Giving patients a choice improves quality of life: a multi-centre, investigator-blind, randomised, crossover study comparing letrozole with anastrozole
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Letrozole
Anastrozole
Aromatase inhibitor
Crossover study
Exemestane
Results from large controlled clinical trials have identified the third-generation aromatase inhibitors (AIs) as the first significant therapeutic advance in the adjuvant treatment of hormone receptor-positive (HR+) early breast cancer in postmenopausal women since the introduction of tamoxifen. Although all 3 agents, letrozole, exemestane and anastrozole, provide benefits compared with a 5-year course of tamoxifen, the optimum strategy for adjuvant AI therapy has not yet been defined. AIs have been studied upfront, in sequence with tamoxifen, in therapy switch strategies after 2-3 years of tamoxifen, and after the completion of standard adjuvant tamoxifen. Clearly, only upfront treatment with an AI can address the peak risk of relapse during the first 2-3 years after surgery, and both letrozole and anastrozole significantly reduce relapses compared with tamoxifen in this setting. Switching to exemestane or anastrozole benefits women who are disease-free following 2-3 years of tamoxifen, and women who have successfully completed the standard 5 years of tamoxifen can benefit from extended adjuvant letrozole therapy. Ongoing studies will help to determine the optimum treatment strategy, and answer other important questions, such as whether the AIs differ clinically, what influence HR expression profiles have on outcomes, and what long-term toxicities may be associated with these highly effective agents.
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There is mounting evidence that aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment for postmenopausal women with oestrogen receptor positive breast cancer. Nevertheless, tamoxifen still remains a useful and relatively nontoxic treatment, and further work is necessary to determine which patients need an AI. In terms of cost-effectiveness, letrozole has been estimated to be superior to tamoxifen. Anastrozole, letrozole and exemestane have not been compared directly in an adjuvant setting but letrozole proved superior to anastrozole in patients with advanced breast cancer. Although tumour receptor phenotype may be useful in selection for tamoxifen or AI, the evidence is mixed. Optimal sequencing and duration of treatment have yet to be determined. If nationally funded and organised trials could be instigated, these would give timely and reliable data, so that adjuvant endocrine treatment of breast cancer could be tailored to needs of the individual patient.
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The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.
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Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.
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Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; 'FACE-trial'), clinicians have to make their choices today. On the basis of available evidence summarised here and until FACE-data become available, letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting. The background for this recommendation is discussed in the following chapters.
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Abstract BACKGROUND The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first‐line treatments and compared with megestrol acetate as second‐line therapy in postmenopausal women with advanced breast carcinoma. In an open‐label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS At clinically administered doses, the plasma half‐lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41–48 hours, 2–4 days, and 27 hours, respectively. The time to steady‐state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long‐term clinical significance of these differences remains to be elucidated. Cancer 2002;95:2006–16. © 2002 American Cancer Society. DOI 10.1002/cncr.10908
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<i>Background:</i> The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression. <i>Patients and Methods:</i> Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for ≧24 weeks). <i>Results:</i> Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9–82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6–78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2–63.7%) with a median TTP of 5.1 months. <i>Conclusions:</i> Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.
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