Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: a report from the European Osteosarcoma Intergroup.
OBJECTIVE
Chemotherapy-induced toxicity is an independent prognostic indicator in several cancers. We aimed to determine whether toxicity was related to survival and histological response in high-grade localised extremity osteosarcoma. We undertook a retrospective analysis of patients treated within three consecutive randomised controlled trials (RCTs) of the European Osteosarcoma Intergroup.


METHODS
Between 1982 and 2002, 533 patients were randomised to six cycles of doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Toxicity data were collected prospectively and graded according to the World Health Organisation (WHO) criteria. Standard univariate and multivariate models were constructed to examine the relationship between reported toxicity, survival, and histological response.


RESULTS
Five- and 10-year overall survival was 57% (95% confidence interval (CI) 52-61%) and 53% (49-58%), respectively. Grades 3-4 oral mucositis (hazard ratio (HR) 0.51, 95% CI 0.29-0.91), grades 1-2 nausea/vomiting (HR 0.37, 95% CI 0.16-0.85), grades 1-2 thrombocytopenia (HR 0.49, 95% CI 0.27-0.87), good histological response (HR 0.42, 95% CI 0.27-0.65), and distal tumour site (HR 0.45, 95% CI 0.28-0.71) were associated with improved survival in multivariate analysis. The only factors that were independently associated with histological response were older age (odds ratio (OR) 0.18, 95% CI 0.04-0.72) and chondroblastic tumour (OR 0.28, 95% CI 0.10-0.77), both being associated with a significantly lower chance of achieving a good response.


CONCLUSIONS
Chemotherapy-induced toxicity predicts survival in patients with localised extremity osteosarcoma. Investigation of the pharmacogenomic mechanisms of constitutional chemosensitivity underlying these observations will present opportunities for personalising treatment and could lead to improved outcomes.
Department of Oncology, University College Hospital, London, UK.
Anne
A
McTiernan
Rachel C
RC
Jinks
Matthew R
MR
Sydes
Barbara
B
Uscinska
Jane M
JM
Hook
Martine
M
van Glabbeke
Vivien
V
Bramwell
Ian J
IJ
Lewis
Antonie H M
AH
Taminiau
Marianne A
MA
Nooij
Pancras C W
PC
Hogendoorn
Hans
H
Gelderblom
Jeremy S
JS
Whelan
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D012516:Osteosarcoma / Q000188:drug therapy*; D011446:Prospective Studies; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D004317:Doxorubicin; D002945:Cisplatin