Standard Traditional Meta-Analysis Different times since start of treatment Mantel-Haenszel approach

Analysis of a Single Time Interval (1) TreatmentDeathsSurvivorsTotal A B Total Treatment A: Observed deaths = 0 = 6 Expected deaths = E = (11 × 26)/55 = Variance= V = (11 × 44 × 26 × 29)/55 2 × 54) = Odds ratio = OR = (6/20)/5/24) = Log (OR)= LOR= 0.365

Analysis of a Single Time Interval (2) Log (OR)= LOR approx = (0 – E)/V= Variance (LOR)= 1/V = SD = % CI (LOR)= (0.358 – 1.96 × 0.669) to ( × 0.669) = ( , 1.669) 95% CI (OR)= (0.38, 5.41)

Analysis of Multiple Time Intervals Time Interval0EV 123:123: :010203: E1E2E3:E1E2E3: V1V2V3:V1V2V3: Meta-analysis  0  E  V log (OR)= (  0 -  E)/  V etc.

Standard Traditional Meta-Analysis Different hospitals within a trial

Standard Traditional Meta-Analysis Checking the assumptions: is the hazard ratio between treatments constant between different circumstances (time since treatment began, prognostic factors, hospitals, etc)? Power to test these assumptions is generally weak - need biological insight: e.g. ER+ve vs ER-ve

‘New’ Forms of Meta-Analysis Different trials Different trials with ‘slightly’ different regimens Different trials with ‘slightly’ different definitions of prognostic factors that influence drug response

‘New’ Forms of Meta-Analysis What contributes to differences between trials? Regimens used? General health of patients? Support services?

Increase in Breast Cancer Risk with Use of ERT and EPRT Increase in risk StudyHRT Typeper 5 years of use Magnusson et al. a ERT16% EPRT40% Schairer et al. a ERT 1% EPRT40% Ross et al. c ERT 6% EPRT24% a Int J Cancer 1999; 81: b JAMA 2000; 283: c J Natl Cancer Inst 2000; 92: B056-2

Breast Cancer B1

Day of Cycle Estradiol (pg/ml) Progesterone (ng/ml) Day of Cycle Relative Labelling Index Breast Cell Proliferation B051

Breast cell mitotic rate on continuous-combined estrogen- progestin replacement therapy is more than double that of estrogen replacement therapy. Hofseth et al. (JCEM 1999; 84: ).

B123

PREMPRO mg CE/2.5 mg MPA ORTHO-PREFEST 1 mg E2/0.09 mg norgestimate for 3 days every 6 days FEMHRT 5 µg EE2/1 mg norethindrone acetate H026

Approaches to Reducing Breast Progestin Exposure with HRT 1.Use of progestin for days every 3 months. Ettinger et al. (Obstet Gynecol 1994; 83: ). Williams et al. (Obstet Gynecol 1994; 84: ). E060

Approaches to Reducing Breast Progestin Exposure with HRT 2.Use an intra-uterine device - delivers local progestin with little systemic effect. Shoupe et al. (N Engl J Med 1991; 325: ). E060

Approaches to Reducing Breast Progestin Exposure with HRT 3.Use of intra-vaginal route of delivery - 50-fold gain in endometrial concentration for equal blood level of progesterone. Miles et al. (Fertil Steril 1994; 62: ). Fanchin et al. (Obstet Gynecol 1997; 90: ). E060

Meta-Analysis or Large Trial Problems The study does not address the right question. E.g. the WHI uses EPRT as the HRT arm.

TR034

First author% fat calories (year)Intervention Premenopausal Woods (1989)25 Hagerty (1988)25 Rose (1987)21 Boyd (1997)21 Williams (1989)20 Goldin (1994)20 Woods (1996)20 Ingram (1987)18 Schaefer (1995)18 Bogga (1995)12 Postmenopausal Crighton (1992)24 Prentice (1990)20 Ingram (1987)18 Heber (1991)10 All studies All above excluding Bagga (1995) and Heber (1991) Estradiol level (relative to baseline) Hor018

Hormonal Breast Cancer Chemoprevention in Premenopausal Women How do we prove that breast cancer prevention will occur? (a) Randomized trials? (b) Common sense? Mammographic changes? Breast cell proliferation? (c) Show that the proposed chemopreventive regimen is an ‘acceptable’ contraceptive? This route means that the regimen has to be inexpensive.

Hormonal Breast Cancer Chemoprevention in Premenopausal Women Can we maintain the protection against ovarian cancer and endometrial cancer afforded by the Pill?

Hormonal Breast Cancer Chemoprevention in Premenopausal Women Menopausal symptoms QOL Bone CVD Stroke DVT Mode of delivery: oral; patch; intra-nasal

Hormonal Breast Cancer Chemoprevention in Premenopausal Women How is this development going to be paid for? Our approach: Deslorelin + Add-back E 2 TP 4 : Treat uterine fibroids - compare to current treatment Treat endometriosis - compare to current treatment Treat PMS? Hormonal contraception? Current studies: Can bone be preserved while bleeding is controlled in fibroids while endometriosis is controlled

What does the FDA Demand? GNRH agonist plus add-back –Estradiol + Testosterone + Progesterone –Only permitted to do Estradiol

O028

Intra-Ovarian Estradiol and Ovarian Cancer Risk The observed 25% lower serum E 2 in Japanese women is predicted on the basis of in vitro results to produce a 3.2-fold reduction in their ovarian cancer rate cf U.S. women; decreasing to 4.2 when adjustment is made for earlier age at menarche and decreased parity. Great need is find out what is driving cell proliferation in vivo. Only in this way will we be sure that new formulations of hormonal contraceptives will not lose the chemopreventive benefits of OCs. For example, does Depot Provera prevent ovarian cancer? O041

Ovarian Cancer Mitogens for ovarian ‘epithelium’: FSH and E2 (at an intra-ovarian level) - E2 action blocked by P4 Needs: what are cell proliferation changes in the menstrual cycle? Study cystadenomas?

Standard Traditional Meta-Analysis Adjusting for prognostic factors

Standard Traditional Meta-Analysis Adjusting for prognostic factors Cox Proportional hazard approach

Standard Traditional Meta-Analysis What is the final survival curve comparison?

GN028