Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Standard Treatment Options

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.[1-8] Current regimens for the treatment of localized Ewing tumor of bone (ETB) achieve event-free survival (EFS) and overall survival (OS) of approximately 70% at 5 years after diagnosis.[9]

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide, also known as VAdriaC, alternating with ifosfamide and etoposide.[9] 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.[2,9,10] 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.[11] The use of high-dose VAdriaC has shown promising results in small numbers of patients.[11] Forty-four patients treated with high-dose VAdriaC and ifosfamide/etoposide had an 82% 4-year EFS.[12] However, in a trial of the former Children's Cancer Group (CCG), 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.[13]

Local control can be achieved by surgery and/or radiation. Surgery is generally the preferred approach if the lesion is resectable.[14,15] 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.[16] 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.[8] 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.[5] 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 the 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.[16] 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.[17] Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[18]

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.[1,2,19] 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.[3] Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.[1]

Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length.[18] When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure.[20] 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 higher 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.[21]

For patients with residual disease following attempt at surgical resection, the Intergroup Ewing Sarcoma Study 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 second malignancy.[22]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• A closed Children’s Oncology Group (COG) study randomly assigned patients with nonmetastatic disease to receive dose-intensive chemotherapy (i.e., alternating VAdriaC with ifosfamide and etoposide) with filgrastim (G-CSF) on a 21-day or 14-day schedule to determine whether increasing the dose intensity of all drugs simultaneously through a reduction of the interval between chemotherapy cycles, known as interval compression, improves survival. The experimental interval compression arm is based on a nonrandomized pilot study that used hematopoietic growth factors to promote interval-dose compression to shorten courses of chemotherapy from 21 days to 14 days.[23]



• COG-AEWS07P1 is a pilot clinical trial that is investigating the addition of vincristine, topotecan, and cyclophosphamide (VTC) to a treatment regimen that uses interval compression of VAdriaC with ifosfamide and etoposide for patients with localized Ewing family of tumors (EFT). All chemotherapy cycles are 14 days duration. If feasible, this new regimen will become the experimental arm in a planned group-wide phase III clinical trial for patients with EFT.

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.

References

1. 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.  [PUBMED Abstract]
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Granowetter L, Womer R, Devidas M, et al.: Comparison of dose intensified and standard dose chemotherapy for the treatment of non-metastatic Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone and soft tissue: a Pediatric Oncology Group-Children's Cancer Group phase III trial. [Abstract] Med Pediatr Oncol 37: A-038, 172, 2001. 
    
    
14. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
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23. Womer RB, Daller RT, Fenton JG, et al.: Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing's sarcomas and soft tissue sarcomas in children. Eur J Cancer 36 (1): 87-94, 2000.  [PUBMED Abstract]
    
    

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