15 januari 2025: Raadpleeg ook literatuurlijsten niet-toxische middelen en behandelingen specifiek bij borstkanker van arts-bioloog drs. Engelbert Valstar.

En zie ook in gerelateerde artikelen

15 januari 2025: Bron: Eur J Cancer 2024 Dec:213:115072

Doelgerichte trial-emulatie  van de 8 belangrijkste medicijnen die worden gebruikt voor patiënten met uitgezaaide borstkanker geeft in de klinische praktijk bij 7 van de 8 medicijnen dezelfde resultaten dan werden gerapporteerd in gerandomiseerde fase III studies. Doelgerichte trial-emulatie  betekent dat resultaten uit vooral observatiestudies maar ook niet placebo gecontroleerde gerandomiseerde studies zouden kunnen worden gebruikt voor prognoses en gepersonaliseerde behandelingen.

Omdat fase III studies veel tijd vergen en ook heel duur zijn lijkt doelgerichte trial-emulatie een uitstekend alternatief, ook bij andere vormen van kanker gezien de resultaten uit deze studie bij borstkankerpatiënten die gebaseerd is op de bevindingen op de doorlopende Franch ESME-MBC studie

In onderstaande grafiek zie je de 8 fase III studies die werden meegenomen in de studie: 




Ik heb een stukje tekst voorafgaande aan bovenstaande grafiek vertaald met hulp van google translate. Ik heb links gemaakt naar artikelen over in onderstaande beschrijving genoemde studies.

Van de 8 vergeleken medicijnen via doelgerichte trial-emulaties bereikten:

  • EMILIA- en AVADO-emulaties alle volledige statistische significantieovereenkomst (SA), schattingsovereenkomst (EA) en gestandaardiseerde verschilovereenkomst (SD), en bevestigden het statistisch significante effect ten gunste van T-DM1 in EMILIA, en de afwezigheid van algehele overlevingseffect van bevacizumab in AVADO.
  • PALOMA-2- en PALOMA-3-emulaties bereikten EA en SD, maar slaagden er niet in om SA te bereiken. Er werd inderdaad geen significant effect op OS waargenomen in beide RCT's (HRRCT PALOMA-2 = 0,96, 95%CI 0,78–1,18 en HRRCT PALOMA-3 = 0,81, 95%CI 0,64–1,03), terwijl de emulaties een positief en significant effect van palbociclib op OS lieten zien (HRRWD PALOMA-2 = 0,81, 95%CI 0,72–0,92 en HRRWD PALOMA-3 = 0,81, 95%CI 0,69–0,95).
  • RIBBON-1-emulatie, die een statistisch significant schadelijk effect van bevacizumab rapporteerde, bereikte ook EA en SD.
  • De emulatie van MONALEESA-2 bereikte zowel SA als SD. Het positieve en statistisch significante effect van het toevoegen van ribociclib werd inderdaad versterkt in de emulatie, met overlappende CI's (HRRRWD=0,55, 95%CI 0,39–0,79) versus HRRCT=0,76, 95%CI 0,63–0,93).
  • De emulatie van CLEOPATRA bereikte alleen SA. Een positief en statistisch significant effect van de trastuzumab-pertuzumab-combinatie werd bereikt met een grotere omvang in de emulatie (HRRRWD=0,44, 95%CI 0,36–0,55 versus HRRCT=0,68, 95%CI 0,56–0,84).
  • Ten slotte bereikte alleen de BOLERO-2-emulatie geen van de overeenkomsten. De emulatie toonde een negatief en statistisch significant effect, terwijl de RCT niet doorslaggevend was en een positief maar niet-significant effect aantoonde van het toevoegen van everolimus aan exemestaan ​​(HRRRWD=1,25, 95%CI 1,06–1,47 versus HRRCT=0,89, 95%CI 0,73–1,10). bereikten:

Het volledige studierapport is gratis in te zien en daarin kunt u ook zien welke 8 van de oorspronkelijk voorgekozen 13 medicijnen werden gekozen voor een vergelijking met resultaten uit gerandomiseerde fase III studies. Klik op de titel van het abstract en zie ook in de referenties en gerelateerde artikelen onderaan dit abstract:

Cover Image - European Journal of Cancer, Volume 213, Issue

Highlights

Trial emulation from RWD can provide similar OS effect sizes to RCT in MBC.
Too few patients involved in real-life settings can make emulation unfeasible.
Residual confounders remain the main cause of potential discrepancies.
Emulation offers new insights for addressing questions not answered by an RCT.
Emulation could endorse comparative effectiveness in single-arm trials.

Abstract

Background

Demonstration of trial emulation ability to benchmark randomised controlled trials (RCTs) from real-world data (RWD) is required to increase confidence in the use of routinely collected data for decision making in oncology.

Methods

To assess the frequency with which emulation findings align with RCTs regarding effect size on overall survival (OS) in metastatic breast cancer (MBC), 8 of 13 pre-selected pivotal RCTs in MBC were emulated using data from 32,598 patients enrolled in the French ESME-MBC cohort between January 1, 2008 and December 31, 2021. Adjustment methods and confounders were selected a priori for each emulation; stabilized weight was the reference method to mitigate confounding. Concordance in OS hazard ratios with associated 95 % confidence intervals between RCTs and emulations were assessed used predefined metrics based on statistical significance, estimates, and standardized differences.

Results

The effect sizes were consistent with RCT results in 7 out of the 8 emulations; 4 emulations achieved full statistical significance agreement; 5 emulations had a point estimate included in the RCT CI (estimate agreement); 6 emulations reported no significant differences between RCT and emulation (standardized difference agreement). Discrepancies related to residual confounders and significant shifts in prescription practices post-drug approval may arise in some cases.

Conclusion

Target trial emulation from RWD combined with appropriate adjustment can provide conclusions similar to RCTs in MBC. In oncology, this methodology offers opportunities for confirming the impact on long-term survival, for expanding indications in patients excluded from RCTs and for comparative effectiveness in single-arm trials using external control arms.


Ethics approval and consent to participate

ESME research program received approval from an independent ethics committee (Comité de Protection des Personnes Sud-Est II-2015–79). The ESME MBC was authorized by the database French data protection authority in 2013 (registration ID 1704113; authorization no. DE-2013–117) and complementary authorization in compliance with the applicable European regulations was obtained on October 14th, 2019 regarding the ESME research data warehouse. No formal dedicated informed consent was required, but all patients were informed about the use of their electronically recorded data and can access, rectify, limit, or require withdrawal of their data on a dedicated web platform at any time. In compliance with the applicable European regulations, a complementary authorization was obtained on October 14th, 2019 regarding the ESME research data warehouse.

Funding

This study was supported by the National French Research and Technology Association (ANRT) and Roche (France) via CIFRE doctoral fellowship no. 2020/1054. The ESME MBC cohort receives financial support from an industrial consortium (AstraZeneca, Daiichi Sankyo, Pfizer, Roche, MSD, Pierre Fabre, Eisai, Gilead, Seagen and Lilly). Data collection, analysis, and publication are managed entirely by UNICANCER independently of the industrial consortium. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

CRediT authorship contribution statement

Alison Antoine: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Methodology, Funding acquisition, Formal analysis, Conceptualization. David Pérol: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Funding acquisition, Conceptualization. Mathieu Robain: Resources, Project administration, Funding acquisition, Data curation, Conceptualization. Thomas Bachelot: Validation, Resources, Writing – review & editing. Rémy Choquet: Project administration, Funding acquisition. William Jacot: Validation, Resources, Writing – review & editing. Béchir Ben Hadj Yahia: Project administration, Funding acquisition. Thomas Grinda: Writing – review & editing, Validation, Resources. Suzette Delaloge: Writing – review & editing, Validation, Resources. Christine Lasset: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Funding acquisition. Youenn Drouet: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Methodology, Formal analysis, Conceptualization.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alison Antoine received a grant from the National French Agency for Research and Technology (ANRT) and Roche (France) via CIFRE (“Industrial Agreements for Training through Research”) doctoral fellowship no. 2020/1054. Rémy Choquet and Béchir Ben Hadj Yahia are employed by Roche. Suzette Delaloge is an Associate Editor for [European Journal of Cancer] and was not involved in the editorial review or the decision to publish this article. All remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Acknowledgments

We thank UNICANCER network and all the 18 French Comprehensive Cancer Centres (FCCCs) for providing the data and each ESME local coordinator for managing the project at the local level and the ESME Scientific Group and Strategic Committee for their ongoing support. The 18 participating FCCCs included: I. Curie, Paris/Saint-Cloud; G. Roussy, Villejuif; I. Cancérologie de l′Ouest, Angers/Nantes; C. F. Baclesse, Caen; ICM Montpellier; C. L. Bérard, Lyon; C. G.-F. Leclerc, Dijon; C. H. Becquerel, Rouen; I. C. Regaud, Toulouse; C. A. Lacassagne, Nice; Institut de Cancérologie de Lorraine, Nancy; C. E. Marquis, Rennes; I. Paoli-Calmettes, Marseille; C. J. Perrin, Clermont Ferrand; I. Bergonié, Bordeaux; C. P. Strauss, Strasbourg; I. J. Godinot, Reims; and C. O. Lambret, Lille. We also thank Cancéropôle Lyon Auvergne Rhône-Alpes and FR3728 BioEEnViS for their financial support via a “Mobility” grant; David Pau, MSc and Cyril Esnault, MSc for kind consideration to the study; all members of the Ph.D. supervisory committee: Michel Cucherat, MD, PhD, Marie-Laure Delignette-Muller, PhD, Roch Giorgi, MD, PhD, and Raphaël Porcher, PhD, for advices and relevant methodological expertise; and Sophie Darnis, PhD, for editorial support.

Consent for publication

Not applicable.

Appendix A Supplementary material (1)

Supplementary material
.

Data Availability

The dataset analyzed in the current study is issued from the Epidemio-Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Data Platform. The database of the ESME program, including the database of the MBC cohort are currently not accessible. In accordance with the regulatory frame applicable to the ESME Data Platform, data is only available via a secure cloud computing service with limited access to authorized persons; access authorizations to the secure cloud computing service are available from the corresponding author upon reasonable request. Each demand will be examined on a case-by-case basis by the UNICANCER ESME scientific committee. Moreover, subset of data (2008–2014) is made available on the Health Data Hub (https://www.health-data-hub.fr/).

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