DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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O
N
CH 3
CH 3
CH 3 O CH 3
N
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Tamoxifen
O
CYP2D6
(CYP2B6, CYP2C9,
CYP2C19, CYP3A)
CYP3A4/5
(CYP2C9 + other
CYPs)
N-desmethyl-tamoxifen
Figure 63–1. Tamoxifen and its metabolites.
CYP2D6
The combination of tamoxifen and a gonadotropin-releasing
hormone analog in premenopausal women (to reduce high estrogen
levels resulting from tamoxifen effects on the gonadal-pituitary
axis) yields better response rates and improved overall survival than
either drug alone (Klijn et al., 2000).
The NOLVADEX Adjuvant Trial Organization (NATO) study
indicated an overall disease-free survival advantage for patients
receiving tamoxifen versus placebo. Five years of adjuvant therapy
with tamoxifen yielded superior results compared to 1 or 2 years of
therapy (Swedish Breast Cancer Cooperative Group, 1996; Early
Breast Cancer Trialists’ Collaborative Group, 1998). Therefore,
although the optimal duration of tamoxifen has not been fully determined,
randomized trials have demonstrated superiority of 5 years
over shorter durations. One clinical trial evaluating the administration
of tamoxifen for >5 years failed to show benefit of continued
therapy and a trend toward worse outcomes in women who received
tamoxifen therapy over a longer duration (Fisher et al., 2001).
Tamoxifen also has shown effectiveness (a 40-50% reduction
in tumor incidence) in initial trials for preventing breast cancer in
women at increased risk (Vogel et al, 2010). These studies were
prompted by preclinical experiments showing prevention of tumors
in animal models and also by the observation of reduced contralateral
new primary breast tumors in women receiving adjuvant tamoxifen
for early-stage breast cancer (Early Breast Cancer Trialists’
Collaborative Group, 1998; Fisher et al., 2001). Tamoxifen only
reduces ER+ tumors without affecting ER-negative tumors, which
contribute disproportionately to breast cancer mortality.
OH
4-hydroxy-tamoxifen
CYP3A4/5
CH 3 CH 3
N
N
H
O H
OH
Endoxifen
SULT1A1
SULT1A1
Sulfate
metabolites
Toxicity. The common adverse reactions to tamoxifen
include vasomotor symptoms (hot flashes), atrophy of
the lining of the vagina, hair loss, nausea, and vomiting.
These may occur in ≤25% of patients and rarely are sufficiently
severe to require discontinuation of therapy.
Menstrual irregularities, vaginal bleeding and discharge,
pruritus vulvae, and dermatitis occur with increasing
severity in postmenopausal women.
Tamoxifen also increases the incidence of endometrial cancer
by 2- to 3-fold, particularly in postmenopausal women who receive
20 mg/day for ≥2 years. In general, tamoxifen-associated endometrial
cancers are reported as low-grade and early-stage tumors.
Standard practice guidelines from the National Comprehensive
Cancer Network alert physicians to the evaluation of abnormal vaginal
bleeding in women with an intact uterus.
Tamoxifen increases the risk of thromboembolic events,
which increase with the age of a patient and also in the perioperative
period. Hence, it often is recommended to discontinue tamoxifen
prior to elective surgery. Because tamoxifen is associated with
thromboembolism, some authorities suggest that the pretreatment
evaluation of breast cancer patients should include screening for
coagulation abnormalities (factor V Leiden, protein C, antithrombin
III defects) and for a history of thromboembolic disease. Presence of
these risk factors should lead to exclusion of women from treatment.
Note that no clear causative association between the presence of the