Chemotherapy is the backbone of treatment for Ewing sarcoma (ES):
- Multi-agent chemotherapy is essential for long-term survival in patients with local and metastatic disease. Prior to routine use of systemic chemotherapy in addition to local control, less than 10% of patients with ES survived.
- Following staging investigations, induction chemotherapy is initiated prior to local control. Standard induction chemotherapy consists of six cycles over 12 weeks and is followed by local control at week 13. This helps to achieve a reduction in the soft tissue component of the tumor and initiate bone healing.
- Chemotherapy is resumed as soon as possible after surgery, or is continued during radiation if this is the method of local control.
- Current standard practice includes 14 cycles in total, each two weeks apart as per the completed Children’s Oncology Group study protocol AEWS0031 regimen B.
Effective chemotherapy agents include:
- Alkylating agents such as ifosfamide (I) cyclophosphamide (C)
- Plant alkaloids vincristine (V), etoposide (E),
- Cytotoxic antibiotics doxorubicin (adriamycin) (D) and dactinomycin (A)
A European Intergroup Cooperative Ewing Sarcoma (EICES) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide, and identified a trend toward better EFS for patients with localized Ewing sarcoma when treatment included etoposide (GER-GPOH-EICESS-92).
Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide.
European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.
Duration of primary chemotherapy ranges from 6 months to approximately 1 year
The Euro-Ewing study: (EURO-EWING-INTERGROUP-EE99) the primary objective is to compare the event-free and overall survival of ES patients treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without RT and/or surgery. Patients who receive RT alone for local control are stratified by pretreatment tumor volume for post-radiation therapy.
Also see: ClinicalTrials.gov
NB :- Doxorubicin and dactinomycin can potentially interact with radiation and produce increased cardiac toxicity. The problem can be prevented by avoiding concurrent administration of these therapies.
- Alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide has been shown to be superior to vincristine-doxorubicin-cyclophosphamide alone.
- The Children’s Oncology Group study (AEWS0031) showed that compression of chemotherapy cycles into 2 weeks instead of 3 weeks improved survival. Overall, there was a 76% vs 65% event free survival and 91% VS 85% overall survival at 4y for the compressed cycle regimen (B). This forms the basis for current standard of care in the treatment of Ewing sarcoma.
- Treatment related toxicity is a significant concern for these patients with prolonged periods of pancytopenia resulting in increased infection risk and prolongation of treatment. Anthracycline toxicity resulting in cardiomyopathy is also a major clinical concern. AEWS0031 found no significant increase in toxicity with the compressed regimen of chemotherapy cycles when patients are supported with G-CSF.
Important historical studies showing improved survival or prognostic indicators in Localized ES Family of tumors:
Study |
Therapy /Variable |
5-year event free survival |
IESS- 1 |
VAC |
24% |
POG-CCG |
VACD |
54% |
St Judes (ES-79) |
Tumor Size (using VACD) |
82% (3yr EFS) |
UKCCSG |
Tumor site (using VACD) |
52% |
CESS-81 |
Tumor viability (using VACD) Tumor Volume |
79% (3yr EFS)
80% |
Metastatic disease at diagnosis, certain cytogenetic abnormalities (including gain of 1q and loss of 16q), and age >14y confer a worse prognosis.
Ongoing clinical trials continue to investigate additional approaches which include:
- Topotecan, vinblastine and celecoxib
- High dose myeloablative chemotherapy followed by autologous stem cell rescue is being studied, especially in recurrent or metastatic disease.
- International collaboration continues with trials such as the EURO-E.W.I.N.G 99, a trial with patients entered from both European centers and centers across North America.
Prognosis:
- Metastatic disease has a poor prognosis with only approximately 30% surviving long term.
- Localized disease fares much better with current 5 yr EFS of 65-75% depending upon patient age, tumor location and response to chemotherapy.
Future Directions:
Molecular targeted therapies are being developed. As many as 85% of Ewing’s tumors are EWS-FLI1 positive and may serve as a tumor specific molecular target. One approach is based on the fact that the EWS-FLI1 oncogene product may function as a promoter for the vascular endothelial growth factor (VEGF). This is the basis for both the current anti-angiogenesis therapy with vinblastine/celecoxib, and is also likely to be addressed in a future trial with the use of an anti-VEGF antibody currently being explored in recurrent Ewing’s. Use of siRNA nanocapsules also shows considerable promise and is again being investigated in recurrent EWS-FLI1 positive tumors.
