of the ESFT.[6][7] The molecular assay can be performed on relatively small amounts of tissue obtained by minimally invasive biopsies and is capable of providing results faster than cytogenetic analysis.

References:

  1. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999.  

  2. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.  

  3. Urano F, Umezawa A, Yabe H, et al.: Molecular analysis of Ewing's sarcoma: another fusion gene, EWS-E1AF, available for diagnosis. Jpn J Cancer Res 89 (7): 703-11, 1998.  

  4. Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999.  

  5. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008.  

  6. Meier VS, Kühne T, Jundt G, et al.: Molecular diagnosis of Ewing tumors: improved detection of EWS-FLI-1 and EWS-ERG chimeric transcripts and rapid determination of exon combinations. Diagn Mol Pathol 7 (1): 29-35, 1998.  

  7. Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001.  

Stage Information

For patients with confirmed Ewing sarcoma, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary site, depending on the site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning.[1] Additional pretreatment staging studies should include bone scan, CT scan of the chest, and bone marrow aspiration and biopsy. Positron emission tomography using fluorine-18-fluorodeoxyglucose is an optional staging modality.[2][3] A staging modality under evaluation but not required on current clinical trials is molecular analysis of bone marrow for the presence of fusion transcript. In certain studies, determination of pretreatment tumor volume is an important variable.

For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur.

References:

  1. Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51 (2): 163-70, 2008.  

  2. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007.  

  3. Gerth HU, Juergens KU, Dirksen U, et al.: Significant benefit of multimodal imaging: PET/CT compared with PET alone in staging and follow-up of patients with Ewing tumors. J Nucl Med 48 (12): 1932-9, 2007.  

Treatment Option Overview

Patients should be evaluated by specialists from all disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained prior to biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved prior to or during the biopsy so that the incision can be placed in an acceptable location. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[1] The radiation oncologist and pathologist should be consulted prior to biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology.

The successful treatment of patients with Ewing sarcoma family of tumors (ESFT) requires systemic chemotherapy [2][3][4][5][6][7][8] in conjunction with either surgery or radiation therapy or both modalities for local tumor control.[9][10][11][12][13] In general, patients receive preoperative chemotherapy prior to instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. In the Euro-Ewing study (EURO-EWING-INTERGROUP-EE99), patients who receive radiation alone for local control are stratified by pretreatment tumor volume for postradiation therapy. Most patients with metastatic disease have a good initial response to preoperative chemotherapy; however, in most cases, the disease is only partially controlled or recurs.[14][15][16][17] Patients with lung as the sole metastatic site have a better prognosis than patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.

Chemotherapy for Ewing Sarcoma

Multidrug chemotherapy for ESFT always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols use cyclophosphamide as well. Certain protocols incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma (EICES) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide, and identified a trend toward better EFS for patients with localized Ewing sarcoma when treatment included etoposide (GER-GPOH-EICESS-92).[18][Level of evidence: 1iiA] Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide,[6] while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[8] Duration of primary chemotherapy ranges from 6 months to approximately 1 year.

Local control for Ewing tumor of bone

Treatment approaches for ESFT titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity. While surgery is effective and appropriate for patients who can undergo complete resection with acceptable morbidity, children who have unresectable tumors or who would suffer loss of function are treated with radiation therapy alone. Those who undergo gross resections with microscopic residual disease may benefit from adjuvant radiation therapy. Randomized trials that directly compare both modalities do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias.

For patients who undergo gross total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. Investigators from St. Jude Children’s Research Hospital reported 39 patients with localized ESFT who received both surgery and radiation. Local failure for patients with positive and negative margins was 17% and 5%, respectively, and overall survival (OS) was 71% and 94%, respectively.[12] However, in a large retrospective Italian study, 45 Gy adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival.[13] It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.

Thus, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional compromise by definitive surgery. Adjuvant radiation therapy should be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close margins.

When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.[19]

High-Dose Therapy with Stem Cell Rescue for Ewing Tumor of Bone

For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[20][21][22][23][24][25][26][27] In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved. The study showed no benefit for HSCT compared with historical controls.[25] Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT. The role of high-dose therapy followed by stem cell rescue is being investigated in a Euro-Ewing clinical trial for patients that present with pulmonary metastases.

Ewing Tumor of Bone/Specific Sites

Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites: pelvis,[28][29][30] femur,[31][32] humerus,[33] hand and foot,[34][35] chest wall/rib,[36][37][38][39] head and neck,[40] and spine.[41][42][43]

Extraosseous Ewing Sarcoma

Extraosseous Ewing sarcoma (EOE) is biologically similar to Ewing sarcoma arising in bone. Until recently, most children and young adults with EOE were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing tumor of bone (ETB). Currently, patients with EOE are eligible for studies that include ETB.

From 1987 to 2004, 111 patients with nonmetastatic EOE were enrolled on the RMS-88 and RMS-96 protocols.[44] Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation. The 5-year EFS and OS were 59% and 69%, respectively. In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, IRS Group III, and lack of radiation therapy.

Two hundred thirty-six patients with EOE were entered on studies of the German Pediatric Oncology Group.[45] The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE or; vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The 5-year EFS and OS were 49% and 60%, respectively. Five-year survival was 70% for patients with localized disease and 33% for patients with metastases at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. In a retrospective French study, patients with EOE were treated using a rhabdomyosarcoma regimen (no anthracyclines) or an ETB regimen (includes anthracyclines). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines.[46][47]

Superficial Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue. Two small series suggested that superficial Ewing sarcoma had a better prognosis than tumors arising in other sites, but not all cases had molecular confirmation of diagnosis.[48][49] A larger series of molecularly confirmed cases reported that patients with superficial Ewing sarcoma did well when treated with local control and systemic therapy similar to the therapy used for all other Ewing sarcoma patients.[50]

Second Malignant Neoplasms

Patients treated for ESFT have a significantly higher risk of developing second malignancies than patients in the general population. Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of ESFT,[51][52][53][Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[54][55][56][Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years following diagnosis. Survivors of ESFTs remain at increased risk of developing a second solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field.[57][58] The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.[52][53][Level of evidence: 3iiiDi] The cumulative risk of developing a secondary solid tumor at 10 years after diagnosis appears to be about 1.8%, although this may be higher with longer follow-up.[51][52][53][Level of evidence: 3iiiDi] (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

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  48. Hasegawa SL, Davison JM, Rutten A, et al.: Primary cutaneous Ewing's sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases. Am J Surg Pathol 22 (3): 310-8, 1998.  

  49. Ehrig T, Billings SD, Fanburg-Smith JC: Superficial primitive neuroectodermal tumor/Ewing sarcoma (PN/ES): same tumor as deep PN/ES or new entity? Ann Diagn Pathol 11 (3): 153-9, 2007.  

  50. Terrier-Lacombe MJ, Guillou L, Chibon F, et al.: Superficial primitive Ewing's sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22 (1): 87-94, 2009.  

  51. Paulussen M, Ahrens S, Lehnert M, et al.: Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol 12 (11): 1619-30, 2001.  

  52. Fuchs B, Valenzuela RG, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003.  

  53. Goldsby R, Burke C, Nagarajan R, et al.: Second solid malignancies among children, adolescents, and young adults diagnosed with malignant bone tumors after 1976: follow-up of a Children's Oncology Group cohort. Cancer 113 (9): 2597-604, 2008.  

  54. Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007.  

  55. Kushner BH, Heller G, Cheung NK, et al.: High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors. J Clin Oncol 16 (9): 3016-20, 1998.  

  56. Navid F, Billups C, Liu T, et al.: Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer 44 (7): 983-91, 2008.  

  57. Kuttesch JF Jr, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996.  

  58. Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996.  

Ewing Tumor of Bone: Localized Tumors

Standard Treatment Options

Because most patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation is indicated in the treatment of all patients.[1][2][3][4][5][6][7][8] Current regimens for the treatment of localized Ewing tumor of bone (ETB) achieve event-free survival (EFS) and overall survival of approximately 70% at 5 years after diagnosis.[9]

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide, also known as VAdriaC, alternating with ifosfamide and etoposide.[9] The combination of ifosfamide and etoposide has shown activity in ETB, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when ifosfamide/etoposide was alternated with VAdriaC.[2][9][10] Dactinomycin is no longer used in the United States but continues to be used in the Euro-Ewing studies. Increased doxorubicin dose intensity during the initial months of therapy was associated with an improved outcome.[11] The use of high-dose VAdriaC has shown promising results in small numbers of patients.[11] Forty-four patients treated with high-dose VAdriaC and ifosfamide/etoposide had an 82% 4-year EFS.[12] However, in a trial of the former Children's Cancer Group, which compared a dose-intensified chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide with standard doses of the same regimen, no differences in outcome were observed.[13] This trial did not maintain the dose intensity of alkylating agents for the duration of treatment and did not recapitulate the previously published experience.[12]

In a completed Children's Oncology Group (COG) trial (COG-AEWS0031) 568 patients with newly diagnosed localized extradural Ewing sarcoma family of tumors (ESFT) were randomized between the same chemotherapy (VAdriaC alternating with ifosfamide and etoposide) given every 2 weeks (interval compression) versus every 3 weeks (standard). Patients randomized to the every 2-week interval of treatment had an improved 3-year EFS (76% vs 65%, P = 0.028). There was no increase in toxicity observed with the every 2-week schedule.[14]

Local control can be achieved by surgery and/or radiation. Surgery is generally the preferred approach if the lesion is resectable.[15][16] The superiority of resection for local control has never been tested in a prospective randomized trial. The apparent superiority may represent selection bias. In past studies, smaller more peripheral tumors were more likely to be treated by surgery, and larger, more central tumors were more likely to be treated by radiation therapy.[17] An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis ETB who achieve adequate margins is small.[8] In a series of 39 patients treated at St. Jude Children's Research Hospital, who received both surgery and radiation, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[5] If a very young child has an ETB, surgery may be a less morbid therapy than radiation therapy because of the retardation of bone growth caused by radiation. Another potential benefit for surgical resection of the primary tumor is information concerning the amount of necrosis in the resected tumor. Patients with residual viable tumor in the resected specimen have a worse outcome compared with those with complete necrosis. In a French Ewing study (EW88), EFS for patients with less than 5% viable tumor, 5% to 30% viable tumor, and more than 30% viable tumor was 75%, 48%, and 20%, respectively.[17] Currently, European investigators are studying whether treatment intensification (i.e., high-dose chemotherapy with stem cell rescue) will improve outcome for patients with a poor histologic response. Radiation therapy should be employed for patients who do not have a surgical option that preserves function and should be used for patients whose tumors have been excised but with inadequate margins. Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.[18]

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of ETB. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1][2][19] The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. Radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with ETB using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose following 39.6 Gy to the entire bone showed no difference in local control or EFS.[3] Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.[1]

Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length.[20] When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure.[21] A retrospective analysis of patients with ETB of the chest wall compared patients who received hemithorax radiation therapy with those who received radiation therapy to the chest wall only. Patients with pleural invasion, pleural effusion, or intraoperative contamination were assigned to hemithorax radiation therapy. EFS was longer for patients who received hemithorax radiation, but the difference was not statistically significant. In addition, most patients with primary vertebral tumors did not receive hemithorax radiation and had a lower probability for EFS.[22]

For patients with residual disease following attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091 [POG-8850]) recommends 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. No radiation therapy is recommended for those who have no evidence of microscopic residual disease following surgical resection.

Radiation therapy is associated with the development of second malignant neoplasms. A retrospective study noted that those patients who received 60 Gy or more had an incidence of second malignancy of 20%. Those who received 48 Gy to 60 Gy had an incidence of 5%, and those who received less than 48 Gy did not develop a second malignancy.[23]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.  

  2. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998.  

  3. Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998.  

  4. Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998.  

  5. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al.: Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 104 (2): 367-73, 2005.  

  6. Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004.  

  7. Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999.  

  8. Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006.  

  9. Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003.  

  10. Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998.  

  11. Smith MA, Ungerleider RS, Horowitz ME, et al.: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma. J Natl Cancer Inst 83 (20): 1460-70, 1991.  

  12. Kolb EA, Kushner BH, Gorlick R, et al.: Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol 21 (18): 3423-30, 2003.  

  13. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009.  

  14. Womer RB, West DC, Krailo MD, et al.: Randomized comparison of every-two-week v. every-three-week chemotherapy in Ewing sarcoma family tumors (ESFT). [Abstract] J Clin Oncol 26 (Suppl 15): A-10504, 2008.  

  15. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999.  

  16. Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000.  

  17. Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001.  

  18. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007.  

  19. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al.: Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 60 (3): 830-8, 2004.  

  20. Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003.  

  21. La TH, Meyers PA, Wexler LH, et al.: Radiation therapy for Ewing's sarcoma: results from Memorial Sloan-Kettering in the modern era. Int J Radiat Oncol Biol Phys 64 (2): 544-50, 2006.  

  22. Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002.  

  23. Kuttesch JF Jr, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996.  

Ewing Sarcoma: Metastatic Tumors

Prognosis of patients with metastatic disease is poor.[1] Current therapies for patients who present with metastatic disease achieve 6-year event-free survival (EFS) of approximately 28% and overall survival (OS) of approximately 30%.[2] For patients with lung/pleural metastases only, 4-year EFS is approximately 40%. Patients with only bone/bone marrow metastases have a 4-year EFS of approximately 28% and patients with combined lung and bone/bone marrow metastases have a 4-year EFS of approximately 14%.[1] Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation.[3]

Standard Treatment Options

Standard treatment for patients with metastatic Ewing tumor of bone (ETB) utilizing alternating vincristine, doxorubicin, cyclophosphamide, and ifosfamide/etoposide combined with adequate local control measures applied to both primary and metastatic sites often results in complete or partial responses; however, the overall cure rate is 20%.[1][2][4][5] In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide and actinomycin-D.[2] In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard dose intensity.[2] This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[2]

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of the ETB. Such an approach will result in local control of tumor with acceptable morbidity in most patients.[6][7][8] Radiation therapy to the primary tumor as well as to the sites of metastatic disease should be considered but may interfere with delivery of chemotherapy if too much bone marrow is included in the field. Metastatic sites of disease in bone and soft tissues should receive fractionated radiation therapy doses totaling between 45 Gy and 56 Gy. All patients with pulmonary metastases should undergo whole-lung radiation, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[1][9][10] Radiation doses are modulated based on the amount of lung to be radiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated.

More intensive therapies, many of which incorporate high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support, have not shown improvement in EFS rates for patients with bone and/or bone marrow metastases.[2][11][12] The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is currently unknown.[11] European investigators use high-dose chemotherapy and stem cell support for patients with extrapulmonary metastatic sites. Use of high-dose therapy and autologous stem cell reconstitution for patients with metastases at extrapulmonary sites is an investigator choice in the Euro-Ewing study (EURO-EWING-INTERGROUP-EE99 [COG-AEWS0331]). It is not being studied as a randomized prospective question, but the study will acquire data about the outcome of patients treated with this consolidation. Melphalan, at nonmyeloablative doses, has proved to be an active agent in an upfront window study for patients with metastatic disease at diagnosis, however, the cure rate remained extremely low.[13]

Treatment Options Under Clinical Evaluation

The following are examples of international clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

  • EURO-EWING-INTERGROUP-EE99 (COG-AEWS0331): A randomized study for patients with pulmonary metastases only, which is evaluating standard chemotherapy and peripheral blood stem cell transplant versus standard chemotherapy and bilateral lung radiation, is being conducted in Europe and certain cancer centers in the United States. The Children's Oncology Group (COG) member institutions are participating in a limited way in the Euro-Ewing study. Specifically, the study is open through the COG for patients who present with metastases limited to the lung. They will be enrolled in the Euro-Ewing study and will be randomly assigned to receive chemotherapy or high-dose therapy with autologous stem cell reconstitution following induction chemotherapy and local control.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998.  

  2. Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007.  

  3. Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998.  

  4. Cangir A, Vietti TJ, Gehan EA, et al.: Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 66 (5): 887-93, 1990.  

  5. Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001.  

  6. Arai Y, Kun LE, Brooks MT, et al.: Ewing's sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy. Int J Radiat Oncol Biol Phys 21 (6): 1501-8, 1991.  

  7. Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.  

  8. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998.  

  9. Madero L, Muñoz A, Sánchez de Toledo J, et al.: Megatherapy in children with high-risk Ewing's sarcoma in first complete remission. Bone Marrow Transplant 21 (8): 795-9, 1998.  

  10. Spunt SL, McCarville MB, Kun LE, et al.: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23 (2): 93-8, 2001.  

  11. Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001.  

  12. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003.  

  13. Luksch R, Grignani G, Fagioli F, et al.: Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours. Eur J Cancer 43 (5): 885-90, 2007.  

Ewing Sarcoma: Recurrent Tumors

Standard Treatment Options

Recurrence of Ewing tumor of bone (ETB) is most common within 2 years of initial diagnosis (approximately 80%).[1][Level of evidence: 3iiA] The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival following recurrence is approximately 10% to 15%.[1][2][3][4][Level of evidence: 3iiA] Time to recurrence is the most important prognostic factor. Patients who recurred greater than 2 years from initial diagnosis had a 5-year survival of 30% versus 7% for patients who recurred within 2 years.[1][Level of evidence: 3iiA] Patients with both local recurrence and distant metastases have a worse outcome than patients with either isolated local recurrence or metastatic recurrence alone.[1][2][Level of evidence: 3iiA] Isolated pulmonary recurrence was not an important prognostic factor.[1][Level of evidence: 3iiA]

The selection of treatment for patients with recurrent disease depends on many factors, including the site of recurrence and prior treatment, as well as individual patient considerations. Combinations of chemotherapy such as cyclophosphamide, topotecan or irinotecan, and temozolomide are active in recurrent Ewing sarcoma family of tumors and can be considered for these patients.[5][6][7][8] High-dose ifosfamide (3 g/M2/day for 5 days = 15 g/M2) has shown activity in patients who recurred after therapy which included standard ifosfamide (1.8 g/M2/day for 5 days = 9 g/M2).[9][Level of evidence: 3iiiDiv] Ifosfamide and etoposide may be active in patients who have not previously received these therapies.[10] Aggressive attempts to control the disease, including myeloablative regimens, have been used but there is no evidence at this time to conclude that myeloablative therapy is superior to standard chemotherapy.[11][12][Level of evidence: 3iiiDiii] Surveys of patients undergoing allogeneic stem cell transplantation for recurrent ETB did not show improved event-free survival when compared with autologous stem cell transplantation and was associated with a higher complication rate.[13][14][15] Radiation therapy to bone lesions may provide palliation, though radical resection may improve outcome.[2] Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation.[2] Residual disease in the lung may be surgically removed.

Treatment Options Under Clinical Evaluation

The following are examples of national or international clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site 

  • COG-ADVL0821: A phase II trial of cixutumumab, an anti-IGF1 receptor monoclonal antibody.
  • NO21157: A phase II trial of an anti-IGF1 receptor monoclonal antibody.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Leavey PJ, Mascarenhas L, Marina N, et al.: Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 334-8, 2008.  

  2. Rodriguez-Galindo C, Billups CA, Kun LE, et al.: Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999. Cancer 94 (2): 561-9, 2002.  

  3. Shankar AG, Ashley S, Craft AW, et al.: Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol 40 (3): 141-7, 2003.  

  4. Bacci G, Longhi A, Ferrari S, et al.: Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Eur J Surg Oncol 32 (9): 974-9, 2006.  

  5. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.  

  6. McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006.  

  7. Hunold A, Weddeling N, Paulussen M, et al.: Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer 47 (6): 795-800, 2006.  

  8. Wagner LM, McAllister N, Goldsby RE, et al.: Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48 (2): 132-9, 2007.  

  9. Ferrari S, del Prever AB, Palmerini E, et al.: Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma. Pediatr Blood Cancer 52 (5): 581-4, 2009.  

  10. Miser JS, Kinsella TJ, Triche TJ, et al.: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5 (8): 1191-8, 1987.  

  11. Burdach S, Jürgens H, Peters C, et al.: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma. J Clin Oncol 11 (8): 1482-8, 1993.  

  12. Gardner SL, Carreras J, Boudreau C, et al.: Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma. Bone Marrow Transplant 41 (10): 867-72, 2008.  

  13. Burdach S, van Kaick B, Laws HJ, et al.: Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 11 (11): 1451-62, 2000.  

  14. Gilman AL, Oesterheld J: Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma. Bone Marrow Transplant 42 (11): 761; author reply 763, 2008.  

  15. Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.  

More Information

About PDQ  

Additional PDQ Summaries  

Important:  

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


This information is provided by the National Cancer Institute.

This information was last updated on December 4, 2009.

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