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

Abstract

AimBrostallicin 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>60years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel. MethodsPatients were randomised in a 2:1 ratio between IV brostallicin 10mg/m2 and doxorubicin 75mg/m2 once every 3weeks for a maximum of six cycles. Disease stabilisation at 26weeks (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. ResultsOne 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 1year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment. ConclusionBrostallicin 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.