Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863)

Abstract

Background: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance.

Patients and methods: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS).

Results: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times.

Conclusion: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.