Pituary Disorders
regimen may improve biochemical remission rates in an additional one-third of subjects.61
In a patient with partial somatostatin analog
although this benefit is generally noted in subjects with modest IGF-1 elevations. Another option involves surgical debulking of macroadenomas to improve the subsequent response to somatostatin analogs.23
Finally, in a patient with somatostatin analog resistance, consideration of radiation therapy may be warranted.65
analog, substitution of pegvisomant for the somatostatin analog may be considered.64
Radiation Therapy
Radiation therapy is usually considered as an adjunctive therapy in subjects with active disease despite surgery and/or medical therapy, or to limit the need for lifelong medical therapy.28,65,66
There are two main
types of radiotherapy for patients with acromegaly: conventional fractionated radiotherapy and stereotactic radiosurgery.
Fractionated radiotherapy is typically administered in daily doses of 160–180 cGray (cGy) over a five- to six-week period up to a total dose of 4,500–5,000 cGy. Using strict remission criteria, such as a glucose-suppressed GH value of less than 1 ng/ml and a normal IGF-1 value, conventional fractionated radiation therapy results in biochemical cure in 10–60 % of subjects.67–70
Stereotactic radiosurgery includes a number of modalities, such as Gamma Knife® (Elekta AB, Stockholm, Sweden), CyberKnife® (Accuray Incorporated, Sunnyvale, CA, US), and a linear accelerator that delivers high-energy photons. Another option is use of proton particles.71
In
acromegaly, most experience with stereotactic radiosurgery involves Gamma Knife radiosurgery, which is usually delivered by a cobalt-60 gamma radiation source as a single treatment. With Gamma Knife
1. Alexander L, Appleton D, Hall R, et al., Epidemiology of acromegaly in the Newcastle region, Clin Endocrinol (Oxf), 1980;12:71–9.
2. Daly AF, Rixhon M, Adam C, et al., High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium, J Clin Endocrinol Metab, 2006;91:4769–75.
3. Molitch ME, Clinical manifestations of acromegaly, Endocrinol Metab Clin North Am, 1992;21:597–614.
4. Nabarro JD, Acromegaly, Clin Endocrinol (Oxf), 1987;26:481–512. 5. Swearingen B, Barker FG, 2nd, Katznelson L, et al., Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly, J Clin Endocrinol Metab, 1998;83:3419–26.
6. Rajasoorya C, Holdaway IM, Wrightson P, et l., Determinants of clinical outcome and survival in acromegaly, Clin Endocrinol (Oxf), 1994;41:95–102.
7. Mestron A, Webb SM, Astorga R, et al., Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA), Eur J Endocrinol, 2004;151:439–46.
8. Dobrashian RD, O’Halloran DJ, Hunt A, et al., Relationships between insulin-like growth factor-1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly, Clin Endocrinol (Oxf), 1993;38:589–93.
9. Frystyk J, Freda P, Clemmons DR, The current status of IGF-I assays – a 2009 update, Growth Horm IGF Res, 2010;20:8–18.
10. Pokrajac A, Wark G, Ellis AR, et al., Variation in GH and IGF-I assays limits the applicability of international consensus criteria to
124
Addition of cabergoline to patients with partial response to a somatostatin analog may lead to IGF-1 normalization in about half of subjects,63
resistance, either pegvisomant or cabergoline could be added to the somatostatin analog for additive effect. For example, the addition of pegvisomant to a somatostatin analog may result in biochemical control in up to 58 % of subjects and, through dose reduction of both the pegvisomant and somatostatin analog, this regimen may have a cost benefit.62
In a patient with full resistance to a somatostatin
radiosurgery, biochemical remission rates (without the need for medical therapy) are reported to be 17–50 % over a five-year follow-up period.72–74 It has been suggested that time to remission is shorter with Gamma Knife radiosurgery than with conventional radiotherapy, although this is not entirely clear.72,74–76
Periodic withdrawal of medical therapy following radiotherapy should be performed for biochemical assessment. Somastatin analogs are often withheld at the time of radiation therapy because of concern that they may be radioprotective, although this finding is controversial, as it is not supported in all studies.72,74,75,78
The main limitation for radiotherapy is the development of hypopituitarism, which may occur in up to 50 % of patients after five to 10 years.67,79
Radiation-induced secondary tumors and radionecrosis
have been reported in fewer than 2 % of patients undergoing conventional radiotherapy.80,81
In a subject with sleep apnea syndrome, biochemical control may lead to improvement in the sleep disorder, although sleep apnea may persist. Therefore, repeat sleep apnea assessments should be performed and appropriate treatment offered.84,85
Managing Associated Medical Comorbidities The long-term management of acromegaly should also include screening and intervention for the associated comorbidities. For example, cardiovascular comorbidities, including hyperlipidemia, diabetes, and hypertension, should be monitored and treated accordingly. Serial colonoscopy should be performed in patients with polyps found at the baseline colonoscopy and those with persistent acromegaly.82,83
Such monitoring
should be performed in parallel with the acromegaly management. Conclusion
Acromegaly is a multisystem disease that often requires multimodality therapy for control of the tumor, the GH hypersecretion, and the medical consequences. With current therapeutic options, successful disease control should be achieved in the majority of patients. n
local practice, Clin Endocrinol (Oxf), 2007;67:65–70.
11. Katznelson L, Approach to the patient with persistent acromegaly after pituitary surgery, J Clin Endocrinol Metab, 2010;95:4114–23.
12. Giustina A, Melmed S, Acromegaly consensus: the next steps, J Clin Endocrinol Metab, 2003;88:1913–4.
13. Kirchengast S, Hartmann B, Huber J, Serum levels of sex hormones, thyroid hormones, growth hormone, IGF I, and cortisol and their relations to body fat distribution in healthy women dependent on their menopausal status, Z Morphol Anthropol, 1996;81:223–34.
14. Freda PU, Post KD, Powell JS, Wardlaw SL, Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly, J Clin Endocrinol Metab, 1998;83:3808–16.
15. Baier TG, Jenne EW, Blum W, et al., Influence of antibodies against IGF-I, insulin or their receptors on proliferation of human acute lymphoblastic leukemia cell lines, Leuk Res, 1992;16:807–14.
16. Puder JJ, Nilavar S, Post KD, Freda PU, Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly, J Clin Endocrinol Metab, 2005;90:1972–8.
17. Trainer PJ, Editorial: acromegaly – consensus, what consensus?, J Clin Endocrinol Metab, 2002;87:3534–6.
18. Dimaraki EV, Jaffe CA, DeMott-Friberg R, et al., Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up, J Clin Endocrinol Metab, 2002;87:3537–42.
19. Zirkzee EJ, Corssmit EP, Biermasz NR, et al., Pituitary magnetic resonance imaging is not required in the postoperative follow-up
of acromegalic patients with long-term biochemical cure after transsphenoidal surgery, J Clin Endocrinol Metab, 2004;89:4320–4.
20. Bourdelot A, Coste J, Hazebroucq V, et al., Clinical, hormonal and magnetic resonance imaging (MRI) predictors of transsphenoidal surgery outcome in acromegaly, Eur J Endocrinol, 2004;150:763–71.
21. Jane JA, Jr, Starke RM, Elzoghby MA, et al., Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome, J Clin Endocrinol Metab, 2011;96:2732–40.
22. Nomikos P, Buchfelder M, Fahlbusch R, The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’, Eur J Endocrinol, 2005;152:379–87.
23. Petrossians P, Borges-Martins L, Espinoza C, et al., Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs, Eur J Endocrinol, 2005;152:61–6.
24. Saeki N, Iuchi T, Isono S, et al., MRI of growth hormone-secreting pituitary adenomas: factors determining pretreatment hormone levels, Neuroradiology, 1999;41:765–71.
25. Shimon I, Cohen ZR, Ram Z, Hadani M, Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients, Neurosurgery, 2001;48:1239–43; discussion 1244–35.
26. Krieger MD, Couldwell WT, Weiss MH, Assessment of long-term remission of acromegaly following surgery, J Neurosurg, 2003;98:719–24.
27. Carmichael JD, Bonert VS, Mirocha JM, Melmed S, The utility of oral glucose tolerance testing for diagnosis and assessment of
Radiosurgery is generally considered if the tumor is a minimal distance from the optic chiasm, such as 5 mm, owing to concern about optic nerve injury.77
US ENDOCRINOLOGY
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