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ACROMEGALY

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

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ACROMEGALY

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  1. ACROMEGALY Ilan Shimon, MD Rabin Medical Center, Petach-Tiqva

  2. 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

  3. Surgical Outcome in Acromegaly • Experience of the neurosurgeon • Adenoma size • Invasiveness into adjacent structures • Pre-operative GH level

  4. 100 90 80 70 60 50 Remission Rate (%) 40 30 20 10 0 Microadenoma (n=44) Macroadenoma (n=44) Remission of Acromegaly After Transsphenoidal Surgery Microadenomas – 70-90 % Macroadenomas – 40-60 % Shimon I.Neurosurgery. 2001;48:1239

  5. Remission of Acromegaly After Transsphenoidal Surgery

  6. Remission of Acromegaly After Transsphenoidal Surgery (cont’d)

  7. 100 90 80 70 60 Remission Rate (%) 50 40 30 20 10 0 3-6 (n=16) 7-10 (n=26) 11-20 (n=26) >20 (n=10) Adenoma Size (mm) Remission of Acromegaly After Transsphenoidal Surgery According to Adenoma Size Shimon I. Neurosurg. 2001;48:1239

  8. 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

  9. Current Clinical Practice?

  10. Association Between Serum IGF-I and Nadir GH Concentrations Across an OGTT 108 treated patients P<0.0001 Ayuk, et al (unpublished data).

  11. Mortality in Acromegaly 1.0 GH <1 µg/L 0.8 NZ Population GH <2 µg/L 0.6 Probability 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

  12. Factors Influencing Mortality in Acromegaly 1.0 IGF SD Score <2 0.8 NZ Population 0.6 Proportion Surviving IGF SD Score >2 0.4 0.2 0 0 5 10 15 20 25 30 Time (Years) Holdaway IM,JCEM; 2004, 89:667

  13. Long-term Mortality After Transsphenoidal Surgery 1.0 Normal IGF-I 0.8 Elevated IGF-I Cox model predicted survival 0.6 0.4 Patient in remission Patient not in remission 0.2 0.0 0 5 10 15 20 Years after surgery Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419

  14. Nadir GH levels after OGTT in postoperative patients with normal IGF-I Freda PU, et al. 2004, JCEM; 89:495

  15. 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

  16. 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

  17. 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

  18. Pre-operative Treatment With Somatostatin Analogs • Six studies with treated/untreated patients before pituitary surgery • Five studies used subcutaneousOCT • 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 for3-6 months • The criteria for post-operative remission not similar

  19. TOTAL: Pre-operative SRIF 292 Untreated 339 Available Comparative Studies

  20. 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 patientspre-treated for 4-6 months

  21. 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

  22. French Registry Abe & Ludecke Biermasz NR Kristof RA Colao A Stevenaert & Beckers Odds Ratio Plot (Fixed Effects) Mantel-Haenszel chi-square = 0.7341; P = 0.3916

  23. UK Primary Octreotide Study:Individual Growth Hormone Response(sc Oct, Oct-LAR) Bevan JS et al. J Clin Endocrinol Metab. 2002;87:4554-4563.

  24. 120% 100% 80% 60% 40% 20% 0% Baseline 12 Weeks 24 Weeks 48 Weeks Tumor Changes After Primary OCT Therapy Expressed as a Percentage of the Pre-treatment Volume in 20 Macroadenomas Percentage of Original Size Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

  25. (a) (b) 0 -10 -20 -30 -40 -50 -60 -70 0 -10 -20 -30 -40 -50 -60 -70 Microadenomas Lanreotide SR Macroadenomas Shrinkage (%) Shrinkage (%) Octreotide LAR T0 T12 T24 T0 T12 T24 Months of Therapy Months of Therapy Tumor Shrinkage in Patients With Previously Untreated Acromegaly Amato G. Clin Endocrinol. 2002;56:65

  26. 400 300 200 100 Pre-treatment During Treatment 70 60 50 Growth Hormone (µg/L) 40 30 25 20 15 10 5 2.5 % Normal IGF-1: 30% % Normal IGF-1: 53% % Normal IGF-1: 63% % Normal IGF-1: 75% % Normal IGF-1: 86% % Normal IGF-1: 83% Effect of Octreotide on GH Levels in Acromegaly Newman et al. J Clin Endocrinol Metab. 1998;83:3034-3040.

  27. Surgical Debulking Improves Hormonal Control of Acromegaly by SST analogs (OCT, LAN)(retrospective; 1-33 months, 300-1500 g/day) Postoperative washout Baseline Postoperative washout Baseline SST SST Preoperative sst Preoperative sst Petrossians P, JCEM, 2005; 152:61

  28. SSTR2 and SSTR5 expression in GH-secreting adenomas (according to in vivo GH suppression by Octreotide) Saveanu A, JCEM 2001; 86:140

  29. BIM-23244, a bispecific (SSRR2 + SSTR5) analog Saveanu A, JCEM 2001; 86:140

  30. SST2 and D2DR expression in 11 GH-secreting tumors Saveanu A, JCEM 2002; 87:5545

  31. A Chimeric Somatostatin-DopamineMolecule, BIM-23A387 OCT-responsive OCT-partially responsive Saveanu A, JCEM 2002; 87:5545

  32. 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-2309.311.5 >100 0.16

  33. Effect of Infused OCT and SOM230 on IGF-1 Plasma Levels in Rats Weckbecker G, Endocrinology, 2002; 143:4123

  34. GH release in cultured GH-secreting adenomas Incubated with SOM-230 Hofland LJ, JCEM 2004; 89:1577

  35. PRL release in cultured mixed PRL/GH-secreting Adenomas incubated with SOM-230 Hofland LJ, JCEM 2004; 89:1577

  36. In vivo GH suppression 2-8 h after SOM-230 injection N = 8 N = 3 Van der Hoek J, JCEM 2004; 89:638

  37. GHR Antagonist Action • Blocks GH effect • Normalizes IGF-I in 92% of patients Pituitary Tumor GH B2036-PEG X Liver X IGF-I

  38. 800 placebo 600 10 mg Serum IGF-I (ng/ml) 400 15 mg 20 mg 200 0 2 4 8 12 Time (weeks) IGF-I in 112 Patients with AcromegalyTreated with Pegvisomant or Placebo Trainer et al N Eng J Med. 2000:342;1171-1177

  39. 25 20 mg * 15 mg * 20 * P <0.001 vs. placebo Serum GH (ng/ml) 15 10 mg 10 placebo 5 0 2 4 8 12 Time (weeks) Change in Serum GH in Patients With Acromegaly Treated With Daily Pegvisomant or Placebo Trainer et al. NEJM. 2000:342;1171-1177

  40. GH IGF-I Pegvisomant Impact on GH and IGF-I Levels Dose mg 200 20 150 15 100 Delta (%) 50 0 0 –25 15 –50 20 –75 2 4 8 12 Weeks Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:1171-7.

  41. 2500 97% normalization of IGF-1 (n=90) 2000 Serum IGF-1 (ng/mL) 1500 1000 500 55+ 25-39 40-54 16-24 IGF-1 at Baseline and After 12 Months of Pegvisomant Age (years) van der Lely et al. Lancet. 2001;358:1754

  42. No Radiation 4 Radiation 3 Change in Volume (cm3) 2 1 0 -1 -2 -3 0 6 12 18 24 30 36 Time (months) Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for >6 Months van der Lely et al. Lancet. 2001;358:1754

  43. Acromegaly Cotreated with GHR Antagonist and Octreotide van der Lely, JCEM; 2001, 86:478

  44. Cotreatment with Sandostatin-LAR and daily Pegvisomant (10/15 mg) Jorgensen JO, JCEM, 2005; 90:5627

  45. 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

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