Abstract
Event-free survival (EFS) is considered the most reliable surrogate endpoint for overall survival (OS) in randomised controlled trials (RCTs) of adjuvant therapies for malignant tumours. However, the surrogacy of intermediate endpoints such as EFS for OS in trials of patients with osteosarcoma has not been investigated to date. In this study, we investigated the correlation between OS and intermediate endpoints in RCTs of localised osteosarcoma. A systematic search identified 20 relevant RCTs. The correlations between the surrogate endpoints and OS were evaluated using weighted linear regression analyses and by calculating the Spearman rank correlation coefficients (ρ). The strength of the correlation was determined by calculating the coefficient of determination (R2). A total of 5,620 patients were randomly assigned to 45 treatment arms in the eligible 20 RCTs. The correlation between the hazard ratios for EFS and OS was moderate (R2 = 0.456, ρ = 0.440); this correlation tended to be weaker for patients with localised osteosarcoma excluding the patients with metastases. Overall, the trial-level correlation between the surrogate endpoints and OS was not robust in RCTs of osteosarcoma published to date. Hence, the suitability of the intermediate endpoints as surrogates for OS could not be confirmed.
Highlights
Osteosarcoma is the most frequently diagnosed primary malignant bone tumour, with an annual incidence of approximately 800 patients in the United States[1], and 200 in Japan[2]
The correlation between intermediate endpoints and overall survival (OS) has never been investigated in randomised controlled trials (RCTs) for osteosarcoma; ours is the first such investigation to date
event-free survival (EFS) is often selected as the primary endpoint in RCTs of localised osteosarcoma
Summary
Osteosarcoma is the most frequently diagnosed primary malignant bone tumour, with an annual incidence of approximately 800 patients in the United States[1], and 200 in Japan[2]. The prognosis of patients with osteosarcoma has dramatically improved following the introduction of multi-drug combination chemotherapy regimens. The investigators recommended MAP alone as the standard regimen for osteosarcoma, including in the poor responders[5]. In Japan, IFM is combined with MAP as postoperative chemotherapy for patients who respond poorly to MAP preoperatively[6]; randomised phase 3 trials are currently underway to verify the effectiveness of this combination regimen[7]. We conducted a meta-analysis of all published RCTs of localised osteosarcoma to investigate the suitability of the intermediate endpoints including EFS and pathological response rate (RR) as surrogates for OS
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