Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor ASCO 6/2021 update

The Ewing’s family of tumors includes Ewing’s sarcoma of bone, non-bone Ewing’s sarcoma, peripheral primitive neuroectodermal tumors (PNET) and Askin’s tumor (PNET of the chest wall). 

Ewing’s sarcomas occur most frequently in the second decade of life and account for three to four percent of childhood and adolescent cancers. However, Ewing’s sarcoma can occur at any age, even in the very elderly. Ewing’s sarcoma of the bone most commonly involves the arms and legs, pelvis, chest and spine, and skull. Non-bone Ewing’s sarcoma most commonly involves the trunk, extremities, head and neck, and retroperitoneum (the area outside or behind the tissue that lines the abdomen) Common sites for PNET are the chest, abdomen/pelvis, extremities, and head and neck.

The incidence of Ewing’s in children and adolescents is 2.1 per million.1  Only about 30% of patients with Ewing’s sarcoma are over age 20. In children and adolescents, oncologists typically prescribe a combination of five drugs given in an alternating order for up to a year. This combination therapy is able to cure around 70% of young patients with localized disease. 

Evidence suggests that roughly 75% of patients with Ewing’s sarcoma present with localized disease, and that 80% or more of these patients may be curable with combined modality therapy with chemotherapy, radiation therapy and surgery.3 For those who present with metastatic disease the cure rate is 20 to 30%.

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 incorporates the skills of the primary care physician, pediatric surgical sub-specialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.2

Cause of Ewing's Sarcoma

At the present time, there is no known relationship between inherited genetic alterations and the majority of cases of Ewing’s sarcoma. However, the majority of Ewing’s sarcomas are associated with a chromosomal rearrangement involving chromosome 11 and chromosome 22. This rearrangement changes the position and function of genes, causing a fusion of genes referred to as a “fusion transcript.” Over 90% of individuals with Ewing’s sarcoma have an abnormal fusion transcript involving two genes known as EWS and FLI1. This important discovery has led to improvements in diagnosing Ewing’s sarcoma and the development of novel precision cancer medicines to treat the disease.

Ewing’s is very rare in children of African or Asian decent. Hernias and Ewing’s sarcoma may share a common embryologic pathway; both conditions may be affected by genetic factors or in-utero (before birth) exposures to toxins. With regard to parental occupation, it has been suggested by several investigators that certain occupations, particularly farming, may increase the risk of Ewing’s sarcoma in the workers’ children. A study from Australia found that an increased incidence of Ewing’s sarcoma in children whose mothers worked on farms around the time of conception and during pregnancy. The risk doubled when the mothers handled pesticides and insecticides. The same relationship was true for fathers, but was less significant.17-19

Treatment of Ewing’s Sarcoma

Localized Ewing’s sarcoma affects only the bone in which it developed and the tissues next to the bone, such as muscle and tendon. There is no detectable spread of the cancer to other areas of the body as detected by computed tomography (CT) or magnetic resonance imaging (MRI) scans.

A multi-modality approach is the most effective treatment for Ewing’s sarcoma and requires that patients be treated by a multi-disciplinary team.The primary cooperative group evaluating Ewing’s sarcoma treatment in the U.S. is the Children’s Cancer Study Group.

Treatment of localized Ewing’s sarcoma requires both local and systemic therapy. Local therapy consists of surgery alone, radiation therapy alone or both radiation and surgery. Surgery and Radiation are directed at eradication of the primary tumor. Systemic therapy is treatment directed at eliminating cancer cells throughout the body, and may consist of a combination of chemotherapy drugs and/or precision cancer medicines.

Surgery

The ultimate goal of surgery for localized Ewing’s sarcoma is to remove the cancer without amputation. The specific type of surgery a patient undergoes depends on the location and extent of the cancer. For surgery to be successful, the cancer and a large margin of healthy tissue surrounding the cancer must be removed. Even with the advent of chemotherapy as systemic treatment and radiation as local treatment, surgery is still an important component of treatment for Ewing’s sarcoma.

Radiation Therapy

Radiation therapy (also known as radiotherapy) uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing.

Ewing’s sarcoma is relatively sensitive to radiation, and conventional radiation therapy plays a major role in treatment. When radiation therapy is given to patients with Ewing’s it is usually given with chemotherapy.

Similar to surgery, radiation therapy is a local treatment used to eliminate cancer in a specific area. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Radiation therapy may be externally or internally delivered.1

Side Effects of Radiation Therapy: Although patients do not feel anything while they are receiving radiation treatment, the effects of radiation gradually build up over time. Large doses of radiation can cause skin damage in the areas receiving radiation. Large doses of radiation to patients with Ewing’s sarcoma can damage blood vessels and nerves.

Several late effects of radiation therapy in children including: atrophy, fibrosis, bone growth abnormalities, impairment of mobility, edema, and peripheral nerve injury have been well documented.4

The most worrisome side effect among long-term survivors is second cancers due to radiation. One Italian study involving 597 long-term survivors with Ewing’s sarcoma found that the risk of second cancer after radiation therapy for Ewing’s sarcoma was higher than after other childhood and adolescent cancers treated in the same manner.5 Some researchers have suggested that postoperative radiotherapy should be avoided when surgery is accomplished with adequate margins (no evidence of cancer near the edge of the tissue that was removed).

Combined Modality Therapy

The main improvement in the treatment of localized Ewing’s sarcoma over the past 30 years has been the advent of combination chemotherapy. Chemotherapy is often delivered before surgery or radiation therapy (neoadjuvant chemotherapy) and after surgery or radiation therapy (adjuvant therapy).

The most common approach for the treatment of localized Ewing’s sarcoma is to remove as much tumor as possible surgically, deliver local radiation to eradicate microscopic tumor not removed by surgery, and administer systemic (whole-body) combination therapy to eradicate micrometastases (very small areas of cancer that may have spread to other parts of the body).

Researchers from St Jude Children Research Center have reported five-year survival rates of 90% and a local recurrence rate of 11% using a multi-modality approach. Patients who had positive surgical margins (evidence of cancer at the edge of the tissue that was surgically removed) had a local recurrence rate of 17% compared to 5.2 percent for those with no tumor in the surgical margins. These same authors reported 10-year survival rates of 75.5%2 Patients with disease originating in bone had better survival than patients with disease originating in soft tissue.

Radiation Therapy and Chemotherapy for Localized Ewing’s Sarcoma

Patients who have inoperable tumors or tumors in sites not suitable for surgery are treated with radiation therapy and chemotherapy. The local recurrence rate is ~30% and overall survival is reported to be greater than 65% Patients who were older or who had larger tumors had worse outcomes. In addition, radiation doses below 40 Gy are associated with an increased rate of local recurrence3 suggesting that high-dose radiation may help to eradicate the cancer.

Researchers from Italy reported that neoadjuvant and adjuvant chemotherapy may improve outcomes of patients with localized Ewing’s sarcoma.4  They treated 157 patients with localized Ewing’s with neoadjuvant chemotherapy followed by surgery, surgery plus radiation, or radiation only. After surgery and/or radiation therapy, all patients received adjuvant chemotherapy. Five-year survival without a cancer recurrence was 71%, which as better than previous results achieved without neoadjuvant chemotherapy.

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Intensive Chemotherapy: Researchers from Memorial Sloan-Kettering reported that a high-dose, short-term chemotherapy regimen improves outcomes of patients with localized Ewing’s sarcoma.5 The drugs used in this intensive regimen were cyclophosphamide, doxorubicin, ifosfamide and etoposide. The researchers reported a four-year event-free survival of 89% in patients with localized disease.

Metastatic & Recurrent Ewing’s Sarcoma

Ewing’s sarcoma that has spread from the initially affected bone to one or more sites in the body, distant from the site of origin, is called metastatic. The most common site to which Ewing’s sarcoma spreads, or metastasizes, is the lungs. The mainstay of treatment for metastatic Ewing's sarcoma is intensive multi-agent chemotherapy with or without autologous stem cell transplant.  In many instances it may also be necessary to treat the primary tumor with surgery (with or without radiation therapy) for optimal results. In some instances, the chance of a cure or relief of symptoms can be improved by treating metastatic tumors with surgery or radiation therapy after the administration of systemic therapy.

Treatment of Recurrent Ewing’s Sarcoma

Ewing’s sarcoma that has not responded to treatment or has returned after an initial response to treatment is considered recurrent. The most common site for recurrence is the lungs. A long interval between the primary diagnosis and the appearance of recurrent disease is associated with a better prognosis.

Treatment includes chemotherapy, surgery, radiotherapy and autologous stem cell transplant or participation on a clinical trial.  The selection of further treatment after a relapse depends on many factors, including the site of recurrence and prior treatment, as well as other individual patient considerations. In some instances, treatment is given only to relieve symptoms.

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Areas of active exploration to improve the treatment of recurrent Ewing’s sarcoma include the following:

Development of Precision Cancer Medicines

Precision cancer medicines and the companion tests used to identify them are increasingly important in the management of cancer.  Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Testing is currently done on a tissue sample from the cancer however “liquid biopsies” can also be utilized. Once a genetic abnormality is identified, a specific targeted therapy can be used to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells in many situations. All sarcoma patients should undergo NGS testing to identify any cancer causing mutations that can be targeted with a precision cancer medicine.  Ewing’s sarcoma is caused by specific cancer driving mutations. 

TX216: The most common cancer causing mutation is fusion of two genes called EWSR1 and FLI1. FLI1 is part of a group called ETS genes, and when EWSR1 fuses with FLI1, an abnormal transcription factor protein is created that interacts with DNA in a way that causes cells to grow abnormally and develop cancer in the bone or soft tissue. TK216 is a novel inhibitor of ETS proteins and work by interrupting the interactions between this abnormal protein and the genes that drive the cancer’s growth.15

Reports suggest that almost half of the patients treated with TK216 experienced clinical benefits – either complete response or stable disease – and two patients achieved a complete remission with no evidence of recurrence for over one and two years. Learn more...

High-Dose Chemotherapy with Autologous Stem Cell Transplantation is an effective salvage treatment (treatment given after the cancer has not responded to other treatments) for selected patients with metastatic Ewing’s sarcoma and been evaluated as part of an initial overall treatment strategy.16

Researchers enrolled 240 “high risk” Ewings sarcoma patients to be treated with Vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy. Patients were then treated with an additional 7 courses of standard chemotherapy (vincristine, dactinomycin, ifosfamide (VAI) or a single treatment with high-dose BuMel.

After a median follow-up of 7.8 years, results showed that patients who received BuMel had a significantly better outcome. Three-years from treatment 69% of BuMel treated patients survived without a sarcoma recurrence compared to 56% of those treated with VAI. The treatment benefit of BuMel persisted 8 years from treatment and appears durable.

An additional benefit to BuMel was a significantly shorter treatment duration. The study authors concluded that “the reliable demonstration of EFS and OS improvement indicates that BuMel may be considered as a standard of care for patients with localized Ewings fulfilling the definition of high-risk disease used in this trial and no contraindication to BuMel.

Surgery for Ewing’s Sarcoma

Surgery is an integral part of the treatment of localized Ewing’s sarcoma and in selected cases of metastatic or recurrent Ewing’s sarcoma. Reconstructive surgery is also an important component of the overall management of Ewing’s sarcoma requiring the skills of an orthopedic surgeon or other sub-speciality surgeons specializing in the area of the primary tumor site. Surgery is increasingly being performed following initial treatment with chemotherapy and/or radiotherapy to reduce the tumor mass. This strategy is adopted in order to decrease the size of the tumor before surgery, often in an attempt to avoid amputation.

Types of Surgery Performed for Ewing’s Sarcoma

Amputation: In the past, complete removal of the affected limb was the main treatment for patients with Ewing’s sarcoma and resulted in the cure of approximately 20% of patients. With the use of neoadjuvant (before surgery) chemotherapy, limb preservation is now possible in over 70 to 80% of patients with localized Ewing’s sarcoma.1,2 When primary treatment involves limb preservation, amputation is often used to treat recurrences.

Limb Salvage Surgery for Localized Ewing’s Sarcoma: Wide local excision after neoadjuvant chemotherapy is the most common approach to the treatment of patients with localized Ewing’s sarcoma. Wide local excision involves surgical removal of the cancer along with some surrounding normal tissue.

Surgery for Metastatic or Recurrent Ewing’s Sarcoma: It is important that the initial surgery remove as much cancer (both the primary cancer and operable areas of metastatic cancer) as possible. Surgery for metastatic lung nodules often involves the removal of only a small part of the lung, but may occasionally involve more extensive lung surgery or even removal of an entire lung. When cancer is present in both lungs, a separate incision for each lung is usually performed.

Recurrence of Ewing’s sarcoma following initial treatment is most common in the lung. Patients with recurrent Ewing’s sarcoma confined to the lungs can often be treated successfully with surgery. Complete surgical removal of the recurrent cancer is linked with better prognosis.

Reconstructive Surgery: There are a number of procedures for limb reconstruction after surgical removal of the primary Ewing’s sarcoma. These include bone grafts (using the patient’s own bone or bone from a donor) and prosthetic implants.

Rotationplasty is a technique used commonly in patients with Ewing’s sarcoma that involves the lower femur or upper tibia. This technique is used when the tumor is large and amputation is the only option. It is called a rotationplasty because the distal (far) portion of the leg is rotated 180 degrees and reattached to the thigh. The concept of the rotation is for the ankle to become a functional knee joint when the length of the leg is adjusted to match the opposite knee. This is difficult to visualize and it is recommended that families view a video of the actual procedure in order to understand what is taking place. These video tapes can also be downloaded from several web sites on Ewing’s sarcoma.

Reconstructive Surgery: Most of the surgical research in patients with Ewing’s sarcoma is in the field of reconstructive surgery. Patients and families will need to carefully review the large array of options and the latest prostheses available following limb salvage surgery. Some of these options will be complex and difficult to understand, but they can dramatically affect quality of life following surgery for Ewing’s sarcoma. It is important to understand these options before making a decision with the operating surgeon.

References:

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  15. https://meetinglibrary.asco.org/record/195666/abstract
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  19. Ferris, ITJ, Berbel TO, Ortega GJA, et al. Risk factors for pediatric malignant bone tumors. An Pediatr (Barc). 2005;63:537-547.