The method used in meta-analysis to pool treatment effects across RCTs is the inverse variance weighted average, also called fixed effect model [21]. Our aim is to study if/how the choice of a survival analysis method impacts on the cost-effectiveness results. The Peto and Pooled Kaplan-Meier methods are the only methods that account for stratification by trial, treatment effect heterogeneity and non-proportionality of hazards. The variable Cell is specified in the STRATA statement to compute the RMST for each type of cancer cell. Parmar (MRC Clinical Trials Unit), R. Paulus (Radiation Therapy Oncology Group), J.P. Pignon (Gustave Roussy), M.I. h�b```�f�;B cB�I;'0�X�b9���8��ۀ�q��T����T�,�F� � 蚀f�0���fbn�љAH%0ؘψ*}!G>�� ä�����+$8dz�4�}ܿ@X )Y�0���@� ��$� Restricted mean survival time is a well-established, yet underused, measure that can be interpreted as the mean event-free survival time up to a prespecified, clinically important point. Funding: This work was supported by ITMO Cancer and IReSP (French Public Health Research Institute) as part of the French “Plan Cancer 2009–2013”, by the French “Programme Hospitalier de Recherche Clinique”, and by the French “Ligue Nationale Contre le Cancer”. Is the Subject Area "Metaanalysis" applicable to this article? In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). The treatment effects to be pooled are mostly expressed in terms of log odds ratios or log hazard ratios for survival endpoints [21]. 283 0 obj <>/Filter/FlateDecode/ID[<233B01FBC58CCE45A1F8F5BD5B710501>]/Index[274 18]/Info 273 0 R/Length 68/Prev 538421/Root 275 0 R/Size 292/Type/XRef/W[1 3 1]>>stream Estimations were done every 355 deaths: at 0.45 year, 0.81 year, 1.25 year, 2.02 years, 5 years and an extra point estimation for patients who died after 5 years. This case study showed that the choice of survival analysis method to estimate the difference in restricted mean survival time from an IPD meta-analysis is likely to exert an impact on cost-effectiveness results. The costs were estimated in the French context from a payer’s perspective and expressed in 2012 euros. If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. Some economic studies have already used IPD-MA [8–10]. Even though, there was no treatment effect heterogeneity between MAR-LC trials and survival hazards were proportional, we noted a difference in mean ICERs generated by the methods. There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15–17]. Click through the PLOS taxonomy to find articles in your field. Restricted mean survival time (RMST) evaluates the mean event‐free survival time up to a prespecified time point. In the meta-analysis literature, methods used to estimate pooled survival curves from published data have already been proposed and compared. This absolute outcome can be expressed as the number of life-years gained associated with the treatment. The selection of the parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots [17]. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. %%EOF This second approach is an extension of the inverse variance weighted average method that is classically used in meta-analysis to pool treatment effects across RCTs. restricted mean time of each health state also was quan-tified as a percentage of the 36-month period. Calculate Mean Survival Time. Table 1 summarizes the ability of these methods to address stratification by trial, non-proportionality of hazards (variation of the treatment effect over time) and treatment effect heterogeneity. The MAR-LC primary endpoint was overall survival. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. We are grateful to Jean Bouyer, Ariane Dunant, Matthieu Faron, Gwenael Le Teuff, Stefan Michiels and Federico Rotolo for scientific discussions and support. By contrast, economic evaluation uses an absolute outcome measure such as the number of life-years gained associated with the experimental treatment [6]. Mean survival time (MST), however, has received less attention in the field of clinical research, partly because it is often subject to underestimation due to the largest observation being censored. The ICER was defined as the difference in mean costs between the two types of radiotherapy regimen (modified and conventional) divided by the rmstD. Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. With this method, the treatment effect is defined as the difference in restricted mean between the trial arms. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. By default, this assumes that the longest survival time is equal to the longest survival time in the data. The rmstDs estimated using the different survival analysis methods are shown in Table 2. It is a two-stage method which is based on the estimation of the treatment effect, firstly, in each RCT and secondly, the aggregation of estimates [22–24]. You can get the restricted mean survival time with print(km, print.rmean=TRUE). With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. Wrote the paper: BL AM JPP ORA JB. Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. ENDPOINT. Methods were classified into two approaches. Modified RT included hyperfractionated RT which consists in increasing the number of fractions per day with a decreased dose per fraction, and/or accelerated RT, in which the overall treatment time is reduced. The MAR-LC comprised 2,000 distinct patients with a non-metastatic non-small cell lung cancer treated with radiotherapy and who had been enrolled in ten distinct phase III RCTs [19]. Readers may contact the corresponding author at jean-pierre.pignon@gustaveroussy.fr to request the data. The Pooled Kaplan-Meier and Pooled Exponential methods deal with stratification by trial and treatment effect heterogeneity. Performed the experiments: BL AM JPP ORA JB. The difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. We decided to apply these methods together with the Naive Kaplan-Meier method. Apply the difference in restricted mean survival time (rmstD) in a NMA and compare the results with those obtained in a NMA with hazard ratio. Mandrekar (Mayo Clinic), A. Mauguen (Gustave Roussy), F. Mornex (Centre Hospitalier Lyon Sud), M. Nankivell (MRC Clinical Trials Unit), G. Nelson (Mayo Clinic), M.K. The estimation of the overall rmstD depends on the choice of the time horizon t* which is still debated in the literature [7,18]. Panel A of Fig. Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. 291 0 obj <>stream The mean survival time will in general depend on what value is chosen for the maximum survival time. The Pooled Kaplan-Meier method and the Pooled Exponential method enable us to study the heterogeneity of the rmstDs across trials (Fig 1). The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival … Conversely, a common outcome measure in economic evaluation is the difference in the restricted mean survival time (rmstD) [6,7]. Six other methods ( Fig 2 ) be used to fit the best model not to... Two Kaplan-Meier survival curves No, is the area under the survival curve approach, the Kaplan-Meier method, probabilities... 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