Neoadjuvant Epirubicin Plus Ifosfamide Beats Histotype-Tailored Regimens For High-Risk Sarcoma DFS

Neoadjuvant full-dose epirubicin plus ifosfamide offers longer disease-free survival than histotype-tailored chemotherapy for high-risk localised sarcoma

medwireNews: Tailoring neoadjuvant chemotherapy for high-risk soft-tissue sarcoma by histotype does not improve patient disease-free survival (DFS) compared with a standard epirubicin and ifosfamide neoadjuvant regimen, ISG-STS 1001trial findings demonstrate.

“Formally, this is a negative trial because it does not show any advantage of histotype-tailored chemotherapy over standard chemotherapy in resectable high-risk soft-tissue sarcoma of the extremities or trunk wall”, explain Alessandro Gronchi, from Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and co-workers.

“However, the observation of a statistically significant and clinically relevant difference in [DFS] and overall survival at 3 years averaging 20% in favour of standard chemotherapy over the histotype-tailored neoadjuvant chemotherapy group, represents new data in support of the efficacy of neoadjuvant standard chemotherapy”, they emphasize.

The phase III international trial included patients with one of five different histotypes of sarcoma of the extremities or trunk wall. All patients had localised disease with at least one of the high-risk features of high malignancy grade, 5 cm or longer diameter, or deep location in the investing fascia.

In all, 145 patients were randomly assigned to receive three cycles of full-dose chemotherapy, defined as epirubicin 60 mg/m2 on days 1 and 2 of a 21-day cycle alongside ifosfamide 3 g/m2 per day on days 1, 2 and 3.

A further 142 patients were assigned to receive chemotherapy tailored to their histotype using the best available trial information, the authors explain.

This included 97 patients with undifferentiated pleomorphic sarcoma who were given gemcitabine 900 mg/m2 over 90 minutes on days 1 and 8 of a 21-day cycle plus docetaxel 75 mg/m2 for 1 hour on day 8, and 64 patients with high-grade myxoid liposarcoma who were treated with trabectedin 1.3 mg/m² via 24-hour continuous infusion every 21 days.

The 70 patients with synovial sarcoma received high-dose ifosfamide 14 g/m² by external infusion pump for 14 days of each 28-day cycle, while the 27 patients with malignant peripheral nerve sheath tumours were given intravenous etoposide 150 mg/m² plus intravenous ifosfamide 3 g/m² per day on days 1, 2 and 3 of a 21-day cycle. Twenty-eight patients with leiomyosarcoma received intravenous gemcitabine 1800 mg/m² for 180 minutes and dacarbazine 500 mg/m2 for 20 minutes on day 1 of a 14-day cycle.

By the third futility analysis, after a median of 12.3 months, the projected DFS rate at 46 months was estimated to be 62% for the patients given the standard chemotherapy regimen versus 38% for the patients given histotype-tailored chemotherapy. This represented a significant difference with a hazard ratio of 2.0.

“These results contrasted sharply with the estimated minimum clinically worthwhile effect given in the study protocol (ie, HR 0.667)”, the researchers say, and therefore resulted in the Independent Data Monitoring Committee recommending that patient entry to the trial to be closed.

Although the rate of local failure-free survival at 46 months was estimated to be comparable in the standard and tailored chemotherapy groups (86 vs 85%), both overall survival (84 vs 69%, HR=2.687) and metastasis-free survival (74 v 45%, HR=2.147) were significantly better with the standard chemotherapy regimen.

And exploratory analysis indicated that the standard regimen offered better DFS in all tumour histotypes, except for high-grade myxoid liposarcoma, in which tailored treatment was equivalent to standard therapy.

Nevertheless, the researchers emphasize that their findings should not be “interpreted as the failure of a histology-driven chemotherapy”, and believe that the search for optimal histology-driven chemotherapy regimens should continue.

“[P]resent clinical practice guidelines already assume that adjuvant or neoadjuvant chemotherapy in patients with high-risk localised soft-tissue sarcoma is not standard practice, but regard it as an option that can be proposed to the patient in conditions of uncertainty for shared decision making”, the authors conclude.

“Although awaiting the amended final analysis of this trial, we believe that the data provided in this Article further support proposing a short full-dose anthracycline-based neoadjuvant chemotherapy to patients with a high-risk localised soft-tissue sarcoma of the extremities and trunk wall.”


Gronchi A, Ferrari S, Quagliuolo V, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol; Advance online publication 9 May 2017. DOI:

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