Transcript PowerPoint-presentatie

Can we really treat endometriosis?
Johannes L.H. Evers, Maastricht, Netherlands
Belek, Turkey, 6 October 2011,
Annual Congress of the Turkish Society of Reproductive Medicine
Belek, Turkey, 6 October 2011
Objectives
To investigate the following hypotheses:
1.
2.
3.
4.
We understand endometriosis
Endometriosis is a progressive disease
We can treat endometriosis
We have good evidence for all of this
Belek, Turkey, 6 October 2011
Evidence-based medicine
is the integration of
(patho)physiological
mechanisms and the
outcome of top-quality
clinical research
David Sackett
Belek, Turkey, 6 October 2011
Preface
Belek, Turkey, 6 October 2011
Hypothesis 1
Endometriosis
Measles is the disease
The spots are the symptoms
Belek, Turkey, 6 October 2011
Hypothesis 2
You cannot cure the disease
by removing the symptoms
2 ımportant pıtfalls
When to perform Second Look
Laparoscopy?
How to deal wıth spontaneous
progressıon/regressıon?
Belek, Turkey, 6 October 2011
6 months drug treatment
Number of implants
20
18
FLL
16
14
12
10
# implants
8
SLL+2
6
4
2
0
SLL
Danazol x 6 months
Evers, Fertil Steril,1985
Placebo group
- better 5/17 (29%)
- same 4/17 (24%)
- worse 8/17 (47%)
Br Med J. 1987
January 31; 294(6567):
272–274.
E J Thomas and I D Cooke
Belek, Turkey, 6 October 2011
Preamble
Endometriosis is a dynamic process
Belek, Turkey, 6 October 2011
Preamble
Endometriosis is a dynamic process
Lesions come and lesions go
Belek, Turkey, 6 October 2011
Preamble
Endometriosis is a dynamic process
Lesions come and lesions go
This depends on:
Aggression: reflux menstruation
Defense: peritoneal immune system
Belek, Turkey, 6 October 2011
Preamble
Endometriosis is a dynamic process
Lesions come and lesions go
This depends on:
Aggression: reflux menstruation
Defense: peritoneal immune system
How can we modulate this process?
Belek, Turkey, 6 October 2011
Surgery Drugs
Belek, Turkey, 6 October 2011
Surgery
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Belek, Turkey, 6 October 2011
Drugs
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Belek, Turkey, 6 October 2011
Hypothesis
Endometriosis is a dynamic process
You can remove the implants by surgery
Occult implants will remain, and grow
You can inactivate (hide) implants by drugs
They will regrow after the end of therapy
Pain
Belek, Turkey, 6 October 2011
Surgery Drugs
Belek, Turkey, 6 October 2011
Hierarchy of major study designs
interventional
RCT
cohort
validity
cross-sectional
case control
case reports / case series
observational
Belek, Turkey, 6 October 2011
Drugs
Belek, Turkey, 6 October 2011
Endometriosis : pelvic pain
drug - placebo
12
Medical treatment
10
danazol
placebo
MPA
OC
GnRHa
GnRHa+
8
6
4
2
0
Start
3 months
6 months
follow-up
Belek, Turkey, 6 October 2011
Surgery
Belek, Turkey, 6 October 2011
Endometriosis : pelvic pain
LUNA + ablation
12
10
8
Surgery
Controls
6
4
2
0
Start
3 months
6 months
Sutton, 1997
Belek, Turkey, 6 October 2011
Endometriosis : pelvic pain
LUNA + ablation
12
10
8
Surgery
Controls
6
4
2
0
Start
3 months
6 months
Sutton, 1997
Belek, Turkey, 6 October 2011
Improvement pain
Abbott et al, 2004
F&S 82: 878-84
Belek, Turkey, 6 October 2011
Long term follow-up of pain surgery
VAS score
Abbott et al. 2003
Belek, Turkey, 6 October 2011
Number Needed to Treat
Pain relief surgery
Pain relief controls
ARI
NNT
95 % Confidence Interval
36/52 = 69 %
13/50 = 26 %
43 %
3
2–6
Sutton, 1997
Abbott, 2004
Belek, Turkey, 6 October 2011
Pain conclusion
Medical treatment works
Surgical treatment works
Medical treatment will only suppress
endometriosis temporarily
Surgical treatment will only remove visible
lesions
Infertility
Belek, Turkey, 6 October 2011
Surgery Drugs
Belek, Turkey, 6 October 2011
Drugs
Belek, Turkey, 6 October 2011
Ovulation suppression for endometriosis
24 trials
OR pregnancy drugs versus
placebo or no treatment
Drugs vs
Placebo
OR 95% CI
0.79 0.54-1.14
No treatment
0.80 0.51-1.24
Hughes et al, Cochrane 2007
Belek, Turkey, 6 October 2011
Ovulation suppression for endometriosis
24 trials
OR pregnancy drugs versus
placebo or no treatment
Drugs vs
Placebo
OR 95% CI
0.79 0.54-1.14
No treatment
0.80 0.51-1.24
Hughes et al, Cochrane 2007
AUTHORS' CONCLUSIONS:
There is no evidence of benefit in the use of
ovulation suppression in subfertile women with
endometriosis who wish to conceive.
Belek, Turkey, 6 October 2011
Surgery
Belek, Turkey, 6 October 2011
Grading endometriosis
Type
Clinical findings
Complicated
Implants
Adhesions
Cysts
Simple
Implants
Occult
---
Belek, Turkey, 6 October 2011
Grading endometriosis
Type
Clinical findings
Complicated
Implants
Adhesions
Cysts
Simple
Implants
Occult
---
Belek, Turkey, 6 October 2011
Grading endometriosis
Type
Clinical findings
Complicated
Implants
Adhesions
Cysts
Simple
Implants
Occult
---
Belek, Turkey, 6 October 2011
Grading endometriosis
Type
Clinical findings
Complicated
Implants
Adhesions
Cysts
Simple
Implants
Occult
---
Belek, Turkey, 6 October 2011
2 questions:
Does endometriosis affect fertility?
Belek, Turkey, 6 October 2011
2 questions:
Does endometriosis affect fertility?
If so, will treatment restore fertility?
Belek, Turkey, 6 October 2011
Hierarchy of major study designs
interventional
RCT
cohort
validity
cross-sectional
case control
case reports / case series
observational
Belek, Turkey, 6 October 2011
The best option: RCT
Sow - at random - endometrium in
peritoneal cavity of one group of
healthy female volunteers and not in
the other, and compare fertility
(cf. Ridley JH, Edwards IK: Experimental endometriosis in the human
Am J Obstet Gynecol 76: 783-790, 1958)
Belek, Turkey, 6 October 2011
Hierarchy of major study designs
interventional
RCT
cohort
validity
cross-sectional
case control
case reports / case series
observational
Belek, Turkey, 6 October 2011
Prospective cohort study
unselected
young
women
20 years follow-up:
live birth rates
Belek, Turkey, 6 October 2011
Prospective cohort study
?
?
?
women with
unexplained
subfertility
?
10 years untreated follow-up:
live birth rates
Belek, Turkey, 6 October 2011
The second best option, rephrased
Study spontaneous PR in untreated
controls of RCT’s
Compare to PR in women with
unexplained subfertility
Belek, Turkey, 6 October 2011
Spontaneous PR in RCT Controls
P ats
P reg n
PR
T h o m as,’8 7
17
4
24%
B ayer,’8 8
36
17
47%
T elim aa,’8 8 a
14
6
43%
T elim aa,’8 8 b
14
6
43%
F ed ele,’9 2
36
17
47%
O verto n ,’9 4
18
7
39%
RCT’s medical treatment
Belek, Turkey, 6 October 2011
Spontaneous PR in RCT Controls
E n d o c an ,’9 7
G IS E ,’9 9
P ats
P reg n
PR
169
29
17%
45
13
29%
RCT’s surgical treatment
Spontaneous PR in RCT Controls
P a ts
P re g n
PR
M e d ica l
135
57
42%
S u rg ica l
214
42
20%
2 RCT’s surgical treatment
6 RCT’s medical treatment
Spontaneous PR in RCT Controls
P a ts
P re g n
PR
M e d ica l
135
57
42%
S u rg ica l
214
42
20%
w e ig h te d a v e ra g e
28%
9 5 % C I 2 4 -3 4 %
2 RCT’s surgical treatment
6 RCT’s medical treatment
Spontaneous pregnancy rates
Pats
Pregn
PR
Present review Endometriosis
349
99
28%
Adamson,1996 Endometriosis
1063
360
34%
Taylor &
Collins,1992
2026
669
33%
Unexplained
subfertility
Adamson, WCE Yokohama, 1996
Taylor & Collins, Unexplained Infertility, 1992
Belek, Turkey, 6 October 2011
surgery
Belek, Turkey, 6 October 2011
ENDOCAN – 1997 Canada
172 surgery
169 controls
29% PR surgery
17% PR controls
Removal of lesions + lysis
of adhesions
GISE – 1999 Italy
51 surgery
49 controls
20% PR surgery
22% PR controls
Removal of lesions +
lysis of adhesions
Belek, Turkey, 6 October 2011
Jacobson et al. 2003
Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C. Laparoscopic
surgery for subfertility associated with endometriosis (Cochrane Review). In: The
Cochrane Library, Issue 2, 2003. Oxford: Update Software.
Belek, Turkey, 6 October 2011
Number Needed to Treat
PR surgery
PR controls
ARI
NNT
95 % Confidence Interval
60/223 = 26.9 %
39/214 = 18.2 %
8.7 %
12
6 - 111
Can we treat Endometriosis?
Evidence for drug effect
Pain: ovulation suppression works
Subfertility: no effect
Evidence for surgery effect
Pain: NNT 3 (95% CI 2 – 6)
Subfertility: NNT 12 (95% CI 6 – 111)
Belek, Turkey, 6 October 2011
Control & treated pats
50
45
40
35
30
25
20
15
10
5
0
C E
Untreated controls, 7 RCTs
Endocan
Fedele
Bayer
Telimaa a
Telimaa b
Overton
GISE
Thomas
Endocan C
Endocan E
Belek, Turkey, 6 October 2011
Control & treated pats
50
45
40
35
30
25
20
15
10
5
0
C E
Untreated controls, 7 RCTs
Endocan
Fedele
Bayer
Telimaa a
Telimaa b
Overton
GISE
Thomas
Endocan C
Endocan E
Belek, Turkey, 6 October 2011
Control & treated pats
50
45
40
35
30
25
20
15
10
5
0
C E
Untreated controls, 7 RCTs
Endocan
Fedele
Bayer
Telimaa a
Telimaa b
Overton
GISE
Thomas
Endocan C
Endocan E
www.endometriosis.ca
Hummelshoj 01/2006