Elsevier

The Lancet Oncology

Volume 18, Issue 6, June 2017, Pages 812-822
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(17)30334-0Get rights and content

Summary

Background

Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy.

Methods

For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m2 per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010–023484–17, and is closed to patient entry.

Findings

Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75–28·20), the projected disease-free survival at 46 months was 62% (95% CI 48–77) in the standard chemotherapy group and 38% (22–55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22–3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis.

Interpretation

In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma.

Funding

European Union grant (Eurosarc FP7 278472).

Introduction

Despite optimum local treatment, about 50% of patients with localised adult-type soft-tissue sarcoma of the extremities and trunk will develop distant metastases and die of metastatic disease.1, 2 For this reason, several trials of adjuvant chemotherapy have been done during the past four decades. In 2008, an update of published data from a previous meta-analysis,3, 4 including more than 1900 patients, confirmed a statistically significant 10% absolute reduction in the overall proportion of patients with disease recurrence and a 6% improvement in overall survival with adjuvant chemotherapy. These results remained significant even after adding the last negative study, published afterwards.5 Additionally, only one randomised neoadjuvant study6 has compared preoperative chemotherapy and surgery with or without radiotherapy versus surgery with or without radiotherapy alone. The results of this study were negative, although the study was not powered to detect any difference between the two groups because it did not recruit the target accrual. Another study7 found a significant benefit in overall survival for neoadjuvant chemotherapy plus hyperthermia. In essence, the controlled evidence provided so far on adjuvant or neoadjuvant chemotherapy in soft-tissue sarcoma is conflicting. The largest trials were negative but were confounded by heterogeneous patient populations in regard to risk factors or by suboptimum doses of chemotherapy, or both.

Distinct histotypes are now recognised to be sensitive to specific cytotoxic drugs in the metastatic setting.8, 9, 10, 11, 12, 13 A histotype-tailored approach has gained momentum in the medical treatment of advanced disease in the past few years14, 15 as a possible way to overcome resistance.

Research in context

Evidence before this study

We searched PubMed for all randomised trials that involved adjuvant or neoadjuvant chemotherapy in localised soft tissue sarcoma, published in English between Jan 1, 1980, and Dec 30, 2016. We used the following search terms: “soft tissue”, “sarcoma”, “adjuvant chemotherapy”, “neoadjuvant chemotherapy”, “anthracycline”, “Ifosfamide”, “randomized”, and “trial”. We identified 20 randomised phase 3 clinical trials on adjuvant chemotherapy, one phase 2 clinical trial on neoadjuvant chemotherapy, and two meta-analyses. Results of the trials are conflicting, with negative results from the largest studies and positive results from the smaller ones.

Added value of this study

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. However, the observation of a statistically significant and clinically relevant difference in disease-free survival 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.

Implications of all the available evidence

Available evidence on the efficacy of neoadjuvant chemotherapy is conflicting, but available clinical practice guidelines regard this approach as an option that can be proposed to the patient in conditions of uncertainty for shared decision making. Although we await the amended final analysis of this trial, the data provided so far support a short chemotherapy regimen of full-dose anthracycline plus ifosfamide neoadjuvant in patients with high-risk localised soft-tissue sarcoma of the extremities and trunk wall.

To assess this hypothesis, the Italian Sarcoma Group (ISG), in collaboration with the Spanish Sarcoma Group (GEIS), the French Sarcoma Group, and the Polish Sarcoma Group, started a trial in patients with high-risk soft-tissue sarcoma of the extremities or trunk wall (ISG-STS 1001), to compare standard full-dose anthracycline plus ifosfamide versus a histotype-tailored neoadjuvant chemotherapy in five major soft-tissue sarcoma histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumours, and undifferentiated pleomorphic sarcoma. These five histological subtypes account for 80% of all high-risk soft-tissue sarcoma of the extremities and trunk wall and have an expected high metastatic risk.1 This study assessed the efficacy of trabectedin in high-grade myxoid liposarcoma;11, 12 gemcitabine plus dacarbazine in leiomyosarcoma;9 ifosfamide in synovial sarcoma;8 etoposide plus ifosfamide in malignant peripheral nerve sheath tumour;13 and gemcitabine plus docetaxel in undifferentiated pleomorphic sarcoma.10 The histotype-tailored regimens of etoposide plus ifosfamide and gemcitabine plus docetaxel were based on weaker data than the other three regimens because we found little available evidence on other histology-driven regimens for malignant peripheral nerve sheath tumour or undifferentiated pleomorphic sarcoma. For all five histotypes, we selected the histotype-tailored drugs with the best available evidence and compared them with standard chemotherapy.

Section snippets

Study design and participants

This is an international, open-label, randomised, controlled, phase 3, multicentre trial comparing a short full-dose standard regimen with a histotype-tailored regimen as neoadjuvant chemotherapy for localised high-risk soft-tissue sarcoma. Patients were enrolled in 32 hospitals in Italy, Spain, France, and Poland.

Patients were eligible if they were aged 18 years or older (no upper age limit was set); had a histologically proven and centrally reviewed (before randomisation) diagnosis of

Results

Between May 19, 2011, and May 13, 2016, 435 patients were registered and 287 were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy; figure 1). 286 patients were included in the third futility analysis; one patient was assigned to standard chemotherapy at the time of the third futility analysis and was excluded from the analysis. Clinical and pathological characteristics are shown in table 1. The intention-to-treat population included two

Discussion

This phase 3 trial in patients with localised high-risk soft-tissue sarcoma of the extremities and trunk wall closed in advance, when 286 patients had been recruited, after a futility analysis showing that the histotype-tailored group performed significantly worse in both disease-free survival and overall survival than the standard chemotherapy group.

No per-protocol analysis was done because practically all patients randomly assigned to a group started the assigned treatment protocol. Analyses

References (32)

  • Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data

    Lancet

    (1997)
  • RJ Canter et al.

    A synovial sarcoma preoperative nomogram supports a survival benefit to ifosfamide based chemotherapy and improves risk stratification for patients

    Clin Cancer Res

    (2008)
  • X Garcia-del-Muro et al.

    Randomized phase II study comparing gemcitabine plus dacarazine versus dacarbazine alone in patients previously treated soft tissue sarcoma. A Spanish Group for Research in Sarcoma study

    J Clin Oncol

    (2011)
  • RG Maki et al.

    Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002

    J Clin Oncol

    (2007)
  • F Grosso et al.

    Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study

    Lancet Oncol

    (2008)
  • BC Widemann et al.

    SARC 006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1) associated high grade malignant peripheral nerve sheath tumors (MPNSTs)

    Proc Am Soc Clin Oncol

    (2013)
  • Cited by (0)

    View full text