Tamoxifen Anastrozole

Prototype agent Anastrozole Tamoxifen Flutamide Leuprolide... 

Eastell, R., Hannon, R.A., Cuzick, J., Dowsett, M., Clack, G. and Adams, J.E. (2006) Effect of an aromatase inhibitor on bmd and bone turnover markers 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). Journal of Bone and Mineral Research, 21, 1215-1223. 

Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, Mackey JR, Beckmann MW, Clack G. Effect of anastrozole on bone mineral density 5-year results from the anastrozole, tamoxifen, alone or in combination trial. J Clin Oncol 2008 26 1051-8. 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

Options for adjuvant hormonal therapy in postmenopausal women include aromatase inhibitors (e.g. anastrozole, letrozole, or exemestane) either in place of or after tamoxifen. Adverse effects with aromatase inhibitors include hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea. 

Toremifene has similar efficacy and tolerability as tamoxifen and is an alternative to tamoxifen in postmenopausal patients. Fulvestrant is a second-line intramuscular agent with similar efficacy and safety when compared to anastrozole in patients who progressed on tamoxifen. 

Aromatase inhibitors (including anastrozole, letrozole, aminoglutethimide, exemestane, formestane, testolactone), selective estrogen receptor modulators—SERMs (including raloxifene, tamoxifen, toremifene), clomiphene, cyclofenil, fulvestrant Diuretics, amiloride, bumetanide, canrenone, chlorthalidone, etacrynic acid, furosemide, indapamide, metolazone, spironolactone, thiazides, triamterene... 

The increasing clinical importance of tamoxifen in the 1980s prompted development of drugs that indirectly target the estrogen receptor, for example the aromatase inhibitor anastrozole (ARIMIDEX ), a selective inhibitor of estrogen biosynthesis [28]. Progress in treatment of hormone-dependent prostate cancer followed advances in breast cancer, with demonstration that... 

Eulvestrant has been evaluated in two randomised phase III trials in postmenopausal women with advanced disease after progression on prior antiestrogen therapy. In both trials, fulvestrant was at least as effective as anas-trozole. In a prospectively designed combined analysis of the results from both trials, median time to progression (TTP) was 5.5 months for fulvestrant versus 4.1 months for anastrozole [172]. Eulvestrant and tamoxifen have been compared as first-line treatments in a trial including post-menopausal women with advanced breast cancer. In this study, the between-treatment difference was non-significant (median TTP 6.8 versus 8.3 months) [173]. 

Despite the significant benefit that tamoxifen has bestowed on breast cancer patients, the third-generation aromatase inhibitors are rapidly replacing tamoxifen as the first-Une treatment for breast cancers. In this chapter, focus will be given to three representative small-molecule aromatase inhibitors for breast cancer exemestane (1, Aromasin ), anastrozole (2, Arimidex ), and letrozole (3, Femara ). 

Anastrozole, a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis. Figures 40-2 and 40-5), is effective in some women whose breast tumors have become resistant to tamoxifen (see Chapter 54). Letrozole is similar. Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrozole and letrozole, it is approved for use in women with advanced breast cancer (see Chapter 54). 

In a series of studies from Italy an attempt was made to determine whether giving anastrozole 1 mg/day and/or tamoxifen 20 mg/day could prevent gynecomastia and breast pain due to bicalutamide 150 mg/day (72). In a 48-week double-blind study tamoxifen reduced the symptoms but anastrozole did not. 

The risk of venous thromboembolism in women taking anastrozole is lower than that in women taking tamoxifen (1.6% versus 2.4%) (9), but still higher than in the untreated population. Cases of pulmonary embolism have been reported in an 80-year-old woman taking anastrozole (10) and a 72-year-old woman taking letrozole (11). 

Carpal tunnel syndrome has been reported in six patients taking aromatase inhibitors (29). Most subsequently experienced relief after withdrawal and/or switching to tamoxifen. In clinical trials of anastrozole and exemestane, carpal tunnel syndrome occurred in about 3% (30,31,32). 

In 34 post-menopausal women with early breast cancer anastrozole 1 mg/day for 28 days had no effect on the pharmacokinetics of tamoxifen 20 mg/day (38). 

Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T the ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer results of the ATAC... 

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists Group. Comprehensive side effect profile of anastrozole and tamoxifen as adjuvant treatment for early stage breast cancer long term safety analysis of the ATAC trial. Lancet Oncol 2006 7 633 13. 

Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R, von Euler M, Baum M. The effect of anastrozole on the pharmacokinetics of tamoxifen in postmenopausal women with early breast cancer. Br J Cancer 1999 79(2) 311-5. 

Others have suggested that patients be treated for a period with tamoxifen and then switched to anastrozole... 

This study has again confirmed that endometrial problems can be induced by tamoxifen early in the course of treatment and that these problems do not arise with aromatase inhibitors, which may actually reduce the endometrial changes induced by tamoxifen. The idea that the new oral aromatase inhibitors might well replace tamoxifen in breast cancer was tentatively advanced in SEDA-26 (p. 445) and has now been supported by some of the material cited above, as well as by a panel consensus (25). Citing efficacy and safety data on anastrozole, exemestane, and letrozole, the authors concluded that third-generation aromatase inhibitors may be considered first-line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women and may also be used for preoperative therapy of breast cancer. 

When tamoxifen 20 mg/day was compared with equieffective doses of anastrozole in 668 patients with advanced breast tumors that were hormone receptorpositive or of unknown receptor status, tamoxifen produced too high a rate of thromboembolism and vaginal bleeding to be considered the treatment of choice (51,52). 

Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J din Oncol 2000 18(22) 3748-57. 

Beer B et al (2010) Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 398 1791-1800... 

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