GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

Abstract

Background: First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients.

Methods: This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734).

Results: Forty-three patients were enroled, median age 17 years (range, 3-40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41-74%) with an EFS of 50.0% (95% CI, 36-68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57-100%) and 71.0% (CI, 54-94%); for HR 36.0% (CI, 20-65%) and 29.0% (CI, 15-56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56-97%) and 31.0% for >18 years (95% CI, 15-66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively).

Conclusions: Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.

Figure 1

Treatment details and road map. The mP6 regimen consisted of cycles 1, 2 and 4 with cyclophosphamide 4.2 g m⁻², doxorubicin 75 mg m⁻² and vincristine 2 mg m⁻² (CDV); and cycles 3 and 5 with ifosfamide 9 g m⁻² and etoposide 500 mg m⁻² (IE). Doxorubicin was administered in 1 h infusion after administration of dexrazoxane (CardioxaneR) at 10 : 1 dose of doxorubicin. In April of 2012 an amendment to the protocol was approved after the EMA recommendation to contraindicate dexrazoxane in patients less than 18 years. Thereafter, patients less than 18 years received Doxorubicin in 4 h infusion with no prior Dexrazoxane. After each cycle of chemotherapy, granulocyte colony-stimulating factor was used to shorten the duration of neutropaenia. Whenever possible, surgical resection was performed after cycle 3 of chemotherapy. RT was given after mP6 chemotherapy. HR patients received gemcitabine 1000 mg m⁻² iv over 90 min on day 1 and day 8, and docetaxel 100 mg m⁻² over 2–4 h on day 8 of a 21-day cycle, 2 cycles (G+D regimen). The duration of docetaxel infusion was initially over 2 h and subsequently determined based upon the myelosuppression effect. If the patient recovered rapidly before the 21-day cycle, the infusion was prolonged up to 4 h. Prophylactic medications were provided on days 1 and 8 with IV ondansetron and on day 8 IV ranitidine, diphenhydramine and dexamethasone. All patients received filgrastim 5 μg kg⁻¹ subcutaneously once a day from day 9 until haematological recovery.

Figure 2

Kaplan–Meier plots of EFS and OS. (A) All patients, (B) stratified by standard and high risk and (C) stratified by age <18 and ⩾18.

Figure 3

Multivariate survival analyses. (A) Kaplan–Meier plot of OS stratified according to the combination of age and risk groups, (B) Cox model for OS: hazard ratios, 95% confidence intervals and statistical significance.