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Letrozole

An Updated Review of its Use in Postmenopausal Women with Advanced Breast Cancer

  • Adis Drug Evaluation
  • Published:
American Journal of Cancer

Summary

Abstract

Letrozole is a highly selective nonsteroidal aromatase inhibitor. In postmenopausal women with advanced breast cancer, letrozole inhibits whole body aromatization by >98% and reduces plasma levels of estrone, estradiol and estrone sulfate by 74 to >95%. It also significantly inhibits aromatase activity and significantly reduces endogenous estrogen levels within breast tumors.

Letrozole is superior to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer. In a large, well designed trial, letrozole recipients were significantly less likely than tamoxifen recipients to experience disease progression or treatment failure and significantly more likely to experience an objective response or clinical benefit. The survival rate was significantly higher in letrozole than in tamoxifen recipients at 1 and 2 years.

In the second-line treatment of postmenopausal women with advanced breast cancer, letrozole was at least as effective as megestrol and was superior to aminoglutethimide, according to the results of three large, well designed trials. Letrozole 2.5 mg/day recipients were significantly more likely than letrozole 0.5 mg/day recipients or megestrol recipients to achieve an objective response in one trial, while no difference between the three treatment groups was seen in a second study. However, in this study, a significantly lower risk of disease progression and treatment failure was seen in letrozole 0.5 mg/day than in megestrol recipients. In the other trial, letrozole 2.5 mg/day, compared with megestrol, recipients were significantly less likely to experience treatment failure and had significantly longer durations of objective response and clinical benefit. Compared with aminoglutethimide recipients, letrozole recipients were significantly less likely to experience disease progression or treatment failure, and had significantly prolonged survival.

Second-line therapy with letrozole was associated with a significantly higher overall response rate than anastrozole in postmenopausal women with advanced breast cancer.

Letrozole was generally well tolerated in postmenopausal women with advanced breast cancer with adverse events tending to be of mild-to-moderate severity. Letrozole had similar tolerability to tamoxifen in the first-line treatment of advanced breast cancer. In terms of second-line treatment, letrozole appeared to be better tolerated than megestrol, aminoglutethimide or anastrozole.

Conclusion: Letrozole is an effective option in the first- and second-line treatment of postmenopausal women with advanced who have hormone receptor-positive disease or disease of unknown receptor status. Letrozole is superior to tamoxifen in the first-line treatment of advanced breast cancer and at least as effective as megestrol, with better tolerability, in the second-line treatment of advanced breast cancer.

Pharmacodynamic Properties

Administration of letrozole 0.5 or 2.5 mg/day inhibited aromatization bys >98% in postmenopausal women with advanced breast cancer. Furthermore, letrozole 2.5 mg/day was associated with more complete inhibition of whole body aromatization than anastrozole 1 mg/day in a crossover study involving 12 postmenopausal women with advanced breast cancer. Aromatase levels were detectable in none of the 12 patients during letrozole administration (>99.1% inhibition) and in 11 of 12 patients during anastrozole administration (mean inhibition of 97.3%). A significant reduction from baseline in in situ aromatase activity was seen in nine out of ten breast tumors exposed to letrozole 2.5 mg/day.

Plasma levels of estrone, estradiol and estrone sulfate were reduced from baseline by 74 to >95% in postmenopausal women with advanced breast cancer who received letrozole 0.1 to 5 mg/day. In addition, significantly greater suppression of estrone and estrone sulfate was seen with administration of letrozole 2.5 mg/day, compared with administration of anastrozole 1 mg/day. A significant reduction from baseline in endogenous estrogen levels (estrone plus estradiol levels) within breast tumors was seen with administration of letrozole 2.5 mg/day to postmenopausal women with breast cancer.

Letrozole showed antitumor activity in amousemodel of postmenopausal hormone-dependent breast cancer. Tumor weights were significantly lower in recipients of letrozole, compared with controls.

Letrozole is highly selective for aromatase. Administration of letrozole 0.1 to 2.5 mg/day to postmenopausal women with advanced breast cancer did not significantly alter serum levels of aldosterone, thyroxine, liothyronine (triiodothyronine), thyroid-stimulating hormone, cortisol, 17α-hydroxyprogesterone, androstenedione, luteinizing hormone or follicle-stimulating hormone.

No statistically significant differences between letrozole and placebo recipients were seen with regards to changes from baseline in lipid levels in a double-blind, randomized study in healthy postmenopausal women. Similarly, no significant changes from baseline in lipid levels were seen in a noncomparative study in women with no active breast disease. However, significant increases from baseline in total cholesterol and low-density lipoprotein cholesterol levels were seen in postmenopausal women with metastatic breast cancer who received letrozole 2.5 mg/day in another noncomparative study.

Levels of bone resorption markers (urinary pyridinoline and deoxypyridinoline or serum levels of C-telopeptide crosslinks) were significantly increased from baseline in two studies in postmenopausal women who received letrozole 2.5 mg/day for 3 or 6 months. Serum estradiol levels were significantly reduced (versus baseline or placebo) in these studies and it should be noted that bone mineral density was not measured. Further studies are needed to determine the clinical significance of the observed changes in bone resorption markers.

In a mouse model of postmenopausal hormone-dependent breast cancer, administration of letrozole 5 to 60 μg/day was associated with significantly lower uterine weights, compared with controls.

Pharmacokinetic Properties

A mean maximum plasma concentration of 107 nmol/L was achieved a median of 1.98 hours after administration of a single dose of letrozole 2.5mg to postmenopausal women with advanced breast cancer. The systemic absorption of letrozole was almost complete (systemic bioavailability of 99.9%) with a large volume of distribution (1.87 L/kg). The pharmacokinetics of letrozole 2.5 mg/day did not differ between younger (age range 52 to 66 years) and older (age range 70 to 76 years) postmenopausal women with advanced breast cancer, although a slight decrease in the rate, but not the extent, of letrozole absorption was seen in the fed, compared with the fasting, state in 12 healthy men.

The major route of elimination of letrozole is by metabolism, via the cytochrome P450 enzyme system, to a pharmacologically inactive carbinol metabolite. Approximately 90% of the administered letrozole dose was recovered in the urine as unchanged drug plus its metabolites.

Exposure to letrozole was significantly increased in patients with severe hepatic impairment who received a single dose of letrozole. Renal impairment did not affect the pharmacokinetics of letrozole in volunteers or in women with advanced breast cancer.

Compared with administration of letrozole alone, the letrozole area under the plasma concentration-time curve was significantly reduced by a mean of approximately 40% after concomitant administration of letrozole 2.5 mg/day and tamoxifen 20 mg/day in postmenopausal women with advanced breast cancer. However, the pharmacokinetics of tamoxifen were not significantly altered by concomitant administration of letrozole.

Therapeutic Efficacy

Letrozole is superior to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer. In a double-blind, randomized, multicenter study involving postmenopausal women with advanced breast cancer, recipients of letrozole 2.5 mg/day were significantly less likely than recipients of tamoxifen 20 mg/day to experience disease progression (the primary endpoint) [hazards ratio (HR) 0.70, 95% confidence interval (CI) 0.60 to 0.82] or treatment failure (HR 0.71, 95% CI 0.61 to 0.82) and were significantly more likely to experience an objective response [odds ratio (OR) 1.71, 95% CI 1.26 to 2.31] or clinical benefit (OR 1.55, 95% CI 1.19 to 2.01). The survival rate was significantly higher in letrozole than in tamoxifen recipients at 1 (83 vs 75%) and 2 (62 vs 57%) years.

Letrozole is a cost effective alternative to first-line treatment with tamoxifen in postmenopausal women with advanced breast cancer, according to the results of Canadian and UK decision-analysis modelling studies. In the Canadian study, letrozole and anastrozole were associated with costs of $Canl2 500 and $Canl9 600 per quality-adjusted progression-free year gained, compared with tamoxifen. In the UK study, letrozole, compared with tamoxifen, had a mean incremental cost of £500 per life-year gained.

Letrozole is at least as effective as megestrol in the second-line treatment of postmenopausal women with advanced breast cancer, according to the results of two large, double-blind, randomized, multicenter studies. In these studies, postmenopausal women with advanced breast cancer received letrozole 0.5 or 2.5 mg/day or megestrol 160 mg/day (the women had received prior antiestrogen therapy). No significant difference between treatment arms in the objective response rate (primary endpoint) was seen in one study, while in the other study letrozole 2.5 mg/day was the superior treatment (letrozole 0.5 mg/day vs letrozole 2.5 mg/day OR 0.42, 95% CI 0.23 to 0.76 and letrozole 2.5 mg/day vs megestrol OR 1.82, 95% CI 1.02 to 3.25). The duration of objective response was significantly longer in letrozole 2.5 mg/day, compared with megestrol, recipients in this same study (33 vs 17.9 months). No significant between-group differences were seen in either study in the clinical benefit rate. In one study, a significantly lower risk of disease progression (HR 0.80, 95% CI 0.64 to 0.99) and treatment failure (HR 0.78, 95% CI 0.63 to 0.96) was seen in letrozole 0.5 mg/day, compared with megestrol, recipients, although there was no significant between-group difference in the time to death. In the other trial, the risks of disease progression (HR 1.35,95% CI 1.04 to 1.75), treatment failure (HR 1.47,95% CI 1.15 to 1.89) and death (HR 1.34 95% CI 1.02 to 1.76) were significantly higher in letrozole 0.5 mg/day, compared with letrozole 2.5 mg/day, recipients. In addition, the risk of treatment failure was significantly lower (HR 0.77, 95% CI 0.61 to 0.99) and the median duration of clinical benefit was significantly longer (23.5 vs 14.5 months) in letrozole 2.5 mg/day recipients than in megestrol recipients. Letrozole and megestrol recipients had similar health-related quality-of-life scores in these studies.

A third large, randomized, multicenter study examining the second-line treatment of postmenopausal women with advanced breast cancer compared letrozole 0.5 or 2.5mg once daily with aminoglutethimide 250mg twice daily. There were no significant between-group differences in objective response rate or the rate of clinical benefit, although the risks of disease progression (HR 0.72, 95% CI 0.57 to 0.92), treatment failure (HR 0.70, 95% CI 0.55 to 0.88) and death (HR 0.64, 95% CI 0.49 to 0.85) were significantly lower in letrozole 2.5 mg/day recipients than in aminoglutethimide recipients. In addition, the risk of death was significantly lower in letrozole 2.5 mg/day, compared with letrozole 0.5 mg/day, recipients (HR 0.74, 95% CI 0.56 to 0.98).

Second-line therapy with letrozole 2.5mg once daily, compared with anastrozole 1mg once daily, resulted in a significantly higher objective response rate (19.1 vs 12.3%; secondary endpoint) in postmenopausal women (n = 713) with locally advanced or metastatic breast cancer in a nonblind, randomized, multicenter study. There was no significant between-group difference in the time to disease progression (primary endpoint). Patient preference was greater for letrozole than for anastrozole in a single-blind crossover study.

A significantly higher objective response rate (31.2 vs 13.0 %; primary endpoint) was seen with administration of letrozole lmg once daily than with administration of the second-generation aromatase inhibitor fadrozole lmg twice daily in a double-blind, randomized, multicenter study in postmenopausal women with advanced breast cancer.

Subgroup analyses showed that second-line therapy with letrozole was effective in postmenopausal women with advanced breast cancer who had predominantly visceral metastases. Historically, hormonal therapy has been considered less effective in patients with visceral metastases, compared with those who have predominantly bone or soft tissue metastases.

Letrozole appears to be a cost-effective option in the second-line treatment of postmenopausal women with advanced breast cancer, although data from prospective studies are lacking.

Tolerability

Letrozole was generally well tolerated in postmenopausal women with advanced breast cancer with adverse events tending to be of mild-to-moderate severity. The most common drug-related adverse effects experienced by letrozole 0.5 or 2.5mg recipients included nausea (6 to 13%), hot flushes (3 to 16%), hair thinning (4 and 6%) and fatigue (3 to 6%).

Letrozole had similar tolerability to tamoxifen in the first-line treatment of postmenopausal women with advanced breast cancer. Thromboembolic adverse events, irrespective of whether or not they were related to drug therapy, occurred in 1% of letrozole recipients and 2% of tamoxifen recipients. Overall (both treatment groups), 7% of patients discontinued therapy (most of the discontinuations for adverse events were for tumor-related symptoms associated with disease progression).

In the second-line treatment of postmenopausal women with advanced breast cancer, letrozole 0.5 or 2.5 mg/day recipients were significantly less likely than megestrol recipients to experience body weight increase (3 and 4 vs 13%), appetite increase (2 and 1 vs 11%), dyspnea (24 and 23 vs 38%), vaginal bleeding (3 and 0.5 vs 8%) or cardiovascular adverse events (11 and 10 vs 20%). In contrast, significantly more letrozole 2.5 mg/day recipients, compared with letrozole 0.5 mg/day or megestrol recipients, experienced headache (23 vs 12 and 12%).

In the second-line treatment of postmenopausal women with advanced breast cancer, letrozole 0.5 and 2.5 mg/day recipients were less likely than aminoglutethimide recipients to experience drug-related rash (1 and 3 vs 11%), somnolence (3 and 3 vs 7%) or abdominal pain (2 and 0.5 vs 5%).

The pooled incidence of adverse events was significantly lower in letrozole 2.5mg once daily than in anastrozole lmg once daily recipients (43 vs 65%) in a single-blind crossover study in postmenopausal women with advanced breast cancer receiving second-line therapy.

Dosage and Administration

In the US and Europe, letrozole is currently indicated for the first-line treatment of postmenopausal women with locally advanced or metastatic breast cancer that is hormone receptor positive or of unknown receptor status and in the treatment of advanced breast cancer in postmenopausal women who have disease progression after antiestrogen therapy. The recommended oral dosage of letrozole is 2.5mg once daily. No dosage adjustment is needed in elderly patients. Dosage adjustment is not needed in patients with renal impairment if their creatinine clearance is >-0.6 L/h (>-10 ml/min), according to US prescribing information. While no dosage adjustment is needed in patients with mild-to-mo derate hepatic impairment, US and European prescribing information recommend caution in administering letrozole to patients with severe hepatic impairment.

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Authors and Affiliations

  1. Adis International Inc., 860 Town Center Drive, Langhorne, PA, 19047, USA

    Gillian M. Keating & Blair Jarvis

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  1. Gillian M. Keating
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  2. Blair Jarvis
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Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: S. Chan, Department of Clinical Oncology, City Hospital, Nottingham, United Kingdom; M. de Lena, Operative Unit of Medical Oncology, Oncology Institute, Bari, Italy; J.M. Dixon, Breast Research Unit, Western General Hospital, Edinburgh, United Kingdom; W.J. Gradishar, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA; H.T. Mouridsen, Department of Oncology, The Finsen Center, Copenhagen, Denmark; S. Pyrhönen, Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

Data Selection

Sources: Medical literature published in any language since October 1998 on Letrozole, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘Letrozole’ or ‘CGS 20267’. EMBASE search terms were ‘Letrozole’ or ‘CGS 20267’. AdisBase search terms were ‘Letrozole’ or ‘CGS 20267’. Searches were last updated Sep 20 2002.

Selection: Studies in patients with breast cancer who received Letrozole. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic.

Index terms: Letrozole, breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, dosage and administration.

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Keating, G.M., Jarvis, B. Letrozole. Am J Cancer 1, 351–371 (2002). https://doi.org/10.2165/00024669-200201050-00007

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