A pooled estimate of the treatment effect is obtained by aggregating the treatment effects across RCTs. https://doi.org/10.1371/journal.pone.0150032.s006. 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. Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. We retained the exponential model. Three kinds of between-group constrast metrics (i.e. Survival curves for the two arms in MAR-LC estimated using Naive Kaplan-Meier and Stewart-Parmar, Peto-month, Peto-year and Peto-quintiles are respectively shown in S1âS4 Figs. Yes 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. Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. First, it addresses stratification by trial, treatment effect heterogeneity, and non-proportionality of hazards. There is a considerable body of methodological research about the restricted mean survival time as alternatives to the hazard ratio approach. The method used in meta-analysis to pool treatment effects across RCTs is the inverse variance weighted average, also called fixed effect model [21]. For more information about PLOS Subject Areas, click No, Is the Subject Area "Randomized controlled trials" applicable to this article?
With this method, stratification by trial and treatment effect heterogeneity are addressed but the treatment effect is assumed to be constant over time (proportional hazards assumption). I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. The mean survival time will in general depend on what value is chosen for the maximum survival time. List of the members of the MAR-LC Collaborative group: R. Arriagada (Gustave Roussy/Karolinska Institutet), K. Bae (Radiation Therapy Oncology Group), D. Ball (Peter MacCallum Cancer Centre and the University of Melbourne), M. Baumann (University of Dresden), K. Behrendt (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology), C.P. The cost of disease progression was assessed using the post-progression survival time. We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study By Béranger Lueza, Audrey Mauguen, Jean-Pierre Pignon, Oliver Rivero-Arias, Julia Bonastre and null null First, we showed that the survival analysis methods have different abilities to address the specificities of the hierarchical structure of IPD meta-analysis. These methods were developed for summary data and are not applicable to IPD meta-analysis. Similarly, in the Pooled Exponential method, all observations (at any time) are used to fit the best model. 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. 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 difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. 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*�@�� There was no treatment effect heterogeneity between trials (p = 0.37, Higgins I² = 8%). Gustave Roussy, Service de biostatistique et dâépidémiologie, Villejuif, France, Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A.
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). Calculate Mean Survival Time. 1 shows the difference in RMST to all-cause mortality comparing PWID and persons who did not … Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. With the second approach, we selected one parametric model as Wei et al [18]. 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 treatment effects to be pooled are mostly expressed in terms of log odds ratios or log hazard ratios for survival endpoints [21]. MAR-LC trials compared conventional radiotherapy (RT) regimen with modified RT regimen and are listed in S1 Table. Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, Spain, Affiliations All these methods have never been applied to assess the rmstD for economic evaluation. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. A challenge in individual patient data … This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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. 274 0 obj
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Conversely, in a recent paper, Wei and colleagues [18] compared three different methods to estimate the rmstD from IPD-MA but they did not study cost-effectiveness. The difference in restricted mean survival between PWID and people who did not inject drugs was − 0.19 years (95% CI: -0.29, − 0.09). endstream
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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. 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]. Discover a faster, simpler path to publishing in a high-quality journal. Our aim is to study if/how the choice of a survival analysis method impacts on the cost-effectiveness results. 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]. No, Is the Subject Area "Non-small cell lung cancer" applicable to this article? By contrast, the Peto-year and the Peto-quintiles methods yield different results because they are based on larger time intervals which provide less uncertainty in the rmstD estimation, possibly at the cost of being biased as they provide notably lower estimations for the rmstD as compared to the other studied methods. In each trial, the mean cost per patient for RT and medical transportation were estimated from the number of RT fractions received. Unlike median survival time, it is estimable even under heavy censoring. 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. Through this case study, we showed that different survival analysis methods used to estimate the difference in restricted mean survival time (rmstD) from IPD-MA may lead to different cost-effectiveness results. broad scope, and wide readership â a perfect fit for your research every time. 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. Methods were classified into two approaches. Peto-month, Peto-year and Peto-quintiles survival curves differed as they were not based on the same time interval (S2âS4 Figs). Performed the experiments: BL AM JPP ORA JB. They ranged from 1.7 month in the Peto-quintiles method to 2.5 months in the Pooled Exponential method. In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. 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. When different lengths of follow-up is an issue (e.g. Code is available from the authors upon request. Radiotherapy and acute esophagitis unit costs were computed as the mean lump sum per corresponding diagnosis-related group in the French prospective payment scheme. 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. 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). %%EOF
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. restricted mean time of each health state also was quan-tified as a percentage of the 36-month period. We applied Stewart and Parmar methodology [25] to estimate the pooled survival curve for the experimental arm using the pooled hazard ratio and the naive Kaplan-Meier survival curve in the control group. 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 … Some economic studies have already used IPD-MA [8â10]. The rmstDs are then pooled across trials. 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. Yes Background: Restricted mean survival time (RMST) is an underutilized estimand in time-to-event analyses. Bonner (University of Alabama-Birmingham), H. Choy (The University of Texas Southwestern), S.E. Then, parametric models can be used to estimate the difference in mean survival time beyond the trialsâ follow-up. By default, this assumes that the longest survival time is equal to the longest survival time in the data. 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 [22â24]. The results of the cost-effectiveness analysis were presented using the incremental cost-effectiveness ratios (ICER) expressed as the cost per life-year gained and cost-effectiveness acceptability curves [29]. Each trial is represented by a square, the center of which denotes the difference in restricted mean survival time (rmstD) for that trial comparison, with the horizontal lines showing the 95% CIs. However, the trials included in a meta-analysis may have different lengths of follow-up. OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). 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). RT-induced toxicity costs were estimated using the presence of acute severe esophageal toxicity. Cox models indicated that nonobese participants had a decreased rate of AF … Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations Is the Subject Area "Metaanalysis" applicable to this article? Guyot and colleagues [30] pointed out that survival outcome in CEAs should be estimated with the same statistical method used for efficacy. 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. ENDPOINT. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. No, Is the Subject Area "Radiation therapy" applicable to this article? In each bootstrap replicate, modified RT was both more effectiveâirrespective of the survival analysis method usedâand more expensive than conventional RT. endstream
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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, It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … PLoS ONE 11(3): We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. Alternatively, similarly to the Stewart-Parmar method and to the method used in a number of studies reviewed by Guyot and colleagues [30], one could fit a parametric model to compute the survival function in the control arm. This would allow estimating the difference in mean survival time with lifetime extrapolation. With a ceiling ratio of ⬠25,000 per life-year gained, the probability of modified RT being cost-effective ranged from 31% with Peto-quintiles to 68% with the Pooled Exponential method (Fig 2). here. The funding sources had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. Commonly to other case studies, our results were driven by the characteristics of our clinical data. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. With this approach, the pooled difference in restricted mean survival time (rmstD) is obtained aggregating the rmstDs estimated in each trial using an inverse variance weighted average. https://doi.org/10.1371/journal.pone.0150032.t001. The purpose is to give more weight to trials that yield more information about the treatment effect and thus have a lower variance. %PDF-1.6
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By contrast, economic evaluation uses an absolute outcome measure such as the number of life-years gained associated with the experimental treatment [6]. If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. https://doi.org/10.1371/journal.pone.0150032.s004, https://doi.org/10.1371/journal.pone.0150032.s005. Stewart-Parmar and Peto methods are based on the aggregation of the hazard ratios across RCTs using the inverse variance weighted average. MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; RT: Radiotherapy. Details on the methods are provided in Table 1 and in the S1 Supporting Information. The rmstDs estimated using the different survival analysis methods are shown in Table 2. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. The acceptability curve represents the proportion of the replicates where modified RT is cost-effective for a range of different willingness-to-pay. There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15â17]. Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria SklodowskaâCurie Memorial Cancer Center and Institute of Oncology). Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations Yes With the second approach, the rmstD is based on the aggregation of rmstDs estimated in each RCT [18]. 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 curve up to that point. The selection of the parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots [17]. Our future prospects include a simulation study in order to be able to generalize the results found in this case study. 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. The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. The difference may be even larger in case of treatment effect heterogeneity or non-proportionality of hazards. The primary endpoint that will be evaluated in this NMA is the primary endpoint determined in the standard meta-analysis (MA): overall survival. The size of the square is directly proportional to the amount of information contributed by the trial. CHART: Continuous Hyperfractionated Accelerated Radiation Therapy; CHARTWEL: CHART Week-End Less; CI: confidence interval; CT: chemotherapy; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio for Modified RT versus Conventional RT; MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; NCCTG: North Central Cancer Treatment Group; PCMI: Peter MacCallum Institute; RTOG: Radiation Therapy Oncology Group; RT: Radiotherapy; *: see reference [19] for further details and for the trials references. ODS Graphics must be enabled for graphs to be produced. However, small differences between rmstDs led to substantial differences between ICERs (Table 2). Table 1. 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. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. However, the choice of the extrapolation model is critical and the sensitivity of the results should be tested [17]. [18] showed that this method led to similar results as the non-parametric Pooled Kaplan-Meier method. This is consistent with our findings in which the Pooled Kaplan-Meier and Pooled Exponential methods led to similar rmstD estimations (Fig 1). The individual patient data meta-analysis (IPD-MA) has become the gold standard for obtaining the best evidence for treatment effects (e.g. Yes Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials. 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]. These methods lead to the most optimistic acceptability curves. The mean total cost per patient was ⬠25,331 (95% CI: ⬠23,630â⬠27,115) for conventional RT and ⬠29,659 (95% CI: ⬠27,845â⬠31,507) for modified RT, corresponding to a mean incremental cost of ⬠4,328 (95% CI: ⬠1,830â⬠6,804). Second, we considered an actuarial method developed by Richard Peto [26] which is often used in oncology [1,2,19]. 283 0 obj
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With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. Mean costs, differences in the restricted mean survival time (rmstD) and ICERs were associated with 95% non-parametric bootstrap percentile confidence intervals (CI). The difference between two arms in the restricted mean survival time is an alternative to the hazard ratio. The non-parametric bootstrap was performed using 1,000 replicates and was stratified by trial to take into account data clustering. We decided to apply these methods together with the Naive Kaplan-Meier method. 3-5 It is equivalent to the area under the Kaplan-Meier curve from the beginning of the study through that point. We especially thank Dr Cécile Le Péchoux for her help discussing clinical assumptions. The difference in restricted mean survival time (rmstD(t∗)), the area between two survival curves up to time horizon t∗, is often used in cost-effectiveness analyses to estimate the treatment effect in randomized controlled trials. No, Is the Subject Area "Oncology" applicable to this article? see [1,2]). However, all the survival analysis methods we studied in this paper can provide an estimation of the difference in mean survival time with lifetime extrapolation. 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. For more information about PLOS Subject Areas, click However, these studies failed to acknowledge data clustering or did not justify the choice of the method used to estimate the rmstD. 0r�n��`����:&��{��)g�fQ�B��b�3��F9���%��Î�^[m�u+dz�{c�P'(���'��ˑ�u���%�j�6&���
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