Abstract P2-09-08: Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05)
Authors: Blok EJ , Kroep JR , Meershoek-Klein Kranenbarg EM , Duym-de Carpentier M , Putter H , van den Bosch J , Maartense E , van Leeuwen-Stok AE , Liefers G-J , Nortier JWR , Rutgers EJT , van de Velde CJH 
Published: March 2017

Abstract
The implementation of adjuvant aromatase inhibitors (AI) has contributed significantly to an ongoing improvement in survival of early breast cancer patients, but the impact of extended AI on toxicity after use in the initial 5 years has not yet been studied. Earlier, it was established that even after 5 years of adjuvant tamoxifen, extended letrozole for 5 years was comparable to the earlier reported toxicities, without an effect on overall quality of life. The aim of the current study is to assess the reported toxicity in the IDEAL trial, investigating extended letrozole after 5 years of endocrine therapy.
The Dutch phase III IDEAL trial was designed to study the optimal duration of extended adjuvant letrozole, by randomizing to either 2.5 or 5 years of letrozole after the completion of 5 years of any endocrine therapy. All patients were disease-free at the time of randomization. The primary outcome of this study, disease free survival after extended endocrine therapy, will be reported separately. Toxicity data were collected every 6 months in the first year, and annually thereafter until study completion.
1824 patients were included in the trial, of which 26 patients never started with therapy (n=1798). In total, 3434 adverse events were reported by 1283 patients, causing 360 (20%) patients to stop therapy due to these events. In total, 643 patients randomized to 5 years of therapy reported 1834 AEs (71.2%), whereas 640 patients on 2.5 years of therapy reported 1587 events (71.5%). In the 5 year AI group, 1456 (80%) of the AEs were reported within the initial 2.5 years causing 177 patients to stop therapy in this period, versus 29 patients who stopped due to toxicity after the therapy extension beyond 2.5 years. There was no significant difference in the proportion of grade 3/4 events between both groups (2.5yr: 9.8%, 5yr: 9.7%, X2 p=0.52). Most reported AEs were arthralgia (n=248, 13.8% of all patients , 8.9% grade 3/4), hot flushes (n=215, 12%, 6.5% grade 3/4), osteoporosis (n=181, 10%, 2.2% grade 3/4), fatigue (n=156, 8.7%, 5.1% grade 3/4) and a decrease in joint function (n=114, 6.3%, 3.5% grade 3/4). In total, only one grade 5 AE was reported, which was unrelated to the treatment (bleeding and sepsis after cholecystectomy).
Although the toxicity pattern is comparable to regular AI based adjuvant therapy, the percentage of specific adverse events like arthralgia and hot flushes is lower than expected. This observation is possibly a selection bias, since patients who encountered side effects during regular adjuvant therapy could have been less willing to participate in this trial. Remarkably, low numbers of AEs and therapy refusal due to toxicity were reported after therapy extension beyond 2.5 years. In conclusion, extended adjuvant endocrine therapy shows an acceptable toxicity pattern, and therapy extension beyond 2.5 years up to 5 years is well tolerated and safe.
Citation Format: Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg EM, Duym-de Carpentier M, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, van de Velde CJH. Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-08.