Overview of Ewing's Sarcoma

Overview of the Ewing’s Sarcoma Family of Tumors

Ewing’s Sarcoma

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)

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). The incidence of Ewing’s in children and adolescents is 2.1 per million.1 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.

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 At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and 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. The majority of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials.

Evidence suggests that roughly 75 percent of patients with Ewing’s sarcoma present with localized disease, and that 80 percent 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 percent.4 These figures represent results from the most recent treatment strategies which are significantly better than in the past.

For details about the treatment of Ewing’s sarcoma, click on the appropriate stage:
Localized 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.

Metastatic 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.

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.

Localized Ewing’s Sarcoma

Overview

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.

The following is a general overview of treatment for localized Ewing’s sarcoma. Treatment may consist of surgery, radiation therapy, chemotherapy, or all three modalities. Multi-modality treatment is treatment using two or more techniques; this is increasingly recognized as an important approach for increasing a patient’s chance of cure or prolonging survival.

The multi-modality approach to treatment for Ewing’s sarcoma requires that patients be treated by a multi-disciplinary team consisting of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others. An experienced team is best found in specialty cancer centers that treat many patients with Ewing’s sarcoma. Engaging a multidisciplinary team at one of these centers helps ensure that the patient receives treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. The primary cooperative group evaluating Ewing’s sarcoma treatment in the U.S. is the Children’s Cancer Study Group.

The Role of Surgery for Ewing’s Sarcoma

Overview

Ewing’s sarcoma is a relatively rare cancer and is best treated in specialized medical centers. These centers will have a multidisciplinary team of specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, 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.

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 subspeciality 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 percent of patients. With the use of neoadjuvant (before surgery) chemotherapy, limb preservation is now possible in over 70 to 80 percent 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.

Strategies to Improve Treatment:

The progress that has been made in the treatment of Ewing’s sarcoma has resulted from improvements in surgery, chemotherapy and radiation therapy, as well as from doctor and patient participation in clinical studies. Future progress in the treatment of Ewing’s sarcoma will result from continued participation in clinical research. Currently, there are several areas of active exploration aimed at improving the treatment of localized 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.

The Role of Radiation Therapy for Ewing’s Sarcoma

Overview

Radiation therapy (also known as radiotherapy) uses high-energy rays to damage or kill cancer cells by preventing them from growing and dividing. 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. External radiation delivers high-energy rays directly to the tumor site from a machine outside the body. Internal radiation, or brachytherapy, involves the implantation of a small amount of radioactive material in or near the cancer.

Optimal treatment of patients with Ewing’s sarcoma often requires more than one therapeutic approach. Thus, it is important for patients to be treated at a medical center that can offer multi-modality treatment involving radiation oncologists, orthopedic surgeons, pediatric oncologists, and rehabilitation specialists.

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.

External Beam Radiation Therapy

Radiation therapy is delivered to areas of cancer from a machine outside the body, called a linear accelerator, or from a shielded repository of a powerful isotope, such as cobalt 60. External beam radiation therapy is most often administered in conjunction with chemotherapy. In some instances, patients with advanced disease are treated with radiation therapy alone for relief of symptoms. Conventional radiation therapy is administered over a course of five to seven weeks.

The main effect of radiation therapy is to prevent local and regional recurrences (cancer recurrence in the area of the primary tumor). A recent review suggests that radiation therapy can prevent local cancer recurrence in 58 to 93 percent of patients.[1]

Surgery, Radiation Therapy and Chemotherapy for Localized Ewing’s Sarcoma

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 chemotherapy to eradicate micrometastases (very small areas of cancer that may have spread to other parts of the body). Radiation therapy has no effect on distant metastatic disease.

Researchers from St Jude Children Research Center have reported the outcomes of 39 patients with localized Ewing’s sarcoma treated with definitive surgery, radiation therapy and chemotherapy.[2] They reported a five-year survival of 90 percent and a local recurrence rate of 11 percent. 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 percent compared to 5.2 percent for those with no tumor in the surgical margins.

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. Researchers at St Jude Children’s Research Center have reported the outcomes of 79 patients with Ewing’s sarcoma treated with low-dose or high-dose radiation and chemotherapy with vincristine, actinomycin D, and cyclophosphamide with alternating cycles of ifosfamide and etoposide.[3] The local recurrence rate was 30 percent. Overall survival was 65 percent. Patients who were older or who had larger tumors had worse outcomes. In addition, radiation doses below 40 Gy were associated with an increased rate of local recurrence.

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. Researchers from Emory University have described several late effects of radiation therapy in children including: atrophy, fibrosis, bone growth abnormalities, impairment of mobility, edema, and peripheral nerve injury.[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).

Strategies to Improve Treatment

Significant progress has been made in the treatment of Ewing’s sarcoma. Future progress in the treatment of Ewing’s sarcoma will result from continued participation in appropriate clinical trials. There are several areas of active exploration aimed at improving the treatment of Ewing’s sarcoma with radiation therapy.

Intraoperative Radiation Therapy (IORT): Intraoperative radiation therapy (IORT) is a single dose of radiation therapy that is delivered directly to the area of surgery during the operation. IORT is performed in specially-equipped operating rooms. During IORT, the radiation doctor can see the area being treated, and sensitive normal structures, such as blood vessels and nerves, can be moved away from the radiation beam. Results from some studies evaluating IORT indicate that cancer may recur less often in the area of the surgery.[6]

Three-dimensional Conformal Radiation Therapy and Intensity Modulated Radiation Therapy: Three-dimensional conformal radiation therapy can precisely target radiation to the areas where cancer cells may be located and therefore, minimize side effects from radiation to normal structures such as the liver, stomach and kidneys. Intensity modulated radiation therapy is a newer method of precisely delivering specified doses of radiation to cancer cells. Neither of these techniques have been evaluated for treatment of Ewing’s sarcoma, although both techniques are probably utilized for this purpose in many radiation oncology centers.[7], [8]

Brachytherapy: Brachytherapy is the placement of a radioactive material directly into the cancer at the time of surgery. This technique has not been systematically studied in patients with Ewing’s sarcoma. However, promising results in controlling local disease have been reported.[9],[10]

Treatment of Localized Ewing’s Sarcoma

Effective 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 usually consists of a combination of chemotherapy drugs.

The delivery of systemic therapy in addition to local treatment is necessary to maximize a patient’s chance of cure. Most patients diagnosed with localized Ewing’s sarcoma actually have micrometastases that are undetectable by current procedures. Micrometastases are cancer cells that have spread beyond the area of the original cancer. The presence of micrometastases may cause Ewing’s sarcoma recurrence following local treatment with surgery alone, radiation alone or surgery plus radiation. Thus, systemic therapy is nearly always given to patients with Ewing’s sarcoma to treat undetectable micrometastases. Typically, patients undergo chemotherapy before (neoadjuvant) and after (adjuvant) surgery with or without radiation.

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. For more details go to: The Role of Surgery in Ewing’s Sarcoma.

Radiation Therapy

Radiation Therapy is used to prevent local recurrences following complete or incomplete surgery. Even with complete surgical resection some patients will have a local recurrence without the administration of large doses of radiation therapy and chemotherapy. Radiation therapy is also given to patients who cannot undergo surgery because of the location or in an attempt to avoid amputation. For more details go to: The Role of Radiation Therapy for Ewing’s Sarcoma.

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).

Surgery, Radiation Therapy and Chemotherapy for Localized Ewing’s Sarcoma: 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 to administer systemic combination chemotherapy to eradicate micrometastases. Researchers from St Jude Children Research Center have reported the outcomes of 39 patients with localized Ewing’s sarcoma treated with definitive surgery, radiation therapy and chemotherapy.[1] Chemotherapy consisted of vincristine, actinomycin D, cyclophosphamide, and doxorubicin with alternating cycles of ifosfamide and etoposide. Five-year survival was 90 percent, and only 11 percent of patients experienced a recurrence in the area where the cancer originated (local recurrence). Patients who had positive surgical margins (evidence of cancer at the edge of the tissue that was removed) had a local recurrence rate of 17 percent compared to 5.2 percent for those with no tumor in the surgical margins. This study shows that multimodality therapy is very effective for treating favorable risk patients. In a more recent publication these same authors reported five- and 10-year survival rates of 84.5 percent and 75.8 percent, respectively.[2] Patients with disease originating in bone had better survival than patients with disease originating in soft tissue.

Chemotherapy and Radiation Therapy: Patients with Ewing’s sarcoma who have inoperable tumors or tumors in sites not suitable for surgery are generally treated with radiation therapy and chemotherapy. Researchers at St Jude Children’s Research Center have reported the outcomes of 79 patients with Ewing’s sarcoma treated with low-dose or high-dose radiation and chemotherapy with vincristine, actinomycin D, and cyclophosphamide with alternating cycles of ifosfamide and etoposide.[3] The local recurrence rate was 30 percent and the overall survival was 65 percent. Patients who were older or who had larger tumors were more likely to experience a local recurrence. Patients who had received radiation doses below 40 Gy were also more likely to experience a local recurrence, suggesting that high-dose radiation may help to eradicate the cancer.

Researchers from Italy have 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 vincristine, doxorubicin, and cyclophosphamide followed by ifosfamide and actinomycin. Patients were then treated with 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 percent, which as better than previous results achieved without neoadjuvant chemotherapy.

Intensive Chemotherapy: Researchers from Memorial Sloan-Kettering have 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 percent in patients with localized disease. There was no apparent improvement in patients with metastatic disease using this more intensive regimen.

Metastatic 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. Metastatic Ewing’s is typically difficult to control, though patients with lung metastases have a better prognosis than patients with other distant metastases.

Chemotherapy for Metastatic Ewing’s Sarcoma

Patients with metastatic Ewing’s sarcoma have disease that has spread to various parts of the body, necessitating systemic (whole-body) therapy. 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 chemotherapy.

The current standard chemotherapy regimen is a combination of drugs which includes: Adriamycin® (doxorubicin), Oncovin® (vincristine), Cytoxan® (cyclophosphamide) and Actinomycin D® (dactinomycin). On the basis of non-randomized trials (trials which provide less conclusive evidence than randomized trials), many physicians use a regimen of Oncovin, Adriamycin and Cytoxan (VAdriaC), alternating with Ifex® (ifosfamide) and Vepesid® (etoposide) for the treatment of Ewing’s sarcoma. Dactinomycin has been dropped from this regimen because it has not been seen as a crucial component when Ifex and etoposide are added.[1][2]

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.

The prognosis for patients with recurrent or progressive Ewing’s sarcoma is poor. Researchers from England have reported that among 64 patients who relapsed after initial therapy, average survival from the time of relapse was only 14 months. [1] Treatment of this group of patients included chemotherapy, surgery, radiotherapy and autologous stem cell transplant. Patients who relapsed while receiving initial therapy did worse than patients who relapsed later. A shorter duration of first remission was also linked with worse survival.

Researchers from St. Jude Children’s Hospital have reported the outcomes of 71 patients with recurrent Ewing’s sarcoma.[2] In this study, 34 patients had distant recurrence, 25 had local recurrence and 12 had both. Overall, five-year relapse-free survival was 18 percent. Among patients who had a recurrence more than two years after diagnosis, five-year relapse-free survival was 35 percent. Patients with a local recurrence had a five-year relapse-free survival of 22 percent compared to 18 percent for those with a distant recurrence. Patients with both local and distant recurrences had a five-year relapse-free survival of 8%. Patients with local recurrences who underwent radical surgery had better survival than those not undergoing radical surgery. These authors also suggested that patients with isolated pulmonary (lung) metastasis benefited from radiation therapy.

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.

Surgery for Recurrent Ewing’s Sarcoma

For patients who have a recurrence of their Ewing’s sarcoma, the goal of surgery is the same as for patients with localized Ewing’s sarcoma: removal of the cancer without amputation. Patients who have had a recurrence of their Ewing’s sarcoma in the lungs should be carefully assessed to determine whether their cancer can be removed surgically because some may be successfully treated with aggressive surgical removal. Surgery is generally only considered after completion of salvage chemotherapy. For more information go to The Role of Surgery for Ewing’s Sarcoma.

Radiation Therapy for Recurrent Ewing’s Sarcoma

Radiation therapy can be used after systemic chemotherapy to treat local areas of cancer in order to improve the chances of cure or for symptom relief. For more information go to The Role of Radiation Therapy for Ewing’s Sarcoma.

Chemotherapy for Recurrent Ewing’s Sarcoma

Combination chemotherapy is the primary treatment for patients with recurrent Ewing’s sarcoma. Regimens for the treatment of recurrent disease usually use different chemotherapy agents that have different mechanisms of action than those used for initial treatment. However, if patients have a significant disease-free interval after discontinuation of initial therapy they may respond to drugs in the original treatment regimen. At the present time there are no standard chemotherapy regimens for patients with recurrent disease.

Conventional-Dose Chemotherapy: Researchers from Saudi Arabia treated 27 adult patients with recurrent Ewing’s sarcoma with a regimen of Vepesid® (etoposide), Ifex® (ifosfamide) and Platinol® (cisplatin).[3] One patient had a complete response (a complete disappearance of detectable cancer), 30 percent of patients had a partial response (a partial disappearance of detectable cancer), and 33 percent of patients had stable disease. The researchers considered this an active regimen for symptom relief.

Researchers from the United Kingdom evaluated Platinol-based combination chemotherapy in 39 patients with recurrent Ewing’s sarcoma.[4] One patient had a complete response and nine patients had a partial response, for an overall response rate of 26 percent. Six responding patients proceeded to autologous stem cell transplantation.

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:

Improvement in Chemotherapy Treatment: Combination chemotherapy has significantly improved the outcomes of patients with metastatic Ewing’s sarcoma. However, the majority of patients with metastatic Ewing’s are not cured and will ultimately die of recurrent disease. It is extremely important to continue to investigate new therapies for patients with Ewing’s sarcoma. Given the rarity of this disease it is important that all patients with metastatic Ewing’s sarcoma be treated in a specialized center on a protocol designed to improve outcomes of treatment.

Testing of New Drugs or Combinations of Drugs: Patients with recurrent or refractory Ewing’s sarcoma often receive new drugs or drug combinations. Researchers from Germany have evaluated the combination of Hycamtin® (topotecan) and Cytoxan and conclude that this is an active
drug combination.[8]

High-Dose Chemotherapy with Autologous Stem Cell Transplantation: Several small pilot studies have evaluated the use of high-dose chemotherapy with autologous stem cell transplantation in patients with relapsed or recurrent Ewing’s sarcoma. [7][8] The results of these studies suggest that this treatment may be an effective salvage treatment (treatment given after the cancer has not responded to other treatments) for selected patients with metastatic Ewing’s sarcoma. Researchers from the University of Washington treated 55 consecutive patients with a relapse of Ewing’s sarcoma between 1985 and 2002.[9] Thirteen patients with response relapse had an autologous stem cell transplant. Nine of the 13 patients in this study received two consecutive (tandem) transplants and most received a total body irradiation or total bone irradiation regimen. The five year survival of chemotherapy responsive patients was 46 percent versus 0 percent for those that did not respond. Overall survival of chemotherapy-responsive patients was 75 percent among those who received an autologous stem cell transplant and 20 percent among those who did not receive an autologous stem cell transplant.

A French study reviewed the outcomes of 46 adult patients treated with high-dose chemotherapy and autologous stem cell transplantation between 1987 and 2000.[10] Half the patients have been followed for more than seven years. Five-year overall survival was 63 percent and progression-free survival was 47 percent. Six of the nine patients receiving tandem transplants and two of four receiving a single transplant are still alive. There were no treatment-related deaths in either study.

The role of autologous stem cell transplantation in the initial treatment of patients with metastatic disease has not been extensively explored. [11][12][13] Researchers from the University of Minnesota reported that autologous stem cell transplants in newly diagnosed patients with Ewing’s sarcoma had a three-year overall survival of 54 percent.[14] These authors suggested further study of autologous stem cell transplantation in the initial treatment of Ewing’s sarcoma. A study of 21 children with Ewing’s sarcoma was recently reported by researchers in Poland.[15] They observed that eight of 11 patients transplanted in remission remained in remission while all 10 patients transplanted in relapse died. They concluded that poor-risk patients with metastatic Ewing’s sarcoma who respond to initial therapy may benefit from a consolidative stem cell transplant.

Researchers from France have reported the outcomes of 97 newly diagnosed patients with Ewing’s sarcoma who were treated with five cycles of chemotherapy followed by an autologous stem cell transplant in those who had a complete or partial response.[16] Seventy-five of the 97 patients received high-dose busulfan and melphalan followed by autologous stem cell transplant. Event-free survival after transplant was 47 percent for the entire group, 52 percent for those with lung metastasis and 36 percent for those with bone metastasis. Only one patient with bone marrow involvement survived. These authors suggested that a randomized trial would be needed to prove a benefit of high-dose therapy.

Radiation Therapy: Ewing’s sarcoma is a radiosensitive cancer and many of the more modern radiation therapy techniques may improve outcomes by eradicating residual disease after chemotherapy administration.

Targeted Therapies: New drugs are being developed which target enzyme pathways necessary for cancer survival. One such enzyme system is the tyrosine kinase pathway. This enzyme has been targeted by a drug called Gleevec® (imatinib) which has been used successfully to treat patients with chronic myeloid leukemia (CML).Preclinical studies suggest that Gleevec may also be effective against Ewing’s sarcoma cells since they rely on the same enzyme as CML cells. Clinical trials of Gleevec for the treatment of Ewing’s sarcoma have begun or should begin in the near future. Another targeted therapy, Iressa® (gefitinib), has produced a partial response in at least one patient with refractory Ewing’s sarcoma.[17]Researchers are looking at a number of molecular targets for the development of other targeted therapies.[18]

References:

1Arndt CAS and Crist WM. Common musculoskeletal tumors of childhood and adolescence. Medical Progress. New England Journal of Medicine 1999;341:242-352.

2Bernstein M, Kovar H, Paulussen M, et al. Ewing’s sarcoma family of tumors: current management. Oncologist 2006;11:503-519.

3Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al. Efficacy of combined surgery and irradiation for localized sarcoma family of tumors. Pediatric Blood Cancer 2004;43:229-236.

4Holcombe EG, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. The New England Journal of Medicine 2003;348:694-701.

[1] Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al. Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatric Blood Cancer. 2004;43:229-236.

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

[3] Krasin MJ, Rodriguez-Galindo C, Billups CA, et al. Definitive irradiation in mulitidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. International Journal of Oncology Biology Physics 2004;60:830-838.

[4] Bacci G, Mercuri M, Longhi A, et al. Neoadjuvant chemotherapy for Ewing’s tumour of bone: recent experience in the Rizzoli Orthopaedic Institute. European Journal of Cancer 2002;38:2243-51.

[5] Kolb EA, Kushner BH, Gorlick R, et al. Long-term even-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. Journal of Clinical Oncology 2004;21:3423-3430.

[6] 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 Societe Francaise des Cancers de l’Enfant. Journal of Clinical Oncology 2006;24:3997-4002.

[7] Wendelin G, Lackner H, Schwinger W, et al. Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. Pediatric Hematology Oncology 2005;27:449-451.

[8] Bernsterin 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. Journal of Clinical Oncology 2006;24:152-159.

[9] Daw NC, Furman WL, Stewart CF, et al. Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Childrens Oncology Group Study. Journal of Clinical Oncology 2005;23:6172-6180.

[10] McAllister WR and Lessnick SL. The potential for molecular therapeutic targets in Ewing’s sarcoma. Current Treatment Options in Oncology 2005;6:461-471.

[1] 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 study. Journal of Clinical Oncology 2004;22:2873-2876.

[2] Grier H, Krailo M, Tarbell N, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. New England Journal of Medicine. 2003;348:694-701.

[3] Milano GM, Cozza R, Ilani I, et al. High histologic and overall response to dose intensification of ifosfamide, carboplatin, and etoposide with cyclophosphamide, doxorubicin, and vincristine in patients with high-risk Ewing’s sarcoma family tumors:The Bambino Gesu Children’s Hospital experience. Cancer2005;106:1838-1845.

[4] Navid F, Santana VM, Billups CA, et al. Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas: the St. Jude Children’s Hospital experience. Cancer 2006;106:1846-1856.

[5] Wendelin G, Lackner H, Schwinger W, et al. Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. Pediatric Hematology Oncology 2005;27:449-451.

[6] Bernsterin 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. Journal of Clinical Oncology 2006;24:152-159.

[7] Barker LM, Pendergrass TW, Sanders JE, et al. Survival after recurrence of Ewing’s sarcoma family of tumors. Journal of Clinical Oncology. 2005;23:4354-4362.

[8] Laurence V, Pierga J-Y, Barthier S, et al. Long-term follow-up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing’s sarcoma. American Journal of Clinical Oncology. 2005;28:301-309

[9] Barker LM, Pendergrass TW, Sanders JE, et al. Survival after recurrence of Ewing’s sarcoma family of tumors. Journal of Clinical Oncology. 2005;23:4354-4362.

[10] Laurence V, Pierga J-Y, Barthier S, et al. Long-term follow-up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing’s sarcoma. American Journal of Clinical Oncology. 2005;28:301-309.

[11] Fraser CJ, Weigel BJ, Perentisis JP, et al. Autologous stem cell transplantation for high-risk sarcoma and other pediatric solid tumors. Bone Marrow Transplantation 2006;37:175-181.

[12] Drabko K, Zawitkowska-Klaczynska J, Wojcik B, et al. Megachemotherapy followed by autologous stem cell transplantation in children with Ewing’s sarcoma. Pediatric Transplantation 2005;9:618-621.

[13] 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 Societe Francaise des Cancers de l’Enfant. Journal of Clinical Oncology 24:3997-4002.

[14] Fraser CJ, Weigel BJ, Perentisis JP, et al. Autologous stem cell transplantation for high-risk sarcoma and other pediatric solid tumors. Bone Marrow Transplantation 2006;37:175-181.

[15] Drabko K, Zawitkowska-Klaczynska J, Wojcik B, et al. Megachemotherapy followed by autologous stem cell transplantation in children with Ewing’s sarcoma. Pediatric Transplantation 2005;9:618-621.

[16] 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 Societe Francaise des Cancers de l’Enfant. Journal of Clinical Oncology 24:3997-4002.

[17] Daw NC, Furman WL, Stewart CF, et al. Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Childrens Oncology Group Study. Journal of Clinical Oncology 2005;23:6172-6180.

[18] McAllister WR and Lessnick SL. The potential for molecular therapeutic targets in Ewing’s sarcoma. Current Treatment Options in Oncology 2005;6:461-471.

[1] 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 2003;40:141-147.

[2] Rodriguez-Galindo C, Billups CA, Kun LE, et al.Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979-199. Cancer 2002;94:561-569.

[3] El Weshi A, Memon M, Raja M, et al. VIP (etoposide, ifosfamide, cisplatin) in adult pateitns with recurrent or refractory Ewing sarcoma family of tumors. American Journal of Clinical Oncology 2004;27:529-534.

[4] Whelan JS, McTiernan A, Kakouri E, et al. Carboplatin-based chemotherapy for refractory and recurrent Ewing’s tumours. Pediatric Blood Cancer. 2004;43:237-242.

[5] Barker LM, Pendergrass TW, Sanders JE, et al. Survival after recurrence of Ewing’s sarcoma. Journal of Clinical Oncology 2005;23:4354-4362.

[6] Laurence V, Pierga J-Y, Barthier S, et al. Long-term follow-up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing’s sarcoma. American Journal of Clinical Oncology. 2005;28:301-309.

[7] McTiernan A, Driver D, Michelagnoli M P, 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. Annals of Oncology. 2006;17:1301-1305.

[8] Hunold A, Weddeling N, Paulussen M, et al. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatric Blood Cancer 2006;47:795-800.

[9] Wendelin G, Lackner H, Schwinger W, et al. Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. Pediatric Hematology Oncology 2005;27:449-451.

[10] 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. Journal of Clinical Oncology 2006;24:152-159.

[11] Daw NC, Furman WL, Stewart CF, et al. Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Childrens Oncology Group Study. Journal of Clinical Oncology 2005;23:6172-6180.

[12] McAllister WR and Lessnick SL. The potential for molecular therapeutic targets in Ewing’s sarcoma. Current Treatment Options in Oncology 2005;6:461-471.

[1] Aksnes LH, Hall KS, Folleraas G et al. Management of high-grade bone sarcomas over two decades: The Norwegian Radium Hospital Experience. Acta Oncol 2006;45:38-46.

[2] Wafa H, Grimer RJ. Surgical options and outcomes in bone sarcoma. Expert Rev Anticancer Ther. 2006;6:239-248.

[1] Donaldson SS. Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 2004;42:471-476.

[2] Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al. Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatric Blood Cancer. 2004;43:229-236.

[3] Krasin MJ, Rodriguez-Galindo C, Billups CA, et al. Definitive irradiation in mulitidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. International Journal of Oncology Biology Physics 2004;60:830-838.

[4] Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. International Journal of Oncology, Biology, Physics. 2004;60:265-274.

[5] Bacci G, Longhi A, Barbieri E, et al. Second malignancy in 597 patients with Ewing’s sarcoma of bone treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Journal of Pediatric Hematology and Oncology 2005;27:517-520.

[6] Sakayama K, Kidani T, Fujibuchi T, et al. Definitive intraoperative radiotherapy for musculoskeletal sarcomas and malignant lymphoma in combination with surgical excision. Int J Clin Oncol. 2003;8:174-179.

[7] DeLaney TF, Trofimov AV, Engelsman M, et al. Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control. 2005;12:27-35.

[8] Marec-Berard P, Philip T. Ewing sarcoma: the pediatrician’s point of view. Pediatr Blood Cancer. 2004;477-480.

[9] Ozaki T, Hillman A, Rube C, et al. The impact of introperative brachytherapy on surgery of Ewing’s sarcoma. J Cancer Res Clin Oncol. 1997;123:53-56.

[10] Merchant TE, Parsh N, del Valle PL, et al. Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2000;46:427-432.

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