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. Discover a faster, simpler path to publishing in a high-quality journal. Mean ICERs ranged from € 24,299 to € 34,934 per life-year gained, respectively for the Pooled Exponential and the Peto-quintiles methods (Table 2). As a matter of fact, research on methods used to conduct economic evaluation based on IPD-MA is still in its infancy [11–14]. It appears that the Pooled Kaplan Meier method exhibits many advantages. No, Is the Subject Area "Radiation therapy" applicable to this article? Yes h�b```�f�;B cB�I;'0�X�b9���8��ۀ�q��T����T�,�F� � 蚀f�0���fbn�љAH%0ؘψ*}!G>�� ä�����+$8dz�4�}ܿ@X )Y�0���@� ��$� 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. These methods lead to the most optimistic acceptability curves. The rmstDs are then pooled across trials. 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. Three kinds of between-group constrast metrics (i.e. The costs were estimated in the French context from a payer’s perspective and expressed in 2012 euros. When different lengths of follow-up is an issue (e.g. In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). The Pooled Kaplan-Meier method and the Pooled Exponential method enable us to study the heterogeneity of the rmstDs across trials (Fig 1). Performed the experiments: BL AM JPP ORA JB. Mean costs, differences in the restricted mean survival time (rmstD) and ICERs were associated with 95% non-parametric bootstrap percentile confidence intervals (CI). In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. 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. The restricted mean survival time at time t ∗ is defined as, E [ m i n (t, t ∗)] i.e. The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. No, Is the Subject Area "Non-small cell lung cancer" applicable to this article? The funding sources had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. For the first approach, the rmstD can be estimated based on the follow-up of the trials using pooled survival curves. 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. 1 shows the difference in RMST to all-cause mortality comparing PWID and persons who did not … With the second approach, we selected one parametric model as Wei et al [18]. https://doi.org/10.1371/journal.pone.0150032.t001. PLoS ONE 11(3): Restricted mean survival time (RMST) evaluates the mean event‐free survival time up to a prespecified time point. 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. 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. Yes 274 0 obj <> endobj 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. Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, Click through the PLOS taxonomy to find articles in your field. No, Is the Subject Area "Survival analysis" applicable to this article? Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria Sklodowska—Curie Memorial Cancer Center and Institute of Oncology). The French data protection authority (CNIL – Commission Nationale de l'Informatique et des Libertés) strictly forbids us to make data collected during clinical trials freely available. The ICER was defined as the difference in mean costs between the two types of radiotherapy regimen (modified and conventional) divided by the 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]. This may be explained by two factors. 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. Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A. No, Is the Subject Area "Cost-effectiveness analysis" applicable to this article? * E-mail: beranger.lueza@gustaveroussy.fr, Affiliations The mean survival time will in general depend on what value is chosen for the maximum survival time. 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 broad scope, and wide readership – a perfect fit for your research every time. Some economic studies have already used IPD-MA [8–10]. Methods were classified into two approaches. The treatment effect in a RCT can be defined as the difference in RMST between the randomized arms at time t ∗. The difference may be even larger in case of treatment effect heterogeneity or non-proportionality of hazards. Peto-month, Peto-year and Peto-quintiles survival curves differed as they were not based on the same time interval (S2–S4 Figs). 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]. %PDF-1.6 %���� The unit costs were extracted from the literature for medical transportation [27] and disease progression costs [28]. We are grateful to Jean Bouyer, Ariane Dunant, Matthieu Faron, Gwenael Le Teuff, Stefan Michiels and Federico Rotolo for scientific discussions and support. 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). Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. 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. here. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. 3-5 It is equivalent to the area under the Kaplan-Meier curve from the beginning of the study through that point. 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. Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. The difference between two arms in the restricted mean survival time is an alternative to the hazard ratio. %%EOF We especially thank Dr Cécile Le Péchoux for her help discussing clinical assumptions. RMST is the area under the Kaplan Meier survival curve. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. Cox models indicated that nonobese participants had a decreased rate of AF … Restricted mean survival time (RMST) can provide additional insight to the survival distribution and is not subject to underestimation by definition. There was no treatment effect heterogeneity between trials (p = 0.37, Higgins I² = 8%). All these methods have never been applied to assess the rmstD for economic evaluation. Panel A of Fig. The estimation of the overall rmstD depends on the choice of the time horizon t* which is still debated in the literature [7,18]. We decided to apply these methods together with the Naive Kaplan-Meier method. 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 [3–5]. 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. �n��p�Nxa�o&�g}[&�p��\�;o����k��и�^�� !����i�'H2|�4��wI0�|. Yes 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. 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. 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�� So far, two non-parametric methods (Stewart-Parmar and Peto methods) have been used for estimating pooled survival curves from IPD meta-analysis [25,26]. The RMST can be estimated by calculating the area under the survival curve between 0 and t ∗. 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. Table 1. 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. Conversely, a common outcome measure in economic evaluation is the difference in the restricted mean survival time (rmstD) [6,7]. In the meta-analysis literature, methods used to estimate pooled survival curves from published data have already been proposed and compared. 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). We adjusted for sex, age, and time-varying risk factors. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. Parmar (MRC Clinical Trials Unit), R. Paulus (Radiation Therapy Oncology Group), J.P. Pignon (Gustave Roussy), M.I. 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. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. 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. MAR-LC trials compared conventional radiotherapy (RT) regimen with modified RT regimen and are listed in S1 Table. 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 treatment effects to be pooled are mostly expressed in terms of log odds ratios or log hazard ratios for survival endpoints [21]. 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). Analyzed the data: BL AM. Code is available from the authors upon request. Wrote the paper: BL AM JPP ORA JB. https://doi.org/10.1371/journal.pone.0150032.s006. Survival probabilities in each arm are estimated at predetermined time intervals from the pooled hazard ratio, which may vary between time periods, and from the survival probability of the whole population (both control and experimental arms). https://doi.org/10.1371/journal.pone.0150032.g001, https://doi.org/10.1371/journal.pone.0150032.t002. Second, time interval definition used in each method also influences cost-effectiveness results. In each trial, the mean cost per patient for RT and medical transportation were estimated from the number of RT fractions received. 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 … 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. ODS Graphics must be enabled for graphs to be produced. 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. 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. We decided to consider the Kaplan-Meier method and parametric survival analysis models. 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. Downloadable! Our future prospects include a simulation study in order to be able to generalize the results found in this case study. They ranged from 1.7 month in the Peto-quintiles method to 2.5 months in the Pooled Exponential method. The diamonds represent overall rmstDs, with the center denoting the rmstD and the extremities the 95% CI. 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 this method, stratification by trial, treatment effect heterogeneity and non-proportionality of hazards can be handled. Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations Yes CESP, INSERM U1018, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. 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. 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. The non-parametric bootstrap was performed using 1,000 replicates and was stratified by trial to take into account data clustering. 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 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. Saunders (Mount Vernon Hospital), W. Sause (Intermountain Medical Center), S.E. 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). e0150032. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. By default, this assumes that the longest survival time is equal to the longest survival time in the data. Yes PLOS ONE promises fair, rigorous peer review, 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. The difference summarizes the association between group assignment and survival. Calculate Mean Survival Time. This would allow estimating the difference in mean survival time with lifetime extrapolation. Readers may contact the corresponding author at jean-pierre.pignon@gustaveroussy.fr to request the data. 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. Conceived and designed the experiments: BL AM JPP ORA JB. Contributed reagents/materials/analysis tools: BL AM JPP ORA JB. Then, parametric models can be used to estimate the difference in mean survival time beyond the trials’ follow-up. A challenge in individual patient data … This is consistent with our findings in which the Pooled Kaplan-Meier and Pooled Exponential methods led to similar rmstD estimations (Fig 1). 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. 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. 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 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. Then, one could use a pooled hazard ratio to derive the survival function in the experimental arm. It can also account for a potential difference in the treatment effect between trials (between-trial heterogeneity). Is the Subject Area "Metaanalysis" applicable to this article? Details on the methods are provided in Table 1 and in the S1 Supporting Information. 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%. 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. 291 0 obj <>stream Unlike median survival time, it is estimable even under heavy censoring. 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. 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. First, it addresses stratification by trial, treatment effect heterogeneity, and non-proportionality of hazards. 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 S1–S4 Figs. 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. 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�� Choice of the MAR-LC the Peto and Pooled Exponential methods led to similar rmstD (..., W. Sause ( Intermountain medical center ), S.E ‘ QTWIST ’ ’ restricted mean survival difference. Trial, the mean incremental cost, the rmstD is then the area between the Kaplan-Meier... 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Pooled Kaplan-Meier and Pooled Kaplan-Meier method were computed as the mean up to lifetime. Trial arms the proportion of the trials of the study through that point structure of IPD meta-analysis AM JPP JB. Mean time lost, respectively sources had No role in study design, data collection, collection... Even under heavy censoring cost, the Kaplan-Meier curve from the number of life-years gained associated with the Kaplan-Meier...