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.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.j.gelderblom@lumc.nl.
H
H
Gelderblom
Department of Medical Oncology, Centre Leon Berard, Lyon, France.
J Y
JY
Blay
London Sarcoma Service, University College Hospital, London, United Kingdom.
B M
BM
Seddon
Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom.
M
M
Leahy
Department of Medical Oncology, Centre Leon Berard, Lyon, France.
I
I
Ray-Coquard
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
S
S
Sleijfer
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
J M
JM
Kerst
Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
P
P
Rutkowski
Department of Medical Oncology, University Hospital of Essen, Essen, Germany.
S
S
Bauer
Headquarters, EORTC, Brussels, Belgium.
M
M
Ouali
Headquarters, EORTC, Brussels, Belgium.
S
S
Marreaud
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
R J H M
RJ
van der Straaten
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
H-J
HJ
Guchelaar
Health Science Center, University of Texas at San Antonio, San Antonio, TX, USA.
S D
SD
Weitman
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
P C W
PC
Hogendoorn
Department of Surgery, Klinikum Mannheim, University of Heidelberg, Germany.
P
P
Hohenberger
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005060:Europe; D005787:Gene Frequency; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D006146:Guanidines; D007527:Isoenzymes; D011758:Pyrroles; D004317:Doxorubicin; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; C455279:brostallicin
Brostallicin; Doxorubicin; GST; Randomised phase II study; Soft tissue sarcoma