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

H Gelderblom, JY Blay, BM Seddon, M Leahy, I Ray-Coquard, Stefan Sleijfer, JM Kerst, P Rutkowski, S Bauer, M Ouali, S Marreaud, RJHM van der Straaten, HJ Guchelaar, SD Weitman, PCW Hogendoorn, P Hohenberger

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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 10 mg/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 gluthatione 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. (C) 2013 Elsevier Ltd. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)388-396
Number of pages9
JournalEuropean Journal of Cancer
Volume50
Issue number2
DOIs
Publication statusPublished - 2014

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