Download
slide1 n.
Skip this Video
Loading SlideShow in 5 Seconds..
These slides were released by the speaker for internal use by Novartis PowerPoint Presentation
Download Presentation
These slides were released by the speaker for internal use by Novartis

These slides were released by the speaker for internal use by Novartis

236 Vues Download Presentation
Télécharger la présentation

These slides were released by the speaker for internal use by Novartis

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. These slides were released by the speaker for internal use by Novartis

  2. Risk/benefit analysis: tamoxifen vs aromatase inhibitors • Edith A Perez • (Mayo Clinic, Jacksonville, FL; Mayo Foundation, Rochester, MN, USA)

  3. Tamoxifen Hot flushes Genitourinary symptoms Endometrial cancer Thromboembolism Favorable effects on lipids? Reduction in baseline CVD? Protective effect on bone AIs Hot flushes Arthralgia/arthritis Myalgia Bone loss/fractures vs tamoxifen Increase in CVD & hypercholesterolemia? Fewer gynecological symptoms Fewer endometrial cancers Fewer thromboembolic and DVT events (including grade 3–5) Adverse event profiles

  4. Hot flushes reported in adjuvant AI trials • Significant reduction vs tamoxifen with upfront AI (anastrozole, letrozole) • No significant reduction vs tamoxifen with sequential tamoxifen-AI therapy (exemestane, anastrozole) • Significant increase vs placebo with extended adjuvant letrozole ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  5. Gynecological symptoms/endometrial cancer reported in adjuvant AI trials • Compared with tamoxifen • Significant reduction in vaginal bleeding, vaginal discharge, endometrial biopsies • Non-significant reduction in endometrial cancer • Compared with placebo • Significant reduction in vaginal bleeding ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  6. Thromboembolic (TE) events reported in adjuvant AI trials • Compared with tamoxifen • Significant reduction in TE events including venous TE, deep venous TE and SAEs • Compared with placebo • No difference in incidences of TE events or stroke/transient ischemic attack ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  7. Arthralgia reported in adjuvant AI trials • In upfront and switching trials • All AIs associated with significant increase in arthralgia vs tamoxifen • AIs 5.4–36% vs tamoxifen 3.6–29% • In extended adjuvant setting • Significant increase in arthralgia vs placebo ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  8. CV disease reported in adjuvant AI trials Within the limitations of trial methodology and cross-trial comparisons, data suggest • Non-significant increase in CV events: AI vs tamoxifen • ATAC • BIG 1-98 • IES • ABCSG-8/ARNO • No difference in CV events: AI vs placebo • MA.17 core analysis • post-unblinding analysis Letrozole is not licensed in all European countries for use in the early adjuvant setting ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  9. Cardioprotective effect of tamoxifen • EBCTCG experience at 15 years1 • Subset of ~15,000 women treated with 5 years of tamoxifen vs control • 189 vs 169 vascular deaths (tamoxifen vs control, NS) • 32 trials comparing tamoxifen with control group: metastatic, adjuvant, and prevention settings2 • > 52,000 patients • Relative risk ratio for fatal MIs, tamoxifen vs control: 0.62 (95% CI: 0.41–0.93) 1. EBCTCG Lancet 2005;365:1687–717; 2. Braithwaite et al. J Gen Intern Med 2003;18:937–47

  10. Hypercholesterolemia reported in adjuvant AI trials Data from adjuvant AI trials suggest • Non-significant increase in hypercholesterolemia: AI vs tamoxifen • ATAC: 9% vs 3.5% (p = NR) • BIG 1-98: All grades: 43.5% vs 19.1% (p = NR) Grade 1: 35.1% vs 17.3% (p = NR) • ITA: 9.3% vs 4.0% (p = 0.04) • IES: NR • ABCSG-8/ARNO: NR • No difference in hypercholesterolemia: AI vs placebo (fasting) • MA.17: 16% vs 16% (p = 0.79) NR: not reported Letrozole is not licensed in all European countries for use in the early adjuvant setting Arimidex PI www.arimidex.com Sept 2005; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

  11. Differences in data capture In BIG 1-98 cholesterol data were collected every 6 months Simpler data collection in the ATAC trial – non-specific request to report AE

  12. BIG 1-98 targeted AE: cholesterol • All grades: 43% vs 19% • Measurements: 90% non-fasting, variable time of day • ≥ grade 1 hypercholesterolemia: any cholesterol measurement above ULN at 6-month visit • No central laboratory measurements

  13. 15 Letrozole Tamoxifen 10 Total cholesterol (mmol/L*) 5 0 18 60 0 6 12 42 48 54 30 36 24 Months Let 3209 Tam 3226 2606 2599 2660 2671 2546 2588 2264 2255 1716 1679 1253 1226 863 831 698 695 527 519 6 25 Effect of letrozole vs tamoxifen on total serum cholesterol† Cholesterol values remained stable in the letrozole arm and decreased in the tamoxifen arm by ~12% *To convert mmol/L to mg/dL, multiply by 39 Perez E. Personal communication

  14. Lipid lowering effect of tamoxifen? • Yes • Tamoxifen studies • 10 trials, 6 vs placebo; 657 patients • Decrease in cholesterol seen in all studies • Median decrease: 12.5% (range 3–17) • Decrease due to LDL cholesterol Herrington & Klein Womens Health Issues 2001;11:95102

  15. Effect of AI on lipid levels vs placebo • ATENA1 and MA.17 lipid substudy2 • Increase in serum cholesterol observed 6 months after tamoxifen discontinuation • No relevant difference between two treatment groups for any lipid parameters • LEAP study3 (early results) • Anastrozole (n = 29), exemestane (n = 32) and letrozole (n = 29) have similar, non-detrimental effects on serum lipids in postmenopausal women • Conclusion • AIs lack the lipid-lowering effects of tamoxifen 1. Markopoulos et al. Anticancer Drugs 2005;16:879–83; 2. Wasan et al. Ann Oncol 2005;16:707–15 3. McCloskey et al. Breast Cancer Res Treat 2005;94:(abstract 2052)

  16. Osteoporosis/fractures reported in adjuvant AI trials • Compared with tamoxifen • Upfront trials: significant increase in osteoporosis and/or fractures • Switching trials: significant increase in osteoporosisSignificant increase or trend for increase in fractures • Compared with placebo • Significant increase in new patient-reported osteoporosis • No significant increase in fracture rate ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57;Coombes et al.N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Boccardo et al. J Clin Oncol 2005;23:5138–47;Goss et al. J Natl Cancer Inst 2005;97:1262–71; Mincey & Perez ASCO Edu Book 2005;27–34

  17. Management of AEs Bone loss, osteoporosis and fractures • Tamoxifen protects against bone loss in postmenopausal women • HRT – contraindicated in patients with BC • Routine monitoring, calcium/vitamin D supplements • Bisphosphonates prevent bone loss • Efficacy differs between agents • Early generation oral bisphosphonates often poorly tolerated • CTIBL more rapid than ‘natural’ postmenopausal bone loss – may need more potent IV agents CTIBL, cancer treatment-induced bone loss HRT, hormone replacement therapy

  18. Letrozole + upfront ZOL Letrozole + delayed ZOL Overall difference p value Mean D in BMD(total hip) +1.40% -2.10% 3.50% < 0.001 Z-FAST, ZO-FAST and E-ZO-FAST RANDOMIZE Upfront zoledronic acid 4 mg q 6 months + Letrozole (2.5 mg/day) x 5 years Delayed* zoledronic acid 4 mg q 6 months + Letrozole (2.5 mg/day) x 5 years BMD at 12 months1 Accrual completed: ZO-FAST, n = 1066; Z-FAST, n = 602; E-ZO-FAST: n = 500 *Initiation of zoledronic acid determined by post-baseline BMD 1. Brufsky et al. J Clin Oncol 2005;23:12s(abstract 533)

  19. NCCTG N03CC Upfront or delayed bisphosphonate for women receiving letrozole after tamoxifen Inclusion criteria • Postmenopausal • Prior tamoxifen • T-score ≥ -2.0 SD (n = 550) RANDOMIZE Upfront zoledronic acid 4 mg q 6 months Delayed* zoledronic acid 4 mg q 6 months Letrozole x 5 years Calcium, vitamin D (all patients) *Initiation of zoledronic acid determined by post-baseline BMD T-score < -2.0 SD 10/05: enrollment complete; PI: BA Mincey

  20. ASCO bone health guidelines • BMD screening in breast cancer • All women aged > 65 years • All women aged 60–64 years with risk factors • Postmenopausal women of any age receiving AIs • Premenopausal women with medical/surgical premature menopause • Repeat BMD annually after initial exam • Treatment • T-Score > -1.5: lifestyle, reassurance • T-Score -1.5 to -2.5: calcium, vitamin D • T-Score <-2.5: bisphosphonates Hillner et al.J Clin Oncol 2003;21:4042–57

  21. Effect of AIs on QoL • Censoring at recurrence may underestimate QoL advantage of AIs • No significant adverse effects of AIs on QoL reported in adjuvant trials to date • AI vs tamoxifen: anastrozole (ATAC), exemestane (IES) • AI vs placebo: letrozole (MA.17) Fallowfield et al.J Clin Oncol 2004;22:4261–71; Fallowfield et al.J Clin Oncol 2006;24:910–17; Whelan et al.J Clin Oncol 2005;23:6931–40

  22. Adverse event profilesConclusions • Tamoxifen associated with thromboembolic and gynecological events • AIs generally well tolerated but associated with some bone loss and arthralgia • Tamoxifen protects against postmenopausal bone loss • Routine monitoring, calcium/vitamin D supplements can minimize fracture risk in most patients • Bisphosphonates can prevent AI-associated bone loss • Further investigation of effects on cardiovascular system and lipid metabolism • Beneficial effects of tamoxifen • No increase in cardiovascular disease or hypercholesterolemia, letrozole vs placebo (MA.17) • AEs associated with AIs generally more preventable or manageable than AEs associated with tamoxifen