Recurrent Ewing's Sarcoma

Overview

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 following is a general overview of treatment for recurrent Ewing’s sarcoma. Treatment may consist of surgery, chemotherapy, or a combination of the two. Multi-modality treatment, which is treatment using two or more techniques, 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 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.

Treatment of Recurrent Ewing’s Sarcoma

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.

High-Dose Chemotherapy with Autologous Stem Cell Transplantation: High-dose chemotherapy with autologous stem cell support (autologous stem cell transplantation) is increasingly being evaluated for the treatment of recurrent Ewing’s sarcoma and can now be considered a “standard” approach.

Researchers from the University of Washington have reported that high-dose chemotherapy and autologous stem cell transplantation may improve survival in patients with a chemotherapy-responsive relapse of Ewing’s sarcoma. [5] The study involved 55 patients who were treated for a relapse of Ewing’s sarcoma between 1985 and 2002. Among the patients who were responsive to chemotherapy, 13 had an autologous stem cell transplant; nine of these 13 patients received two transplants in a procedure known as a “tandem transplant.” Five-year survival was 46 percent among patients who responded to chemotherapy and 0% among patients who did not respond to chemotherapy.   The overall survival of patients who responded to chemotherapy was 75 percent for those who received a stem cell transplant and 20 percent for those who did not receive a stem cell transplant.  Patients who had a relapse-free interval greater than two years also had an improved survival.

A French study reviewed the outcomes of 46 adult patients treated with high-dose chemotherapy and autologous stem cell transplantation between 1987 and 2000.[6] Five-year overall survival was 63 percent and survival without cancer progression was 47 percent. Six of the nine patients receiving tandem transplants and two of four receiving a single transplant are alive.

Researchers from the United Kingdom have reported that high-dose chemotherapy with autologous peripheral blood stem cell support results in a five-year event-free survival (survival without cancer progression or recurrence) of 38 percent in patients with relapsed or refractory Ewing’s sarcoma.[7]

These data confirm that long-term event-free survival can be attained in patients with recurrent or refractory Ewing’s sarcoma treated with high-dose chemotherapy. However, the most effective regimen or regimens have yet to be determined. Of major interest is the apparent improved effectiveness of tandem transplants.

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 recurrent 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. 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]

Increased Dose Intensity of Chemotherapy: Ewing’s sarcoma is generally responsive to chemotherapy and may be responsive to increasing doses of chemotherapy drugs.

Supportive Care: Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) have been used to shorten the duration of severe neutropenia and to decrease the incidence of febrile neutropenia in patients with Ewing’s sarcoma receiving intensive chemotherapy.[9][10]

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 pathway 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 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.[11] Researchers are looking at a number of molecular targets for the development of other targeted therapies.[12]

References


[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.