Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line

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Eur
J Cancer.
2006 Dec;42(18):3178-85. Epub 2006 Oct 12.
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).

Beex
L
, Rose
C
, Mouridsen
H
, Jassem
J
, Nooij
M
, Estape
J
, Paridaens
R
, Piccart
M
, Gorlia
T
, Lardenoije
S
, Baila
L
.
Department of Medical Oncology, 452 Radboud
University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The
Netherlands, and Department of Oncology, Lund University Hospital,
Sweden.

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.