Progression-free survival as a surrogate for overall survival in advanced/recurrent gastric cancer trials: a meta-analysis.
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ABSTRACT:
SUBMITTER: Paoletti X
PROVIDER: S-EPMC4994928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer.MethodsThe GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated.ResultsIndividual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS.ConclusionsDFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.
| S-EPMC4202244 | biostudies-literature
Project description:Background:Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types. Methods:In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors. Results:Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest (r2 = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, r2= 0.66; platinum/paclitaxel, r2= 0.44; triplet combinations, r2= 0.22; biologicals, r2= 0.30. The median PPS increased over time for the experimental (Ptrend = 0.03) and control arms (Ptrend = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS (r2 = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger (r2 = 0.64) than where the median PPS was longer (r2 = 0.48). Conclusions:In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies.
| S-EPMC6080081 | biostudies-literature
Project description:BackgroundProgression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology. Validation of PFS as a surrogate must be done for each indication and each intervention. We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics.MethodsWe conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation).ResultsWe identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy.ConclusionsAlthough most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.
| S-EPMC7250908 | biostudies-literature
Project description:BACKGROUND:The correlation between overall survival (OS) and progression-free survival (PFS) has been evaluated in patients with metastatic or advanced gastric cancer who have received first-line and/or second-line chemotherapy. However, no corresponding analysis has been done for patients who have undergone third-line or later-line chemotherapy. METHODS:A total of 303 patients from the Phase II/III studies of apatinib were pooled (the Phase II study as a training data set, the Phase III study as a testing data set). Landmark analyses of PFS at 2 months from randomization were performed to minimize lead time bias. The Cox proportional hazard model was used to test for the significance effect of PFS rate at 2 months in predicting OS. Additionally, the PFS/OS correlations were evaluated by the normal induced copula (National Institute for Health and Care Excellence) estimation model. RESULTS:The median OS was 3.37 months (95% confidence interval 2.63-3.80) in patients who experienced progression at 2 months and 5.67 months in patients who did not (95% confidence interval 4.83-6.67; P<0.0001). Compared with patients who did not progress at 2 months, the adjusted hazard ratio for death was 3.39 (95% confidence interval 1.79-6.41; P<0.0001) for patients who experienced progression at 2 months. Moreover, the correlation of PFS/OS was 0.84 (95% confidence interval 0.74-0.90). Similar results were found in the testing data set. CONCLUSION:These results indicate that PFS correlates strongly with OS, suggesting PFS may be a useful early endpoint for patients with advanced gastric cancer who have undergone third-line or later-line chemotherapy. These observations require prospective validation.
| S-EPMC4410904 | biostudies-literature
Project description:Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods. A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan-Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R2. Heterogeneity was explored by meta-regression. We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R2 = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R2 = 0.89, 95%CI 0.78-0.98, and 0.80, 95% CI 0.63-0.96, respectively). Interaction p-values obtained by meta-regression confirmed the robustness of results. In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.
| S-EPMC7796103 | biostudies-literature
Project description:BackgroundWe aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma.MethodsRandomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model.ResultsSeventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73.ConclusionsPFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ≤ 0.73 has the potential to predict a significant improvement in OS.
| S-EPMC9239497 | biostudies-literature
Project description:Apatinib is reported to significantly improve the overall survival (OS) of patients with advanced gastric cancer who have previously failed second-line chemotherapy. However, it is not well understood whether apatinib acts by improving progression or by prolonging post-progression survival. Here, based on phase III clinical trial data, the mediating effect of apatinib on patient overall survival was systematically quantified, through progression-free survival (PFS), post-progression survival (PPS), and the disease control rate (DCR). PFS was the primary mediator of the association between apatinib treatment and OS, with an indirect-effect mean survival time ratio of 1.63 (95%CI 1.35-1.97), which mediated 93.5% of the treatment effect. The DCR was also a significant mediator among secondary efficacy endpoints, and had an indirect-effect mean survival time ratio of 1.47 (95%CI 1.20-1.79, 50.9% mediated). Both primary and other targets of the DCR had similar results. The results indicated that apatinib treatment prolongs progression-free survival rather than post-progression survival, and in turn, leads to improved overall survival. Additionally, our study highlights the value of mediation analysis in clinical trials in providing additional information to build upon traditional primary analysis.
| S-EPMC5438734 | biostudies-literature
Project description:BACKGROUND:Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials. METHODS:We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose. FINDINGS:After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0·71 (95% CI 0·29-0·90) with a random-effects assumption, 0·85 (0·59-0·95) with a fixed-effects assumption, and 0·89 (0·68-0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81-0·99), which decreased to 0·93 (0·74-0·98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0·55, 0·03-0·84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0·85 (0·51-0·96). INTERPRETATION:PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials. FUNDING:None.
| S-EPMC4443445 | biostudies-literature
Project description: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 (?). 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, ??=?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.
| S-EPMC7244479 | biostudies-literature
Project description:This paper considers methods for estimating the association between progression-free and overall survival in oncology trials. Copula-based, nonparametric, and illness-death model-based methods are reviewed. In addition, the approach based on an underlying illness-death model is generalized to allow general parametric models. The performance of these methods, in terms of bias and efficiency, is investigated through simulation and also illustrated using data from a clinical trial of treatments for colon cancer. The simulations suggest that the illness-death model-based method provides good estimates of Kendall's τ across several scenarios. In some situations, copula-based methods perform well but their performance is sensitive to the choice of copula. The Clayton copula is most appropriate in scenarios, which might realistically reflect an oncology trial, but the use of copula models in practice is questionable.
| S-EPMC6585767 | biostudies-literature