Letrozole (Femara (R)) is a third-generation, nonsteroidal aromatase inhibitor. Adjuvant therapy with letrozole is more effective than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, and extended adjuvant therapy with letrozole after the completion of adjuvant tamoxifen therapy is more effective than placebo in this patient population; letrozole is generally well tolerated. Ongoing trials will help answer outstanding questions regarding the optimal duration of letrozole therapy in early breast cancer and its efficacy compared with other third-generation aromatase inhibitors such as anastrozole. In the meantime, letrozole should be considered a valuable option in the treatment of postmenopausal women with hormone-responsive early breast cancer, both as adjuvant and extended adjuvant therapy. Pharmacological Properties Letrozole is a potent, highly selective inhibitor of aromatase; the inhibition of aromatase activity prevents the conversion of androgens to estrogens in the peripheral tissues. Reductions in whole body aromatization, aromatase activity in breast tumours, and plasma/serum levels of estrone, estradiol and estrone sulfate were seen with letrozole in postmenopausal women with breast cancer. Letrozole suppresses aromatization, plasma estrogen levels and estrogen levels within tumours to a greater extent than anastrozole, although the clinical significance of this is not clear. In general, extended adjuvant therapy with letrozole did not have deleterious effects on serum lipid levels in postmenopausal women with early breast cancer, according to the results of a substudy of the well designed, placebo-controlled MA-17 trial. Letrozole and anastrozole had generally similar effects on lipid levels. Letrozole reduced bone mineral density, according to the results of another MA-17 substudy. The results of this substudy support the results of other trials showing increases in markers of bone turnover in patients receiving letrozole. The third-generation aromatase inhibitors had generally similar effects on bone turnover. Absorption of oral letrozole is rapid and complete and steady state is achieved in 2-6 weeks with administration of letrozole 2.5 mg once daily. The cytochrome P450 (CYP) 3A4 and CYP2A6 isozymes metabolize letrozole to a pharmacologically inactive carbinol metabolite. Renal excretion of a glucuronide conjugate of the carbinol metabolite of letrozole represents the major route of drug clearance. Clinical Efficacy The efficacy of adjuvant and extended adjuvant therapy with. letrozole in postmenopausal women with hormone-responsive early breast. cancer was examined in two large, randomized, double-blind, multicentre trials: BIG 1-98 and MA-17. Adjuvant therapy with letrozole was more effective than tamoxifen in postmenopausal women with early breast cancer, according to the results of the BIG 1 - 98 trial. In the primary core analysis, significantly fewer disease-free survival events (primary endpoint) occurred with letrozole than with tamoxifen after a median duration of follow-up of 25.8 and 60.5 months. Letrozole recipients were also significantly less likely than tamoxifen recipients to experience systemic disease-free survival events; disease-free survival events excluding a second, nonbreast cancer; recurrence; or distant recurrence. Results of the monotherapy analysis, which only involved women who received continuous therapy with letrozole or tamoxifen and excluded recipients of sequential therapy, also revealed significantly fewer disease-free survival events with letrozole than with tamoxifen after a median 51 and 76 months of follow-up. Censoring the patients who selectively crossed over to letrozole after the tamoxifen monotherapy arm was unblinded revealed significant benefit with letrozole versus tamoxifen for several endpoints, including overall survival. Sequential therapy with tamoxifen followed by letrozole or letrozole followed by tamoxifen showed no benefit over 5 years' monotherapy with letrozole, according to the results of the sequential therapy analysis from the BIG 1-98 trial (median duration of follow-up of 71 months). Extended adjuvant therapy with letrozole significantly improved disease-free survival in postmenopausal women with early breast cancer, according to the results of the placebo-controlled MA-17 trial. Compared with placebo recipients, letrozole recipients had a 43% relative reduction in the risk of disease-free survival events (primary endpoint) in the interim analysis (median follow-up of 2.4 years) and a 42% relative reduction in the final analysis (median follow-up of 2.5 years). In addition, there was a 40% relative reduction in the risk of distant recurrence with letrozole versus placebo. There was no significant between-group difference in overall survival, although a prespecified subgroup analysis revealed that overall survival was significantly improved with letrozole versus placebo in node-positive patients. Extended adjuvant therapy with letrozole did not have an adverse impact on overall health-related quality of life. Tolerability Letrozole was generally well tolerated when administered as adjuvant or extended adjuvant therapy in postmenopausal women with early breast cancer in the BIG 1-98 and MA-I 7 trials. Adverse events were generally in keeping with the estrogen deprivation associated with letrozole therapy. In both trials, the majority of adverse events were of grade I or 2 severity. In the BIG 1-98 trial, adverse events (all grades) that Occurred in significantly more patients receiving adjuvant therapy with letrozole than tamoxifen included arthralgia, fracture, cardiac failure, 'other cardiovascular events' and hypercholesterolaemia, although hypercholesterolaemia was of mild severity in the majority of affected patients. By contrast, tamoxifen recipients were significantly more likely than letrozole recipients to experience hot flashes, thromboembolic events, night sweats and vaginal bleeding. The incidence of cardiovascular events was low in both letrozole and tamoxifen recipients. Grade 1-5 peripheral atherosclerotic events and 'other cardiovascular events', and grade 3-5 cardiac failure and 'any cardiac event' occurred in significantly more letrozole than tamoxifen recipients. Thromboembolic events of all grades occurred in significantly more tamoxifen than letrozole recipients. With extended adjuvant therapy in the MA-17 trial, adverse events (all grades) that occurred in significantly more letrozole than placebo recipients included hot flashes/flushes, arthralgia, myalgia, arthritis, anorexia and alopecia. Significantly more letrozole than placebo recipients had newly diagnosed osteoporosis; however, there was no significant between-group difference in the incidence of clinical fractures. Moreover, there was no significant difference between letrozole and placebo recipients in the incidence of cardiovascular events or hypercholesterolaemia. Letrozole recipients were significantly less likely than placebo recipients to experience vaginal bleeding. Pharmacoeconomic Considerations Markov modelling studies suggested that both adjuvant and extended adjuvant therapy with letrozole were cost effective in postmenopausal women with early breast cancer from the perspective of US, Canadian and UK healthcare systems. Incremental cost-effectiveness ratios were all below generally accepted cost-effectiveness thresholds.
