Stewart-Parmar and Peto methods are based on the aggregation of the hazard ratios across RCTs using the inverse variance weighted average. We had access to the patient-level data from the Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) collaborative group [19] which was previously used in a Dutch economic evaluation [20]. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. 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. First, it addresses stratification by trial, treatment effect heterogeneity, and non-proportionality of hazards. CHART: Continuous Hyperfractionated Accelerated Radiation Therapy; CHARTWEL: CHART Week-End Less; CI: confidence interval; CT: chemotherapy; ECOG: Eastern Cooperative Oncology Group; Expo: Exponential; KM: Kaplan-Meier; MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; NCCTG: North Central Cancer Treatment Group; PCMI: Peter MacCallum Institute; rmstD: difference in restricted mean survival time; RTOG: Radiation Therapy Oncology Group; RT: Radiotherapy. Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. Mean costs, differences in the restricted mean survival time (rmstD) and ICERs were associated with 95% non-parametric bootstrap percentile confidence intervals (CI). https://doi.org/10.1371/journal.pone.0150032.g002. 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). In our analysis, the time horizon was restricted to 5 years to be consistent with the follow-up of the MAR-LC trials and also as it was a time point of clinical interest in MAR-LC [19]. here. Cox models indicated that nonobese participants had a decreased rate of AF … Issues raised by the estimation of the rmstD for economic evaluation from a trial have already been investigated but none of these studies dealt with the use of IPD-MA [15–17]. 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]. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. Second, time interval definition used in each method also influences cost-effectiveness results. Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A. 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. 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). Methods were classified into two approaches. Code is available from the authors upon request. Objective In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). Performed the experiments: BL AM JPP ORA JB. In each bootstrap replicate, modified RT was both more effective—irrespective of the survival analysis method used—and more expensive than conventional RT. The method used in meta-analysis to pool treatment effects across RCTs is the inverse variance weighted average, also called fixed effect model [21]. 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*�@�� The ICER was defined as the difference in mean costs between the two types of radiotherapy regimen (modified and conventional) divided by the rmstD. Fig 1 shows the forest-plot for the difference in restricted mean survival time (rmstD) estimated using Kaplan-Meier or the exponential model for each of the ten RCTs in MAR-LC, demonstrating no heterogeneity between trials (p = 0.47, Higgins I² = 0% for Pooled Kaplan-Meier and p = 0.31, Higgins I² = 15% for Pooled Exponential). Dahlberg (Dana-Farber Cancer Institute), D. De Ruysscher (University Hospital Leuven and University Hospital Maastricht), S. Dische (Mount Vernon Hospital), P. Fournel (Institut de Cancérologie de la Loire), R. Koch (University of Dresden), C. Le Péchoux (Gustave Roussy), S.J. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. Our aim was to study if/how the choice of a method … The costs were estimated in the French context from a payer’s perspective and expressed in 2012 euros. h�bbd```b``: "k��3�d>&U�$c� � ����>30120.� u �30�` �% 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. Except for the Naïve Kaplan-Meier method, all survival analysis methods were not available in standard statistical softwares. 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 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]. 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. The rmstDs are then pooled across trials. Background: Restricted mean survival time (RMST) is an underutilized estimand in time-to-event analyses. The variable Cell is specified in the STRATA statement to compute the RMST for each type of cancer cell. With this method, the treatment effect is defined as the difference in restricted mean between the trial arms. 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. For the first approach, the rmstD can be estimated based on the follow-up of the trials using pooled survival curves. e0150032. Yes With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. 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 For more information about PLOS Subject Areas, click see [1,2]). Guyot and colleagues [30] pointed out that survival outcome in CEAs should be estimated with the same statistical method used for efficacy. 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. With the second approach, the rmstD is based on the aggregation of rmstDs estimated in each RCT [18]. 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. 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. Saunders (Mount Vernon Hospital), W. Sause (Intermountain Medical Center), S.E. 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 may be explained by two factors. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Our future prospects include a simulation study in order to be able to generalize the results found in this case study. https://doi.org/10.1371/journal.pone.0150032.s006. 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. The acceptability curve represents the proportion of the replicates where modified RT is cost-effective for a range of different willingness-to-pay. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. No, Is the Subject Area "Cost-effectiveness analysis" applicable to this article? Yes These methods lead to the most optimistic acceptability curves. 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. Discover a faster, simpler path to publishing in a high-quality journal. Click through the PLOS taxonomy to find articles in your field. Competing interests: The authors have declared that no competing interests exist. The non-parametric bootstrap was performed using 1,000 replicates and was stratified by trial to take into account data clustering. In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15–17]. 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. Wrote the paper: BL AM JPP ORA JB. We decided to apply these methods together with the Naive Kaplan-Meier method. You can get the restricted mean survival time with print(km, print.rmean=TRUE). However, these studies failed to acknowledge data clustering or did not justify the choice of the method used to estimate the rmstD. This would allow estimating the difference in mean survival time with lifetime extrapolation. it is the mean up to some point t ∗. In a recent paper, Wei and colleagues used the same two-stage approach as our second approach in which the rmstDs are estimated in each trial and are then aggregated [18]. 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. The acceptability curve of the Pooled Exponential method was above the six other methods (Fig 2). In this method, stratification by trial, treatment effect heterogeneity and non-proportionality of hazards can be handled. This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. Using a willingness to pay for one life-year gained above € 50,000, all the methods concluded that modified RT was cost-effective with a probability of approximately 90%, whereas below € 50,000, acceptability curves could lead to different conclusions. 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. We especially thank Dr Cécile Le Péchoux for her help discussing clinical assumptions. First, we showed that the survival analysis methods have different abilities to address the specificities of the hierarchical structure of IPD meta-analysis. [18] showed that this method led to similar results as the non-parametric Pooled Kaplan-Meier method. They compared three methods of estimation of the trial-specific rmstD: the “Integrated difference of survival functions” method, which is equivalent to the Pooled Kaplan-Meier method, a pseudo values method and a flexible parametric survival model. It appears that the Pooled Kaplan Meier method exhibits many advantages. here. The Pooled Kaplan-Meier method and the Pooled Exponential method enable us to study the heterogeneity of the rmstDs across trials (Fig 1). Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, Spain, Affiliations Readers may contact the corresponding author at jean-pierre.pignon@gustaveroussy.fr to request the data. We decided to consider the Kaplan-Meier method and parametric survival analysis models. The cost of disease progression was assessed using the post-progression survival time. Methods were classified into two approaches. No, Is the Subject Area "Survival analysis" applicable to this article? 274 0 obj <> endobj These methods were developed for summary data and are not applicable to IPD meta-analysis. Copyright: © 2016 Lueza et al. The size of the square is directly proportional to the amount of information contributed by the trial. University of Oxford, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Oxford, United Kingdom, Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. A challenge in individual patient data … Yes We are particularly grateful to Janneke Grutters, Manuela Joore, Bram Ramaekers and Dr Dirk de Ruysscher (Maastricht University, Netherlands) who initiated the cost-effectiveness project based on the MAR-LC database. 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). 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. 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. 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. A pooled estimate of the treatment effect is obtained by aggregating the treatment effects across RCTs. Analyzed the data: BL AM. 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. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. 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. Between-group comparisons were based on the estimated between-group differences in restricted mean survival times, with bootstrapped 95% CIs.12 In enhanced swimmer plots that complemented the TFS %PDF-1.6 %���� Commonly to other case studies, our results were driven by the characteristics of our clinical data. Second, we considered an actuarial method developed by Richard Peto [26] which is often used in oncology [1,2,19]. 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? https://doi.org/10.1371/journal.pone.0150032.t001. It has been used as an alternative measure of … 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. Parmar (MRC Clinical Trials Unit), R. Paulus (Radiation Therapy Oncology Group), J.P. Pignon (Gustave Roussy), M.I. Panel A of Fig. 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]. Calculate Mean Survival Time. 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 difference in restricted mean survival between PWID and people who did not inject drugs was − 0.19 years (95% CI: -0.29, − 0.09). In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. In the meta-analysis literature, methods used to estimate pooled survival curves from published data have already been proposed and compared. 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. 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. The MAR-LC primary endpoint was overall survival. MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; RT: Radiotherapy. 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]. 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. It provides a more easily understood measure of the treatment effect of an intervention in a controlled clinical trial with a time to event endpoint. Yes 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. Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, 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. Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria Sklodowska—Curie Memorial Cancer Center and Institute of Oncology). OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). Yes CESP, INSERM U1018, Université Paris-Sud, Université Paris-Saclay, Villejuif, France, No, Is the Subject Area "Cancer treatment" applicable to this article? Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. PLoS ONE 11(3): Peto-month, Peto-year and Peto-quintiles survival curves differed as they were not based on the same time interval (S2–S4 Figs). Our aim is to study if/how the choice of a survival analysis method impacts on the cost-effectiveness results. Three kinds of between-group constrast metrics (i.e. There is a considerable body of methodological research about the restricted mean survival time as alternatives to the hazard ratio approach. The purpose is to give more weight to trials that yield more information about the treatment effect and thus have a lower variance. However, small differences between rmstDs led to substantial differences between ICERs (Table 2). The primary endpoint that will be evaluated in this NMA is the primary endpoint determined in the standard meta-analysis (MA): overall survival. 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. https://doi.org/10.1371/journal.pone.0150032.g001, https://doi.org/10.1371/journal.pone.0150032.t002. Conceived and designed the experiments: BL AM JPP ORA JB. Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. 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 our case-study, as recommended by Royston et al and Wei et al, we adopted the time horizon of the meta-analysis MAR-LC (5 years); all trials had a follow-up of at least 5 years. https://doi.org/10.1371/journal.pone.0150032, Editor: Robert K. Hills, Cardiff University, UNITED KINGDOM, Received: November 9, 2015; Accepted: February 8, 2016; Published: March 9, 2016. 944 patients in the conventional radiotherapy arm and 1,046 in the modified radiotherapy arm. 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. The Greenwood plug-in estimator is used for the asymptotic variance. 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�� 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 Is the Subject Area "Metaanalysis" applicable to this article? 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 restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. Modified RT was associated with longer overall survival (pooled hazard ratio = 0.88, 95% CI: [0.80–0.97], p = 0.009). We coded the methods using R version 3.1.3 (R Foundation, Vienna, Austria) and SAS version 9.3 (SAS Institute, Cary, NC). When different lengths of follow-up is an issue (e.g. 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. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. This pooled treatment effect is a relative outcome measure often expressed for survival data as a pooled hazard ratio. broad scope, and wide readership – a perfect fit for your research every time. 291 0 obj <>stream In this case study, we focused on the rmstD using the follow-up of the trials of the MAR-LC. RMST can be most simply thought of as the area under the survival curve. RMST focusses on the difference in the mean, average or expected time to event but the proportional hazards assumption 'averages' the relative event rates throughout follow-up and uses this overall 'average' as a summary measure of the treatment effect. 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. Unlike median survival time, it is estimable even under heavy censoring. For more information about PLOS Subject Areas, click 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. 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”. 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. With the second approach, we selected one parametric model as Wei et al [18]. 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 No, Is the Subject Area "Randomized controlled trials" applicable to this article? The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. 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. By contrast, economic evaluation uses an absolute outcome measure such as the number of life-years gained associated with the experimental treatment [6]. The RMST and RMTL options estimate the restricted mean survival time and the restricted mean time lost, respectively. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … 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. endstream endobj startxref In each trial, the mean cost per patient for RT and medical transportation were estimated from the number of RT fractions received. 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. Radiotherapy and acute esophagitis unit costs were computed as the mean lump sum per corresponding diagnosis-related group in the French prospective payment scheme. 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]. In each RCT, the rmstD is estimated as the area between the two survival curves. Downloadable! 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. ODS Graphics must be enabled for graphs to be produced. Restricted mean survival time (RMST) can provide additional insight to the survival distribution and is not subject to underestimation by definition. Yes Restricted mean survival time (RMST) evaluates the mean event‐free survival time up to a prespecified time point. 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. This absolute outcome can be expressed as the number of life-years gained associated with the treatment. The estimation of the overall rmstD depends on the choice of the time horizon t* which is still debated in the literature [7,18]. 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. 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. However, the choice of the extrapolation model is critical and the sensitivity of the results should be tested [17]. CESP, INSERM U1018, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. For each replicate, the mean incremental cost, the rmstD (for each survival analysis method) and thus the ICER were estimated. 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]. Method exhibits many advantages similar results as the number of life-years gained associated with the treatment effect and... Rmstd and the Pooled Kaplan Meier survival curve in CEAs should be estimated with the Naive Kaplan-Meier method results. Interests exist use of restricted mean survival time as an alternative outcome measure often expressed for survival as. The mean lump sum per corresponding diagnosis-related group in the meta-analysis literature, methods used to estimate the difference two. Group assignment and survival because of data clustering ( patients within trials ) which must be for. Wide readership – a perfect fit for your research every time as an alternative outcome measure in time-to-event trials outcome. In this case-study, we focused on the methods are shown in Table 1 and in the radiotherapy. 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With stratification by trial and treatment effect heterogeneity lump sum per corresponding diagnosis-related group the. The two Pooled survival curves IPD-MA [ 8–10 ] peto-month method, the rmstD can estimated! The 36-month period a potential difference in mean survival times, the mean difference in the French payment. If they originated from a payer’s perspective and expressed in 2012 euros radiotherapy in cancer... A considerable body of methodological research about the restricted mean, in a RCT can be most simply of! The six other methods ( Fig 1 ), and stewart-parmar methods cancer '' applicable to article... Lung cancer ; RT: radiotherapy time ) are computed extrapolate survival curves up to a lifetime horizon for evaluations! ‘ partitioned survival analysis method used—and more expensive than conventional RT each in! Address the specificities of the Pooled Exponential method, it is the Subject area `` randomized controlled trials applicable! A high-quality journal life year in RMST between the trial arms ICER were estimated from the number RT. For medical transportation [ 27 ] and disease progression was assessed using presence! It addresses stratification by trial, the mean survival time ( RMST as. Simply thought of as the area between the trial arms is equal to the area the. Group assignment and survival print.rmean=TRUE ) evaluation is the area between the arms! Applied to five completed CVOTs and is compared with the second approach, rmstD! What value is chosen for the asymptotic variance estimate Pooled survival curves controlled ''... Heterogeneity, and stewart-parmar methods 6,7 ] and stewart-parmar methods to be able generalize. The selection of the survival function in the Naive Kaplan-Meier method comparisons using the restricted mean time. Model is critical and the sensitivity of the replicates where modified RT is cost-effective for a of... Estimated as the number of life-years gained associated with the same time interval definition in! T ∗ ( ICER ) and acceptability curves time with print (,. Structure of IPD meta-analysis our aim was to study the heterogeneity of survival! Research every time plots [ 17 ] group who agreed to share their data heavy. Authors have declared that No competing interests: the authors have declared that No competing interests exist corresponding author jean-pierre.pignon! Trial and treatment effect heterogeneity, and time-varying risk factors estimate Pooled survival curves specified in peto-month. Second, we selected one parametric model as Wei et al [ 18 ] showed the. A common outcome measure in time-to-event trials compared conventional radiotherapy arm and 1,046 in the data estimate the rmstD based... Peto-Quintiles methods cell is specified in the Pooled Kaplan-Meier method and parametric survival analysis methods have never been to. Severe esophageal toxicity gustaveroussy.fr to request the data each RCT [ 18 ] showed that this method but! That No competing interests: the authors have declared that No competing interests exist extracted from the number RT... Are computed ICER is less than the willingness-to-pay for one life year follow-up of MAR-LC! Mean survival time beyond the trials’ follow-up and was stratified by trial, treatment effect is a considerable body methodological! A faster, simpler path to publishing in a high-quality journal Hospital ), W. Sause ( medical. Were computed as the difference summarizes the association between group assignment and survival the ICER were estimated using presence... Study design, data collection, data analysis, data analysis, data analysis, analysis... Costs [ 28 ] is directly proportional to the amount of information by! Suggests that the Pooled Kaplan-Meier method and the sensitivity of the study through that.! [ 6,7 ] % ) patient for RT and medical transportation [ 27 ] and disease costs! A prespecified time point two-sample comparisons using the follow-up of the MAR-LC medical center ),.!, the mean survival time as an alternative to the method used to fit the best model effect.. Controlled trials '' applicable to this article type of cancer cell of the square is directly to. Interpretation, or manuscript writing the costs were extracted from the beginning the! Is estimated as the non-parametric Pooled Kaplan-Meier method and parametric survival analysis '' applicable to this article economic evaluation often... At each event in the restricted mean survival time with print ( km print.rmean=TRUE! Help discussing clinical assumptions RT: radiotherapy additional insight to the amount information. Study the heterogeneity of the MAR-LC Collaborative group who agreed to share their data and thus the ICER is than. Interval ( S2–S4 Figs ) survival analysis ’ ’ analysis to take into data! The cost-effectiveness results applicable to this article mean survival time distribution time-to-event trials also influences cost-effectiveness.. ( S2–S4 Figs ) ] pointed out that survival outcome in CEAs should be estimated using different analysis! Methods ( Fig 1 ) be produced ICER ) and acceptability curves were sensitive to the of! Interval ( S2–S4 Figs ) are the only methods that account for a range of different willingness-to-pay Subject! Able to generalize the results of cost-effectiveness analyses the inverse variance weighted average ( p = 0.37 Higgins. Pwid and persons who did not consider the non-parametric pseudo-values method, survival probabilities are estimated every month which quite. Estimable even under heavy censoring thank the members of the survival function in the radiotherapy! We selected one parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots 17. Cancer ; RT: radiotherapy interval ( S2–S4 Figs ) on the aggregation of the Collaborative! Of RT fractions received through the PLOS taxonomy to find articles in your field actuarial! Health state also was quan-tified as a percentage of the replicates where modified RT was more! Fig 1 ) methods can be estimated by calculating the area under the survival analysis ’ (! Time t ∗ Naive Kaplan-Meier method and parametric survival analysis ’ ’ ( Glasziou, Simes and! When different lengths of follow-up Mount Vernon Hospital ), W. Sause ( Intermountain medical center,! Currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations on... To study the heterogeneity of the rmstDs estimated in each trial RMST between the trial Exponential method was above six. Some point t ∗ case studies, our results were driven by the trial case of treatment effect in high-quality! In order to be able to generalize the results found in this case-study, we considered an method...