Transcript Standard Traditional Meta

Standard Traditional
Meta-Analysis
•Different times since start of treatment
•Mantel-Haenszel approach
Analysis of a Single Time Interval (1)
Treatment
Deaths
Survivors
Total
A
B
Total
6
5
11
20
24
44
26
29
55
Treatment A: Observed deaths = 0
Expected deaths = E
Variance
Odds ratio
=V
= OR
Log (OR)
= LOR
=6
= (11 × 26)/55
= 5.200
= (11 × 44 × 26 × 29)/552 × 54) = 2.234
= (6/20)/5/24)
= 1.440
= 0.365
Analysis of a Single Time Interval (2)
Log (OR)
LORapprox
Variance (LOR)
SD
95% CI (LOR)
95% CI (OR)
= 0.365
= (0 – E)/V = 0.358
= 1/V
= 0.448
= 0.669
= (0.358 – 1.96 × 0.669)
to
(0.358 + 1.96 × 0.669)
= (- 0.953, 1.669)
= (0.38, 5.41)
Analysis of Multiple Time Intervals
Time Interval
0
E
V
1
2
3
:
01
02
03
:
E1
E2
E3
:
V1
V2
V3
:
0
E
V
Meta-analysis
log (OR)
etc.
= (0 - E)/V
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
(1) Make bold, simplifying assumptions; look at as wide a
range of data as possible; be critical but not
pernickety. Do not be disturbed if the data does not
exactly fit the model.
(2) It is important not to place too much reliance on any
single piece of evidence, since some data is bound to
be misleading if not plain wrong.
(3) Make no assumptions that can not be doubted from
time to time.
(4) Almost all aspects of life are engineered at the
molecular level, and without understanding molecules
we can only have a very sketchy understanding of life
itself.
See Francis Crick "What Mad Pursuit".
‘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
HRT Type
Increase in risk
per 5 years of use
Magnusson et al.a
ERT
EPRT
16%
40%
Schairer et al.a
ERT
EPRT
1%
40%
Ross et al.c
ERT
EPRT
6%
24%
Study
aInt
J Cancer 1999; 81:339-344.
bJAMA 2000; 283:485-535.
cJ Natl Cancer Inst 2000; 92:328-332.
B056-2
Hawaii/Los Angeles MEC Study: HRT use
HRT
W
AA
NH
JA L-US
L-NUS
Never
36% 56% 54% 40% 50%
63%
Past
HRT
20% 23% 18% 14% 20%
20%
Current
ERT
14% 11% 11% 15% 12%
7%
Current
EPRT
30% 10% 19% 30% 18%
10%
Breast Cancer
500
Inc rate / 100,000
100
10
1
30
40
50
60
70
Age (years)
B1
Breast Cell Proliferation
Estradiol
(pg/ml)
Progesterone
(ng/ml)
400
20
300
15
Relative Labelling Index
2.5
2
1.5
10
200
1
100
5
0.5
0
1
3
5
7
9
11
13
15
Day of Cycle
17
19
21
23
25
27
0
0
11
3
55
77
9
11
13
13
15
17
17
19
19
21
23
23
25
27
Day of Cycle
B051
Breast cell mitotic rate on continuous-combined estrogenprogestin replacement therapy is more than double that of
estrogen replacement therapy.
Hofseth et al. (JCEM 1999; 84:4559-4565).
HRT and Mammographic Densities:
*
BI-RADS Changes in the PEPI Trial
BI-RADS Categorization:
(1)
(2)
(3)
(4)
Entirely fatty
Fatty with scattered fibroglandular tissue
Heterogeneously dense
Extremely dense
Women with an increase in
Estrogen
Progestin
BI-RADS Category after 12 months
________________________________________________________________________
†
Placebo
CEE (0.625 mg/d)
CEE (0.625 mg/d)
CEE (0.625 mg/d)
CEE (0.625 mg/d)
‡
Placebo
Placebo
MPA (10 mg/d; 12 days/mo)
MPA (2.5 mg/d)
MP (200 mg/d; 12 days/mo)
0%
3.5%
23.5%
19.4%
16.4%
*
Greendale et al. (Ann Int Med 1999; 130:262-269).
CEE = conjugated equine estrogens.
‡
MPA = medroxyprogesterone acetate.
MP = micronized progesterone.
†
B123
PREMPRO
0.625 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 12-14 days every 3 months.
Ettinger et al. (Obstet Gynecol 1994; 83: 693-700).
Williams et al. (Obstet Gynecol 1994; 84: 787-793).
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: 1811-1813).
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; 62:485-490).
Fanchin et al. (Obstet Gynecol 1997; 90: 396-401).
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
600
1991-96
500
Inc rate / 100,000
400
1973-78
300
200
100
20
30
40
50
Age (years)
60
70
80
First author
(year)
% fat calories
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
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
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 E2TP4 :
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
Risk of
Breast Cancer and Postmenopausal
Serum Estradiol Concentrationa
Serum E2 Concentration
(pmol/L)
Odds Ratio
(with 95% CI)
<30.7
30.7-41.0
>41.0
1.0
2.5 (1.0-6.4)
5.0 (2.0-12.5)
(p < 0.001)
a
Thomas et al. (Br J Cancer 1997; 76: 401-405).
O028
Intra-Ovarian Estradiol and Ovarian Cancer Risk
The observed 25% lower serum E2 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?
80
60
40
20
0
10
30
50
70
90
GN028