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Eur J Cancer. 2014 Jan;50(2):388-96. doi: 10.1016/j.ejca.2013.10.002. Epub 2013 Nov 8.

Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study.

Author information

1
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.j.gelderblom@lumc.nl.
2
Department of Medical Oncology, Centre Leon Berard, Lyon, France.
3
London Sarcoma Service, University College Hospital, London, United Kingdom.
4
Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom.
5
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
6
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
7
Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
8
Department of Medical Oncology, University Hospital of Essen, Essen, Germany.
9
Headquarters, EORTC, Brussels, Belgium.
10
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
11
Health Science Center, University of Texas at San Antonio, San Antonio, TX, USA.
12
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
13
Department of Surgery, Klinikum Mannheim, University of Heidelberg, Germany.

Abstract

AIM:

Brostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS >60 years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel.

METHODS:

Patients were randomised in a 2:1 ratio between IV brostallicin 10mg/m(2) and doxorubicin 75 mg/m(2) once every 3 weeks for a maximum of six cycles. Disease stabilisation at 26 weeks (primary end-point) was considered a 'success'. Further testing of brostallicin was warranted if ≥ 35 'successes' were observed in the first 72 eligible patients treated with brostallicin. In addition, patients were genotyped for glutathione S transferase (GST) polymorphisms.

RESULTS:

One hundred and eighteen patients were included (79 brostallicin and 39 doxorubicin). Brostallicin was well tolerated in comparison to doxorubicin with less grade 3-4 neutropenia (67% versus 95%), grade 2-3 systolic dysfunction (0% versus 11%), alopecia (17% versus 61%) and grade 2-3 mucositis (0% versus 18%). For brostallicin versus doxorubicin, 'successes' were observed in 5/77 versus 10/36, progression free survival at 1 year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1 year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment.

CONCLUSION:

Brostallicin cannot be recommended at this dose and schedule in this patient population as first-line therapy. GSTA1 genotype may be predictive for doxorubicin efficacy but warrants further study.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00410462.

KEYWORDS:

Brostallicin; Doxorubicin; GST; Randomised phase II study; Soft tissue sarcoma

PMID:
24215845
DOI:
10.1016/j.ejca.2013.10.002
[Indexed for MEDLINE]

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