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Aromatase inhibitors in the era of Evidence Based Medicine dr. Vivianne Tjan-Heijnen UMC St Radboud NKI symposium 29 juni 2005.

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Presentation on theme: "Aromatase inhibitors in the era of Evidence Based Medicine dr. Vivianne Tjan-Heijnen UMC St Radboud NKI symposium 29 juni 2005."— Presentation transcript:

1 Aromatase inhibitors in the era of Evidence Based Medicine dr. Vivianne Tjan-Heijnen UMC St Radboud NKI symposium 29 juni 2005

2 Aromatase inhibitors in the era of Evidence Based Medicine Evidence or believe That is the question

3 What does a patient expect when receiving a treatment? That the treatment  is proven to be effective  has no unnecessary side-effects  has no unpleasant surprises The patient wants some certainty

4 Letrozole Non-steroidal (Type II) Steroidal (Type I) Anastrozole NC CN N N N Exemestane O CH 2 O CH 3 H3CH3C NCCN N N N H3CH3CCH 3 All aromatase inhibitors are equal, but some are more equal than others

5 Clinical pharmacology of newer-generation AIs AnastrozoleLetrozoleExemestane Daily clinical dose1mg2.5mg25mg Effects on corticosteroids No YesNo Half-life 41 hours 2–4 days27 hours Time to steady state plasmalevels 7 days 60 days 7 days** Androgenic metabolites No Yes Class of AI Type II Type I % of E 2 suppression Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

6 Anastrozole versus Exemestane in patients with visceral metastases Cameron et al. Proc ASCO 2004; abs 628

7 Anastrozole versus Letrozole 2 nd line Time to progression Rose et al. EJC 2003

8 % RFS years % node +ve Age % ER/PR+ve IES HR RFS 0.83* ATAC BIG ITA ARNO/ABCSG MA17 Anastrozole Letrozole Exemestane ABCSG Follow up *ER + population

9 Aromatase inhibitors in early breast cancer Anastrozole 1 Letrozole 2 Exemestane 3 Initial adjuvant therapy Efficacy vs tamoxifen Tolerability Switching from tamoxifen Efficacy vs tamoxifen Tolerability Extended adjuvant setting Efficacy vs placebo Tolerability Full risk:benefit profile ? 1) ATAC trialists’ Lancet 2005; Boccardo et al. ASCO 2005; Jakesz et al. SABCS 2004; Jakesz et al. ASCO ) Thurlimann St. Gallen 2005; Goss et al. NEJM ) Coombes et al. NEJM 2004

10 Neoadjuvant Anastrozole (OR%) Mastectomy / inoperable at baseline (n=344) 47% 35% AT ORR (%) 36% 26% AT ORR (%) Calliper Ultrasound A vs T: OR 1.65 (CI 1.06, 2.56) p=0.026A vs T: OR 1.60 (CI 1.00, 2.55) p= /18888/18855/15641/156 Statistically significant difference in favour of anastrozole

11 Indirect comparison with letrozole trial Objective response rate (%) OR (%) LT L vs T AT A vs T Ultrasound 3525p= p=0.048 Eiermann et al. Ann Oncol 2001; 12: 1527–1532.

12 Efficacy Conclusions Head to head studies in advanced breast cancer demonstrate similar efficacy of aromatase inhibitors There are no direct comparisons of aromatase inhibitors in early breast cancer  Indirect comparisons in primary endpoints show similar efficacy Differences in pharmacology do not seem to translate into differences in clinical efficacy

13 ASCO technology assessment 2004 In breast cancer therapy, ASCO currently recommends the use of the AI ‘that has been studied in the setting most closely approximating any individual patient’s clinical circumstance’ Winer et al. JCO 2005

14 Anno 2005: Evidence is what matters

15 Safety Differences in pharmacology do not seem to translate into differences in clinical efficacy Do these differences translate into different side effect profiles ? Focus on bone and cardio vascular effects

16 Interactions with the cytochrome P450 system AnastrozoleLetrozoleExemestane Inhibits CYP1A2, CYP2C9 at relatively high concentration No activity on CYP2A6 or CYP2D6 Metabolised by N-dealkylation, hydroxylation and glucuronidisation Strongly inhibits CYP2A6 Moderately inhibits CYP2C19 Metabolised by CYP3A4 and CYP2A6 No inhibition of CYP1A2, CYP2C9, CYP2D6, CYP2E1 or CYP3A4 Metabolised by CYP3A4 and aldoketoreductase Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16

17 Anastrozole 10mg: ACTH stimulation cortisol and aldosterone Adapted from: Plourde et al. J Ster Biochem Mol Biol 1995; 53: 175–9; Esparza-Guerra, Buzdar. Proc ASCO 2001; 20 (Pt 2): 52b, Abstr 1954

18 Adapted from: Bajetta E et al. Eur J Cancer 1999; 35: 208–13 Letrozole: ACTH stimulation cortisol and aldosterone LET = letrozole p=0.04 p=0.015 Baseline 30min 60min Time after ACTH stimulation nmol/L nmol/L Baseline30min60min Time after ACTH stimulation Baseline 1 month (2.5mg LET) 3 months (2.5mg LET)AldosteroneCortisol

19 Safety ATAC vs. BIG 1-98 vs. IES Upfront Anastrozole in favour of tamoxifen (ATAC): hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events and venous thromboembolic events. Letrozole in favour of tamoxifen (BIG 1-98): hot flashes, vaginal bleeding and thromboembolic events. Switch Exemestane in favour of tamoxifen (IES): vaginal bleeding, cramps and venous thromboembolic events. 1) ATAC trialists’ Lancet 2002,2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. NEJM 2004

20 Safety ATAC vs. BIG 1-98 vs. IES BIG 1-98ATAC (1 st analysis) ATAC (2 nd analysis) Cardiac death26 L, 13 T19 A, 20 T49 A, 46 T Cerebrovascular death7 L, 1 T3 A, 13 T14 A, 21 T IES Myocardial infarct: 20 exemestane; 8 tamoxifen Cardiac death / cerebrovascular death: to be reported 1) ATAC trialists’ Lancet 2002, 2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. SABCS 2004

21 Safety Bone In all adjuvant trials aromatase inhibitors lead to more fractures than tamoxifen  both in upfront and switching trials 1-3 Effects on bone do not seem to increase over time 1 1) ATAC trialists’ Lancet 2005; 2) Thurlimann St. Gallen 2005; 3) Coombes et al. SABCS 2004

22 Estimated change (95% CI) in lumbar spine BMD over time Estimated % changes from baseline lumbar spine BMD 4 Anastrozole 7158 Tamoxifen year 2 year Exe Tam Let Plac Coleman EBCC 2004 abs 289, Coleman SA 2004 Abs 401, Perez Abs 404

23 BMD after 1 year AI Lumbar Spine (% change)Total Hip (% change) Year 1 Ari (n=71) -2.6 (-3.3 to –1.8) -1.7 (-2.3 to –1.0) Tam (n=69) 1.2 (0.4 to 2.0) 0.8 (0.1 to 1.6) Exe (n=101) -2.9 (-3.6 to -2.1) -2.1 (-2.7 to –1.6) Tam (n=105) 0.02 (-0.7 to 0.7) 0.5 (0.0 to 1.0) Eastell R, et al. ASMBR 2003 abstract Coleman RE et al. SABCS 2004 abstract 401

24 Fracturen UPFRONTSEQUENTIEEL ATAC anastrozol vs tam BIG 1-98 letrozol vs tam IES-031 exemestanevs tam ABCSG8/ARNO95 anastrozol vs tam FU: 36 mnd 5.9% vs 3.7% (p< ) FU: 26 mnd 5.8% vs 4.1% (P=0.0006) FU: 37,4 mnd 3.9% vs 2.9% (p=0.06) FU: 28.0 mnd 2.4% vs 1.2% (significant)

25 Safety Conclusions Differences in potency and pharmacology do seem to translate into differences in side effect profiles Longer follow up is needed to confirm this With 68 months of follow up in ATAC anastrozole has the most robuust safety data

26 Evidence or believe It is not a question ! My patients with breast cancer expect me to be sure of what I am doing

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28 VOOR DE DISCUSSIE

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30 Hortobagyi ASCO 2005 Conclusions about AIs Upfront AI is clearly more effective/better tolerated than upfront TAM. AIs reduce events from the beginning. This is a fact. Crossover from TAM to an AI after 2-5 years of TAM is clearly effective. However, %/year of TAM-treated pts develop treatment failure before crossover. The superiority of crossover regimens over AI upfront is a hypothesis only. Until proven otherwise an AI upfront should be the preferred strategy.


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