Outcomes of metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated within the BERNIE study: a randomised, phase II study evaluating the addition of bevacizumab to chemotherapy

Highlights

• This is the first series of paediatric metastatic NRSTS treated in a randomised phase II trial including a biologic agent.

• The addition of the anti-angiogenic agent to the standard chemotherapy did not show significant improvement in survival.

• This series may be considered benchmark for this disease category for developing future investigational studies.

Abstract

Purpose

We analysed the cohort of paediatric patients with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated in the BERNIE protocol, i.e. open-label, multicentre, randomised phase II study evaluating the role of bevacizumab (BO20924/ITCC-006; ClinicalTrials.gov: NCT00643565).

Methods

Eligible patients were randomised 1:1 to add or not add bevacizumab to nine courses of intensive multi-drug chemotherapy, followed by 12-month maintenance chemotherapy (plus surgery and radiotherapy). The primary end-point was event-free survival (EFS); secondary objectives were objective response rate (ORR) and overall survival (OS).

Results

From 2008 and 2013, 49 NRSTS patients (out of 154 cases) were treated, 26 in the standard arm and 23 in the bevacizumab arm. ORR was seen in 10 out of 36 evaluable cases (27.7%), i.e. 4/18 standard arm cases and 6/18 bevacizumab arm cases. Two-year EFS was 27.3% (95% confidence interval [CI] 13.9–42.5) for all NRSTS patients, i.e. 34.9% (95% CI 14.6–56.2) for bevacizumab arm and 22.9% (95% CI 7.1–43.9) for standard arm (p-value = 0.19). Three-year OS (median follow-up 48.6 months) was 35.2%, with no differences in the two arms. Time to event and time to death were 16.3 and 17.2 months for bevacizumab arm and 2.1 and 7.6 months for standard arm, respectively. Patients not receiving any local treatment on primary disease had a worse outcome as compared to others. Treatment results were better for patients receiving surgical resection and worse for those who did not receive any specific treatment.

Conclusion

The addition of the anti-angiogenic agent to the standard chemotherapy did not show statistically significant improvement in survival in metastatic NRSTS.

Introduction

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of distinct mesenchymal malignant neoplasms, many of them being more common in adults and very rare in children [1]. The prognosis of NRSTS patients depends on various variables (e.g. histologic type and grade, tumour size, extent of surgical resection) [[2], [3], [4], [5], [6], [7]], but among them, the presence of distant metastases is the main prognostic factor and generally results in a dismal outcome [[8], [9], [10]].

NRSTS are rare in children and metastatic disease at onset is a very uncommon occurrence: in a large series from the Milan centre, only 6 out of 182 cases had synchronous distant metastases at the time of diagnosis [5]. The largest published cohorts of paediatric metastatic NRSTS included only 25 [8], 26 [9] and 14 cases [10], and the progression-free survival rates were reported under 20%.

Given the limited data on the natural history and best treatment options of childhood metastatic NRSTS, over the years therapeutic approaches have been based on principles taken from the management of rhabdomyosarcoma (RMS) (which is a clearly distinct entity) or, alternatively, derived from the experience coming from adult populations. In addition, the management of children and adolescents with metastatic NRSTS is a challenge because of the uncertain sensitivity of these tumours to conventional chemotherapy and for the need of local treatment of metastases (often difficult). New effective treatment approaches are indeed highly necessary.

Given this situation of uncertainty, with the lack of valid therapies or studies dedicated to paediatric patients with metastatic NRSTS, the European paediatric Soft tissue sarcoma Study Group (EpSSG) decided to include these patients in the same protocol designed for metastatic RMS, i.e. the BERNIE protocol [11]. The BERNIE study was developed by EpSSG in cooperation with the European Innovative Therapies for Children with Cancer (ITCC) Consortium, sponsored by F. Hoffmann-La Roche Ltd., with the aim of evaluating the addition of bevacizumab—a monoclonal anti-vascular endothelial growth factor (VEGF) antibody—to the conventional intensive multi-drug chemotherapy derived from the treatment of RMS. The main result of the BERNIE study has been already reported, with a main focus on the primary end-point (efficacy of the addition of bevacizumab) and safety data [11]. The current paper describes the clinical characteristics and the updated results in the cohort of patients with metastatic NRSTS.