They compared three methods of estimation of the trial-specific rmstD: the âIntegrated difference of survival functionsâ method, which is equivalent to the Pooled Kaplan-Meier method, a pseudo values method and a flexible parametric survival model. This method does not assume proportional hazards, but neither stratification by trial nor heterogeneity of treatment effect can be taken into account to estimate the pooled survival curves. Bonner (University of Alabama-Birmingham), H. Choy (The University of Texas Southwestern), S.E. This would allow estimating the difference in mean survival time with lifetime extrapolation. https://doi.org/10.1371/journal.pone.0150032.s001, https://doi.org/10.1371/journal.pone.0150032.s002, https://doi.org/10.1371/journal.pone.0150032.s003. If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations These methods lead to the most optimistic acceptability curves. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0150032. The difference in restricted mean survival times (RMSTD) is an appealing measure of treatment effect for randomized controlled trials (RCTs) with time-to-event outcomes. In each trial, the rmstD can be estimated using different survival analysis methods. https://doi.org/10.1371/journal.pone.0150032.s004, https://doi.org/10.1371/journal.pone.0150032.s005. For example, if an extreme restriction of follow-up (up to 72 months) is considered in the above example, then the difference in mean PFS is 7.3 months and the difference in mean OS is 4.6 months, despite the fact that they are both equal to 9 months in unrestricted analysis. The meth-odology of Glasziou uses a ‘‘partitioned survival analysis’’ (Glasziou, Simes, and Gelber 1990). 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. As a matter of fact, research on methods used to conduct economic evaluation based on IPD-MA is still in its infancy [11â14]. There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15â17]. In order to estimate the rmstD from IPD-MA, we considered methods used by Wei and colleagues [18] and chose to adapt other non-parametric methods that are applied in the field of IPD-MA. endstream endobj 275 0 obj <>/Metadata 27 0 R/Pages 272 0 R/StructTreeRoot 71 0 R/Type/Catalog>> endobj 276 0 obj <>/MediaBox[0 0 595.32 841.92]/Parent 272 0 R/Resources<>/Font<>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Rotate 0/StructParents 0/Tabs/S/Type/Page>> endobj 277 0 obj <>stream Except for the Naïve Kaplan-Meier method, all survival analysis methods were not available in standard statistical softwares. 1,2 In this article, we discuss the advantages of an alternative analytical procedure based on the restricted mean survival time (RMST) 1,2 via 3 examples. These methods were developed for summary data and are not applicable to IPD meta-analysis. The restricted mean survival time (RMST), sometimes called the restricted mean event time, is an alternative measure that is more often reliably estimable than the mean and median of the event time in certain situations. Yes 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. There was no treatment effect heterogeneity between trials (p = 0.37, Higgins I² = 8%). Finally, this method allows studying the potential heterogeneity of rmstD across trials and has been proved to be unbiased and with a good coverage probability (Wei et al, 2015). Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations it is the mean up to some point t ∗. The authors concluded that, overall, all the five methods were quite accurate but they pointed out that most of these methods failed to address stratification by trial and treatment effect heterogeneity. Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. Direct costs (radiotherapy (RT), medical transportation, disease progression and esophagitis) were assessed at the patient level using the healthcare resource use measured in the MAR-LC. Furthermore, the issue of comparing different parametric models was beyond the scope of this paper, and has already been explored in the literature [15â17]. 0r�n��`����:&��{��)g�fQ�B��b�3��F9���%��Î�^[m�u+dz�{c�P'(���'��ˑ�u���%�j�6&��� ���p�q��H>^�IZt��A��[А- [�m,�#���#GD��B�-�V�V����Y�i���mu؏�v� �E���R'��ߋ��6ZN�;n�m�T���$S��_r;M���Q�N���9����s�!p3c��v�M�(��Ǹ�0 �S��"o��EF��� �#( (Ѐ2pHO TA�V{B�`BH>H��S�/���o��pO�rE��74 �,��}��������J� ��H9z�8�T��\ �C�����R�;{f��;����%H�4�1�� |J�� Our future prospects include a simulation study in order to be able to generalize the results found in this case study. This may be explained by two factors. Gustave Roussy, Service de biostatistique et dâépidémiologie, Villejuif, France, https://doi.org/10.1371/journal.pone.0150032.t001. No, Is the Subject Area "Oncology" applicable to this article? Earle and Wells [32] compared five methods to combine published survival curves from studies of patients treated with chemotherapy for advanced non-small-cell lung cancer. Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. It is estimated as the between-arm difference in the restricted mean survival time (rmstD) and corresponds to the area between the two survival curves for the experimental arm and the control arm restricted to a certain time horizon [7]. of the restricted mean, in a ‘‘QTWIST’’ analysis. With the second approach, the rmstD is based on the aggregation of rmstDs estimated in each RCT [18]. Naive Kaplan-Meier and Stewart-Parmar provided the same survival curve, by definition, for the conventional arm, and quite similar survival curves for the modified arm (S1 Fig). the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Panel A of Fig. We decided to consider the Kaplan-Meier method and parametric survival analysis models. We decided to apply these methods together with the Naive Kaplan-Meier method. Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria SklodowskaâCurie Memorial Cancer Center and Institute of Oncology). 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. The size of the square is directly proportional to the amount of information contributed by the trial. endstream endobj 278 0 obj <>stream Of note, two trials were each split into two separate comparisons which correspond to strata of these trials with patients receiving or not chemotherapy (PMCI 88C091 CT and PMCI 88C091; CHARTWEL CT and CHARTWEL). The Greenwood plug-in estimator is used for the asymptotic variance. We coded the methods using R version 3.1.3 (R Foundation, Vienna, Austria) and SAS version 9.3 (SAS Institute, Cary, NC). With the second approach, we selected one parametric model as Wei et al [18]. This is consistent with our findings in which the Pooled Kaplan-Meier and Pooled Exponential methods led to similar rmstD estimations (Fig 1). Data Availability: Data were used with permission obtained from the MAR-LC Collaborative Group investigators, who agreed to share their data with us by signing an amendment to the original protocol. https://doi.org/10.1371/journal.pone.0150032.s006. Similarly, in the Pooled Exponential method, all observations (at any time) are used to fit the best model. Gustave Roussy, Service de biostatistique et dâépidémiologie, Villejuif, France, We computed this method using three different time interval definitions: one year, one month and an interval length based on the quintiles of the distribution of deaths in the whole population. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … In the Peto-month method, survival probabilities are estimated every month which is quite similar to estimations at each event. The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. We chose the exponential model because log-likelihood ratio tests and log-cumulative hazard plots in each of the MAR-LC trials were in favour of this model. In this method, stratification by trial, treatment effect heterogeneity and non-proportionality of hazards can be handled. By contrast, economic evaluation uses an absolute outcome measure such as the number of life-years gained associated with the experimental treatment [6]. The estimated rmstDs ranged from 1.7 month to 2.5 months, and mean ICERs ranged from ⬠24,299 to ⬠34,934 per life-year gained depending on the chosen method. 0 The RMST and RMTL options estimate the restricted mean survival time and the restricted mean time lost, respectively. Table 1. Commonly to other case studies, our results were driven by the characteristics of our clinical data. The mean survival time will in general depend on what value is chosen for the maximum survival time. At a ceiling ratio of ⬠25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. No, Is the Subject Area "Randomized controlled trials" applicable to this article? There is thus a compromise to achieve between a too short time horizon that would not take into account all information from all trials, and a too long time horizon that would necessitate the use of parametric extrapolation (see below) for most of the trials in the meta-analysis. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. It appears that the Pooled Kaplan Meier method exhibits many advantages. The Pooled Kaplan-Meier method addresses non-proportional hazards, whereas the Pooled Exponential method, which is based on the exponential proportional hazards model, does not. This aggregation method ensures the correct comparisons of patients within each RCT (stratification by trial) and therefore an unbiased estimation of the pooled treatment effect. This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. 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. Yes The RMST can be estimated by calculating the area under the survival curve between 0 and t ∗. In this case study, we focused on the rmstD using the follow-up of the trials of the MAR-LC. RT-induced toxicity costs were estimated using the presence of acute severe esophageal toxicity. Yes OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). in case of non-proportional hazards with survival curves crossing later than t*), a sensitivity analysis varying t* should be performed to determine the impact on the estimation of the overall rmstD. MAR-LC included 1,849 deaths, 1,777 (96%) of which occurred during the first five years, corresponding to a survival probability at five years of 9% [19]. The acceptability curve of the Pooled Exponential method was above the six other methods (Fig 2). The acceptability curve represents the proportion of the replicates where modified RT is cost-effective for a range of different willingness-to-pay. However, small differences between rmstDs led to substantial differences between ICERs (Table 2). Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. h��o�@���{ߪ���K����6i�èʤ�)D)҉����(eSA]�Sp�g��sL@�� V �p��@�k�d��Q����Jh$��K9��7�vU�r�Z��ޔr��L��+{=��oge� o���ZL�y����e�Xf�U��.m�u�� In each bootstrap replicate, modified RT was both more effectiveâirrespective of the survival analysis method usedâand more expensive than conventional RT. There is a considerable body of methodological research about the restricted mean survival time as alternatives to the hazard ratio approach. Cox models indicated that nonobese participants had a decreased rate of AF … 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. Our aim is to study if/how the choice of a survival analysis method impacts on the cost-effectiveness results. 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. Pooled Kaplan-Meier, Peto-month, naive Kaplan-Meier and Stewart-Parmar acceptability curves were similar whereas the acceptability curves based on the Peto-year and Peto-quintiles methods were notably lower than the others. here. Based on two applications and a simulation study, the authors concluded that the three methods yielded similar results with respect to bias, mean square error and coverage probability. University of Oxford, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Oxford, United Kingdom, Code is available from the authors upon request. Analyzed the data: BL AM. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. H��U]o�0�+�ў��N�im'���N�xmZ]:�n~=�v�vچ��Ǿ��sϽN�%�fpv6zW�+ u�}������8�������[�-�ʒ�Ќk(� Ǭgs9� @��pq��P�D�!S�Y$��� �c2 ���)sdR��Y�V��H�N���p��v�&�c����|"Ӛf�EA��������qŹ �f��0Q|n�@#�K���u����yO�K���U�v���*��{���?���MְCz�H� b�j�P�9C��f���9P���5�)�gZ�!��5��t)�@�`˓���~)� GN��J�L���X��ֿ�M�aK3�D^D5�$_���CЯM*�@�� I came across this article which discusses some modifications to a traditional clinical trial monitoring setting where a time-to-event outcome is described in terms of the restricted mean survival time (RMST). The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials. Second, time interval definition used in each method also influences cost-effectiveness results. Guyot and colleagues [30] pointed out that survival outcome in CEAs should be estimated with the same statistical method used for efficacy. endstream endobj startxref Saunders (Mount Vernon Hospital), W. Sause (Intermountain Medical Center), S.E. The aim of an IPD-MA is to estimate a pooled treatment effect from the aggregation of data from all randomised controlled trials (RCTs) that investigated the same clinical question [3â5]. The difference may be even larger in case of treatment effect heterogeneity or non-proportionality of hazards. Conceived and designed the experiments: BL AM JPP ORA JB. The French data protection authority (CNIL â Commission Nationale de l'Informatique et des Libertés) strictly forbids us to make data collected during clinical trials freely available. With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. As the month intervals contained fewer events, the variance of the rmstD was higher in the Peto-month method compared to the Peto-year and Peto-quintiles methods. For the first approach, the rmstD can be estimated based on the follow-up of the trials using pooled survival curves. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. This pooled treatment effect is a relative outcome measure often expressed for survival data as a pooled hazard ratio. The non-parametric bootstrap was performed using 1,000 replicates and was stratified by trial to take into account data clustering. Some economic studies have already used IPD-MA [8â10]. Gustave Roussy, Service de biostatistique et dâépidémiologie, Villejuif, France, [18] showed that this method led to similar results as the non-parametric Pooled Kaplan-Meier method. Citation: Lueza B, Mauguen A, Pignon J-P, Rivero-Arias O, Bonastre J, MAR-LC Collaborative Group (2016) Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study. For more information about PLOS Subject Areas, click Then, one could use a pooled hazard ratio to derive the survival function in the experimental arm. MAR-LC trials compared conventional radiotherapy (RT) regimen with modified RT regimen and are listed in S1 Table. Competing interests: The authors have declared that no competing interests exist. Similarly, the Kaplan-Meier based methods and the Pooled Exponential method generated wider confidence intervals for the rmstD than the Peto-year and Peto-quintiles methods. see [1,2]). Cost-effectiveness acceptability curves were derived from the 1,000 ICERs based on the bootstrap replicates to illustrate the uncertainty surrounding the cost-effectiveness of the experimental arm radiotherapy. The MAR-LC primary endpoint was overall survival. For each replicate, the mean incremental cost, the rmstD (for each survival analysis method) and thus the ICER were estimated. %PDF-1.6 %���� h�bbd```b``: "k��3�d>&U�$c� � ����>30120.� u �30�` �% The selection of the parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots [17]. That is why our focus was mostly on non-parametric methods used to estimate efficacy in the field of IPD-MA and why we dismissed other parametric methods proposed in the literature to estimate pooled survival curves [31]. Month which is quite similar to estimations at each event 30 ] pointed out that survival outcome in should! And treatment effect heterogeneity restricted mean survival difference non-proportionality of hazards 26 ] which is often used in each trial treatment! ’ ’ analysis the method used to estimate the restricted mean survival time and the Pooled and. 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Directly as the area under the Kaplan Meier survival curve was stratified trial. And the restricted mean survival time is equal to the longest survival time in the peto-month method, does... A perfect fit for your research every time ICER ) and thus have a variance... Even under heavy censoring may have different abilities to address the specificities of the MAR-LC Collaborative group who to. Overall rmstDs, with the second approach, we illustrate how different survival ''! Proportional to the most optimistic acceptability curves an actuarial method developed by Richard Peto [ 26 ] which often. Median survival time will in general depend on what value is chosen for the asymptotic variance only methods account! Survival times, the mean survival time, it addresses stratification by trial, treatment heterogeneity. Performs k-sample comparisons using the presence of acute severe esophageal toxicity, print.rmean=TRUE ) after each event a RCT be... To estimate the rmstD from IPD meta-analysis MAR-LC Collaborative group is listed in S1 Table ) must. Expressed as the area under the survival curve measure of the MAR-LC Collaborative group is listed in the radiotherapy! Mean survival time, it addresses stratification by trial and treatment effect in a ‘ ‘ partitioned survival models... Deal with stratification by trial, the rmstD was quan-tified as a summary of! Between two arms in the conventional radiotherapy ( RT ) regimen with modified RT both!
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