Insights adjusting for non-adherence in randomized clinical trials: a reanalysis of an adjuvant trial of tamoxifen duration in early breast cancer
A partir d'une nouvelle analyse des données d'un essai de phase III incluant 3 830 patientes atteintes d'un cancer du sein de stade précoce et évaluant l'intérêt de poursuivre un traitement par tamoxifène, cette étude compare la survie sans maladie invasive et la survie globale en fonction de la méthode statistique utilisée : l'une prenant en compte la non-adhésion thérapeutique, l'autre pas
Background : Several randomized clinical trials provide evidence of the survival benefit of extended adjuvant tamoxifen in women with estrogen receptor (ER)-positive early breast cancer (BC). However, non-adherence may lead to underestimate treatment effects using intention to treat (ITT) methods. We reanalyzed a randomized trial using contemporary statistical methods adjusting for non-adherence.
Methods : The TAM01 study was a phase 3 trial including women with early BC, who had completed 2–3 years of adjuvant tamoxifen between 1986 and 1995. Participants were randomly assigned to continue tamoxifen up to 10 years or to discontinue the treatment at randomization. Invasive disease-free survival (iDFS) and overall survival (OS) were estimated using marginal structural models (MSM) and rank preserving structural failure time model (RPSFTM).
Results : Of 3830 patients enrolled, 2485 were randomized to extended tamoxifen, and 1345 to treatment discontinuation. The 10-year non-adherence rate in the extended group was 27.2%. Among women with ER-positive BC (n = 2402), extended tamoxifen was associated with a 45% and 21% relative improvement in iDFS by MSM and RPSFTM, respectively (Hazard Ratio (HR), 0.55; 95% Confidence Interval (CI), 0.48–0.64 and HR, 0.79; 95%CI, 0.67–0.95, respectively), a considerable greater benefit than in the ITT analysis (HR, 0.90; 95%CI, 0.81–0.99). The OS reanalysis revealed a substantial benefit of extended tamoxifen (MSM: HR, 0.70; 95%CI, 0.59–0.83; RPSFTM: HR, 0.85; 95%CI, 0.67–1.04), compared to the ITT analyses (HR, 0.94; 95%CI, 0.84–1.07).
Conclusion : This analysis emphasizes both the importance of adherence to hormonotherapy in hormone-receptor positive early BC and the usefulness of more complex statistical analyses.
British Journal of Cancer , article en libre accès, 2023