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, J. Y. Blay, B. M. Seddon, M. Leahy, I. Ray-Coquard, S. Sleijfer, J. M. Kerst, P. Rutkowski, S. Bauer, M. Ouali, S. Marreaud, R. J H M Van Der Straaten, H. J. Guchelaar, Steven D Weitman, P. C W Hogendoorn, P. Hohenberger

Research output: Contribution to journalArticle

18 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/m2 and doxorubicin 75 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)388-396
Number of pages9
JournalEuropean Journal of Cancer
Volume50
Issue number2
DOIs
StatePublished - Jan 2014

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Sarcoma
Doxorubicin
Drug Therapy
Genotype
Pharmacogenomic Testing
brostallicin
Mucositis
Alopecia
Combination Drug Therapy
Neutropenia
Glutathione Transferase
Disease-Free Survival
Appointments and Schedules
Therapeutics
Safety
Survival
DNA
Population

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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, J. Y.; Seddon, B. M.; Leahy, M.; Ray-Coquard, I.; Sleijfer, S.; Kerst, J. M.; Rutkowski, P.; Bauer, S.; Ouali, M.; Marreaud, S.; Van Der Straaten, R. J H M; Guchelaar, H. J.; Weitman, Steven D; Hogendoorn, P. C W; Hohenberger, P.

In: European Journal of Cancer, Vol. 50, No. 2, 01.2014, p. 388-396.

Research output: Contribution to journalArticle

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
Gelderblom, H. ; Blay, J. Y. ; Seddon, B. M. ; Leahy, M. ; Ray-Coquard, I. ; Sleijfer, S. ; Kerst, J. M. ; Rutkowski, P. ; Bauer, S. ; Ouali, M. ; Marreaud, S. ; Van Der Straaten, R. J H M ; Guchelaar, H. J. ; Weitman, Steven D ; Hogendoorn, P. C W ; Hohenberger, P. / 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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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/m2 and doxorubicin 75 mg/m2 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.",
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T1 - Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma

T2 - 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, J. Y.

AU - Seddon, B. M.

AU - Leahy, M.

AU - Ray-Coquard, I.

AU - Sleijfer, S.

AU - Kerst, J. M.

AU - Rutkowski, P.

AU - Bauer, S.

AU - Ouali, M.

AU - Marreaud, S.

AU - Van Der Straaten, R. J H M

AU - Guchelaar, H. J.

AU - Weitman, Steven D

AU - Hogendoorn, P. C W

AU - Hohenberger, P.

PY - 2014/1

Y1 - 2014/1

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/m2 and doxorubicin 75 mg/m2 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.

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/m2 and doxorubicin 75 mg/m2 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.

KW - Brostallicin

KW - Doxorubicin

KW - GST

KW - Randomised phase II study

KW - Soft tissue sarcoma

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