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.
The following is a general overview of treatment for metastatic 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. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
The multi-modality approach to treatment for metastatic 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.
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
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of metastatic Ewing’s sarcoma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Two sources of information about ongoing clinical trials are ecancertrials.com and cancer.gov.
Areas of active exploration to improve the treatment of metastatic 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 patients with metastatic Ewing’s sarcoma be treated in a specialized center on a protocol designed to improve outcomes of treatment.
Increased Dose Intensity of Chemotherapy: Researchers from Italy have reported that a regimen of Ifex, Paraplatin® (carboplatin) and Vepesid (ICE) combined with Cytoxan, Adriamycin and Oncovin (CAV) may improve survival of poor-risk patients with Ewing’s sarcoma.3 They reported a three-year survival of 67 percent for 18 poor risk patients treated with this ICE plus CAV regimen, which was a significant improvement over less intensive regimens.
Researchers from St Jude Children’s research center have reported that an intensified Oncovin, Adrimycin, Cytoxan, Ifex and Vepesid neoadjuvant regimen was associated with a high response rate in patients with high-risk sarcomas including Ewing’s.4 The goal of this study was to produce a maximum response prior to performing an autologous stem cell transplant.
Supportive Care: Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) have been used to shorten the duration of severe neutopenia and to decrease the incidence of febrile neutropenia in patients with Ewing’s sarcoma receiving chemotherapy.5,6
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
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. Cancer 2005;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 ClinicalOncology 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.