Chemotherapy

IE has shown activity in Ewing sarcoma. A large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE was alternated with VDC.[9,12]

The use of high-dose VDC has shown promising results in small numbers of patients. A single-institution study of 44 patients treated with high-dose VDC and IE showed a 4-year EFS rate of 82%.[13]

However, in an intergroup trial of the Pediatric Oncology Group and the Children's Cancer Group, which compared an alkylator dose-intensified VDC/IE regimen with standard alkylator doses of the same VDC/IE regimen, no differences in outcome were observed.[14] Unlike the single-institution trial, this trial did not maintain the dose intensity of cyclophosphamide for the duration of treatment.[13]

In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).[10]

In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).[10]

Patients randomly assigned to the every-2-week interval of treatment had an improved 5-year EFS rate (73% vs. 65%, P = .048).

In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).[10]

There was no increase in toxicity observed with the every-2-week schedule.

In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).[10]

With longer follow-up of 10 years, interval-compressed VDC/IE continued to demonstrate superior EFS. OS was also significantly higher with this regimen than with VDC/IE given every 3 weeks.[15]

The European Ewing 2008R1 trial evaluated 284 patients with standard-risk Ewing sarcoma, defined as localized disease with favorable histological response to initial chemotherapy and/or an initial tumor volume of less than 200 mL. All patients received VIDE chemotherapy followed by vincristine, dactinomycin, and ifosfamide (VAI) (male) or vincristine, dactinomycin, and cyclophosphamide (VAC) (female) consolidation therapy. During the sixth cycle of consolidation, patients were randomly assigned to therapy with either the addition of zoledronic acid for nine 28-day cycles or no maintenance therapy.[16]

The European Ewing 2008R1 trial evaluated 284 patients with standard-risk Ewing sarcoma, defined as localized disease with favorable histological response to initial chemotherapy and/or an initial tumor volume of less than 200 mL. All patients received VIDE chemotherapy followed by vincristine, dactinomycin, and ifosfamide (VAI) (male) or vincristine, dactinomycin, and cyclophosphamide (VAC) (female) consolidation therapy. During the sixth cycle of consolidation, patients were randomly assigned to therapy with either the addition of zoledronic acid for nine 28-day cycles or no maintenance therapy.[16]

Outcomes were similar between patients who received zoledronic acid and patients who did not receive maintenance therapy (3-year EFS rates, 84.0% vs. 81.7%).

The European Ewing 2008R1 trial evaluated 284 patients with standard-risk Ewing sarcoma, defined as localized disease with favorable histological response to initial chemotherapy and/or an initial tumor volume of less than 200 mL. All patients received VIDE chemotherapy followed by vincristine, dactinomycin, and ifosfamide (VAI) (male) or vincristine, dactinomycin, and cyclophosphamide (VAC) (female) consolidation therapy. During the sixth cycle of consolidation, patients were randomly assigned to therapy with either the addition of zoledronic acid for nine 28-day cycles or no maintenance therapy.[16]

Patients who received zoledronic acid experienced higher rates of renal, neurological, and gastrointestinal toxicities.

EE2012 was a European investigator–initiated, open-label, randomized, controlled, phase III trial that took place in ten countries. Between 2014 and 2019, 640 patients were enrolled and were randomly allocated (1:1) to either the European or COG treatment regimens (320 patients in each treatment group). The European treatment regimen for induction included VIDE, and the consolidation regimen included vincristine, dactinomycin, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1). The COG treatment regimen for induction included interval-compressed VDC/IE, and the consolidation regimen included vincristine and cyclophosphamide, with ifosfamide and etoposide or busulfan and melphalan (group 2).[11][Level of evidence B1]

EE2012 was a European investigator–initiated, open-label, randomized, controlled, phase III trial that took place in ten countries. Between 2014 and 2019, 640 patients were enrolled and were randomly allocated (1:1) to either the European or COG treatment regimens (320 patients in each treatment group). The European treatment regimen for induction included VIDE, and the consolidation regimen included vincristine, dactinomycin, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1). The COG treatment regimen for induction included interval-compressed VDC/IE, and the consolidation regimen included vincristine and cyclophosphamide, with ifosfamide and etoposide or busulfan and melphalan (group 2).[11][Level of evidence B1]

The 3-year EFS rate was 61% for patients in group 1 and 67% for patients in group 2 (adjusted hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.55–0.92 in favor of group 2).

EE2012 was a European investigator–initiated, open-label, randomized, controlled, phase III trial that took place in ten countries. Between 2014 and 2019, 640 patients were enrolled and were randomly allocated (1:1) to either the European or COG treatment regimens (320 patients in each treatment group). The European treatment regimen for induction included VIDE, and the consolidation regimen included vincristine, dactinomycin, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1). The COG treatment regimen for induction included interval-compressed VDC/IE, and the consolidation regimen included vincristine and cyclophosphamide, with ifosfamide and etoposide or busulfan and melphalan (group 2).[11][Level of evidence B1]

The probability that the true HR for group 2 with interval-compressed VDC/IE was less than 1 was greater than 0.99.

EE2012 was a European investigator–initiated, open-label, randomized, controlled, phase III trial that took place in ten countries. Between 2014 and 2019, 640 patients were enrolled and were randomly allocated (1:1) to either the European or COG treatment regimens (320 patients in each treatment group). The European treatment regimen for induction included VIDE, and the consolidation regimen included vincristine, dactinomycin, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1). The COG treatment regimen for induction included interval-compressed VDC/IE, and the consolidation regimen included vincristine and cyclophosphamide, with ifosfamide and etoposide or busulfan and melphalan (group 2).[11][Level of evidence B1]

The investigators concluded that dose-intensive induction chemotherapy with the VDC/IE regimen was more effective, less toxic, and shorter in duration for patients with all stages of newly diagnosed Ewing sarcoma than the VIDE regimen.