Chemotherapy for Ewing Sarcoma

An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[28][Level of evidence A1] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histological response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive maintenance therapy with either seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.

An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[28][Level of evidence A1] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histological response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive maintenance therapy with either seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.

There was no significant difference in EFS or overall survival (OS) between patients who received VAC and patients who received VAI.

An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[28][Level of evidence A1] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histological response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive maintenance therapy with either seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.

The 3-year EFS rate for this low-risk population was 77%.

An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[28][Level of evidence A1] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histological response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive maintenance therapy with either seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.

It is difficult to compare this outcome with that of other large series because the study population excluded patients with poor response to initial therapy or patients with tumors more than 200 mL in volume who received local-control therapy with radiation alone. All other published series report results for all patients who present without clinically detectable metastasis; thus, these other series included patients with poor response and patients with larger primary tumors treated with radiation alone, all of whom were excluded from the EURO-EWING-INTERGROUP-EE99 study.

In a Children's Oncology Group (COG) study (COG-AEWS0031 [NCT00006734]), patients presenting without metastases were randomly assigned to receive cycles of VDC alternating with cycles of IE at either 2-week or 3-week intervals.[24]

In a Children's Oncology Group (COG) study (COG-AEWS0031 [NCT00006734]), patients presenting without metastases were randomly assigned to receive cycles of VDC alternating with cycles of IE at either 2-week or 3-week intervals.[24]

The administration of cycles of VDC/IE at 2-week intervals achieved superior EFS (5-year EFS rate, 73%) than did alternating cycles at 3-week intervals (5-year EFS rate, 65%). With longer follow-up, the advantage of interval-compressed chemotherapy was confirmed.[25]

In a Children's Oncology Group (COG) study (COG-AEWS0031 [NCT00006734]), patients presenting without metastases were randomly assigned to receive cycles of VDC alternating with cycles of IE at either 2-week or 3-week intervals.[24]

The 10-year EFS rate was 70% using interval-compressed chemotherapy, compared with 61% using standard-timing chemotherapy (P = .03). The 10-year OS rate was 76% using interval-compressed chemotherapy, compared with 69% using standard-timing chemotherapy (P = .04).

The EE2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE induction regimen and the North American standard VDC/IE induction regimen. Patients with both localized and metastatic Ewing sarcoma were eligible for the study.[27][Level of evidence B1]

The EE2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE induction regimen and the North American standard VDC/IE induction regimen. Patients with both localized and metastatic Ewing sarcoma were eligible for the study.[27][Level of evidence B1]

The hazard ratios (HRs) for EFS (0.71) and OS (0.62) favored VDC/IE over VIDE. The posterior probabilities were 99% for both EFS and OS, which showed that VDC/IE was superior.

The EE2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE induction regimen and the North American standard VDC/IE induction regimen. Patients with both localized and metastatic Ewing sarcoma were eligible for the study.[27][Level of evidence B1]

Rates of febrile neutropenia were higher with the VIDE regimen. There were no other major differences in acute toxicities between the two regimens.

The EE2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE induction regimen and the North American standard VDC/IE induction regimen. Patients with both localized and metastatic Ewing sarcoma were eligible for the study.[27][Level of evidence B1]

The benefit of VDC/IE over VIDE was seen across subgroups defined by patient age, sex, stage, tumor volume, or country of residence.

The Brazilian Cooperative Study Group performed a multi-institutional trial that incorporated carboplatin into a risk-adapted intensive regimen in 175 children with localized or metastatic Ewing sarcoma.[29][Level of evidence B4]

The Brazilian Cooperative Study Group performed a multi-institutional trial that incorporated carboplatin into a risk-adapted intensive regimen in 175 children with localized or metastatic Ewing sarcoma.[29][Level of evidence B4]

The investigators found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.

The COG performed a prospective randomized trial in patients with localized Ewing sarcoma. All patients received cycles of VDC and cycles of IE. Patients were then randomly assigned to receive or not receive additional experimental cycles of vincristine, cyclophosphamide, and topotecan.[26]

The COG performed a prospective randomized trial in patients with localized Ewing sarcoma. All patients received cycles of VDC and cycles of IE. Patients were then randomly assigned to receive or not receive additional experimental cycles of vincristine, cyclophosphamide, and topotecan.[26]

The 5-year EFS rate was 78% (95% confidence interval [CI], 72%–82%) for those treated with experimental therapy and 79% (95% CI, 74%–83%) for patients treated with standard therapy.

The COG performed a prospective randomized trial in patients with localized Ewing sarcoma. All patients received cycles of VDC and cycles of IE. Patients were then randomly assigned to receive or not receive additional experimental cycles of vincristine, cyclophosphamide, and topotecan.[26]

The experimental therapy did not significantly reduce the risk of events (EFS HR for experimental arm vs. standard arm, 0.86; 1-sided P = .19).