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Frequently Asked Questions and Answers |
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1. What is acromegaly?
Acromegaly is a rare chronic disorder caused by the presence of a pituitary adenoma, which results in the hypersecretion of growth hormone (GH) and subsequent elevation of circulating and locally produced insulin-like growth factor-1 levels (IGF-1). The clinical presentation of acromegaly is characterized by skeletal overgrowth deformities, particularly of the hands, feet and face, cardiovascular disease, neuropathy and respiratory obstruction. If left untreated, acromegaly is associated with substantial morbidity and mortality rates, two- to four-times higher than those found in the general population.1-3
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2. What are the goals of treatment for acromegaly?
The goals of treatment in acromegaly include normalization of GH and IGF-1 levels, reduction in tumour size, prevention of tumour recurrence, and alleviation of significant comorbid features, particularly cardiovascular, pulmonary and metastatic derrangements.4,5 There has been considerable debate on the appropriate level of GH to be achieved when treating acromegaly.6 Normalization of GH levels to less than 2 µg/L (5 mU/L) within 2 hours after a glucose load has been suggested as the primary objective of therapeutic intervention,4 and there is now compelling evidence that lowering GH levels to this target concentration reverses the mortality associated with acromegaly.7,8 Nevertheless, recently published management guidelines suggest that more stringent control of GH levels to less than 1 µg/L (2.5 mU/L) after an oral glucose load may be required.5 A frequently used alternative is to calculate mean GH levels from five measurements in a single day. In this case, the aim is to reduce mean GH levels to less than 2.5 µg/L (6.25 mU/L).6,7,8
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3. What is first-line therapy for acromegaly?
Transsphenoidal surgical excision of the pituitary adenoma is usually first-line therapy in acromegaly. The procedure is associated with normalization of GH levels in approximately 90% of patients with well-defined microadenomas.8-11 Surgical remission rates are lower in patients with macroadenomas because of the large, fibrous, and frequently invasive nature of these tumours, which makes complete resection unlikely.8,11 Unfortunately, macroadenomas constitute the majority of tumours detected in patients with acromegaly on initial presentation.
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4. How are patients with acromegaly refractory to surgical intervention managed?
For patients with acromegaly who are not candidates for surgery, or for whom surgery is unsuccessful, alternative approaches, such as irradiation and pharmacological therapy, are required. In recent years, the use of pituitary irradiation has declined. The technique is commonly associated with adverse effects, including hypopituitarism. Furthermore, following administration of irradiation there is often a prolonged period - sometimes years - before maximal GH suppression is attained, and IGF-1 levels are seldom normalized.12 Pharmacological therapy is indicated for second-line use following surgery and/or irradiation, and in the interim period after irradiation when hormone levels remain elevated. Indeed, recent treatment guidelines propose that pharmacological therapy may be a viable alternative to irradiation for patients who remain refractory to surgical treatment.5
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5. What types of pharmacological therapy are suitable for acromegaly?
The type of pharmacological therapy recommended for acromegaly depends on a number of factors relating to the individual patient, the severity and complications of the disease, and the risk/benefit ratio of the particular treatment modality.4 Long-acting somatostatin analogs, such as octreotide acetate (Sandostatin®), are the mainstay of pharmacological treatment.5 Oral dopamine agonists, such as bromocriptine mesylate (Parlodel®), constitute another therapeutic option. Dopamine agonists are only effective in approximately 10% of patients with acromegaly; however they may be the preferred choice of pharmacological therapy in patients with acromegaly and co-existent hyperprolactinaemia.13 Independent studies and case reports suggest that patients resistant to monotherapy with either agent may benefit from the combined use of Sandostatin® and bromocriptine.5,13,14 Concomitant administration of Sandostatin® and bromocriptine increases the bioavailability of bromocriptine.15
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6. What is Sandostatin®?
Sandostatin® is a long-acting synthetic analog of somatostatin that binds with maximum affinity to the somatostatin receptor subtype SSTR2, and to a lesser extent to SSTR3 and SSTR5.16 Through this interaction, Sandostatin® exerts a number of physiological effects, including alteration of the expression of several hormones. Of note in acromegaly is the potent suppression of GH release, which is 40- to 70-times more potent than that achieved with somatostatin. A single dose of subcutaneous Sandostatin® results in a rapid decline in GH levels within the first hour post-dose, reaching maximal suppression after 3 hours.1 GH levels may remain suppressed for up to 12 hours. Both GH and IGF-1 levels continue to decrease with chronic administration of subcutaneous Sandostatin®; following long-term administration in 10 patients with acromegaly in one study, both GH and IGF-1 levels were significantly lower after 1.5-2 years than after 6-12 months.17 IGF-1 levels were normalized in half of the patients. Sandostatin® differs from natural somatostatin in that its half-life lasts for approximately 90 minutes making it suitable for therapeutic use in patients with acromegaly when administered by subcutaneous injection twice- or three-times daily.
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7. When is it appropriate to treat acromegaly with Sandostatin®?
Sandostatin® is typically used as second-line treatment in patients whose GH levels remain elevated after surgery, or in those patients for whom surgical resection is not an option. 5 Based on the results of independent investigations, it has been proposed that it should also be considered as first-line treatment in patients with acromegaly caused by a macroadenoma, in whom the chances of surgical cure are reduced.18 Recent treatment guidelines also suggest that selected patients with unacceptable anesthetic risk, or cardiovascular and/or pulmonary complications may benefit from primary therapy with Sandostatin®.5 In addition, studies have shown that pre-operative treatment of patients with Sandostatin® can improve surgical outcome, shrinking and softening tumours, facilitating their resection.11,19,20 In one recent study, improved surgical remission was associated with endocrinological remission in patients with microadenomas and potentially respectable macroadenomas given pre-operative treatment with Sandostatin®.11
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8. What are the recommendations for dosage and administration of Sandostatin® in patients with acromegaly?
The recommended starting dose of Sandostatin® in acromegaly is 150 µg/day, given subcutaneously in three 50 µg doses (t.i.d.); however, the dose of Sandostatin® used to treat acromegaly must be individualized for each patient and titrated for optimal response.21 Indeed, a recent study found that men with acromegaly may require a higher dose of Sandostatin® than women due to gender-specific differences in GH sensitivity;22 however, no age-specific effects have been observed.23 The dose of Sandostatin® most commonly found to be effective is 100 µg t.i.d. (300 µg/day), but some patients may require up to 500 µg t.i.d. (1500 µg/day) for maximum effectiveness. In order to achieve a uniform reduction of GH and IGF-1 levels throughout the day, some investigators have reported that Sandostatin® can also be administered by continuous subcutaneous infusion. Studies have demonstrated that when Sandostatin® is administered by this method it avoids the fluctuations in hormone levels seen with intermittent subcutaneous injections24 and produces sustained lower GH and IGF-1 levels;25-27 this may be associated with increased effects on tumour shrinkage.28 GH or IGF-1 levels should be re-evaluated at 6 monthly intervals in order to determine ongoing response.
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9. How does Sandostatin® LAR® differ from subcutaneous Sandostatin®?
The long-acting repeatable (LAR®) formulation of octreotide (Sandostatin® LAR®) consists of octreotide acetate incorporated into microspheres of a biodegradable polymer. It is administered as a single intramuscular injection into the gluteal muscle every 4 weeks. Drug release is governed by the slow degradation of the microspheres in the muscle, but once present in the systemic circulation Sandostatin® LAR® appears to maintain the pharmacological characteristics of subcutaneous Sandostatin®.29 Sandostatin® LAR® is indicated for long-term maintenance therapy in patients with acromegaly for whom medical treatment is appropriate and who have been shown to respond to and tolerate subcutaneous Sandostatin®.21
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10. What are the recommendations for dosage and administration of Sandostatin® LAR® in patients with acromegaly?
Patients currently receiving subcutaneous Sandostatin® can be switched to a 20-mg intramuscular dose of Sandostatin® LAR® given every 4 weeks.21 After 3 months' therapy, the dose of Sandostatin® LAR® can be decreased to 10 mg every 4 weeks or increased to a maximum of 30 mg every 4 weeks, according to response. Assessment of GH and IGF-1 levels should be performed every 6 months.
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11. Do all patients with acromegaly respond to Sandostatin® treatment?
Clinical studies show that Sandostatin® produces a fall in GH serum concentration in approximately 85-90% of patients with acromegaly.30,31 More than 50% of those treated will achieve serum GH levels (5 µg/L and almost 75% of patients will have normalized IGF-1 levels.32 In a recent study in 42 patients with acromegaly, a single dose of Sandostatin® reduced GH levels from a mean basal level of 26 µg/L to less than 5 µg/L in 74% of patients within 6 hours.31 GH levels were suppressed by more than 45% in all but 7% of patients. Endocrinological response rates appear to improve with time during long-term Sandostatin® LAR® therapy. During a recent study, GH levels decreased significantly after 3 months' treatment with Sandostatin® LAR® to 2.1 µg/L after 2 years (p(0.05).33 Baseline GH levels are sometimes predictive of treatment outcome. Indeed, it has been reported that Sandostatin® normalizes GH levels most frequently when baseline GH levels are less than 35-50 µg/L.34 Previous surgery/irradiation does not appear to affect treatment outcome.35 A small number of patients appear to be refractory to Sandostatin® therapy, even at high doses up to 1600 µg/day.34 Independent studies have shown that these refractory tumours may respond to combination therapy with Sandostatin® and bromocriptine.5,15,36,37
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12. What are the clinical benefits of Sandostatin® for patients with acromegaly?
Cardiovascular disease is widely acknowledged as one of the most important complications of acromegaly, accounting for much of the mortality associated with the condition. Long-term studies with both Sandostatin® and Sandostatin® LAR® have shown that normalization of GH and IGF-1 levels is associated with improved cardiac performance in patients with acromegaly.38-40 During a 6-month investigation of Sandostatin® LAR® in acromegaly, recovery of left ventricular hypertrophy occurred in 55% of patients achieving normalized hormone levels.38 Similarly, in another study cardiac performance was normalized in 50% of patients receiving subcutaneous Sandostatin® at a 5-year follow-up.39 Treatment is also particularly effective in reducing the debilitating headaches that are characteristic of acromegaly,32 symptoms of fatigue,41 and sleep apnoea.42 Indeed, in some patients, headache has been relieved within minutes of Sandostatin® administration.43 Studies have shown that other symptoms of acromegaly, including joint pain, arthropathy, excessive perspiration, and carpal tunnel syndrome improve in about 70% of patients with acromegaly during Sandostatin® treatment.32,44-47 Indeed, results from clinical investigations demonstrate that symptomatic improvement occurs with Sandostatin® in acromegaly, even if GH and IGF-1 levels are not normalized.30,48 In one study, for example, clinical improvement was noted in 80% of patients, whereas biochemical improvement was only seen in 53% of those treated.48 Partial relief of symptoms is typically noted within 2-4 weeks after the initiation of an effective dose, and continued improvement has been reported for at least 6 months.49
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13. Does Sandostatin® affect tumour growth and size?
Clinical experience shown that a reduction in tumour size occurs in up to 50% of patients treated with Sandostatin® and Sandostatin® LAR®.32,50,51 The effect is usually evident after 1-2 months' therapy.52-54 Patients typically experience a moderate (less than 50%) reduction in tumour volume with dramatic shrinkage occurring in only sporadic cases. During a recent study in 27 treatment-naïve patients, tumour shrinkage was observed in all patients after 24 weeks' treatment with subcutaneous Sandostatin®.51 GH levels (2 µg/L (5 mU/L) and normalized IGF-1 levels were achieved in 41% of patients. Reduction in tumour volume was similar for microadenomas and macroadenomas. Interestingly, much of the volume reduction occurred within 12 weeks of commencing therapy. Similar effects on tumour shrinkage were seen in 14 of these patients who were subsequently switched to treatment with Sandostatin® LAR® for a further 24 weeks. GH levels (2 µg/L (5 mU/L) were achieved in 71% of patients and IGF-1 levels were normalized in 50% of patients. Median tumour volume was reduced overall by a further 37%. Nine patients had definite further shrinkage, tumour volume was unchanged in four patients, and only one patient showed a small increase in tumour size.
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14. How does Sandostatin® and bromocriptine combination therapy work?
Numerous independent studies have shown that patients unresponsive to Sandostatin® alone will often benefit from the combination of Sandostatin® with bromocriptine.15,36,37 Current management guidelines recommend the co-administration of the two agents in patients whose GH levels remain elevated following treatment with somatostatin analog monotherapy.5 The two drugs exert their inhibitory effects on GH release via separate mechanisms involving different receptors.55 When combined, the bioavailability of bromocriptine is increased and the effects of the two drugs appear to be additive,15,55,56 thus reducing GH and IGF-1 levels to a greater extent.
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15. What are the side effects of Sandostatin® therapy?
Sandostatin® and Sandostatin® LAR® are generally well tolerated. The most frequent side effects are transient burning at the injection site and gastrointestinal complications, such as loose stools, abdominal cramping, nausea and flatulence. Gastrointestinal complications will often resolve within 10 days with the continuation of therapy.32 In the meantime reassuring the patient that this a transient effect, avoiding administration close to mealtime, starting with a smaller dose and then increasing to the effective therapeutic level, can help to minimize any discomfort. Pain at the injection site can be alleviated by rotation of injection sites. Adverse drug reactions that should be monitored include development of gallstones, glucose homeostasis, and thyroid function. In clinical trials hypoglycemia and hyperglycemia occurred in 3% and 16% of patients with acromegaly, respectively. These effects are a result of the mechanism of action of Sandostatin®, which alters the balance between insulin, glucagon and GH.
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References
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| 2. Acromegaly therapy consensus development panel. Consensus statement: Benefit versus risk of medical therapy for acromegaly. Am J Med. 1994;97:468-473. |
| 3. Bates. Does treatment of acromegaly affect life expectancy? Metabolism. 1995;44(Suppl.1):1-5. |
| 4. Melmed S, et al. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab. 1998;83:2646-2652. |
| 5. Melmed S, et al. Guidelines for acromegaly management. J Clin Endocrinol Metab. 2002;87:4054-4058. |
| 6. Trainer PJ. Editorial: acromegaly - consensus, what consensus? J Clin Endocrinol Metab. 2002;87:3534-3536. |
| 7. Orme SM, et al. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom acromegaly study group. J Clin Endocrinol Metab. 1998;83:2730-2734. |
| 8. Swearingen B, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3419-3426. |
| 9. Stewart PM. Current therapy for acromegaly. Trends Endocrinol Metab. 2000;11:128-132. |
| 10. Ahmed S, et al. Outcome of transsphenoidal surgery for acromegaly and its relationship to surgical experience. Clin Endocrinol. 1999;50:561-567. |
| 11. Abe T, Ludecke DK. Effects of pre-operative octreotide treatment on different subtypes of 90 growth hormone secreting pituitary adenomas and outcome in one surgical center. Eur J Endocrinol. 2001;145:137-145. |
| 12. Barkan AL, et al. Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor-1 in patients with acromegaly. J Clin Endocrinol Metab. 1997;82:3187-3191. |
| 13. Jaffe CA, Barkan AL. Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin North Am. 1992;21:713-735. |
| 14. Sermez Y, et al. A case with invasive mixed adenoma developed empty sella syndrome by octreotide and high-dose bromocriptine after surgical treatment and radiotherapy. J Endocrinol. 2000;164:P43. |
| 15. Flogstad AK, et al. A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. J Clin Endocrinol Metab. 1994;79:461-465. |
| 16. Reubi JC, et al. Somatostatin receptor ss1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28:836-846. |
| 17. Lamberts SW, et al. SMS 201-995 induces a continuous decline in circulating growth hormone and somatomedin-C levels during therapy of acromegalic patients for over two years. J Clin Endocrinol Metab. 1987;65:703-710. |
| 18. Ferone D, et al. Treatment options in acromegaly: pharmacotherapy or surgery as primary treatment for acromegaly? Drugs & Aging. 2000;17:81-92. |
| 19. Spinas GA, et al. Pre-operative treatment of 5 acromegalics with a somatostatin analogue: endocrine and clinical observations. Acta Endocrinol. 1987;114:249-256. |
| 20. Colao A, et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab. 1997;82:3308-3314. |
| 21. Sandostatin® LAR® Depot (octreotide acetate for injectable suspension) prescribing information. East Hanover NJ: Novartis Pharmaceuticals, 1998. |
| 22. Engström BE, et al. Men with acromegaly need higher doses of octreotide than women. Clin Endocrinol. 2002;56:73-77. |
| 23. Mulligan T, et al. Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin inhibition in aging. J Am Geriatric Soc. 1999;47:1422-1424. |
| 24. Harris AG, et al. Continuous versus intermittent subcutaneous infusion of octreotide in the treatment of acromegaly. J Clin Pharmacol. 1995;35:59-71. |
| 25. Ducasse MCR, et al. Shrinking of a growth hormone-producing pituitary tumour by continuous subcutaneous infusion of the somatostatin analog SMS 201-995. J Clin Endocr Metab. 1987;65:1042-1046. |
| 26. Roelfsema F, Frolich M. Pulsatile thyrotrophin release and thyroid function in acromegalics before and during subcutaneous octreotide infusion. J Clin Endocrinol Metab. 1991;72:77-82. |
| 27. James RA, et al. A comparison of octreotide delivered by continuous subcutaneous infusion with intermittent injection in the treatment of acromegaly. Eur J Clin Invest. 1992;22:554-561. |
| 28. Tamura M, et al. Preoperative treatment of growth hormone-producing pituitary adenoma with continuous subcutaneous infusion of octreotide. Endocrin J. 1998;45:269-275. |
| 29. Chen TC, et al. Pharmacokinetics and pharmacodynamics and safety of microencapsulated Sandostatin® LAR® acetate in healthy subjects. J Clin Pharmacol. 2000;40:475-481. |
| 30. Vance M, Harris A. Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Arch Intern Med. 1991;151:1573-1578. |
| 31. Vizner B, et al. Effect of octreotide on growth hormone secretion in patients with acromegaly. Acta Clin Croat. 2001;40:175-178. |
| 32. Melmed S. Consensus statement: benefits versus risks of medical therapy for acromegaly. Am J Med. 1994;97:468-473. |
| 33. Heijckmann C, et al. Clinical experience with Sandostatin® LAR® in patients with acromegaly. Netherlands J Med. 2001;59:286-291. |
| 34. Wenzel E, Comi R. Use of octreotide in clinical endocrinology. Endocrinologist. 1991;1:256-264. |
| 35. Newman CB, et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3034-3040. |
| 36. Balsa JA, et al. Varying additive effects of bromocriptine with two somatostatin analogs in cultures of GH-secreting adenomas. Horm Metab Res. 2002;34:435-440. |
| 37. Lamberts SW, et al. A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs. J Clin Endocrinol Metab. 1986;63:16-19. |
| 38. Colao A, et al. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin® LAR® in acromegaly. J Clin Endocrinol Metab. 2000;85:3132-3140. |
| 39. Colao A, et al. Is the acromegalic cardiomyopathy reversible? Effect of a 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance. J Clin Endocrinol Metab. 2001;86:1551-1557. |
| 40. Colao A, et al. Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab. 2002;87:3097-3104. |
| 41. Thomas SG, et al. Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess. Clin Endocrinol. 2002;56:351-358. |
| 42. Ip MSM, et al. Effect of Sandostatin® LAR® on sleep apnoea in acromegaly: correlation with computerized tomographic cephalometry and hormonal activity. Clin Endocrinol. 2001;55:477-483. |
| 43. Ho KY, et al. Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety. Ann Intern Med. 1990;112:173-181. |
| 44. Jenkins PJ, et al. Magnetic resonance imaging (MRI) assessment of carpal tunnel syndrome in acromegaly before and after octreotide treatment. J Endocrinol. 1999;16:AP40. |
| 45. Colao A, et al. Reversibility of joint thickening in acromegalic patients: an ultrasonographic study. J Clin Endocrinol Metab. 1998;83:2121-2125. |
| 46. Quabbe HJ, Plockinger U. Dose-response study and long term effect of the somatostatin analog octreotide in patients with therapy-resistant acromegaly. J Clin Endocrinol Metab. 1989;68:873-881. |
| 47. James RA, et al. The effect of high dose octreotide by continuous subcutaneous infusion (CSI) on fasting lipids and carbohydrate tolerance in acromegaly. J Endocrinol. 1989;123(Suppl):A124. |
| 48. Tauber JP, et al. Long-term effects of continuous subcutaneous infusion of the somatostatin analogue octreotide in the treatment of acromegaly. J Clin Endocrinol Metab. 1989;68:917-924. |
| 49. Sassolas G, et al. The French SMS 201-995 acromegaly study group. Long-term effect of incremental doses of the somatostatin analog SMS 201-995 in 58 acromegalic patients. J Clin Endocrinol Metab. 1990;71:391-397. |
| 50. Colao A, et al. Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumour mass in acromegaly. J Clin Endocrinol Metab. 2001;86:2779-2786. |
| 51. Bevan JS, et al. Primary medical therapy for acromegaly: An open, prospective multicentre study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-1 and tumour size. J Clin Endocrinol Metab. 2002;87:4554-4563. |
| 52. Garcia-Luna PP, et al. Size changes of a growth hormone- and prolactin-producing adenoma during and after Sandostatin® treatment. Horm Res. 1988;29:109-111. |
| 53. Barkan AL, et al. Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201-995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate. J Clin Endocrinol Metab. 1988;67:1040-1048. |
| 54. Barakat S, Melmed S. Reversible shrinkage of a growth hormone-secreting pituitary adenoma by a long-acting somatostatin analogue, octreotide. Arch Intern Med. 1989;149:1443-1445. |
| 55. Lamberts SW, et al. A comparison between the effects of SMS 201-995, bromocriptine and a combination of both drugs on hormone release by the cultured pituitary tumour cells of acromegalic patients. Clin Endocrinol. 1987;27:11-23. |
| 56. Chiodini PG, et al. Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine. J Clin Endocrinol Metab. 1987;64:447-453. |
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