Articles de revues : « Survival endpoint »

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Bensimon, Gilbert. « Survival endpoint : Pro ». Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 3, sup1 (septembre 2002) : S35—S36. http://dx.doi.org/10.1080/146608202320374237.

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Rosenfeld, Jeffrey. « Survival endpoint : Con ». Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 3, sup1 (septembre 2002) : S37—S39. http://dx.doi.org/10.1080/146608202320374246.

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Meininger, Vincent. « Survival endpoint : Summary ». Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 3, sup1 (septembre 2002) : S41—S44. http://dx.doi.org/10.1080/146608202320374255.

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Hahn, Andreas, Andreas Podbielski, Markus M. Heimesaat, Hagen Frickmann et Philipp Warnke. « Binary surrogate endpoints in clinical trials from the perspective of case definitions ». European Journal of Microbiology and Immunology 11, n^o 1 (30 mars 2021) : 18–22. http://dx.doi.org/10.1556/1886.2020.00031.

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AbstractIntroductionSurrogate endpoints are widely used in clinical trials, especially in situations where the endpoint of interest is not directly observable or to avoid long trial periods. A typical example for this case is frequently found in clinical trials in oncology, where overall survival (OS) as endpoint of interest and progression free survival (PFS) as surrogate endpoint are discriminated.MethodsBased on the perspective of case definitions on surrogate endpoints, we provide a formal definition of such endpoints followed by a description of the structure of surrogate endpoints.ResultsSurrogate endpoints can be considered as case definitions for the endpoint of interest. Therefore, the performance of surrogate endpoints can be described using the classical terminology of diagnostic tests including sensitivity and specificity. Since such endpoints always focus on sensitivity with necessarily reduced specificity, efficacy estimates based on such endpoints are in general biased.ConclusionThe abovementioned has to be taken into account while interpreting the results of clinical trials and should not be ignored while planning or conducting a study.

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Schmidt, Rene. « INSP-04. Confirmatory adaptive designs for survival trials with several time-to-event endpoints ». Neuro-Oncology 24, Supplement_1 (1 juin 2022) : i187. http://dx.doi.org/10.1093/neuonc/noac079.700.

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Abstract Confirmatory adaptive designs comprise a range of statistical methods that allow to modify the sample size of an ongoing trial in a data-dependent way without compromising control of the type I error rate. For short-term endpoints (e.g., 3-month response rate), comprehensive methodology of adaptive designs exists. However, clinical trials in oncology often have a special focus on long-term outcome and therefore often choose a time-to-event endpoint as the primary endpoint. Typical examples are progression-free survival (PFS) or overall survival (OS). But subtle statistical problems arise when adaptively analysing survival trials. Classical designs for survival trials are therefore commonly limited to a single primary endpoint, which combines the occurrence of progression, toxicities, deaths, and other events of potential interest into a single statistical measure (composite endpoint). However, the complexity of oncological diseases can be mapped more accurately using multi-stage models, where the occurrence of progressions, toxicities and deaths is modelled jointly instead of combining them into a single composite endpoint. We present and discuss adaptive design methodology for single-arm phase II survival trials for testing hypotheses on the joint distribution of several time-to-event endpoints in the context of multi-state models. We illustrate the methodology using the example of adaptive hypothesis tests for the joint distribution of progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model. The methodology is motivated from application in pediatric oncology.

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Mushtaq, Muhammad Umair, Moazzam Shahzad, Ezza Tariq, Muhammad Arslan, Sara Shahid, Raza Ur Rahman, Faryal Murtaza et al. « Use of Endpoints in Phase III Randomized Controlled Trials for Hematopoietic Stem Cell Transplantation over the Last 15 Years : A Systematic Review ». Blood 138, Supplement 1 (5 novembre 2021) : 4910. http://dx.doi.org/10.1182/blood-2021-146218.

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Abstract Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of a therapy or intervention. Use of clinically meaningful pre-specified endpoints is essential for a successful clinical trial. In this systemic review, we aimed to investigate different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for hematopoietic stem cell transplantation (HCT), and their trends over a span of 15 years. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "hematopoietic stem cell transplantation" AND "Randomized Controlled Trials as Topic" from January 2006 to May 2021. We screened 2223 articles. After excluding duplicates, reviews, and irrelevant articles, 170 articles reporting only phase III RCTs with primary and secondary endpoints on HCT were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 154 phase III RCTs on HCT. DFS was the primary endpoint in 40 (26%) studies, while OS and graft versus host disease (GvHD) were reported as primary endpoints in 40 (26%) and 13 (8%) studies, respectively. Infections, response rate, relapse rate (RR), toxicity/adverse events, quality of life (QoL), non-relapse mortality (NRM)/transplant-related mortality (TRM), GvHD-free survival, and hematological improvement (HI) were used as primary endpoints in 13 (8%), 13 (8%), 12 (8%), 8 (5%), 7 (4.5%), 7 (4.5%), 6 (4%), and 5 (3%) studies respectively. Other infrequently reported primary endpoints are listed in Table 1. Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=26, 40%), toxicity/adverse events (n=33, 21%), and TRM/NRM (n=33, 21%) were commonly reported secondary endpoints. DFS, GvHD, RR, QoL, infections, response rate, disease progression, and hematopoietic engraftment were used as secondary endpoints in 29 (19%), 28 (18%), 21 (14%), 17 (11%), 17 (11%), 13 (8%), 8 (5%), and 8 (5%) studies, respectively. After 2013, decrease in the use of DFS (27% to 25%) and OS (31% to 23%) as a primary endpoint was noted. For secondary endpoints, a higher trend in the use of OS (18% to 30%) and NRM/TRM (18% to 23%) was observed after 2013. (Table 2) Conclusion: Disease-free survival was the most common primary endpoint and overall survival was the most common secondary endpoint in phase III randomized controlled trials for hematopoietic stem cell transplantation over the last 15 years. The use of QoL as an endpoint remained low in RCTs. Newly introduced composite endpoint of GvHD-free relapse-free survival (GRFS) may be considered as a primary endpoint in future prospective studies. Figure 1 Figure 1. Disclosures Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding.

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Narayanan, Siva, Dong Shao, Anshul Shah et Vidya Ramesh. « Use of intermediate clinical endpoints (ICE) as a primary efficacy endpoint in malignant melanoma. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : e21075-e21075. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e21075.

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e21075 Background: Melanoma incidence in the US has seen a considerable increase, from 17.8 (1997) to 24.0 (2013) per 100,000, with localized melanoma accounting for 84% of all cases. Early detection and treatment can improve outcomes considerably, resulting in a 99% survival rate. The FDA, within its accelerated approval program, accepts ICE as a primary endpoint, shortening time for patient access to life saving medications. Our objective was to study use of ICE as a primary endpoint for therapies targeting non-metastatic/early-stage malignant melanoma. Methods: A systematic review was conducted in PubMed to identify clinical trials using ICE as a primary endpoint in early stage (non-metastatic, stage I or II) malignant melanoma. An additional search was conducted in clinicaltrials.gov to identify ICE as a primary endpoint in on-going malignant melanoma trials (assess evidence body being built). Searches were limited to the English language, between November 2011 and October 2016. Studies reporting only overall survival (OS) as the primary endpoint were excluded. Results: Of the 226 titles and abstracts screened from PubMed, seven trials were included in the analysis. Of 440 records screened from www.clinicaltrials.gov, one was included, resulting in eight studies of randomized phase 3 trials. Relapse-free survival (RFS) and disease-free survival (DFS) were reported in 3 trials each, and represent the most frequently reported primary ICE (38% each). RFS/DFS is defined as the time from randomization to recurrence of disease or death, and combined, encompass 75% of reported ICE. Other ICE reported were distant metastasis free interval (DMFI, 1 trial) and lymphnode field relapse (1 trial). One trial reported OS as a co-primary endpoint. Conclusions: Definitions of the most observed ICE in malignant melanoma, namely, RFS and DFS, appear to overlap, warranting further investigation into consolidation of outcomes to better assess the value of intermediate endpoints in early stage malignant melanoma. Findings indicate a slow, but growing body of evidence supporting ICE as a primary endpoint in malignant melanoma, bringing focus to prevention or delay of disease progression to alleviate patient burden.

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Buyse, M. E., K. J. Punt, C. H. Köhne, P. Hohenberger, R. Labianca, H. J. Schmoll, L. Pahlman, A. F. Sobrero et J. Y. Douillard. « Endpoints in adjuvant trials : A systematic review of the literature in colon cancer and proposed definitions for future trials ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 4018. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4018.

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4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.

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Chen, Tai-Tsang. « Milestone survival (MS) : An alternative survival endpoint in cancer immunotherapies. » Journal of Clinical Oncology 33, n^o 15_suppl (20 mai 2015) : e20004-e20004. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.e20004.

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Hammel, Pascal, Ewa Carrier, Mairead Carney, Mark Eisner et Thomas Fleming. « A novel event-free survival endpoint in locally advanced pancreatic cancer ». Therapeutic Advances in Medical Oncology 13 (janvier 2021) : 175883592110595. http://dx.doi.org/10.1177/17588359211059586.

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The treatment paradigm for locally advanced pancreatic cancer (LAPC) is evolving rapidly. The development of neoadjuvant therapies composed of combination therapies and the evaluation of their impact on conversion to borderline resectable (BR) status, resection, and ultimately overall survival (OS) are presently being pursued. These efforts justify re-visiting study endpoints in order to better predict therapeutic effects on OS, by capturing not only the achievement of R0 resection at the end of induction therapy but also the long-term reductions in the rate of local and distal recurrence. The proposed herein event-free survival (EFS) endpoint, with its novel definition specific to LAPC, is formulated to achieve these objectives. It is an analog to disease-free survival (DFS) endpoint in the adjuvant setting applied to the neoadjuvant setting and may be a valuable surrogate endpoint for this patient population.

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Emura, Takeshi, Casimir Ledoux Sofeu et Virginie Rondeau. « Conditional copula models for correlated survival endpoints : Individual patient data meta-analysis of randomized controlled trials ». Statistical Methods in Medical Research 30, n^o 12 (9 octobre 2021) : 2634–50. http://dx.doi.org/10.1177/09622802211046390.

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Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox ( https://CRAN.R-project.org/package=joint.Cox ). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm ( p-value<0.001), whereas disease-free survival remains a valid surrogate at individual level for overall survival in these trials.

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Knox, Jennifer J. « Progression-free survival as endpoint in metastatic RCC ? » Lancet 372, n^o 9637 (août 2008) : 427–29. http://dx.doi.org/10.1016/s0140-6736(08)61040-5.

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Gharzai, Laila A., Ralph Jiang, Elizabeth Jaworski, Krystal A. Morales, Robert Timothy Dess, William C. Jackson, Holly Hartman et al. « Candidate surrogate endpoints in advanced prostate cancer : Aggregate meta-analysis of 143 randomized trials. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 5039. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.5039.

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5039 Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2 > 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.

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Tuma, R. « Progression-Free Survival Remains Debatable Endpoint in Cancer Trials ». JNCI Journal of the National Cancer Institute 101, n^o 21 (14 octobre 2009) : 1439–41. http://dx.doi.org/10.1093/jnci/djp399.

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Masson-Lecomte, Alexandra, Victoire Vaillant, Mathieu Roumiguié, Stéphan Lévy, Benjamin Pradère, Michaël Peyromaure, Igor Duquesne et al. « Oncological Outcomes of Distal Ureterectomy for High-Risk Urothelial Carcinoma : A Multicenter Study by The French Bladder Cancer Committee ». Cancers 14, n^o 21 (6 novembre 2022) : 5452. http://dx.doi.org/10.3390/cancers14215452.

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Upper urinary tract urothelial carcinoma (UTUC) is an uncommon disease and its gold-standard treatment is radical nephroureterectomy (RNU). Distal ureterectomy (DU) might be an alternative for tumors of the distal ureter but its indications remain unclear. Here, we aimed to evaluate the oncological outcomes of DU for UTUC of the pelvic ureter. We performed a multicenter retrospective analysis of patients with UTUC who underwent DU. The primary endpoint was 5-year cancer-specific survival (CSS), followed by overall survival (OS), intravesical recurrence-free (IVR) and homolateral urinary tract recurrence-free (HUR) survivals as secondary endpoints. Univariate and multivariate Cox regressions were performed to assess factors associated with outcomes. 155 patients were included, 91% of which were high-risk. 5-year CSS was 84.4%, OS was 71.9%, IVR-free survival was 43.6% and HUR-free survival was 74.4%. Multifocality, high grade and tumor size were the most significant predictors of survival endpoints. Of note, neither hydronephrosis nor pre-operative diagnostic ureteroscopy/JJ stent were associated with any of the endpoints. Perioperative morbidity was minimal. In conclusion, DU stands as a possible alternative to RNU for UTUC of the pelvic ureter. Close monitoring is mandatory due to the high risk of recurrence in the remaining urinary tract.

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Heller, Glenn, Robert Thomas Mccormack, Thian Kheoh, Matthew Raymond Smith, Robert Dreicer, Fred Saad, Ronald De Wit et al. « Circulating tumor cell (CTC) number as a response endpoint in metastatic castration resistant (mCRPC) compared with PSA across five randomized phase 3 trials. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 5007. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5007.

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5007 Background: Radiographic progression and overall survival (OS) are the traditional clinical benefit measures for mCRPC trials. Reliable indicators of response that occur early are a critical unmet need in practice and clinical research. We explored a week 13 CTC and prostate-specific antigen (PSA) endpoint relative to baseline in 5 prospective randomized phase 3 registration trials that enrolled 5912 pts. OS was the primary endpoint. Methods: CTC number (CellSearch) and PSA values in patients who survived at least 13 weeks were evaluated as response endpoints in COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4 and COMET-1. Pts with missing values at week 13 were considered non-responders. The endpoints considered are shown in Table 1. Results: The discriminatory strength of the response endpoints with respect to OS was estimated using the weighted c-index. To summarize discrimination results for each measure, the mean and the standard deviation based on the weighted c-indices from the 5 studies were computed. Conclusions: CTC0 and CTC conversion endpoints had the highest discriminatory power for OS relative to the % decline in CTC or PSA endpoints. The percent of pts eligible and evaluable for the CTC0 endpoint was significantly higher than the conversion endpoint, 75% vs. 51%, respectively. These two absolute measures of CTC can be considered meaningful response indicators in mCRPC clinical trials. [Table: see text] [Table: see text]

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Eaton, Anne, Terry Therneau et Jennifer Le-Rademacher. « Designing clinical trials with (restricted) mean survival time endpoint : Practical considerations ». Clinical Trials 17, n^o 3 (17 février 2020) : 285–94. http://dx.doi.org/10.1177/1740774520905563.

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Background/aims: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators’ lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. Methods: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. Results: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. Conclusion: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.

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Buyse, Marc, Everardo D. Saad, Tomasz Burzykowski, Meredith M. Regan et Christopher S. Sweeney. « Surrogacy Beyond Prognosis : The Importance of “Trial-Level” Surrogacy ». Oncologist 27, n^o 4 (4 mars 2022) : 266–71. http://dx.doi.org/10.1093/oncolo/oyac006.

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Abstract Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.

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Le Tourneau, C., S. Michiels, H. Gan et L. Siu. « Reporting of endpoints and tracking of failures in randomized trials of radiotherapy or concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer (LA-HNSCC) ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : 6072. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6072.

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6072 Background: Due to their anatomical complexity, the interactive effects of multiple treatment modalities, the difficulties in differentiating scar tissues versus residual disease and second cancers versus tumor recurrence, LA-HNSCC represent a challenging disease for the reporting of endpoints and the tracking of failures. Methods: We retrieved all randomized trials that began accrual on or after 1978, and enrolled previously untreated nonmetastatic HNSCC patients receiving primary (chemo)radiotherapy. The reporting of endpoints and the tracking of failures in these trials were analyzed. Failures were defined as events meeting a pre-specified endpoint definition. Results: Forty trials involving 13,892 patients fulfilled our inclusion criteria. A total of 125 endpoints were identified: primary versus secondary = 34:91, survival-based (e.g., overall survival [OS]) versus surrogate (e.g. locoregional control [LRC]) = 47:78. In 6 trials, no primary endpoint was identified. LRC and OS accounted for 70% of primary endpoints. All but one trial reported at least one secondary endpoint, with a median of 2 per trial (range: 0–5), and as many as 17 different types of secondary endpoints were reported. Among 72 endpoints tracking locoregional failures, 21/72 (29%) did not define locoregional failure, while 46/72 (64%) specified the absence of complete response as a failure. Whether salvage surgery or elective node dissection was performed or not was reported in less than half of the trials. Furthermore, it was usually not specified if residual disease found during these procedures would account for failure or not. The means (i.e. clinical and/or radiological examinations) to ascertain failures and the protocol-specified timing to track failures were reported in 41% and 67% of surrogate endpoints, respectively. The tracking of other types of failure beyond the first failure is not reported by any of the trials. The reporting of second cancers was found in 15/40 (38%) trials, whereas the duration of follow-up was quantified in 31/40 (78%) trials. Conclusions: These results demonstrate the vast heterogeneity in endpoint reporting and tracking of failures in clinical trials of LA-HNSCC. No significant financial relationships to disclose.

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Shahzad, Moazzam, Muhammad Arslan, Sibgha Gull Chaudhary, Raheel S. Siddiqui, Ezza Tariq, Faryal Murtaza, Sara Shahid et al. « Use of Endpoints in Phase III Randomized Controlled Trials for Acute Myeloid Leukemia over the Last 15 Years : A Systematic Review ». Blood 138, Supplement 1 (5 novembre 2021) : 4389. http://dx.doi.org/10.1182/blood-2021-145545.

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Abstract Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of therapy or intervention. We systematically evaluated the proportion of different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for acute myeloid leukemia (AML), and their trends over time. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Randomized Controlled Trials as Topic" from January 2006 to March 2021. We screened 3290 articles. After excluding duplicates, reviews, and irrelevant articles, 241 articles reporting only phase III RCTs with primary and secondary endpoints on AML or its subtypes were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies, and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 241 phase III RCTs on AML. OS was the primary endpoint in 114 (47%) studies, while DFS and complete remission (CR) were reported as primary endpoints in 67 (28%) and 41 (17%) studies, respectively. Safety/adverse events, relapse rate (RR), graft versus host disease (GvHD) free survival, hematological improvement (HI), minimal residual disease (MRD), and non-relapse mortality (NRM) were used as primary endpoints in 10 (4%), 8 (3%), 5 (2%), 4 (2%), 3 (1%), and 2 (1%) studies respectively. Incidence of hospitalization, fungal disease, lung infiltrates, chronic GvHD, and allogeneic stem cell transplant each were used as primary endpoints in 1 (0.4%) study. (Table 1) Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=74, 31%), DFS (n=77, 32%) and CR (n=73, 30%) were commonly reported secondary endpoints. Safety/adverse effects, RR, mortality, quality of life (QoL), HI, MRD, incidence/length of hospitalization, and acute/chronic GvHD were used as secondary endpoints in 35 (14.5%), 15 (6%), 13 (5%), 9 (4%), 9 (4%), 7 (3%), 7 (3%), 5 (2%), and 4 (2%) studies, respectively. After 2013, increase in the use of OS (31% to 52%) and CR (15% to 17%) as a primary endpoint was noted, while the use of DFS as a primary endpoint decreased from 52% to 21%. (Table 1) For secondary endpoints, a higher trend in the use of DFS (19% to 35%) and OS (31% to 45%) and a lower trend in the use of CR (35% to 29%) was observed after 2013. (Table 2) Conclusion: Overall survival and disease-free survival were the most used primary and secondary endpoints in phase III randomized controlled trials for AML. There has been an increase in the use of clinically meaningful and objective endpoint of OS over the past 15 years in AML phase III RCTs. Figure 1 Figure 1. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; Dynavex: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. McGuirk: Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding.

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Topkan, Erkan, Yurday Ozdemir, Ahmet Kucuk, Ozan Cem Guler, Ahmet Sezer, Ali Ayberk Besen, Huseyin Mertsoylu et al. « Low Advanced Lung Cancer Inflammation Index Predicts Poor Prognosis in Locally Advanced Nasopharyngeal Carcinoma Patients Treated with Definitive Concurrent Chemoradiotherapy ». Journal of Oncology 2020 (6 octobre 2020) : 1–10. http://dx.doi.org/10.1155/2020/3127275.

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Purpose. We aimed to retrospectively investigate the prognostic worth of pretreatment advanced lung cancer inflammation index (ALI) in locally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemoradiotherapy (C-CRT). Patients and Methods. A total of 164 LA-NPC patients treated with cisplatinum-based definitive C-CRT were included in this retrospective cohort analysis. The convenience of ideal pre-C-CRT ALI cut-offs affecting survival results was searched by employing the receiver operating characteristic (ROC) curve analyses. The primary endpoint was the link between the ALI groups and overall survival (OS), while cancer-specific survival (CSS), locoregional progression-free survival [LR(PFS)], distant metastasis-free survival (DMFS), and PFS comprised the secondary endpoints. Results. The ROC curve analyses distinguished a rounded ALI cut-off score of 24.2 that arranged the patients into two cohorts [ALI ≥ 24.2 (N = 94) versus < 24.2 (N = 70)] with significantly distinct CSS, OS, DMFS, and PFS outcomes, except for the LRPFS. At a median follow-up time of 79.2 months (range: 6–141), the comparative analyses showed that ALI < 24.2 cohort had significantly shorter median CSS, OS, DMFS, and PFS time than the ALI ≥ 24.2 cohort ( P < 0.001 for each), which retained significance at 5- ( P < 0.001 ) and 10-year ( P < 0.001 ) time points. In multivariate analyses, ALI < 24.2 was asserted to be an independent predictor of the worse prognosis for each endpoint ( P < 0.001 for each) in addition to the tumor stage (T-stage) ( P < 0.05 for all endpoints) and nodal stage (N-stage) ( P < 0.05 for all endpoints). Conclusion. As a novel prognostic index, the pretreatment ALI < 24.2 appeared to be strongly associated with significantly diminished survival outcomes in LA-NPC patients treated with C-CRT independent of the universally recognized T- and N-stages.

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McCahill, Laurence E., Greg Yothers, Saima Sharif, Nicholas J. Petrelli, Samia H. Lopa, Michael J. O'Connell et Norman Wolmark. « A phase II trial of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy plus bevacizumab (bev) for patients (pts) with unresectable stage IV colon cancer and a synchronous asymptomatic primary tumor : Updated results of NSABP C-10 with definitive survival analysis. » Journal of Clinical Oncology 31, n^o 4_suppl (1 février 2013) : 468. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.468.

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468 Background: Surgical resection of asymptomatic primary colon tumor for pts presenting with synchronous yet unresectable metastatic disease is controversial. We published results for the primary endpoint in JCO in September 2012. Here we update the primary endpoint and present definitive survival results. Methods: Eligible pts had ECOG Performance 0 or 1, an asymptomatic colon tumor and unresectable distant metastases. Primary endpoint (PE) was major morbidity, defined as surgical resection or death related to the intact primary tumor. Major morbidity rate of 25% was considered acceptable and the trial had 85% power to rule out a rate of 40%. Secondary endpoints were overall survival and morbidity related to the intact primary requiring hospitalization, transfusion, or interventional procedure. Results: Between March 2006-June 2009, 90 pts were registered and 86 eligible pts with follow-up comprise this analysis. 52% were female and 47% were age 60+. Median follow-up was 61.5 mos. There were 15 (17.4%) major morbidity events, 12 (14.0%) required surgery: obstruction (9), perforation (2), and pain (1). Three (3.5%) resulted in pt death: perforation (2), obstruction (1). Cumulative incidence of major morbidity at 42 mos was 17.7% (95% CI 9.5-26.0%). Fourteen other primary tumor resections were performed: attempted cure (11), other reasons (3). There were 6 secondary endpoint events: 4 obstructions (2 required stents, 2 resolved with conservative management), 2 pts with suspected perforation required percutaneous drainage (1) and hospitalization and antibiotics (1). Median survival was 18.3 mos (95% CI 15.2-24.2). Two year OS rate was 38.7% and 3 year OS rate was 15.1%. Conclusions: The primary endpoint holds with the updated analysis justifying observation for asymptomatic primary colon cancers even in patients with a good clinical response of distant metastases. Clinical trial information: NCT 00321828.

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Amit, Ohad, Will Bushnell, Lori Dodd, Nancy Roach et Daniel Sargent. « Blinded Independent Central Review of the Progression‐Free Survival Endpoint ». Oncologist 15, n^o 5 (11 avril 2010) : 492–95. http://dx.doi.org/10.1634/theoncologist.2009-0261.

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Carlson, Robert H. « Debating Progression-Free versus Overall Survival as a Trial Endpoint ». Oncology Times 34, n^o 13 (juillet 2012) : 32–34. http://dx.doi.org/10.1097/01.cot.0000416578.87137.66.

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ZackheimMD, Herschel S. « Overall Survival as an Endpoint in Cutaneous T-Cell Lymphoma ». Blood 90, n^o 5 (1 septembre 1997) : 2117. http://dx.doi.org/10.1182/blood.v90.5.2117.

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Henkel, Gretchen. « Epoetin Alfa Study Amended to Include Survival as Additional Endpoint ». Oncology Times 23, n^o 7 (juillet 2001) : 51–52. http://dx.doi.org/10.1097/01.cot.0000313801.47479.b3.

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Roberts, S. A. « Determination of Cell Dose–survival Relationships from Endpoint Dilution Assays ». International Journal of Radiation Biology 64, n^o 2 (janvier 1993) : 251–55. http://dx.doi.org/10.1080/09553009314551371.

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Chen, Tai-Tsang. « Milestone Survival : A Potential Intermediate Endpoint for Immune Checkpoint Inhibitors ». Journal of the National Cancer Institute 107, n^o 9 (25 juin 2015) : djv156. http://dx.doi.org/10.1093/jnci/djv156.

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Holstein, Sarah A., Vera J. Suman et Philip L. McCarthy. « Should Overall Survival Remain an Endpoint for Multiple Myeloma Trials ? » Current Hematologic Malignancy Reports 14, n^o 1 (19 janvier 2019) : 31–38. http://dx.doi.org/10.1007/s11899-019-0495-9.

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Parimi, Sunil, Soundouss Raissouni, Yongtao Lin, Jose Gerard Monzon, Patricia A. Tang et Vincent Channing Tam. « Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials. » Journal of Clinical Oncology 33, n^o 3_suppl (20 janvier 2015) : 692. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.692.

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692 Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]

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Vander, M. A., E. A. Lyasnikova, L. A. Belyakova, M. A. Trukshina, V. L. Galenco, I. M. Kim, T. A. Lelyavina et al. « Two-year follow-up of patients with heart failure with reduced ejection fraction receiving cardiac contractility modulation ». Russian Journal of Cardiology 25, n^o 7 (15 août 2020) : 3853. http://dx.doi.org/10.15829/1560-4071-2020-3853.

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Aim. To assess the 2-year prognosis of patients with heart failure with reduced ejection fraction (HFrEF) receiving cardiac contractility modulation (CCM).Material and methods. This single-center observational study included 55 patients (46 men, mean age 53±11 years) with NYHA class II-III HFrEF receiving optimal medical therapy, with sinus rhythm, QRS <130 ms or QRS<150 ms with nonspecific intraventricular conduction delay. NYHA class II and III were established in 76% and 24% of patients, respectively. All patients were implanted with CCM devices between October 2016 and September 2017. Follow-up visits were carried out every 3 months during the 1st year and every 6 months during the 2nd year of observation. The primary composite endpoint was mortality and heart transplantation. Secondary composite endpoints included death, heart transplantation, paroxysmal ventricular tachycardia/ ventricular fibrillation, hospitalizations due decompensated HFResults. The one-year and two-year survival rate was 95% and 80%, respectively. Primary endpoint was observed in 20% of patients. NYHA class III and higher levels of N-terminal pro-brain natriuretic peptide (NTproBNP) were associated with unfavorable prognosis (p=0,014 and p=0,026, respectively). NTproBNP was an independent predictor of survival (p=0,018). CCM contributed to a significant decrease in hospitalizations due to decompensated HF (p<0,0001). The secondary endpoint was observed in 18 (33%) of patients during the 1st year. The predictor for the secondary composite endpoint was NTproBNP (p=0,047).Conclusion. CCM is associated with a significant decrease in hospitalization rate due to decompensated HF. The 2-year survival rate of patients with NYHA class II-III HF receiving CCM was 80%. The NTproBNP level was an independent predictor of survival in patients receiving CMM for 2 years. Further longer-term studies of the CCM efficacy are required.

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Wijngaarde, Camiel A., Marloes Stam, Louise A. M. Otto, Ruben P. A. van Eijk, Inge Cuppen, Esther S. Veldhoen, Leonard H. van den Berg, Renske I. Wadman et W. Ludo van der Pol. « Population-based analysis of survival in spinal muscular atrophy ». Neurology 94, n^o 15 (26 mars 2020) : e1634-e1644. http://dx.doi.org/10.1212/wnl.0000000000009248.

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ObjectiveTo investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA).MethodsWe studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e., none: type 1a/b; head control in supine position or rolling: type 1c; sitting independently: type 2a; standing: type 2b; walking: type 3a/b; adult onset: type 4). We also assessed the need for mechanical ventilation as a surrogate endpoint for survival.ResultsWe included 307 patients with a total follow-up of 7,141 person-years. Median survival was 9 days in SMA type 1a, 7.7 months in type 1b, and 17.0 years in type 1c. Patients with type 2a had endpoint-free survival probabilities of 74.2% and 61.5% at ages 40 and 60 years, respectively. Endpoint-free survival of SMA types 2b, 3, and 4 was relatively normal, at least within the first 60 years of life. Patients with SMA types 1c and 2a required mechanical ventilation more frequently and from younger ages compared to patients with milder SMA types. In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d.ConclusionsShortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d.

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Oulhaj, Abderrahim, Anouar El Ghouch et Rury R. Holman. « Testing for qualitative heterogeneity : An application to composite endpoints in survival analysis ». Statistical Methods in Medical Research 28, n^o 1 (3 juillet 2017) : 151–69. http://dx.doi.org/10.1177/0962280217717761.

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Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection–union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer’s disease.

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Weiss, Emmanuel, Jean-Ralph Zahar, Jeff Alder, Karim Asehnoune, Matteo Bassetti, Marc J. M. Bonten, Jean Chastre et al. « Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials ». Clinical Infectious Diseases 69, n^o 11 (4 février 2019) : 1912–18. http://dx.doi.org/10.1093/cid/ciz093.

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Abstract Background Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. Methods Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. Results The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation–free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7–10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation–free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). Conclusions We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

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Pullen, Matthew F., Katherine Huppler Hullsiek, Joshua Rhein, Abdu K. Musubire, Lillian Tugume, Edwin Nuwagira, Mahsa Abassi et al. « Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials ». Clinical Infectious Diseases 71, n^o 7 (8 janvier 2020) : e45-e49. http://dx.doi.org/10.1093/cid/ciaa016.

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Abstract Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

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Trippa, Lorenzo, Patrick Y. Wen, Giovanni Parmigiani, Donald A. Berry et Brian M. Alexander. « Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials ». Neuro-Oncology 17, n^o 8 (7 janvier 2015) : 1106–13. http://dx.doi.org/10.1093/neuonc/nou345.

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Timothy Chen, T., Richard M. Simon, Edward L. Kom, Stewart J. Anderson, Anne S. Lindblad, Harry Sam Wieand, Harold O. Douglass, Bernard Fisher, J. Michael Hamilton et Michael A. Friedman. « Investigation of disease-free survival as a surrogate endpoint for survival in cancer clinical trials ». Communications in Statistics - Theory and Methods 27, n^o 6 (janvier 1998) : 1363–78. http://dx.doi.org/10.1080/03610929808832163.

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Poad, Heather, Sam Khan, Lorna Wheaton, Anne Thomas, Michael Sweeting et Sylwia Bujkiewicz. « The Validity of Surrogate Endpoints in Sub Groups of Metastatic Colorectal Cancer Patients Defined by Treatment Class and KRAS Status ». Cancers 14, n^o 21 (1 novembre 2022) : 5391. http://dx.doi.org/10.3390/cancers14215391.

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Background and Aim: Findings from the literature suggest that the validity of surrogate endpoints in metastatic colorectal cancer (mCRC) may depend on a treatments’ mechanism of action. We explore this and the impact of Kirsten rat sarcoma (KRAS) status on surrogacy patterns in mCRC. Methods: A systematic review was undertaken to identify randomized controlled trials (RCTs) for pharmacological therapies in mCRC. Bayesian meta-analytic methods for surrogate endpoint evaluation were used to evaluate surrogate relationships across all RCTs, by KRAS status and treatment class. Surrogate endpoints explored were progression free survival (PFS) as a surrogate endpoint for overall survival (OS), and tumour response (TR) as a surrogate for PFS and OS. Results: 66 RCTs were identified from the systematic review. PFS showed a strong surrogate relationship with OS across all data and in subgroups by KRAS status. The relationship appeared stronger within individual treatment classes compared to the overall analysis. The TR-PFS and TR-OS relationships were found to be weak overall but stronger within the Epidermal Growth Factor Receptor + Chemotherapy (EGFR + Chemo) treatment class; both overall and in the wild type (WT) patients for TR-PFS, but not in patients with the mutant (MT) KRAS status where data were limited. Conclusions: PFS appeared to be a good surrogate endpoint for OS. TR showed a moderate surrogate relationship with PFS and OS for the EGFR + Chemo treatment class. There was some evidence of impact of the mechanism of action on the strength of the surrogacy patterns in mCRC, but little evidence of the impact of KRAS status on the validity of surrogate endpoints.

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Halabi, Susan, Akash Roy, Qian Yang, Wanling Xie, William Kevin Kelly et Christopher Sweeney. « Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 5057. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5057.

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5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

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Woodford, Rachel, Deborah Zhou, Peey-Sei Kok, Sally Lord, Ian Marschner, Michael Friedlander et Chee Khoon Lee. « The validity of progression-free survival (PFS) 2 as a surrogate endpoint for overall survival (OS) in randomized controlled trials (RCTs) of advanced solid tumors. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 1516. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.1516.

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1516 Background: OS is the gold-standard endpoint for treatment efficacy in oncology RCTs. However, prolonged follow-up is required to obtain mature data, which impedes regulatory approval of potentially beneficial therapies. Furthermore, increasing therapeutic options including cross over to investigational agents at disease progression often confound OS findings. PFS-2, defined as time from randomization to progression on second-line therapy, has been proposed as a potential surrogate endpoint for OS. Using a meta-analytic approach, we aimed to assess the association between OS and PFS-2, and its validity compared with other surrogate endpoints. Methods: We performed an electronic literature search to identify RCTs of systemic therapies that reported PFS-2 as a pre-specified endpoint with defined follow up protocols. Articles were screened for eligibility and outcome data were extracted. Correlations in the relative treatment difference between treatment arms for OS vs PFS-2, PFS-1, and objective response rate (ORR) were assessed as the comparison of hazard ratios (HR) and odds ratio (OR) respectively. Results: 38 eligible RCTs comprising of 44 analysis units, with 19,031 patients across 8 unique tumor types were identified. The majority received targeted therapies (72.2%), followed by immunotherapy (IO; 26.3%). The correlations of HR-OS/HR-PFS-2, HR-OS/HR-PFS-1 and HR-OS/OR-ORR were r = 0.67 (95% CI 0.08-0.69), r = 0.12 (95% CI 0.00-0.13) and r = 0.21 (95% CI 0.00-0.33) respectively. Correlations between OS with surrogates was assessed in different subgroups according to post-progression survival times (SPP), types of treatment agents and rate of subsequent therapy after progression (table). Conclusions: Across diverse tumors and therapies, treatment effect on PFS-2 has modest to strong correlation with OS, but poor correlations were observed between OS-PFS-1 and OS-ORR respectively. Across all subgroups, PFS-2 performs consistently better than traditional surrogates of PFS-1 and ORR, validating and providing support for use in future RCTs.[Table: see text]

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Ronellenfitsch, Ulrich, Katrin Jensen, Svenja Seide, Meinhard Kieser, Matthias Schwarzbach, Tracy E. Slanger, Bryan Burmeister et al. « Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma : Pooled analysis of individual patient data from randomized controlled trials. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : 4533. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4533.

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4533 Background: Disease-free survival (DFS) is an appealing surrogate endpoint for overall survival (OS) in trials on neoadjuvant or adjuvant cancer therapy, because it is available faster and with less follow-up effort. The aim of this study was to assess if DFS can be a valid surrogate endpoint for OS when comparing neoadjuvant treatment followed by surgery to surgery alone for gastroesophageal adenocarcinoma. Methods: Individual patient data (IPD) from eight randomized controlled trials (n = 1,126 patients) which compared neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma were used for the analysis. Correlation between OS-time and DFS-time was calculated. Kaplan-Meier survival curves and corresponding hazard ratios (HRs) for treatment effects were separately determined for each trial. Subsequently, HRs were pooled in a meta-analysis using a random-effects model. An error-in-variables linear regression model was used to compare observed and predicted values. The minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS was estimated by calculating the surrogate threshold effect. Results: OS-time correlated strongly with DFS-time. HRs for OS and DFS were highly similar for all single trials. The meta-analysis yielded almost identical overall HRs for treatment effects on OS and DFS. The determination coefficient for the association between HRs for OS and DFS was 0.912 (95% confidence interval 0.75-1.0), indicating a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect was calculated at 0.79, indicating that a future trial yielding a hazard ratio for the treatment effect on DFS < 0.79 could be expected with a 95% probability to yield a hazard ratio for the treatment effect on OS < 1. Conclusions: DFS and OS strongly correlate both after neoadjuvant therapy followed by surgery and after surgery alone for gastroesophageal adenocarcinoma. Likewise, the treatment effects on the two endpoints are very similar. Consequently, DFS can be regarded an appropriate surrogate endpoint for OS in trials on neoadjuvant therapy for gastroesophageal adenocarcinoma.

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Galle, Peter R. « Abstract IA15 : Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge ». Clinical Cancer Research 28, n^o 17_Supplement (1 septembre 2022) : IA15. http://dx.doi.org/10.1158/1557-3265.liverca22-ia15.

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Abstract Trial Design and Endpoint Definition in general is more complex in hepatocellular carcinoma compared to other solid tumors. It took decades of research until the first systemic treatment was defined in 2007 as a result of the SHARP and the ASIA-Pacific trials. The demonstration of Sorafenib’s anti-tumor efficacy in advanced HCC to a large extend was owing to the concentration on patients with good liver function, avoiding the confounding impact of liver cirrhosis. In intermediate stage HCC trial design is even more challenging: intermediate stage HCC is a heterogeneous disease with a broad spectrum of tumor burden, variable liver function, and radiological intervention with transarterial chemoembolization (TACE) as a standard procedure which is far beyond standardization. Several trials have been launched either combining TACE with systemic therapy or comparing TACE vs. systemic therapy. Several issues in this setting are questioning overall survival as preferred endpoint: with an expected survival in excess of 2.5 years and several systemic therapies available, the competing risks of death (liver disease) and the contribution of post-trial treatments are increasingly impacting OS and obscuring the effectiveness of the trial-specific intervention. This is exemplified by the TACTICS trial, comparing TACE + Sorafenib with TACE, where a solid PFS benefit for the combination (HR: 0.661) did not translate into OS (HR: 0.861), possibly because of a more than 20% higher rate of post-treatment medication in the TACE-only group. Thus, there is an obvious need for surrogate markers, indicative of increased survival time but shifting overall survival analysis into secondary endpoints. We recently started the ABC-HCC trial, a phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma. Here we are using a pragmatic and real-life endpoint, Time to failure of treatment strategy (TTFS) as primary endpoint. TTFS is defined as Time from randomization until failure of strategy, i.e. radiologic progression or lack of radiologic response AND any of the following: the loss of clinical benefit OR unacceptable toxicity OR liver function deterioration OR therapy not further applicable for other reasons Secondary endpoints comprise OS, Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to loss of systemic treatment options (TTSYS), Progression free survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to deterioration of liver function, Safety, and QoL (Patient Reported Outcome; PRO). The trial includes an exploratory biomarker analysis. The ABC-HCC and other trials will give us information on the role of systemic therapy in intermediate stage HCC in the upcoming years. Citation Format: Peter R Galle. Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA15.

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Ozols, R. F. « Treatment goals in ovarian cancer ». International Journal of Gynecologic Cancer 15, Suppl 1 (2005) : 3–11. http://dx.doi.org/10.1136/ijgc-00009577-200505001-00002.

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Ovarian cancer remains the number one gynecological killer in the Western world. Most ovarian cancer patients present with advanced-stage disease and are treated with cytoreductive surgery followed by combination chemotherapy. While the majority of patients respond to treatment, most will relapse such that the 5-year survival rates for advanced disease are approximately 20–25%. Overall survival and progression-free survival (PFS) are the primary endpoints in clinical trials in patients with advanced ovarian cancer. In patients with early-stage ovarian cancer, PFS may be the preferred trial endpoint, whereas in patients with recurrent ovarian cancer, the primary goal of therapy remains palliation and control of symptoms. Recent studies in recurrent disease have demonstrated that chemotherapy can improve the endpoints of PFS and overall survival, and so they are being used as the primary endpoints for comparing new regimens in phase III trials in relapsed patients. However, it would be easier to compare new treatment modalities if a uniformly accepted instrument was available that could evaluate quality of life and symptom control.

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Wang, Zi-Xian, Hao-Xiang Wu, Li Xie, Wu-Hao Lin, Fei Liang, Jin Li, Zhi-Min Yang et Rui-Hua Xu. « Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials ». Journal for ImmunoTherapy of Cancer 9, n^o 4 (avril 2021) : e002114. http://dx.doi.org/10.1136/jitc-2020-002114.

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BackgroundProgression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS (mPFS), which omits the events of disease progression (but not deaths) within 3 months after randomization.MethodsPubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized trials studying ICIs in advanced solid tumors with available PFS and OS data up to May 2020. Individual patient-level data (IPD) for PFS and OS were reconstructed for eligible trials. A simulation-based algorithm was used to match the reconstructed, disconnected PFS and OS IPD, and 1000 independent simulated datasets of matched PFS-OS IPD were generated for each trial. mPFS durations and statuses were then measured for each of the matched PFS-OS IPD. Trial-level correlation between Cox HRs for PFS or mPFS and HRs for OS was assessed using Pearson correlation coefficient (rp) weighted by trial size; patient-level correlation between PFS or mPFS and OS was assessed using Spearman’s rank correlation coefficient (rs). Findings were further validated using the original IPD from two randomized ICI trials.ResultsFifty-seven ICI trials totaling 29,429 participants were included. PFS HR showed moderate correlation with OS HR (rp=0.60), and PFS was moderately correlated with OS at the patient level (median rs=0.66; range, 0.65–0.68 among the 1000 simulations). In contrast, mPFS HR achieved stronger correlation with OS HR (median rp=0.81; range, 0.77–0.84), and mPFS was more strongly correlated with OS at the patient level (median rs=0.79; range, 0.78–0.80). The superiority of mPFS over PFS remained consistent in subgroup analyses by cancer type, therapeutic regimen, and treatment setting. In both trials with the original IPD where experimental treatment significantly improved OS, mPFS successfully captured such clinical benefits whereas PFS did not.ConclusionsmPFS outperformed PFS as the surrogate endpoint for OS in ICI trials. mPFS is worthy of further investigation as a secondary endpoint in future ICI trials.

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Tatla, Raman, Denis Landaverde, Charles Victor, David Miles et Sunil Verma. « A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials. » Journal of Clinical Oncology 30, n^o 27_suppl (20 septembre 2012) : 129. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.129.

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129 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's funcitonal abilities has led to an emphasis of incorporating quality of life (QoL) measures into clinical trials. The main objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QOL as an endpoint, in addition to conventional efficacy endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, evaluating systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p=0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in the QoL endpoint; of not, instruments of varying validity were utilized. There needs to be a greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

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Imaoka, Hiroshi, Mitsuhito Sasaki, Hideaki Takahashi, Yusuke Hashimoto, Izumi Ohno, Shuichi Mitsunaga, Kazuo Watanabe et al. « Progression-free survival as a surrogate endpoint in advanced neuroendocrine neoplasms ». Endocrine-Related Cancer 24, n^o 9 (septembre 2017) : 475–83. http://dx.doi.org/10.1530/erc-17-0197.

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In oncology clinical trials, overall survival (OS) is considered the gold standard outcome measure. In phase III trials for neuroendocrine neoplasms (NENs), however, progression-free survival (PFS) is more frequently used, as NENs are relatively rare and indolent neoplasms. But this surrogacy of PFS for OS has never been systematically validated. We, therefore, performed a literature-based analysis of phase II and III trials for NENs to evaluate the correlation between PFS and OS in NENs treated with medical treatment. We identified phase II and III clinical trials of medical treatment for advanced NENs based on a systematic electronic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. A total of 20 trials were identified, and 2530 patients and 30 treatment arms were included in the analysis. There was a statistically significant relationship between PFS and OS (rs, 0.587; 95% confidence interval, 0.249–0.925). Conversely, the objective response rate was not significantly correlated with OS. The results of subgroup analyses indicated that the correlation between PFS and OS was higher for study arms that prohibited concomitant therapy with somatostatin analogues than for those that permitted it. The results of the present analysis indicate that PFS is significantly correlated with OS, and suggest that PFS is an acceptable surrogate for OS in clinical trials for NENs.

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Carlson, Robert H. « The Case Against Using Survival as Endpoint for Phase II Trials ». Oncology Times 27, n^o 21 (novembre 2005) : 6–8. http://dx.doi.org/10.1097/01.cot.0000291272.78410.d6.

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Miksad, Rebecca A., Vera Zietemann, Raffaella Gothe, Ruth Schwarzer, Annette Conrads-Frank, Petra Schnell-Inderst, Björn Stollenwerk et Uwe Siebert. « Progression-free survival as a surrogate endpoint in advanced breast cancer ». International Journal of Technology Assessment in Health Care 24, n^o 04 (octobre 2008) : 371–83. http://dx.doi.org/10.1017/s0266462308080495.

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Objectives:Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint.Methods:A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROSfrom observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption.Results:Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n= 4,323) and seventeen T (n= 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROSand HRPFSwas 0.71 for A (p= .0029) and 0.75 for T (p= .0028). While HRPFSwas a statistically significant predictor of HROSfor both A (p= .0019) and T (p= .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROSagreed with observed HROSin 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses.Conclusions:This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.

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Hariharan, N., N. Nair, V. Parmar, R. Hawaldar, P. Padmanaban, V. Vanmali et R. Badwe. « Can pathological complete response serve as a surrogate endpoint for survival ? » Annals of Oncology 26 (mai 2015) : iii6. http://dx.doi.org/10.1093/annonc/mdv115.10.

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Khaki, Ali Raza, Mark P. Lythgoe et Vinay Prasad. « Adjuvant checkpoint inhibitor trials : Is disease-free survival an appropriate endpoint ? » Journal of Cancer Policy 35 (mars 2023) : 100402. http://dx.doi.org/10.1016/j.jcpo.2023.100402.

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