Abstract
AimChemotherapy-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. MethodsBetween 1982 and 2002, 533 patients were randomised to six cycles of doxorubicin 75mg/m2 and cisplatin 100mg/m2. 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. ResultsFive- 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. ConclusionChemotherapy-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.
Highlights
Osteosarcoma is the commonest primary bone sarcoma affecting young people
The prognosis of patients with highgrade localised extremity osteosarcoma improved dramatically with the introduction of multi-disciplinary treatment but over the past two decades there have been no further improvements in survival
If a similar association between toxicity and either histological response or survival was found in patients with osteosarcoma, an understanding of the underlying genetic and other mechanisms which may explain this constitutional chemosensitivity could lead to the testing and development of therapeutic strategies to exploit or circumvent these phenomena, with the prospect of greater individualisation of treatment and improved outcomes
Summary
Osteosarcoma is the commonest primary bone sarcoma affecting young people. The prognosis of patients with highgrade localised extremity osteosarcoma improved dramatically with the introduction of multi-disciplinary treatment (surgical resection in conjunction with perioperative multiagent chemotherapy) but over the past two decades there have been no further improvements in survival.Histological response to pre-operative chemotherapy is strongly related to the outcome, with patients who achieve a good histological response having a better prognosis than those who do not.[1,2,3,4] identifying other factors that are reliably prognostic for survival or predictive of response to treatment has been problematic and, evidence for the influence of several other factors, including histological subtype,[5] has been reported, none routinely influence practice.In other cancers, chemotherapy-induced toxicity has been shown to be an independent prognostic indicator, with those patients who report greater toxicity having improved survival. Prognostic effects of chemotherapy-induced neutropenia have been demonstrated in breast,[7] gastric,[6] lung[7,8] and ovarian cancer[9] in adults; and in children and adolescents receiving maintenance treatment for acute lymphoblastic leukaemia.[10,11] Chemotherapy-induced lymphopenia has been shown to be prognostic in advanced breast cancer, soft-tissue sarcoma, and diffuse large B-cell lymphoma.[12] If a similar association between toxicity and either histological response or survival was found in patients with osteosarcoma, an understanding of the underlying genetic and other mechanisms which may explain this constitutional chemosensitivity could lead to the testing and development of therapeutic strategies to exploit or circumvent these phenomena, with the prospect of greater individualisation of treatment and improved outcomes
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