Guidelines for Acromegaly Management

S. Melmed, F. F. Casanueva, F. Cavagnini, P. Chanson, L. Frohman, A. Grossman, K. Ho, D. Kleinberg, S. Lamberts, E. Laws, G. Lombardi, M. L. Vance, K. Von Werder, J. Wass and A. Giustina for the Acromegaly Treatment Consensus Workshop Participants

Cedars-Sinai Research Institute-UCLA School of Medicine (S.M.), Los Angeles, California 90048; Santiago de Compostela University (F.F.C.), Santiago de Compostela, Spain; University of Milan (F.C.), Milan, Italy; Hospital Bicetre (P.C.), France; University of Illinois (L.F.), Chicago, Illinois; St. Bartholomew’s Hospital (A.G.), London, United Kingdom; Garvan Institute of Medical Research (K.H.), Australia; New York University Medical Center (D.K.), New York, New York; University Hospital of Rotterdam (S.L.), Rotterdam, The Netherlands; University of Virginia (E.L., M.L.V.), Charlottesville, Virginia; School of Medicine (G.L.), Naples, Italy; Schlosspark Klinik (K.V.W.), Berlin, Germany; Radcliffe Infirmary (J.W.), Oxford, United Kingdom; and University of Brescia (A.G.), Brescia, Italy

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: . melmed{at}csmc.edu

In May 2000, an Acromegaly Treatment Workshop was held to develop a consensus statement reflecting the integrated opinions of 68 leading neuroendocrinologists and neurosurgeons worldwide.

Acromegaly is an insidious disorder caused by a pituitary GH-secreting adenoma resulting in high circulating levels of GH and IGF-I (1). Unfortunately, no single therapy is comprehensively successful in controlling the disease and its protean clinical manifestations, and different treatment modes are associated with unique adverse effects and clinical disadvantages (2). Surgery, radiation, and medical treatments are available for lowering GH and IGF-I hypersecretion, controlling pituitary tumor mass effects, and improving morbidity (3). Recent studies provide a compelling rationale for controlling GH and IGF-I secretion as being the most significant determinant of restoring the observed adverse mortality to control rates (4, 5, 6). Regardless of the therapeutic mode, the goal of treatment is to control GH levels to less than 1 µg/liter after an oral glucose load (Fig. 1Go), normalize age- and gender-matched IGF-I levels, ablate or reduce tumor mass and prevent its recurrence, and alleviate significant comorbid features, especially cardiovascular, pulmonary, and metabolic derangements (7, 8).



View larger version (23K):
[in this window]
[in a new window]
 
Figure 1. Control implies GH less than 1 ng/ml after an oral glucose load and normalized age- and gender-matched IGF-I levels. DXRT, Radiation therapy.

 
Achieving Disease Control

Surgery

Transsphenoidal surgery is the procedure of choice for the initial management of acromegaly, and craniotomy is very rarely indicated (4, 5, 9, 10, 11, 12). Uniform biochemical and local anatomic outcome criteria should be applied in determining success for all acromegaly treatments. Complete microadenoma resection and maximal removal of locally impinging tumor and hyperfunctioning macroadenomas are desired anatomic outcomes. Reoperation for surgically accessible residual or recurrent tumor remnants visualized by magnetic resonance imaging (MRI) should be considered in patients who fail to achieve surgical remission as defined by rigorous biochemical criteria. Somatostatin receptor ligand (SRL) pretreatment of patients destined for surgery may be useful in patients with serious medical complications of acromegaly (13), but no data are available on influencing surgical outcomes.

Technical surgical adjuncts such as endoscopy, neuronavigation, intraoperative hormone assays, and intraoperative MRI may improve operative outcome, patient satisfaction, and complication rates, but definitive data on the impact of these procedures on surgical outcomes are not yet available.

Early GH assessment after surgery is useful, and oral glucose tolerance testing and IGF-I assessment should be performed within 2–4 months after surgery and interpreted according to established criteria for defining disease control (8, 14). The results of pituitary surgery are optimal when performed in specialized centers encompassing a team approach to therapy, including expertise in endocrinology, neurosurgery, and pathology. Individual surgical expertise is a major determinant of surgical outcomes and may be defined as a record of peer-reviewed publication of surgical results encompassing both endocrine and surgical evaluation and follow-up; training experience of more than 100 pituitary surgery cases, and annual surgical activity of more than 25 cases/surgeon. Specialized pituitary pathology is desirable, and immunostaining is mandatory for rigorous evaluation of surgical results.

Medical

GH-secreting adenomas express somatostatin receptor forms; the SSTR2 receptor subtype appears to be a particularly important mediator for signals suppressing GH secretion (15). SRLs, administered by sc or im injection, effectively control GH axis biochemical parameters in 50–70% of patients (16, 17, 18) and provide sustained hormone suppression and alleviation of soft tissue manifestations of acromegaly as long as drug administration is continued (19). SRLs are recommended as the mainstay of medical therapy. Oral dopamine agonists are only effective in about 10% of patients, and in selected patients with coexistent hyperprolactinemia, dopamine agonists may be a preferable therapeutic choice, whereas combined use of SRL and dopamine agonist therapy may improve therapeutic efficacy (20). Long-acting depot SRL preparations and longer acting dopaminergic agents are preferred over the short-acting agents (21, 22, 23, 24).

The GH receptor antagonist (25) represents a novel approach for the treatment of acromegaly, particularly in somatostatin analog-resistant patients (26). Although the drug is investigational, and its long-term safety profile remains to be established, it will be especially useful for patients with persistently elevated IGF-I levels.

Radiotherapy

Radiotherapy administered by conventional means (~45–50 Gy total dose) is associated with relatively few adverse events other than hypopituitarism. Administered in fractionated doses not exceeding 1.75 Gy/session, radiotherapy can be considered for nonresectable or residual pituitary disease, medical therapy failure, and/or patient refusal of other modalities. GH and IGF-I levels decrease slowly after fractionated conventional radiotherapy (27, 28), and the most rapid GH decrease occurs in the first 2 yr. Medical therapy, usually with SRLs, is often required to bridge the latency period before the onset of radiation effectiveness. Tumor regrowth after radiotherapy is rarely encountered, but the time course of tumor shrinkage is variable. Radiation therapy choices should be carefully evaluated with an informed team approach, including the patient, endocrinologist, experienced radiation oncologist, and neurosurgeon.

Several forms of radiation therapy are available, including use of the linear accelerator, gamma knife and proton beam, and their efficacy has been enhanced by the availability of stereotactic techniques achieved by computerized imaging and stereotactic technologies to maximize targeting, minimize radiation field scatter, reduce treatment times, and shorten latency to onset of effects (29, 30, 31). Most available data rely on therapy administered a decade or more ago, when criteria for control were not well established, and older technologies were in use. Therefore, it is anticipated that data will become available to ascertain whether advantages provided by the stereotactic approach achieve or improve efficacy and safety. Overall, radiotherapy modalities are viewed as adjunctive therapies to primary surgical and medical interventions (29, 30, 31).

Control of Mass Effects

The expanding pituitary mass may impinge on vital central structures, and alleviation of these effects is an important goal of disease management. Improved standardization for tumor volume assessment is recommended, including the use of three-dimensional tumor analysis and accurate measurement of tumor diameter and distance from critical structures (32). Surgery is immediately effective in debulking tumor mass, and particularly relieves pressure on visual tracts and improves headache. Pretreatment with SRLs may be helpful in shrinking tumor size and potentially improving surgical outcomes, but controlled prospective data are required (13). Tumor shrinkage is rarely observed with dopamine agonists, but occurs with SRLs in approximately 50% of patients who experience a moderate (<50%) decrease in volume, with dramatic shrinkage only in sporadic cases. Shrinkage usually occurs within 3 months of initiating therapy, but some changes are seen even after 1 yr. Doses may be decreased with time, and no evidence of tumor regrowth is apparent if drug treatment is maintained (17). The probability of tumor regrowth occurring if drug treatment is discontinued should be considered, however. Radiotherapy often produces tumor shrinkage, but the very slow onset of action usually requires many years to be manifest. Focused radiotherapy is probably at least as effective as standard techniques and is possibly more rapid in onset, but more data are required.

Relative benefits of treatments for determining disease complications and mortality

Reductions in GH and IGF-I levels are valuable and accurate markers for improvement of the comorbidity associated with acromegaly. Successful surgical adenoma resection significantly and promptly results in mass reduction. Surgery is also of value in debulking selected invasive or large tumors even if they are not completely resectable. Medical therapy may be offered to patients before surgery in an attempt to reduce tumor bulk and lower GH levels, with a comprehensive discussion outlining potential risks vs. benefits of each treatment approach. Clinical judgment should be used as to whether medical therapy should be continued or surgical intervention recommended after evaluation of initial responses to primary SRL treatment. It is recommended that GH and IGF-I assessment be undertaken 2–3 months after medical therapy to establish dose adequacy. Medical therapy has the advantage of not inducing hypopituitarism, and selective long-term sustained GH suppression portends a favorable mortality outcome. However, the potential benefits of preoperative medical therapy in enhancing surgical outcomes are as yet unknown. MRIs should be performed within 6–9 months after surgery, and after initiating medical treatment, MRI should be performed after biochemical parameters have been stabilized.

Comorbidities of acromegaly should be evaluated and treated during and after specific therapy within the clinical context. Aggressive management of cardiovascular disorders, especially hypertension, arrhythmias, and cardiac failure, should be ongoing. Sleep studies should be undertaken in patients with documented respiratory disorders. In patients with sleep apnea, respiratory function should be monitored during and after therapy initiation. Colonoscopy should be performed every 3–5 yr depending upon clinical indications, including family history and previous polyp detection. The presence of other serious comorbidities should be diagnosed and aggressively treated, especially diabetes, arthritis, renal disease, and mandibular dysfunction.

Limitations of Treatment Modes

Surgery

In experienced hands, surgery is not life-threatening, and cumulative major complications, including mortality, visual impairment, and meningitis, occur in less than 2% of patients. Cerebrospinal fluid leak, permanent anterior lobe deficits, diabetes insipidus, and local nasal complications occur in approximately 5% of patients. In inexperienced surgical hands, 3- to 4-fold higher complication rates are encountered (32, 33). Relative contraindications to surgery include patient frailty and physical illness, and comorbidity of acromegaly. Medical pretreatment can be offered to patients with cardiomyopathy, cerebrovascular disease, and/or airway obstruction before undertaking surgery.

Medical

When initiating dopamine agonist therapy, patients should be instructed to start with low, albeit less efficacious, doses of dopamine agonists, because of gastrointestinal side-effects. SRLs are associated with transient gastrointestinal disturbances and the development of asymptomatic gallstones of limited clinical significance primarily during the first 2 yr of therapy. Ultrasound evaluation before treatment initiation is not routinely recommended. However, a commitment to open-ended, long-term SRL therapy is required. Limitations of medical treatment include severe drug intolerance and ongoing drug cost. To date, no serious side-effects of SRLs or dopamine agonists have been encountered that would limit their use (24).

Radiotherapy

In more than 60% of patients, hypopituitarism develops within 5–10 yr. Rarely encountered, but serious, complications occur, including optic neuropathy, temporal lobe radiation injury, and secondary extrapituitary neoplasms, especially in patients with cerebrovascular or organic brain disease (34, 35). The potential neuropsychological effects of radiation and incidence of secondary tumor development require further study. Disadvantages of radiation include the slow rate of GH attenuation (36) and the potential for optic nerve damage when the adenoma is contiguous with optic tracts.

Summary

Treatment of acromegaly is determined by the availability of local neuroendocrine, imaging, and surgical expertise as well as patient access to costly evaluations and therapeutic choices, which may be unique for regions and countries. Nevertheless, controlled GH suppression should be optimized (37). In deciding on appropriate means to achieve biochemical control and relieve mass effects, the treating physician team should balance risk and benefits, and treatment contraindications and side-effects for each patient (2, 38). Factors to be considered include disease severity, tumor mass effect on central structures, tumor expression of somatostatin receptor subtypes, and potential for long-term pituitary damage, especially in younger reproductive-aged patients. In patients who have low GH levels and already have irreversible hypopituitarism, radiation therapy may be preferred because there is no further risk for this complication, although tumor resection often relieves compressive hypopituitarism.

The depicted flowsheet recommends surgery as the first line therapy followed by medical therapy should surgery not be curative. In selected patients with unacceptable anesthetic risk, cardiovascular or pulmonary complications, and macroadenomas not impinging on the optic chiasm, primary SRL therapy may be offered (13, 39). If control is inadequately achieved with maximal doses of SRLs and added dopamine agonists, radiotherapy should be considered or no further action should be proposed, depending on clinical disease activity and degree of biochemical disease persistence. Reoperation or treatment with investigational GH receptor antagonists (25) should be considered for patients resistant to surgical, medical, and radiotherapeutic approaches (26).

In conclusion, considering the potentially serious treatment adverse effects that limit their efficacy, there is consensus that integrated treatment decisions should be made by a team including endocrinologists, surgeons, and radiation therapists. The patient’s choice of therapy should be based upon an informed understanding of the potential disadvantages of therapeutic approaches vs. their effectiveness in managing this complex metabolic disorder, reducing its comorbidities, and ultimately achieving favorable mortality outcomes.

Acknowledgments

Participants in Acromegaly Treatment: A Consensus Workshop 2000— Alberto Angeli, Christopher Auernhammer, Ariel Barkan, Albert Beckers, Domenico Billecci, Cesar Luiz Boguszewski, Marco Boscaro, Pierre-Marc Bouloux, Marcello Bronstein, M. Buchfelder, Philippe Caron, Felipe Casanueva, Franco Cavagnini, Philippe Chanson, R. N. Clayton, Anna Maria Colao, Renato Cozzi, Uberti Ettore Degli, R. Falbush, Lawrence Frohman, Rolf C. Gaillard, Massimo Gerosa, Ezio Ghigo, M. Giovanelli, Massimo Giusti, Andrea Giustina, Yona Greenman, Ashley Grossman, Irene Halperin, Ken Ho, Ivor Jackson, Philippe Jaquet, David Kleinberg, Karen Lam, S. W. J. Lamberts, Edward R. Laws, Giuseppe Opizzi, Stafford Louis Lightman, Gaetano Lombardi, Marco Losa, D. K. Ludecke, Giulio Maira, Franco Mantero, Josef Marek, G. Marini, Ennio Martino, Shlomo Melmed, Francesco Minuto, Hans Orskov, Stephan Petersenn, H. J. Quabbe, Seymour Reichlin, Franco F. Sanchez, Fausto Santeusanio, Massimo Scanarini, Jochen Schopohl, Mario Serio, M. C. Sheppard, Ilan Shimon, Gunther Stalla, Christian Strasburgher, Gudo Tamburrano, George Tolis, Peter J. Trainer, Lely A. Van Der, Mary Lee Vance, J. D. Veldhuis, Klaus Von Werder, John A. Wass, and Susan Webb.

Footnotes

This consensus statement is based upon a workshop (Dr. M. Serio, President) co-sponsored by the Pituitary Society and the Italian Endocrine Society and is supported by an unrestricted educational grant from Ipsen Pharmaceuticals.

Abbreviations: MRI, Magnetic resonance imaging; SRL, somatostatin receptor ligand.

Received November 16, 2001.

Accepted June 17, 2002.

References

  1. Melmed S 1990 Acromegaly. N Engl J Med 322:966–977[Medline]
  2. Melmed S, Jackson I, Kleinberg D, Klibanski A 1998 Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 83:2646–2652[Abstract/Free Full Text]
  3. Frohman LA 1996 Acromegaly: what constitutes optimal therapy? J Clin Endocrinol Metab 81:443–445[Medline]
  4. Swearingen B, Barker FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426[Abstract/Free Full Text]
  5. Abosch A, Tyrrell JB, Lamborn KR, Hannegan LT, Applebury CB, Wilson CB 1998 Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:3411–3418[Abstract/Free Full Text]
  6. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK 1994 Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41:95–102[Medline]
  7. Bates AS, Van’t Hoff W, Jones JM, Clayton RN 1993 An audit of outcome of treatment in acromegaly. Q J Med 86:293–299[Medline]
  8. Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S 2000 Criteria for cure of acromegaly: a consensus statement. J. Clin. Endocrinol Metab 85:526–529
  9. Ross DA, Wilson CB 1988 Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenoma in a series of 214 patients. J Neurosurg 68:854–867[Medline]
  10. Fahlbusch R, Honegger J, Buchfelder M 1992 Surgical management of acromegaly. Endocrinol Metab Clin North Am 21:669–692[Medline]
  11. Jenkins D, O’Brien I, Johnson A, Shakespear R, Sheppard MC, Stewart PM 1995 The Birmingham pituitary database: auditing the outcome of the treatment of acromegaly. Clin Endocrinol (Oxf) 43:517–22[Medline]
  12. Davis DH, Laws Jr ER, Ilstrup DM, Speed JK, Caruso M, Shaw EG, Abboud CF, Scheithauer BW, Root LM, Schleck C 1993 Results of surgical treatment for growth hormone-secreting pituitary adenomas. J Neurosurg 79:70–75[Medline]
  13. Colao A, Ferone D, Cappabianca P, del Basso De Caro ML, Marzullo P, Monticelli A, Alfieri A, Merola B, Cali A, de Divitiis E, Lombardi G 1997 Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab 82:3308–3314[Abstract/Free Full Text]
  14. Freda PU, Wardlaw SL, Post KD 1998 Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 89:353–358[CrossRef][Medline]
  15. Shimon I, Yan X, Taylor JE, Weiss MH, Culler MD, Melmed S 1997 Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors. J Clin Invest 100:2386–2392[Abstract/Free Full Text]
  16. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ 1996 Octreotide. N Engl J Med 334:246–254[Free Full Text]
  17. Newman CB, Melmed S, Snyder PJ, Young WF, Boyajy LD, Levy R, Stewart WN, Klibanski A, Molitch ME, Gagel RF 1995 Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients–a clinical research center study [published erratum appears in J Clin Endocrinology Metab 1995 Nov;80(11):3238]. J Clin Endocrinol Metab 80:2768–2775[Abstract]
  18. Giusti M, Ciccarelli E, Dallabonzana D, Delitala G, Faglia G, Liuzzi A, Gussoni G, Giordano Disem G 1997 Clinical results of long-term slow-release lanreotide treatment of acromegaly. Eur J Clin Invest 27:277–284[Medline]
  19. Chanson P 1997 Predicting the effects of long-term medical treatment in acromegaly. At what cost? For what benefits? Eur J Endocrinology 136:359–61[Medline]
  20. Jaffe CA, Barkan AL 1992 Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin North Am 21:713–735[Medline]
  21. Flogstad AK, Halse J, Bakke S, Lancranjan I, Marbach P, Bruns C, Jervell J 1997 Sandostatin LAR in acromegalic patients: long-term treatment. J Clin Endocrinol Metab 82:23–28[Abstract/Free Full Text]
  22. Caron P, Morange-Ramos I, Cogne M, Jaquet P 1997 Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab 82:18–22[Abstract/Free Full Text]
  23. Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens JL, Mahler C, Beckers A 1998 Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab 83:374–378[Abstract/Free Full Text]
  24. Gillis JC, Noble S, Goa KL 1997 Octreotide long-acting release (LAR). A review of its pharmacological properties and therapeutic use in the management of acromegaly. Drugs 53:681–699[Medline]
  25. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ 2000 Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 342:1171–1177[Abstract/Free Full Text]
  26. Herman-Bonert VS, Zib K, Scarlett JA, Melmed S 2000 Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab 85:2958–2961[Abstract/Free Full Text]
  27. Eastman RC, Gorden P, Glatstein E, Roth J 1992 Radiation therapy of acromegaly. Endocrinol Metab Clin North Am 21:693–712[Medline]
  28. Freda PU, Andreadis CI, Khandji AG, Khoury M, Bruce JN, Jacobs TP, Wardlaw SL 2000 Long-term treatment of prolactin-secreting macroadenomas with pergolide. J Clin Endocrinol Metab 85:8–13[Free Full Text]
  29. Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G 1998 Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. J Neurosurg 88:1002–1008[Medline]
  30. Laws ER, Vance ML 1999 Radiosurgery for pituitary tumors and craniopharyngiomas. Neurosurg Clin N Am 10:327–336[Medline]
  31. Thalassinos NC, Tsagarakis S, Ioannides G, Tzavara I, Papavasiliou C 1998 Megavoltage pituitary irradiation lowers but seldom leads to safe GH levels in acromegaly: a long-term follow-up study. Eur J Endocrinol 138:160–163[Medline]
  32. Ciric I, Ragin A, Baumgartner C, Pierce D 1997 Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 40:225–37[Medline]
  33. Sheaves R, Jenkins P, Blackburn P, Huneidi AH, Afshar F, Medbak S, Grossman AB, Besser GM, Wass JA 1996 Outcome of transsphenoidal surgery for acromegaly using strict criteria for surgical cure. Clin Endocrinol (Oxf) 45:407–413[Medline]
  34. Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M, Rajan B, Traish D 1992 Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 304:1343–1346[Medline]
  35. Tsang RW, Laperriere NJ, Simpson WJ, Brierley J, Panzarella T, Smyth HS 1993 Glioma arising after radiation therapy for pituitary adenoma. A report of four patients and estimation of risk. Cancer 72:2227–2233[Medline]
  36. Barkan AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, Sandler HM 1997 Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82:3187–3191[Abstract/Free Full Text]
  37. Melmed S 1998 Tight control of growth hormone: an attainable outcome for acromegaly treatment. J Clin Endocrinol Metab 83:3409–3410[Free Full Text]
  38. Consensus statement: benefits versus risks of medical therapy for acromegaly 1994 Acromegaly Therapy Consensus Development Panel. Am J Med 97:468–473[Medline]
  39. Newman CB, Melmed S, George A, Torigian D, Duhaney M, Snyder P, Young W, Klibanski A, Molitch ME, Gagel R, Sheeler L, Cook D, Malarkey W, Jackson I, Vance ML, Barkan A, Frohman L, Kleinberg DL 1998 Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 83:3034–3040[Abstract/Free Full Text]