The evidence supporting this protocol is provided by a phase III multicentre North American randomised trial (AEWS1031) done by the Children’s Oncology Group. The purpose of this trial was to test whether the addition of vincristine, topotecan and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated non-metastatic Ewing sarcoma (EWS).r
629 eligible patients with extracranial non-metastatic EWS or primitive neuroectodermal tumour of bone or soft tissue were enrolled. 309 patients were randomly assigned to regimen A (control), which was standard 5 drug interval compressed chemotherapy. The regimen consisted of 5 cycles of vincristine, doxorubicin and cyclophosphamide (VDC); 4 cycles of vincristine and cyclophosphamide (VC) and 8 cycles of ifosfamide and etoposide (IE). The other 320 patients were randomly assigned to regimen B (experimental), which was 5 cycles of VTC; 5 cycles of VDC and 7 cycles of IE. All patients received 6 cycles of induction (12 weeks) and 11 cycles of consolidation (22 weeks). A total of 17 cycles (9 x VDC [5 with doxorubicin and 4 without] with 8 x IE) were used. Each cycle involving VDC or VC had vincristine administered on days 1 and 8.r
Randomisation was stratified according to age at enrolment (<18 years vs ≥ 18 years) and tumour site (pelvic bone, non-pelvic bone, or extraosseous). Event-free survival (EFS) and overall survival (OS) served as co-primary endpoints.r
Efficacyr
| |
5-year EFS rate (%) |
RHR for an EFS event |
5-year OS rate (%) |
RHR for death |
| Entire cohort |
78 |
- |
87 |
- |
Regimen A*
(standard arm) |
78 |
0.86 (95% CI, 0.62 to 1.2);
P=0.192
|
86 |
0.81 (95% CI, 0.54 to 1.2);
P=0.159
|
Regimen B*
(experimental arm) |
79 |
88 |
| Age at enrolment^ |
| Patients < 18 years |
79 |
1.25 (95% CI, 0.82 to 1.9);
P=0.294
|
89 |
1.84 (95% CI, 1.15 to 2.96);
P=0.00993
|
| Patients ≥ 18 years |
75 |
78 |
| Site of tumour^ |
| Pelvic bone primary tumours |
75 |
- |
87 |
- |
| Non-pelvic bone primary tumours |
78 |
Relative to pelvic bone primary tumours
0.84 (95% CI, 0.56-1.26) |
85 |
Relative to pelvic bone primary tumours
1.03 (95% CI, 0.61-1.73) |
| Extraosseous tumours |
85 |
Relative to pelvic bone primary tumours
0.58 (95% CI, 0.33-1.03) |
92 |
Relative to pelvic bone primary tumours
0.61 (95% CI, 0.29-1.29) |
RHR = relative hazard rate
* Regimen A = VDC plus IE, Regimen B = VTC plus VDC plus IE
^ Both treatment arms together
Kaplan Meier curve of EFS and OSr
© J Clin Oncol 2021
While the addition of VTC to interval compressed chemotherapy did not improve survival, the outcomes seen in this trial are the best survival estimates to date for patients with previously untreated non-metastatic Ewing sarcoma.r
Based on the above data, patients with extraosseous primary tumours had the highest 5-year EFS/OS rates with 17 cycles of interval compressed VDC/IE. This could be considered as a treatment option in patients who are young with good ECOG performance status and experiencing minimal toxicity from their treatment.
Toxicityr
There were no differences in toxicities observed between treatment regimens. Patients seemed to tolerate the regimen with usual adverse effects seen (data not shown as not published in journal).
Four patients experienced death as a first event (two each on regimens A and B).
Second malignant neoplasms occurred in 14 patients on regimen A and 13 on regimen B.
Table of second malignant neoplasms in entire cohortr
© J Clin Oncol 2021