FACTOR, Patricia Ann A.

BLOCK H 2003-17964 Neurosurgery Report

Management of GH Producing Pituitary Tumors Because of the significant mortality and morbidity associated with growth hormone excess such as the cardiovascular complications, treatment is imperative (Berg et al. 2010). The goals of treatment should be 1. 2. 3. 4. 5. To bring the chemical measures of acromegaly to normal To control the size of the tumour To reduce the signs and symptoms of the disease To prevent or improve medical conditions related to the disease To prevent premature mortality

The consensus of experts in the field is that transshpenoidal adenomectomy is the surgical approach of choice when it comes to excising pituitary tumors (Arafah and Nasrallah, 2001). For GH producing tumors, excision affords hormonal control of acromegaly and improvement of soft tissue changes. Transsphenoidal adenomectomy is based on the fact that pituitary gland is located in a hollow in the sphenoid bone called the sella turcica at the base of the brain and that there is a direct path to the sella turcica through the sphenoid sinus, located above the roof of the mouth behind the nose. There are 2 approaches to transsphenoidal surgery: sublabial and endonasal. The sublabial approach goes through the upper lip to open a path between the hard palate in the roof of the mouth and the nose, while the endonasal approach goes directly through the back of the nose, making a hole to reach the pituitary tumor. The outcome of surgery is dependent on tumor size, baseline hormone levels, and expertise of the surgeon (Arafah and Nasrallah, 2011). In a study by Freda et al. (1998), patients with increased growth hormone pre-surgery achieved remission in 61% of cases (88% for microadenomas and 53% for macroadenomas). Visual outcome is also improved with surgery. In a study by Seuk et al. (2011), visual acuity was improved in 83% of patients who underwent transsphenoidal surgery. However, a tumor at least 2 cm in diameter is associated with a greatly reduced success rate (Shimon et al., 2001). Surgery comes with risks and there are various complications associated with transsphenoidal surgery such as visual deterioration, diabetes insepidus, and CSF leak. Visual deterioration can happen if there is bleeding that would exert a mass effect on the optic tract or during surgical damage to the optic tract. Diabetes inspeidus can transiently affect the patient when there is surgical damage to the posterior pituitary and ADH cannot be adequately produced. CSF leak can happen if the thin membrane separating the sella turcica is damaged, thus allowing spinal fluid to enter the space. This can become problematic as it can cause meningitis. There are a few contraindications to surgery such as patient refusal, severe cardiomyopathy or respiratory disease, or the lack of an available skilled surgeon. Although surgery is the treatment of choice for GH producing tumors, for most microadenomas and some macroadenomas, approximately 4060%of macroadenomas are unlikely to be controlled with surgery alone and adjunctive treatment with medications and/or radiotherapy may be necessary (Melmed et al., 2009). Currently,

there are 3drug classes which are used in the treatment of acromegaly, dopamine agonists (DAs), somatostatin receptor ligands SRLs, and a GH receptor antagonist (GHRA). Dopamine agonists such as bromocriptine have long been used in hyperfunctioning pituitary adenomas post surgery. Not only do they inhibit the production of excess hormones such as GH and PRL, they have also been shown to decrease tumor size. However, GH and IGF-I levels are only normalised in around 35-40% of patients, and side effects such as nausea, nasal stuffiness, and dizziness are common (Paisley and Trainer, 2003).

Octreotide is somatostatin analogue that binds to the somatostatin receptor subtypes II and V and inhibits GH secretion. It is used in the medical management of GH producing pituitary adenomas associated with a decrease in both serum GH and plasma IGF-I concentrations in 60-80% of treated patients (Newman et al., 1998). Tumor shrinkage of more than 20% has also been shown in around 75% of acromegaly patients receiving these drugs (Melmed et al., 2005) . Pegvisomant is a GH receptor antagonist that is used in other countries albeit not yet available in the Philippines. It blocks the action of growth hormone at the growth hormone receptor to reduce the production of IGF1. It has been shown to normalizes IGF-I levels in 80-90% of patients (Trainer et al., 2000). However, pegvisomant has no effect on the tumor and thus cannot adequately help those with symptoms related to mass effect. In the recent guidelines of the Americal Association of Clinical Endocrinologists for Acromegaly, combination therapy has been discussed. It described some success with combining the medications when one alone didnt work sufficiently. For those who only partially responded to somatostatin analogue treatment, the addition of cabergoline helped 42% of them to achieve normal IGF-1 levels. It has also reported that the combination of somatostatin analogues with pegvisomant often appeared to be more effective in normalising IGF-1 levels than either drug used on its own (Katznelson et al., 2011). For those who do not adequately respond to surgery or are poor surgical candidates, radiotherapy may be given (Arafah and Nasrallah, 2001). Conventional radiotherapy (conformal fractionated radiotherapy) can lower GH levels and normalize IGF-I in over 60% of patients, but maximum response is achieved 10 15 yr after radiotherapy is administered (Barrande et al., 2000) .In a recent study by Weber et al. (2011), it was estimated 5-year tumor growth control was 95.5% after stereotactic fractionated radiotherapy. An alternativeto conventional radiotherapy is single-dose, focused radiotherapy such as that achieved with the Gamma Knife or Linear Accelerator. Five-year remission rates with gamma knife radiotherapy in patients with acromegaly (after surgical debulking) range from 29 to 60% (Attanasio et al., 2003). Associated complications of radiotherapy include: hypopituitarism, optic nerve damage, neurologic dysfunction, and secondary tumors. Up to 60% of patients ultimately develop hormone insufficiency after a median dose of 50 Gy (5000 rad) directed at the skull base. The development of hypopituitarism occurs over 515 years and usually reflects hypothalamic damage rather than primary destruction of pituitary cells. Optic nerve damage occurs as a consequence of edema, tumor hemorrhage, and optic nerve necrosis (Arafah and Nasrallah, 2001). Secondary tumors are also associated with irradiation. There new tumors form as a consequence of potential DNA damage to surrounding tissues. Aside from managing the hormonal derangements and the tumor size, it is also important to manage the comorbities associated with GH secreting pituitary tumors and to prevent premature mortality. The most important comorbidities of acromegaly include hypertension, cardiac dysfunction, diabetes, osteoarthropathy, and obstructive sleep apnea, they can all lead to significant functional disability (Melmed et al., 2009).

Once treatment has been given, be it in the form of surgical or medical, it is important to monitor the patients response. Both GH and IGF-I should be measured to assess the biochemical response to any medical treatment. An OGTT is the preferred test over the random GH measurement and it should be performed every 3-6 months after surgery. Biochemical control is generally defined as a normal IGF-I for age and gender and a GH less than 1.0 ng/ml during an OGTT (Melmed et al., 2009). A repeat MRI 3-6 months post surgery may also be done in order to ascertain if there is tumor growth. A 2D Echo may also be done to assess for cardiomyopathies secondary to increased growth hormone secretion. Lastly, a colonoscopy should be requested as this patients are prone to colon polyps and further evaluation should be done in order to ensure that they are not malignant lesions. References Attanasio R, Epaminonda P, Motti E, Giugni E, Ventrella L, Cozzi R, Farabola M, Loli P, Beck-Peccoz P, Arosio M 2003 Gamma-knife radiosurgery in acromegaly: a 4-year follow-up study. J Clin Endocrinol Metab 88:31053112 Barrande G, Pittino-Lungo M, Coste J, Ponvert D, Bertagna X, Luton JP, Bertherat J 2000 Hormonal and metabolic effects of radiotherapy in acromegaly: long-term results in 128 patients followed in a single center. J Clin Endocrinol Metab 85:37793785

Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, et al. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. Aug 2010;95(8):3648-56. Freda PU, Wardlaw SL, Post KD. Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg. Sep 1998;89(3):353-8. Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly--2011 update: executive summary. Endocr Pract. Jul-Aug 2011;17(4):636-46 Kreutzer J, Buslei R, Wallaschofski H, et al. Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol. Jan 2008;158(1):11-8. Melmed S, Sternberg R, Cook D, Klibanski A, Chanson P, Bonert V, Vance ML, Rhew D, Kleinberg D, Barkan A 2005 A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab 90:44054410 Melmed, S., A. Colao, A. Barkan, M. Molitch, A. B. Grossman, D. Kleinberg, D. Clemmons,P. Chanson, E. Laws, J. Schlechte, M. L. Vance, K. Ho, and A. Giustina.Guidelines for Acromegaly Management: An Update JCEM 2009 94: 1509-1517

Newman CB, Melmed S, George A, et al. Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab. Sep 1998;83(9):3034-40. Paisley AN, Trainer PJ. Medical treatment in acromegaly. Curr Opin Pharmacol. Dec 2003;3(6):672-7. Seuk JW, Kim CH, Yang MS, Cheong JH, Kim JM. Visual outcome after transsphenoidal surgery in patients with pituitary apoplexy. J Korean Neurosurg Soc. 2011 Jun;49(6):339-44. Epub 2011 Jun 30.

Shimon I, Cohen ZR, Ram Z, Hadani M 2001 Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients. Neurosurgery 48:12391243; discussion 12441245 Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-BonertV, VanderLely AJ, Dimaraki EU, Stewart PM, Friend KE, Vance ML, Besser M & Scarlett JA 2000 Treatment ofacromegaly with the growth hormone receptor antagonist pegvisomant. New England Journal of Medicine 342 11711177. Weber DC, Momjian S, Pralong FP, Meyer P, Villemure JG, Pica A. Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitaryfunctional and nonfunctional macroadenoma. Radiat Oncol. 2011 Dec 8;6:169.