Breast cancer survivor offers wisdom at Faulkner satellite center
Call 877-422-3324 today to make an appointment
Make your appointment or second opinion with Dana-Farber today to meet with an onsite specialist.
Can’t get to Boston? Explore our Online Second Opinion service to get expert advice from Dana-Farber oncologists.
Toll-Free Number866-408-DFCI (3324)
Discover the ways to give and how to get involved to support Dana-Farber.
Poet Richard Fox gains insight – and material – through cancer treatment
A family faces cancer in an unfamiliar city – with help
Choosing mastectomy or not: Studying young women's surgical choices
Jeff's targeted therapy has kept his advanced lung cancer at bay.
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.
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:
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
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:
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.
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:
The following tests and procedures may be used to diagnose or stage 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:
The prognosis (chance of recovery) depends on certain factors before and after treatment.
Before treatment, prognosis depends on:
After treatment, prognosis is affected by:
Treatment options depend on the following:
Decisions about surgery may depend on how well the initial treatment with chemotherapy or radiation therapy works.
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 described as either localized or metastatic.
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.
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.
The three ways that cancer spreads in the body are:
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.
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.
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.
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:
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:
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.)
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 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 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.
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.
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 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.
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.
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.
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.
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.
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.
Treatment of metastaticEwing sarcoma family of tumors may include the following:
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.
Treatment of recurrentEwing sarcoma family of tumors may include the following:
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.
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.
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:
Information about the following is included in this summary:
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.
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. 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
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.
immunohistochemical markers, cytogenetics, molecular genetics, and
tissue culture  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. The incidence of Ewing sarcoma family of tumors (ESFTs) is approximately three per 1,000,000 per year and remained unchanged for 30 years. 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.
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. 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:
For EOE, the most common primary sites of disease are:
Approximately 25% of patients will have metastatic disease at diagnosis.
There are two major types of prognostic factors for patients with Ewing sarcoma: pretreatment factors and treatment response factors.
The following are not considered to be adverse prognostic factors for ESFT:
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. Female gender and younger age predict a good histologic response to preoperative therapy. Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence. For patients who receive preinduction and postinduction chemotherapy PET scans, decreased PET uptake following chemotherapy correlated with good histologic response.
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.
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.
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.
Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001.
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.
Suvà ML, Riggi N, Stehle JC, et al.: Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69 (5): 1776-81, 2009.
Tirode F, Laud-Duval K, Prieur A, et al.: Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11 (5): 421-9, 2007.
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.
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.
Kim SY, Tsokos M, Helman LJ: Dilemmas associated with congenital ewing sarcoma family tumors. J Pediatr Hematol Oncol 30 (1): 4-7, 2008.
van den Berg H, Dirksen U, Ranft A, et al.: Ewing tumors in infants. Pediatr Blood Cancer 50 (4): 761-4, 2008.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.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. 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.
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 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. 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), 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. 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. 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.
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.
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.
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.
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. 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. 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.
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.
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.
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. 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  in conjunction with either surgery or radiation therapy or both modalities for local tumor control. 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. 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.
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).[Level of evidence: 1iiA] Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide, while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle. Duration of primary chemotherapy ranges from 6 months to approximately 1 year.
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. 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. 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.
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. 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. 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.
Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites: pelvis, femur, humerus, hand and foot, chest wall/rib, head and neck, and spine.
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. 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. 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.
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. 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.
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,[Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[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. The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.[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.[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.)
Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003.
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.
Shankar AG, Pinkerton CR, Atra A, et al.: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35 (12): 1698-704, 1999.
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.
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.
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.
Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005.
Juergens C, Weston C, Lewis I, et al.: Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47 (1): 22-9, 2006.
Dunst J, Schuck A: Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42 (5): 465-70, 2004.
Donaldson SS: Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 42 (5): 471-6, 2004.
Bacci G, Ferrari S, Longhi A, et al.: Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep 11 (1): 111-20, 2004.
Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al.: Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 43 (3): 229-36, 2004.
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.
Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001.
Miser JS, Krailo M, Meyers P, et al.: Metastatic Ewing's sarcoma(es) and primitive neuroectodermal tumor (PNET) of bone: failure of new regimens to improve outcome. [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-1472, 467, 1996.
Bernstein ML, Devidas M, Lafreniere D, et al.: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 24 (1): 152-9, 2006.
Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008.
Wagner TD, Kobayashi W, Dean S, et al.: Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73 (1): 259-66, 2009.
Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19 (3): 870-80, 2001.
Marina N, Meyers PA: High-dose therapy and stem-cell rescue for Ewing's family of tumors in second remission. J Clin Oncol 23 (19): 4262-4, 2005.
Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004.
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.
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.
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.
Oberlin O, Rey A, Desfachelles AS, et al.: Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Société Française des Cancers de l'Enfant. J Clin Oncol 24 (24): 3997-4002, 2006.
Hawkins D, Barnett T, Bensinger W, et al.: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 34 (5): 328-37, 2000.
Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999.
Sucato DJ, Rougraff B, McGrath BE, et al.: Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop (373): 193-201, 2000.
Bacci G, Ferrari S, Mercuri M, et al.: Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 25 (2): 118-24, 2003.
Bacci G, Ferrari S, Longhi A, et al.: Local and systemic control in Ewing's sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg Br 85 (1): 107-14, 2003.
Ozaki T, Hillmann A, Hoffmann C, et al.: Ewing's sarcoma of the femur. Prognosis in 69 patients treated by the CESS group. Acta Orthop Scand 68 (1): 20-4, 1997.
Ayoub KS, Fiorenza F, Grimer RJ, et al.: Extensible endoprostheses of the humerus after resection of bone tumours. J Bone Joint Surg Br 81 (3): 495-500, 1999.
Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing's sarcoma of the foot. Clin Orthop (420): 230-8, 2004.
Anakwenze OA, Parker WL, Wold LE, et al.: Ewing's sarcoma of the hand. J Hand Surg Eur Vol 34 (1): 35-9, 2009.
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.
Sirvent N, Kanold J, Levy C, et al.: Non-metastatic Ewing's sarcoma of the ribs: the French Society of Pediatric Oncology Experience. Eur J Cancer 38 (4): 561-7, 2002.
Shamberger RC, LaQuaglia MP, Gebhardt MC, et al.: Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 238 (4): 563-7; discussion 567-8, 2003.
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.
Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004.
Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al.: Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 37 (1): 30-5, 2001.
Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005.
Schuck A, Ahrens S, von Schorlemer I, et al.: Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63 (5): 1562-7, 2005.
Spiller M, Bisogno G, Ferrari A, et al.: Prognostic factors in localized extraosseus Ewing family tumors. [Abstract] Pediatr Blood Cancer 46 (10) : A-PD.024, 434, 2006.
Ladenstein R, Pötschger U, Jürgens H, et al.: Comparison of treatment concepts for extraosseus Ewing tumors (EET) within consecutive trials of two GPOH Cooperative Study Groups. [Abstract] Pediatr Blood Cancer 45 (10) : A-P.C.004, 450, 2005.
Castex MP, Rubie H, Stevens MC, et al.: Extraosseous localized ewing tumors: improved outcome with anthracyclines--the French society of pediatric oncology and international society of pediatric oncology. J Clin Oncol 25 (10): 1176-82, 2007.
Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009.
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.
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.
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.
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.
Fuchs B, Valenzuela RG, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003.
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.
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.
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.
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.
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.
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.
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. 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.
Current standard chemotherapy in the United States includes vincristine,
doxorubicin, and cyclophosphamide, also known as VAdriaC, alternating with ifosfamide and
etoposide. 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. 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.
The use of
high-dose VAdriaC has shown promising results in small numbers of patients. Forty-four patients treated with high-dose VAdriaC and ifosfamide/etoposide had an 82% 4-year EFS. 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. This trial did not maintain the dose intensity of alkylating agents for the duration of treatment and did not recapitulate the previously published experience.
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.
Local control can be achieved by surgery and/or radiation. Surgery is
generally the preferred approach if the lesion is resectable. 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. 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. 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. 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. 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.
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. 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. Hyperfractionated
radiation therapy has not been associated with improved local control or decreased morbidity.
Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length. When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure. 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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Prognosis of patients with metastatic disease is poor.
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%. 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%.
Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation.
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%. 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. In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS.
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. 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. 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. The impact of high-dose chemotherapy with
peripheral blood stem cell support for patients with lung metastases is
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Recurrence of Ewing tumor of bone (ETB) is most common within 2 years of initial diagnosis (approximately 80%).[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%.[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.[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.[Level of evidence: 3iiA] Isolated pulmonary recurrence was not an important prognostic factor.[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. 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).[Level of evidence: 3iiiDiv] Ifosfamide and etoposide may be active in patients who have not previously received these therapies. 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.[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. Radiation therapy to bone
lesions may provide palliation, though radical resection may improve outcome. Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation. Residual disease in the lung may be surgically
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gilman AL, Oesterheld J: Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma. Bone Marrow Transplant 42 (11): 761; author reply 763, 2008.
Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.
Additional PDQ Summaries
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 was last updated on December 4, 2009.
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
If you are dealing with the death of a loved one, grief can be a lonely and isolating experience. The Bereavement Program provides support to bereaved family members and friends following the death of a patient.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Expressive Arts Therapy program, sponsored by the Leonard P. Zakim Center for Integrative Therapies, provides adult patients, family members, and caregivers with a variety of options to support well-being during cancer treatment. From live music meditation to painting technique workshops, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Friends' Place provides personal consultations to help cancer patients of all ages cope with changes in physical appearance that result from cancer treatment. Our experienced, compassionate team provides fittings for compression garments or breast prostheses, helps with wigs and other head coverings, and offers make-up and skincare advice.
The Friends' Corner Gift Shop, located on the first floor of the Yawkey Center for Cancer Care, offers a wide selection of unique gifts and everyday items for patients, families and staff.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
Every year, thousands of patients with cancer from around the world come to Dana-Farber for their care. We provide a wide array of logistical and other services for individuals who live outside the United States.
Dana-Farber provides interpreting services for patients whose first language is not English. Interpreters may be requested for any activity, including registration, booking appointments, attending treatments and exams, support groups, and meetings with doctors and other members of your health care team.
Our nutritionists are registered dietitians who can assist you in planning an optimal diet during any stage of your cancer journey, cope with any side effects you may experience, and answer your questions about the latest findings on cancer and nutrition.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
Patients websites help friends and family members stay up-to-date on their loved ones' condition and write messages of support and encouragement.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
In this video, Dr. George Demetri talks about his work in the Sarcoma and Bone Cancer Treatment Center at Dana-Farber/Brigham and Women's Cancer Center