Aromatization of ‘A’ ring of testosterone and androstenedione is the final and key step in the production of estrogens (estradiol/estrone) in the body. In addition to the circulating hormone, locally produced estrogens appear to play an important role in the development of breast cancer.
AROMATASE INHIBITORS
Aromatization of ‘A’
ring of testosterone and androstenedione is the final and key step in the
production of estrogens (estradiol/estrone) in the body. In addition to the
circulating hormone, locally produced estrogens appear to play an important
role in the development of breast cancer. Though some aromatase inhibitors
(AIs) were produced in the past, three recent ‘third generation’ AIs Letrozole, Anastrozole and Exemestane have demonstrated clinical
superiority in the treatment of breast
cancer.
It is an orally active
nonsteroidal compound that
reversibly inhibits aromatization all over the body, including that within the
breast cancer cells, resulting in nearly total estrogen deprivation.
Proliferation of estrogen dependent breast carcinoma cells is suppressed to a
greater extent than with tamoxifen. Letrozole is rapidly absorbed with 100%
oral bioavailability, large volume of distribution, slow metabolism and a t½ of
~40 hours. Randomized clinical trials have established its utility in:
a) Early breast cancer: as adjuvant therapy after
mastectomy in ER+ive cases. Extension of prophylaxis with letrozole beyond the
standard 5 year tamoxifen treatment continues to afford protection, whereas continuation
of tamoxifen is not useful. Survival is prolonged in patients who have positive
axilary lymph nodes.
b) Advanced breast cancer: Current guidelines
recommend letrozole as first line therapy because of longer time to disease
progression and higher response rate obtained with it compared to tamoxifen. It
is also effective as second line treatment when tamoxifen has failed.
Adverse Effects
Hot flushes, nausea,
diarrhoea, dyspepsia and thinning
of hair are the side effects. Joint pain is common and it can accelerate bone
loss, but there is no endometrial hyperplasia or increased risk of endometrial
carcinoma. Risk of venous thromboembolism is also not increased, and there is
no deterioration of lipid profile.
Dose:
2.5 mg BD oral.
LETOVAL, LETROZ,
FEMARA, ONCOLET 2.5 mg tab. Though contraindicated in premenopausal women,
letrozole was clandestinely promoted and tested as an ovulation inducing
fertility drug. This was stopped after media outcry.
Another nonsteroidal
and reversible (Type 2) AI, more potent than letrozole and suitable for single
daily dosing. It accumulates in the body to produce peak effect after 7–10
days. Anastrozole is useful as adjuvant therapy in early ER+ive breast cancer
as well as for palliation of advanced cases in postmenopausal women. In early cases,
tumor recurrence time was found to be longer than with tamoxifen. Risk of new
tumor appearing in the contralateral breast was also lower with anastrozole. A
longer time to disease progression compared to tamoxifen has been obtained in
advanced ER+ive breast cancer. Many tamoxifen resistant cases responded with
increased survival. Side effects are hot flushes, vaginal dryness, vaginal
bleeding, nausea, diarrhoea, thinning of hair. Arthralgia and acceleration of osteoporosis
are prominent. However, it does not predispose to endometrial carcinoma or to
venous thromboembolism.
Dose: 1 mg OD; ALTRAZ, ARMOTRAZ 1 mg
tab.
This steroidal and irreversible (Type 1) inhibitor of aromatase acts like a suicide substrate
by covalent binding to the enzyme. As a result >90% suppression of estradiol
production is obtained. However, like androstenedione, it has weak androgenic
activity. Exemestane has been found beneficial in early breast cancer by
reducing the risk of disease progression when it was substituted for tamoxifen
as adjuvant therapy. In advanced breast cancer, longer survival, increased time
to disease progression and fewer treatment failures have been obtained with
exemestane. It is administered orally and is well tolerated. Adverse effects
are similar to other AIs.
Related Topics
TH 2019 - 2023 pharmacy180.com; Developed by Therithal info.