Surrogate endpoints in advanced sarcoma trials: a meta-analysis

Savina, M.; Litière, Saskia; Italiano, Antoîne; Burzykowski, Tomasz; Bonnetain, Franck; Gourgou, Sophie; Rondeau, Virginie; Blay, Jean‐Yves; Cousin, Sophie; Duffaud, Florence; Gelderblom, Hans; Gronchi, Alessandro; Judson, Ian; Cesne, Axel Le; Lorigan, Paul; Maurel, Joan; Graaf, Winette van der; Verweij, Jaap; Mathoulin‐Pélissier, Simone; Bellera, C.

doi:10.18632/oncotarget.26166

Cited by 9 publications

(3 citation statements)

References 41 publications

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“…Furthermore, in the field of sarcoma, the surrogacy of progression-free survival (PFS) for OS was also investigated using RCTs of advanced soft tissue sarcomas. The correlation between PFS and OS was modest at best; thus, the surrogacy of PFS could not be confirmed in the analyses [18,19]. These observations suggest that confirmation of the correlation between surrogate endpoints and OS is important.…”

Section: Discussionmentioning

confidence: 86%

A meta-analytic evaluation of the correlation between event-free survival and overall survival in randomized controlled trials of newly diagnosed Ewing sarcoma

et al. 2020

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Background: In randomized controlled trials (RCTs) of adjuvant treatment for malignant tumors, event-free survival (EFS) is considered the most acceptable surrogate for overall survival (OS). However, even though EFS has repeatedly been selected as a primary endpoint in RCTs of Ewing sarcoma (ES), the surrogacy of EFS for OS has not been investigated. This study aimed to evaluate the correlation between EFS and OS in RCTs of chemotherapy for newly diagnosed ES using a meta-analytic approach. Methods: We identified seven RCTs of newly diagnosed ES through a systematic review, and a meta-analysis was performed to evaluate the efficacy and adverse events associated with chemotherapy for previously untreated ES. The correlation between EFS and OS was investigated using weighted linear regression analysis and Spearman rank correlation coefficients (ρ). The strength of the correlation was evaluated using the coefficient of determination (R 2). Results: A total of 3612 patients were randomly assigned to 17 treatment arms in the eligible RCTs. The meta-analysis revealed that the hazard ratios for OS and EFS showed significantly better results in the experimental treatment groups with increasing toxicities. The correlation between the hazard ratios for EFS and OS was good (R 2 = 0.747, ρ = 0.683), and the correlation tended to be more favorable in cases of localized ES (R 2 = 0.818, ρ = 0.929). Conclusions: Overall, the trial-level correlation between EFS and OS was good for newly diagnosed ES and was very good in cases of localized disease. EFS may be a useful endpoint in RCTs of ES chemotherapy, and it is worth verifying using individual patient data.

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Section: Discussionmentioning

confidence: 86%

A meta-analytic evaluation of the correlation between event-free survival and overall survival in randomized controlled trials of newly diagnosed Ewing sarcoma

et al. 2020

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“…TTF has been evaluated as a proxy for overall survival in advanced sarcomas; while imperfect for that purpose, it has value as a marker of clinical outcomes. 27 It is possible that patients with less favorable prognoses were preferentially selected to receive multi-agent chemotherapy. Although monotherapy versus multi-agent therapy was not a retained variable in adjusted TTF models, metastatic disease was retained, possibly serving as the prognostic indicator.…”

Section: Discussionmentioning

confidence: 99%

Cardiac events among patients with sarcoma treated with doxorubicin by method of infusion: A real‐world database study

et al. 2022

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Background Administration of doxorubicin by continuous intravenous (CIV) infusion, versus bolus (BOL) administration, has been proposed to mitigate the risk of cardiac events. This study used real‐world data to explore the association between mode of doxorubicin administration and duration of treatment, time‐to‐treatment failure (TTF), and cardiac events. Methods Occurrence of cardiac events after initiation of BOL versus CIV doxorubicin for sarcoma in the International Business Machines MarketScan claims database were compared. Duration of doxorubicin treatment, TTF, and time‐to‐first‐cardiac event (TCE) were evaluated using Kaplan–Meier method and unadjusted and adjusted Cox regression models. Results A total of 196 patients were included in the BOL group and 399 in the CIV group. In unadjusted analyses, there were significant differences between BOL versus CIV for duration of doxorubicin treatment (median 1.4 vs. 2.1 months, p = .002), TTF (median 8.8 vs. 5.6 months, p = .002), and TCE (medians not reached, p = .03). Adjusting for baseline covariates, only TTF remained significant (hazard ratio: 0.71, 95% confidence interval 0.59–0.86, p = .0004), favoring BOL. Conclusions While the risk of cardiac complications was higher with BOL in unadjusted analysis, the risk was no longer present in the adjusted analysis. While we cannot draw causal inferences due to the retrospective, nonrandomized study design, these data suggest that replacing BOL with prolonged CIV administration has not been effective as a strategy to mitigate cardiac events, given community standards of oncologic practice.

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“…Last but not least, the ultimate aim of a clinical trial is to provide evidence of improved OS or improved quality of life. Nonetheless, two recent meta-analyses do not support strong surrogacy properties between PFS and OS in advanced STS randomised clinical trials [58,59]. Consequently, PFS carries the risk of misleading conclusions because of erroneous extrapolation of the results.…”

Section: Discussionmentioning

confidence: 99%

Efficacy thresholds for clinical trials with advanced or metastatic leiomyosarcoma patients: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group meta-analysis based on a literature review for soft-tissue sarcomas

Kantidakis

Litière

Neven

et al. 2021

European Journal of Cancer

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Background: In 2002, the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group reported well-established values for conducting phase II trials for soft-tissue sarcomas. An update is provided for leiomyosarcoma (LMS). Materials and methods: Clinical trials with advanced or metastatic LMS were identified via literature review in PubMed (published 2003e2018, 10 adult LMS patients). End-points

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Surrogate endpoints in advanced sarcoma trials: a meta-analysis

Cited by 9 publications

References 41 publications

A meta-analytic evaluation of the correlation between event-free survival and overall survival in randomized controlled trials of newly diagnosed Ewing sarcoma

A meta-analytic evaluation of the correlation between event-free survival and overall survival in randomized controlled trials of newly diagnosed Ewing sarcoma

Cardiac events among patients with sarcoma treated with doxorubicin by method of infusion: A real‐world database study

Efficacy thresholds for clinical trials with advanced or metastatic leiomyosarcoma patients: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group meta-analysis based on a literature review for soft-tissue sarcomas

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