Clinical trialPhase 3Sarcoma (soft tissue and bone cancer)

Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group

J Clin Oncol · 2012568 eligible patients (284 per group) out of 587 enrolled

Womer RB, West DC, Krailo MD, et al. J Clin Oncol. 2012. 30:4148-54

Study type: Clinical trial
Study name: AEWS0031
Phase: Phase 3
Design: Prospective, open-label randomised controlled trial of the Children's Oncology Group (COG) at 152 institutions; randomisation in blocks of four, stratified by age (17 or younger vs 18 or older) and tumour site (non-pelvic vs pelvic)
Sample size: 568 eligible patients (284 per group) out of 587 enrolled
Source: J Clin Oncol · 2012
Trial registration: NCT00006734

In plain words

Children, teenagers and young adults with Ewing sarcoma that had not spread received the same chemotherapy drugs either every 3 weeks or every 2 weeks; to shorten the gap, a drug that boosts white blood cells was given between cycles. The 2-week schedule reduced recurrence without more side effects, and at 10 years of follow-up it also helped people live longer.

Key results

73% vs 65%

5-year event-free survival (compressed vs standard)

p=0.048; HR 0.74 (95% CI 0.54–0.99)

83% vs 77%

5-year overall survival

p=0.056; HR 0.69 (0.47–1.0)

17.29 vs 22.45 days

Mean cycle duration

p<0.001; median 15 vs 21 days

7.2% vs 8.0%

5-year cumulative incidence of local relapse

p=0.74

16% vs 23%

5-year cumulative incidence of distant or combined local and distant relapse

p=0.058

72% under 18 vs 47% at 18 or older

5-year event-free survival by age (both groups combined)

p<0.001

Event-free survival 70% vs 61%; overall survival 76% vs 69%

10-year follow-up (2023 report)

p=0.03 and p=0.04; no increase in second malignancies

Drugs in this study:Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)Etoposide Filgrastim (Neupogen)

Dose and schedule cards

Interval-compressed VDC/IE every 2 weeks (Ewing sarcoma)

Localised Ewing sarcoma (in AEWS0031: under 50 years); ESMO: preferred first-line regimen [I, B]; in EURO EWING 2012 all stages, aged 2–49On the page “Sarcoma (soft tissue and bone cancer)” · Ewing sarcoma: interval-compressed VDC/IE

Localised Ewing sarcoma (in AEWS0031: under 50 years); ESMO: preferred first-line regimen [I, B]; in EURO EWING 2012 all stages, aged 2–49

Drug	Dose	Route	Schedule
VDC cycles (alternating with IE)
Vincristine	1.5 to 2 mg/m², maximum 2 mg (see notes)	IV	Day 1
Doxorubicin	37.5 mg/m² per day	IV	Days 1 and 2
Cyclophosphamide	1,200 mg/m²	IV, with mesna	Day 1
IE cycles
Ifosfamide	1,800 mg/m² per day	IV, with mesna	Days 1 to 5
Etoposide	100 mg/m² per day	IV	Days 1 to 5
Between cycles
Filgrastim	5 micrograms/kg per day	Subcutaneous or IV (per the label)	From at least 24 hours after chemotherapy until count recovery

Cycle length: Every 14 days, or as soon as ANC is above 750 and platelets above 75,000 per microlitre; VDC and IE alternate
Duration: 14 cycles; local treatment (surgery and/or radiotherapy) from week 13, after 6 cycles; cumulative doxorubicin 375 mg/m²

Doses per AEWS0031 (Figure 1 and the appendix table of the article). The vincristine dose is given as 1.5 mg/m² in Figure 1 of the article and as 2 mg/m² in the abstract and appendix table; both cap it at 2 mg. Filgrastim dose per the FDA label for myelosuppressive chemotherapy (5 micrograms/kg per day, at least 24 hours after chemotherapy and not within the 24 hours before it). Radiotherapy in AEWS0031: 45 Gy to the initial volume and 55.8 Gy to the final volume of unresected tumours, in 1.8 Gy fractions. EURO EWING 2012; place in therapy per ESMO.

On the page “Sarcoma (soft tissue and bone cancer)” · Ewing sarcoma: interval-compressed VDC/IE

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Regimen A: standard intervals every 21 days (284 patients)

14 alternating cycles of VDC and IE. VDC: vincristine on day 1, maximum 2 mg (1.5 mg/m² in Figure 1 of the article; 2 mg/m² in the abstract and appendix table), doxorubicin 37.5 mg/m² on days 1 and 2 (cumulative dose 375 mg/m² for all patients) and cyclophosphamide 1,200 mg/m² on day 1, with mesna; VC cycles (vincristine and cyclophosphamide) also appear in the appendix table. IE: ifosfamide 1,800 mg/m² per day with mesna and etoposide 100 mg/m² per day, days 1 to 5. Filgrastim between cycles until ANC of at least 750 and platelets of at least 75,000 per microlitre. Cycles started every 21 days. Local treatment from week 13 (after 4 cycles).

2Regimen B: compressed intervals every 14 days (284 patients)

The same drugs with the same per-cycle and total doses; cycles started every 14 days or as soon as counts recovered (ANC above 750 and platelets above 75,000 per microlitre) and 24 hours after the last filgrastim dose. Local treatment from week 13 (after 6 cycles). In both regimens, local treatment was complete surgery with clear margins, surgery plus radiotherapy for close or positive margins, or radiotherapy alone: 45 Gy to the initial volume and 55.8 Gy to the final volume of unresected tumours, 50.4 Gy to extraosseous tumours with a complete response, in 1.8 Gy fractions.

Source of the regimen details: Full text of the article in PMC (Figure 1 and appendix table A1) and ClinicalTrials.gov NCT00006734; the filgrastim dose is printed as mg/kg in the PubMed record, which corresponds to the standard dose of 5 micrograms/kg (FDA label)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients under 50 with newly diagnosed localised Ewing sarcoma, peripheral primitive neuroectodermal tumour (PNET) or Askin tumour of bone or soft tissue (excluding intradural soft tissue); no metastases on bone scan, chest CT and bilateral bone marrow aspirates and biopsies (one pulmonary or pleural nodule over 1 cm or more than one nodule over 0.5 cm counted as metastasis); regional lymph node involvement and chest wall tumours with an ipsilateral pleural effusion were allowed. Chemotherapy had to start within 30 days of biopsy; adequate cardiac function (shortening fraction of at least 28% or ejection fraction of at least 55%), renal and liver function.

Endpoints

Primary endpoint: event-free survival (disease progression, second malignancy or death). Overall survival, type of relapse (local, systemic or both), dose intensity and toxicity were also assessed.

Safety and side effects

Toxicity was similar with the two regimens; mean hospital days per cycle were 5.0 vs 5.1 (p=0.43). One toxic death (colitis and sepsis during neutropenia, regimen B). 16 second malignancies (9 with regimen A and 7 with regimen B; p=0.62): 11 acute myeloid leukaemias, 3 osteosarcomas in radiation fields and 2 lymphomas.

Clinical significance and place in guidelines

AEWS0031 made interval-compressed VDC/IE every 2 weeks the standard treatment for localised Ewing sarcoma in North America. In EURO EWING 2012 this regimen was also better than the European VIDE regimen, and the ESMO–EURACAN–GENTURIS–ERN PaedCan 2021 guideline considers it the preferred first-line regimen in Ewing sarcoma [I, B]. The 10-year report (2023) confirmed the event-free and overall survival advantage without an increase in second cancers.

Limitations

Only localised disease and patients under 50 were included, and patients aged 18 or older made up only 12%. Local treatment differed slightly between the groups (radiotherapy alone more often with the compressed regimen; p=0.101). The overall survival difference did not reach significance in the first report. The vincristine dose is reported in two ways in different parts of the article, and the filgrastim dose unit is printed as mg in the PubMed record.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.