Transcript Document

ACROMEGALY
Ilan Shimon, MD
Rabin Medical Center,
Petach-Tiqva
Objectives of Treatment for Acromegaly
• Control and reverse symptoms and signs
• Suppress GH and IGF-1 to control morbidity and
mortality
• Decrease pituitary tumor size
• Control tumor mass effects
• Preserve normal pituitary hormone secretion
Surgical Outcome in Acromegaly
• Experience of the neurosurgeon
• Adenoma size
• Invasiveness into adjacent structures
• Pre-operative GH level
Remission of Acromegaly After
Transsphenoidal Surgery
Microadenomas – 70-90 %
Macroadenomas – 40-60 %
100
Remission Rate (%)
90
80
70
60
50
40
30
20
10
0
Microadenoma (n=44)
Macroadenoma (n=44)
Shimon I. Neurosurgery. 2001;48:1239
Remission of Acromegaly After
Transsphenoidal Surgery
Study
Patients
GH Criteria
ng/mL
Microadenomas
Macroadenomas
Ahmed
1990
139
Mean GH
<2.5
91%
46%
Fahlbusch
1992
224
OGTT <2
72%
50%
Davis
1993
175
Basal/OGTT
<2.5
60%
35%
Osman
1994
79
OGTT
<2.5
84%
Sheaves
1996
100
Mean GH
<2.5
61%
IGF-1
23%
Remission of Acromegaly After
Transsphenoidal Surgery (cont’d)
Study
Patients
GH Criteria
ng/mL
IGF-1
Microadenomas
Macroadenomas
Swearingen
1998
162
OGTT <2
Normal82%
91%
48%
Freda 1998
115
Basal/OGTT
<2
Normal87%
88%
53%
Lissett 1998
73
OGTT
<2.5
59%
14%
Shimon
2001
98
Basal/OGTT
<2
Normal72%
84%
64%
90
Mean GH
<2.5
OGTT <1
Normal68%
79%
56%
De P 2003
Remission of Acromegaly After
Transsphenoidal Surgery According
to Adenoma Size
100
Remission Rate (%)
90
80
70
60
50
40
30
20
10
0
3-6 (n=16)
7-10 (n=26)
11-20 (n=26)
>20 (n=10)
Adenoma Size (mm)
Shimon I. Neurosurg. 2001;48:1239
Acromegaly
• Definition of surgical cure
• Pre-operative medical treatment
• Primary medical treatment
• Improved remission by medical therapy after
surgical debulking
• Multi-recepotor SRIF analogs
• GH receptor antagonist
• Combination therapy
Current Clinical Practice?
Nadir GH
<1 µg/L
Nadir GH
>1 µg/L
IGF-1 Normal
No Treatment
?
IGF-1 Elevated
“Treat”
Treat
Association Between
Serum IGF-I and Nadir GH
Concentrations Across an OGTT
Nadir GH
<1 µg/L
Nadir GH
>1 µg/L
IGF-1 Normal
52 (58%)
37 (42%)
IGF-1 Elevated
34 (13%)
226 (87%)
108 treated patients
Ayuk, et al (unpublished data).
P<0.0001
Mortality in Acromegaly
1.0
GH <1 µg/L
Probability
0.8
NZ Population
GH <2 µg/L
0.6
GH <5 µg/L
0.4
GH >5 µg/L
0.2
0
0
5
10
15
20
25
30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667
Factors Influencing Mortality
in Acromegaly
1.0
Proportion Surviving
IGF SD Score <2
0.8
NZ Population
0.6
IGF SD Score >2
0.4
0.2
0
0
5
10
15
20
25
30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667
Long-term Mortality After Transsphenoidal Surgery
1.0
Normal IGF-I
0.8
Elevated IGF-I
Cox model 0.6
predicted
survival
0.4
Patient in remission
Patient not in remission
0.2
0.0
0
5
10
Years after surgery
Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419
15
20
Nadir GH levels after OGTT in postoperative
patients with normal IGF-I
Freda PU, et al. 2004, JCEM; 89:495
Post-operative Follow-Up With
Normal IGF-1 Values
• 110 post-operative patients with acromegaly
– 76 remission (normal IGF-1)
• 50 normal GH nadir (<0.14 µg/L; group 1)
• 26 abnormal GH nadir (0.3+0.05 µg/L;group 2)
• Longitudinal follow-up 1-6.5 years
– IGF-1 Group 1 normal in all
– IGF-1 Group 2 elevated in 5
• Conclusion: persistent abnormal GH
suppression is associated with
increased risk of recurrence
Freda PU, et al. 2004, JCEM; 89:495
Conclusions
• Evaluate normal ranges of GH and IGF-1 assays
(“know your assay”)
• Patients with evidence of hypersecretion of GH
should be considered for treatment irrespective of
IGF-1 value
• Patients with elevated IGF-1 should be
considered for treatment irrespective of GH value
• Treatment of co-morbidities may be even more
important and may influence the decision to treat
Pre-operative Treatment With
Somatostatin Analogs—
Clinical Studies
• Only few studies with small number of patients
• No randomized placebo-controlled studies
• Most studies with short-acting analogs
• No consistency in pre-operative dosage and
treatment interval
Pre-operative Treatment With
Somatostatin Analogs
• Six studies with treated/untreated patients
before pituitary surgery
• Five studies used subcutaneous OCT
• OCT dose was usually started at 300 µg/day,
and individually increased
• Pre-operative medical therapy was maintained
for 1-39 months before surgery, usually for
3-6 months
• The criteria for post-operative remission not
similar
Available Comparative Studies
Study
OCT
Untreated
Stevenaert—Metabolism 1996
64
108
Colao—JCEM 1997
22
37
Kristof—Acta Neurochir 1999
11
13
Biermasz—JCEM 1999
19
19
Abe—Eur J Endocrinol 2001
90
57
French Acromegaly Registry—
ENEA 2004
OCT/LAN 86
105
TOTAL: Pre-operative SRIF 292
Untreated
339
French Acromegaly Registry–
ENEA 2004, Sorrento;
OCT/LAN (86), Untreated (105)
Surgical Remission Rate
Pre-treated
Untreated
No.
%
No.
%
All
86
55
105
51
Noninvasive
40
67
54
65
Remission rate improved in patients
pre-treated for 4-6 months
Pre-surgical Treatment (292)
Untreated (339)
Summary of 6 Publications
Surgical Remission Rate
Pre-treated
Untreated
No.
%
No.
%
All
292
63.4
339
54.5
Noninvasive
166
83.7
169
74
Odds Ratio Plot
(Fixed Effects)
Mantel-Haenszel chi-square = 0.7341; P = 0.3916
Odds ratio meta-analysis plot [fixed effects]
stratum 1
French Registry
1.14 (0.62, 2.10)
stratum 2
Abe & Ludecke
0.65 (0.28, 1.48)
stratum 3
Biermasz NR
0.61 (0.12, 2.98)
stratum 4
Kristof RA
0.53 (0.07, 3.79)
stratum 5
Colao A
2.84 (0.83, 9.77)
stratum 6
5.74 (1.42, 32.93)
Stevenaert & Beckers
stratum 7
0.98 (0.29, 3.10)
combined [fixed]
1.18 (0.84, 1.66)
0.01
0.1
0.2
0.5
1
2
5
odds ratio (95% confidence interval)
10
100
UK Primary
Octreotide Study:
Individual Growth
Hormone
Response
(sc Oct, Oct-LAR)
Bevan JS et al. J Clin Endocrinol
Metab. 2002;87:4554-4563.
Percentage of Original Size
Tumor Changes After Primary OCT Therapy
Expressed as a Percentage of the Pre-treatment
Volume in 20 Macroadenomas
120%
100%
80%
60%
40%
20%
0%
Baseline
12 Weeks 24 Weeks 48 Weeks
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.
Tumor Shrinkage in Patients With
Previously Untreated Acromegaly
(a)
0
Microadenomas
-10
-10
-20
-20
-30
-40
Shrinkage (%)
Shrinkage (%)
0
(b)
Macroadenomas
-50
-60
-70
T0
Lanreotide SR
-30
-40
Octreotide LAR
-50
-60
-70
T12
Months of Therapy
T24
T0
T12
T24
Months of Therapy
Amato G. Clin Endocrinol. 2002;56:65
Effect of Octreotide on GH Levels
in Acromegaly
Growth Hormone (µg/L)
400
300
200
100
70
60
50
40
30
25
20
15
10
Pre-treatment
During Treatment
5
2.5
% Normal % Normal
IGF-1: 30% IGF-1: 53%
% Normal
IGF-1: 63%
% Normal % Normal % Normal
IGF-1: 75% IGF-1: 86% IGF-1: 83%
Newman et al. J Clin Endocrinol Metab. 1998;83:3034-3040.
Surgical Debulking Improves Hormonal Control
of Acromegaly by SST analogs (OCT, LAN)
(retrospective; 1-33 months, 300-1500 g/day)
Baseline Preoperative Postoperative
sst
washout
SST
Baseline
Postoperative SST
Preoperative washout
sst
Petrossians P, JCEM, 2005; 152:61
SSTR2 and SSTR5 expression in GH-secreting adenomas
(according to in vivo GH suppression by Octreotide)
Saveanu A, JCEM 2001; 86:140
BIM-23244, a bispecific (SSRR2 + SSTR5) analog
Saveanu A, JCEM 2001; 86:140
SST2 and D2DR expression in 11 GH-secreting tumors
Saveanu A, JCEM 2002; 87:5545
A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387
OCT-responsive
OCT-partially responsive
Saveanu A, JCEM 2002; 87:5545
SOM-230, a somatostatin analog with
broad spectrum binding affinity
Receptor subtype affinity (IC50, nM)
Compound
SSTR1
SSTR2
SSTR3
SSTR4
SSTR5
SRIF-14
2.26
0.23
1.43
1.77
0.88
Octreotide
1140
0.56
34
7030
7
Lanreotide
2330
0.75
107
2100
5.2
SOM-230
9.3
1
1.5
>100
0.16
Effect of Infused OCT and SOM230
on IGF-1 Plasma Levels in Rats
Weckbecker G, Endocrinology, 2002; 143:4123
GH release in cultured GH-secreting adenomas
Incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577
PRL release in cultured mixed PRL/GH-secreting
Adenomas incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577
In vivo GH suppression 2-8 h
after SOM-230 injection
N=8
N=3
Van der Hoek J, JCEM 2004; 89:638
GHR Antagonist Action
Pituitary
Tumor
GH
• Blocks GH effect
B2036-PEG
X
Liver
• Normalizes IGF-I in
92% of patients
X
IGF-I
IGF-I in 112 Patients with Acromegaly
Treated with Pegvisomant or Placebo
Serum IGF-I (ng/ml)
800
placebo
600
10 mg
400
15 mg
20 mg
200
0
2
4
8
Time (weeks)
Trainer et al N Eng J Med. 2000:342;1171-1177
12
Change in Serum GH in Patients
With Acromegaly Treated With Daily
Pegvisomant or Placebo
25
20 mg *
15 mg *
20
* P <0.001
vs. placebo
Serum
15
GH
(ng/ml)
10 mg
10
placebo
5
0
2
4
8
Time (weeks)
12
Trainer et al. NEJM. 2000:342;1171-1177
Pegvisomant Impact on GH
and IGF-I Levels
Dose mg
200
150
GH
20
Delta (%)
15
100
50
0
0
–25
15
–50
IGF-I
–75
20
2
4
Weeks
Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:1171-7.
8
12
IGF-1 at Baseline and After
12 Months of Pegvisomant
2500
2000
97% normalization of IGF-1 (n=90)
Serum IGF-1
(ng/mL)
1500
1000
500
16-24
25-39
40-54
Age (years)
55+
van der Lely et al. Lancet. 2001;358:1754
Tumor Volume Changes in
92 Patients Receiving Daily Pegvisomant
for >6 Months
4
No Radiation
Radiation
3
Change
in
Volume
(cm3)
2
1
0
-1
-2
-3
0
6
12
18
24
30
36
Time (months)
van der Lely et al. Lancet. 2001;358:1754
Acromegaly Cotreated
with GHR Antagonist
and Octreotide
van der Lely, JCEM; 2001, 86:478
Cotreatment with Sandostatin-LAR
and daily Pegvisomant (10/15 mg)
Jorgensen JO, JCEM, 2005; 90:5627
IGF-1 before and after 6 weeks of combined treatment
SSTR (LAR/Autogel) analog monthly + Pegvisomant
(up to 80 mg) weekly
Feenstra J et al, Lancet 2005, 365:1644