Clinical trialPhase 3Sarcoma (soft tissue and bone cancer)
Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
Lancet Oncol · 2014455 patients (228 doxorubicin alone and 227 doxorubicin plus ifosfamide)
Judson I, Verweij J, Gelderblom H, et al. Lancet Oncol. 2014. 15:415-23
Study type
Clinical trial
Study name
EORTC 62012
Phase
Phase 3
Design
Open-label randomised controlled phase 3 trial of the EORTC Soft Tissue and Bone Sarcoma Group in 38 hospitals in 10 countries; 1:1 randomisation by minimisation, stratified by centre, performance status, age, liver metastases and histological grade
Sample size
455 patients (228 doxorubicin alone and 227 doxorubicin plus ifosfamide)
Patients with soft tissue sarcoma that had spread or could not be removed by surgery received either doxorubicin alone or doxorubicin together with a second drug, ifosfamide. The combination shrank tumours more often and held the disease back for longer, but it did not clearly help people live longer and it caused more side effects, especially fever with low white blood cells. The combination is therefore mainly chosen when shrinking the tumour is an important goal.
Key results
14.3 vs 12.8 months
Overall survival, median (combination vs doxorubicin alone)
HR 0.83 (95.5% CI 0.67–1.03); p=0.076; not significant
7.4 vs 4.6 months
Progression-free survival, median
HR 0.74 (95% CI 0.60–0.90); p=0.003
26% (60 of 227) vs 14% (31 of 228)
Overall response
p<0.0006
46% vs 13%
Grade 3 and 4 febrile neutropenia
103 of 224 vs 30 of 223
59 months (combination) and 56 months (doxorubicin alone)
Advanced or metastatic unresectable soft tissue sarcoma, first line (ESMO standard [I, A])Cycle length: Every 21 daysOn the page “Sarcoma (soft tissue and bone cancer)” · Advanced soft tissue sarcoma: first line
Advanced or metastatic unresectable soft tissue sarcoma, first line (ESMO standard [I, A])
Up to 6 cycles (or until progression or unacceptable toxicity)
Dose and schedule as in the doxorubicin arm of EORTC 62012 and GeDDiS (6 cycles); FDA label: single agent 60 to 75 mg/m² every 21 days. Baseline and periodic LVEF; dose reduction in hepatic impairment per the label. Place in therapy per ESMO.
Advanced soft tissue sarcoma, first line in patients with good performance status when tumour response is the goal or the histotype is ifosfamide-sensitive (ESMO [I, B]); in EORTC 62012: aged 18–60, performance status 0 or 1Cycle length: Every 21 daysOn the page “Sarcoma (soft tissue and bone cancer)” · Advanced soft tissue sarcoma: first line
Advanced soft tissue sarcoma, first line in patients with good performance status when tumour response is the goal or the histotype is ifosfamide-sensitive (ESMO [I, B]); in EORTC 62012: aged 18–60, performance status 0 or 1
10 g/m² per cycle, divided over 4 days (2.5 g/m² per day)
IV
Days 1 to 4
Mesna
With ifosfamide
Pegfilgrastim
Per protocol
Cycle length
Every 21 days
Duration
Up to 6 cycles
Doses per EORTC 62012: intensified doxorubicin 75 mg/m² (25 mg/m² per day, days 1–3) plus ifosfamide 10 g/m² over 4 days with mesna and pegfilgrastim, every 3 weeks for up to 6 cycles; mesna and pegfilgrastim doses are not given in the abstract (dose details in the full text). Hydration of at least 2 litres a day and monitoring for encephalopathy and renal function. More grade 3–4 toxicity than doxorubicin alone: febrile neutropenia 46%, anaemia 35% and thrombocytopenia 33%. Full regimen page: Doxorubicin and ifosfamide in soft tissue sarcoma.
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
1Doxorubicin alone (228 patients)
Doxorubicin 75 mg/m² IV, as a bolus on day 1 or a 72-hour continuous infusion, every 3 weeks until progression or unacceptable toxicity, for up to 6 cycles.
2Intensified doxorubicin plus ifosfamide (227 patients)
Doxorubicin 75 mg/m² (25 mg/m² per day, days 1 to 3) plus ifosfamide 10 g/m² over 4 days, with mesna and pegfilgrastim, every 3 weeks until progression or unacceptable toxicity, for up to 6 cycles. Mesna and pegfilgrastim doses are not given in the abstract (dose details in the full text).
Source of the regimen details: Abstract of the article and ClinicalTrials.gov NCT00061984; mesna and pegfilgrastim doses are not given in the abstract (dose details in the full text)
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 aged 18 to 60 with WHO performance status 0 or 1 and high-grade (FNCLCC grade 2 or 3), locally advanced unresectable or metastatic soft tissue sarcoma, with measurable disease and evidence of progression within the previous 6 weeks; no prior chemotherapy for advanced disease (prior adjuvant chemotherapy allowed if there was no progression within 6 months of completing it). GIST, osteosarcoma, Ewing sarcoma, embryonal rhabdomyosarcoma, alveolar soft part sarcoma, chondrosarcoma, mesothelioma and desmoplastic small round cell tumour were excluded. Laboratory criteria: ANC of at least 2,000 and platelets of at least 100,000 per mm³, bilirubin no more than 1.8 mg/dL, creatinine no more than 1.4 mg/dL or creatinine clearance above 65 mL/min, and no history of cardiovascular disease (ClinicalTrials.gov record).
Endpoints
Primary endpoint: overall survival in the intention-to-treat population. Secondary endpoints: progression-free survival, response by RECIST, toxicity (CTC version 2.0) and treatment-related mortality.
Safety and side effects
The most common grade 3 and 4 adverse events, all more frequent with the combination (combination vs doxorubicin alone): leucopenia 43% vs 18%, neutropenia 42% vs 37%, febrile neutropenia 46% vs 13%, anaemia 35% vs 5% and thrombocytopenia 33% vs less than 1%.
Clinical significance and place in guidelines
EORTC 62012 kept single-agent doxorubicin as the standard first-line treatment for advanced soft tissue sarcoma and showed that adequate-dose anthracycline plus ifosfamide (AI) is preferred when tumour response and shrinkage would be advantageous. ESMO–EURACAN–GENTURIS 2021 guideline: anthracycline-based first-line treatment is standard [I, A], and adequate-dose AI in ifosfamide-sensitive histotypes with good performance status [I, B].
Limitations
Only patients aged 18 to 60 with performance status 0 or 1 were included, so the results cannot be extended to older or frailer patients. Different histotypes with different sensitivity to ifosfamide were studied together. The overall survival difference was not significant, although the confidence interval (0.67 to 1.03) does not exclude a moderate benefit.
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.
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