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

doi:10.1016/j.ejca.2013.10.002

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

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

28 Citations (Scopus)

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 language	Undefined/Unknown
Pages (from-to)	388-396
Number of pages	9
Journal	European Journal of Cancer
Volume	50
Issue number	2
DOIs	https://doi.org/10.1016/j.ejca.2013.10.002
Publication status	Published - 2014

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Gelderblom, H., Blay, JY., Seddon, BM., Leahy, M., Ray-Coquard, I., Sleijfer, S., Kerst, JM., Rutkowski, P., Bauer, S., Ouali, M., Marreaud, S., van der Straaten, RJHM., Guchelaar, HJ., Weitman, SD., Hogendoorn, PCW., & Hohenberger, P. (2014). 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. European Journal of Cancer, 50(2), 388-396. https://doi.org/10.1016/j.ejca.2013.10.002

Gelderblom, H ; Blay, JY ; Seddon, BM et al. / 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. In: European Journal of Cancer. 2014 ; Vol. 50, No. 2. pp. 388-396.

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title = "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 = "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.",

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

year = "2014",

doi = "10.1016/j.ejca.2013.10.002",

language = "Undefined/Unknown",

volume = "50",

pages = "388--396",

journal = "European Journal of Cancer",

issn = "0959-8049",

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Gelderblom, H, Blay, JY, Seddon, BM, Leahy, M, Ray-Coquard, I, Sleijfer, S, Kerst, JM, Rutkowski, P, Bauer, S, Ouali, M, Marreaud, S, van der Straaten, RJHM, Guchelaar, HJ, Weitman, SD, Hogendoorn, PCW & Hohenberger, P 2014, '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', European Journal of Cancer, vol. 50, no. 2, pp. 388-396. https://doi.org/10.1016/j.ejca.2013.10.002

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. / Gelderblom, H; Blay, JY; Seddon, BM et al.

In: European Journal of Cancer, Vol. 50, No. 2, 2014, p. 388-396.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - 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

AU - Gelderblom, H

AU - Blay, JY

AU - Seddon, BM

AU - Leahy, M

AU - Ray-Coquard, I

AU - Sleijfer, Stefan

AU - Kerst, JM

AU - Rutkowski, P

AU - Bauer, S

AU - Ouali, M

AU - Marreaud, S

AU - van der Straaten, RJHM

AU - Guchelaar, HJ

AU - Weitman, SD

AU - Hogendoorn, PCW

AU - Hohenberger, P

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejca.2013.10.002

DO - 10.1016/j.ejca.2013.10.002

M3 - Article

VL - 50

SP - 388

EP - 396

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

IS - 2

ER -

Gelderblom H, Blay JY, Seddon BM, Leahy M, Ray-Coquard I, Sleijfer S et al. 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. European Journal of Cancer. 2014;50(2):388-396. doi: 10.1016/j.ejca.2013.10.002