Preoperative Short-term Administration of Octreotide for Facilitating Transsphenoidal Removal of Invasive

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1 Preoperative Short-term Administration of Octreotide for Facilitating Transsphenoidal Removal of Invasive Growth Hormone-secreting Macroadenomas Eiji TACHIBANA, Kiyoshi SAITO, and Jun YOSHIDA, Nagoya University School of Medicine, Nagoya Abstract The somatostatin analog octreotide was administered prior to transsphenoidal surgery in three patients with tumors that extended to the suprasellar space and one side of the cavernous sinus. Octreotide, 100 g twice a day, was subcutaneously injected for 2 weeks. Octreotide administration reduced the serum µ growth hormone (GH) levels in these patients from 82 to 22 ng/ml, from 148 to 12 ng/ml, and from 129 to 9 ng/ml. The tumor size shrank by about 50%, and the suprasellar extension disappeared in two patients. The main tumor was sharply dissected from the normal pituitary gland at surgery. In tracavernous portions were removed using a curette. Postoperatively, GH levels were less than 5 ng/ml in two patients, and 8.5 ng/ml in one patient. Follow-up magnetic resonance imaging revealed a small residual tumor in one side of the cavernous sinus in all patients. Follow-up GH levels were less than 5 ng/ml in one patient, and less than 2 ng/ml in two patients treated with bromocriptine. Preoperative administration of octreotide for 2 weeks reduced tumor volume and allowed near-total surgical resec tion of invasive macroadenomas without compromising the treatment course. Residual tumor due to intracavernous extension can be managed with bromocriptine or gamma knife radiosurgery. Key words: acromegaly, cavernous sinus extension, growth hormone-secreting pituitary adenoma, macroadenoma, octreotide, suprasellar extension Introduction Growth hormone (GH)-secreting pituitary adenomas are the second most common type of functioning pituitary tumors. Most GH-secreting pituitary ade nomas are macroadenomas that are present for several years prior to diagnosis. Surgical removal of the tumor remains the treatment of choice for GH secreting adenomas. The surgical goal for function ing adenomas is total removal of the tumor with normalization of elevated hormone levels and preservation of the normal pituitary functions. Therefore, the tumor should be sharply dissected from the normal pituitary gland and totally re moved. However, complete removal of macroade nomas is difficult. Surgical removal can reduce GH levels to 10 ng/ml or less in about 70% of patients and to 5 ng/ml or less in 30% to 60%.5,7,8) Very few patients with an extensive suprasellar tumor or in tracavernous extension can be cured surgically. Received August 31, 1998; Accepted January 29, 1999 Therefore, additional treatments such as irradiation (conventional radiotherapy or gamma knife radio surgery) or medical treatment (bromocriptine or octreotide) are used to treat the residual tumor. However, irradiation takes a long time to achieve normalization of GH levels and induces damage to adjacent tissues such as the optic nerve, hypothala mus, and normal pituitary gland resulting in hypo pituitarism. Bromocriptine can reduce GH levels to 5 ng/ml or less in 20% of patients and induce tumor shrinkage in 10% to 15% of patients.5,7) This drug has the advantage of oral administration and low er cost for postoperative remnant tumor which responds to bromocriptine. Octreotide is a somatostatin analog, with a dura tion of action of up to 8 hours.3.5.7,9) Octreotide is ef fective in 70% to 90% of acromegalic patients and reduces serum GH and insulin-like growth factor levels through its action on somatostatin recep tors.5,9) Reduction of tumor size also occurs in about half of the patients. However, octreotide alone achieves normalization of GH levels in only 30% to 40% of patients and took 1 year or more.4,5) Regrowth

2 of the tumor after cessation of octreotide has also been reported.1) Administration of octreotide for 6 weeks preoperatively achieved significant reduction of GH levels and shrinkage of tumors by day 14.6) Preoperative use has been advocated and surgical resection of the tumor following 3 to 30 weeks of octreotide administration resulted in cure in 60% to 86% of patients.2,6,10) However, such long-term preoperative administration of octreotide is costly and compromises the treatment course. The effect of short-term preoperative octreotide administration on suprasellar or intracavernous extension is unknown. This study investigated the effect of short-term (2 weeks) preoperative administration of octreotide on GH-secreting pituitary macroadenoma with both suprasellar and intracavernous extensions. Materials and Methods Three patients with GH-secreting pituitary adeno mas with suprasellar extension and cavernous sinus invasion were treated with preoperative octreotide and transsphenoidal surgery (Table 1). The patients were one male and two females, aged from 30 to 45 years, with a 3 to 7-year history of acromegaly. Case 3 had a visual disturbance and amenorrhea in addi tion to acromegaly. Serum GH levels were elevated (82 to 148 ng/ml), and did not decline in response to a 75-g oral glucose load in Cases 1 and 2 (not exam ined in Case 3). Octreotide, 100 µg twice a day, was subcutane ously injected for 14 days. Serum GH levels and tumor volume were measured before and after the period of octreotide administration. Serum GH level was assessed following overnight fasting. Tumor volume was calculated by the following formula: 16, where tumor the vertical (V), anteroposterior (AP), and transverse (T) dimensions (cm) of the tumor were measured on magnetic resonance (MR) images. Transsphenoidal surgery was performed on the day following the final administration of octreotide. Patients were followed up in the outpatient clinic for 13 to 30 months. Results Preoperative octreotide administration reduced the serum GH levels from 82 to 22 ng/ml (27% of the pretreatment value) in Case 1, from 148 to 12 ng/ml (8%) in Case 2, and from 129 to 9 ng/ml (7%) in Case 3. Tumor volume was reduced from 7.5 to 3.3 ml (44% of pretreatment size) in Case 2 and 9.1 to 4.8 ml (53%) in Case 3 (Table 2). The reduction of tumor volume resulted mainly from a decrease in tumor height. The suprasellar extension disappeared in Cases 2 and 3 (Figs. 1 and 2). The lateral extension of the tumor into the cavernous sinus decreased to a lesser extent. No reduction of the tumor volume was observed in Case 1. Complications such as inflam mation at the injection site or gallstones were not Table 1 Characteristics of the three patients Table 2 Effect of 2 weeks preoperative octreotide administration on growth hormone (GH)-secreting pituitary adenomas

3 Fig. 1 Case 2. Enhanced T1-weighted sagittal (left) and coronal (center) magnetic resonance (MR) images taken before administration of octreotide demonstrating tumor extension into the suprasellar space and the left cavernous sinus. Enhanced T1-weighted coronal MR image (right) taken on day 14 of octreotide administration showing remarkably reduced tumor height and disappearance of the suprasellar extension. Fig. 2 Case 3. Enhanced T1-weighted coronal magnetic resonance (MR) images taken before (left) and after (center) the 2-week course of octreotide showing marked reduction of the suprasellar extension and slight reduction of the intracavernous extension. Postoperative enhanced T, weighted coronal MR image (right) showing a small remnant tumor in the right cavernous sinus, and the sella packed with a piece of subcutaneous fat. encountered. Transsphenoidal surgery was performed to re move the tumors gross totally in Cases 1 and 2, and subtotally in Case 3. Since the suprasellar extension was markedly decreased in Cases 2 and 3, sharp dissection of the tumor from the normal pituitary gland could be performed under direct microscopic visualization. Following removal of the main tumor, the lateral extension of the tumor into the cavernous sinus was removed using a curette. A small portion of the tumor may have remained in the cavernous sinus in Case 2. The intracavernous portion of the tumor was only partly removed in Case 3 (Fig. 2). All tumors were soft without fibrous change. Postoperatively, GH levels decreased to 3.1 ng/ml in Cases 1 and 2, and to 8.5 ng/ml in Case 3 (Table 2). Bromocriptine was administered in Cases 2 and 3 because of the possibility of remaining tumor in the cavernous sinus. Clinical symptoms gradually im proved in all patients. Follow-up MR imaging showed a small residual tumor in one side of the cavernous sinus in all patients. GH levels at the end of the follow-up period were less than 5 ng/ml in one patient and less than 2 ng/ml in the two patients receiving bromocriptine. Discussion In this study, octreotide was administered for 2 weeks based on the previous results which demon strated that octreotide can reduce GH levels and tumor volume by day 14.6) We selected a lower daily dose, 100 µg twice, for the convenience of the patients. All three of our patients showed decreased GH levels to 7% to 27% of pretreatment values, and two patients showed shrinkage of the tumor to about half, which are similar to previous reports of long er-term administration of octreotide.2,6,10) Although the tumor volume reduction rate did not correlate with surgical cure in our or previous studies,6) the disappearance of the suprasellar extension enabled a sharp dissection of the tumor margin from the

4 normal pituitary gland except for the intracavernous extension. In the previous report, long-term (3 to 30-week) administration of octreotide caused caver nous sinus invasion to disappear or decrease sig nificantly in three of eight patients.2) In our patients, reduction of the intracavernous extension was not remarkable. Preoperative short-term treatment with octreotide apparently cannot reduce lateral exten sion into the cavernous sinus. Preoperative administration of octreotide did not reduce the tumor volume in our Case 1. Neverthe less, the tumor could be gross totally removed, and resulted in a GH level of 4.4 ng/ml without addi tional treatment. This was fortunate since the treat ment of GH-secreting invasive macroadenomas usually requires multiple modalities. Preoperative treatment with octreotide eliminated the suprasellar extension of the tumor in Cases 2 and 3, so the in trasellar tumor could be sharply dissected from the normal pituitary gland, and the intracavernous residual tumor was controlled with bromocriptine. If necessary, the remnant tumor in the cavernous sinus could be treated by gamma knife radiosur gery without damaging the normal pituitary gland since the intrasellar tumor was completely resect ed. The combination of short-term preoperative treat ment with octreotide and transsphenoidal resection is recommended as the short-term (2 weeks) ad ministration of octreotide does not compromise the treatment course, octreotide induces tumor shrink age in some patients and increases the possibility of surgical cure, and remnant tumor in the cavernous sinus following complete resection of the intrasellar and suprasellar tumor can be treated by gamma knife radiosurgery without damaging the normal pituitary function. Further study with an increased number of patients and longer follow-up is neces sary to confirm the effectiveness of this treatment. References 1) Barakat S, Melmed S: Reversible shrinkage of a growth hormone-secreting pituitary adenoma by a long-acting somatostatin analogue, octreotide. Arch Intern Med 149: , ) Barkan AL, Lloyd RV, Chandler WF, Hatfield MK, Gebarski SS, Kelch RP, Beitins IZ: Preoperative treatment of acromegaly with long-acting somatosta tin analog SMS : shrinkage of invasive pitui tary macroadenomas and improved surgical remis sion rate. J Clin Endocrinol Metab 67: , ) Comi R, Gorden P: The response of serum growth hormone levels to the long-acting somatostatin ana log SMS in acromegaly. J Clin Endocrinol Metab 64: 37-42, ) Ducasse MCR, Tauber JP, Tourre A, Bonafe A, Babin TH, Tauber MT, Harris G, Bayard F: Shrinkage of a growth hormone-producing pituitary tumor by con tinuous subcutaneous infusion of the somatostatin analog SMS J Clin Endocrinol Metab 65: ,1987 5) Frohman LA: Therapeutic options in acromegaly. J Clin Endocrinol Metab 72: , ) Lucas-Morante T, Garcia-Uria J, Estrada J, Sausedo G, Cabello A, Alcaniz J, Barcelo B: Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS before transsphenoidal surgery. J Neurosurg 81: 10-14, ) Melmed S: Acromegaly. N Engl J Med 322: , ) Ross DA, Wilson CB: Result of transsphenoidal microsurgery for growth hormone-secreting pitui tary adenoma in a series of 214 patients. J Neuro surg 68: , ) Sassolas G, Harris AG, James-Deidier A, The French SMS Acromegaly Study Group: Long term effect of incremental dose of the somatostatin analog SMS in 58 acromegalic patients. J Clin En docrinol Metab 71: , ) Tsukamoto N, Nagaya T, Kuwayama A, Takano K, Shizume K, Sugita K, Seo H: Octreotide treatment results in the inhibition of GH gene expression in the adenoma of the patients with acromegaly. Endocr J 41: ,1994 Address reprint requests to: K. Saito, M.D., Department of Neurosurgery, Nagoya University School of Medi cine, 65 Tsurumai, Showa-ku, Nagoya , Japan. Commentary The authors report that a mere two-week administra tion o f octreotide was successful as a preoperative treatment in three patients with GH-secreting macro adenomas. Subsequently, the suprasellar extension disappeared prior to transsphenoidal surgery and the tumors, except for the intracavernous parts, could be totally or subtotally removed. It is interesting that this short-term administration was effective for the shrinkage of the suprasellar mass. Most cases of an irregularly shaped suprasellar ex tension in the third ventricle or tumor encasement of the cavernous internal carotid artery are not curable through surgery alone and require postoperative ad juvant therapy for remission. Therefore, preoperative administration is worthwhile in candidates such as those described above because tumor shrinkage by octreotide may transform surgically unresectable cases into resectable ones. However, it is unneces

5 sary to administer octreotide preoperatively to cases with macroadenoma occupying only the suprasellar cistern as these cases can be usually be cured surgi cally. The definition of a biochemical cure for acromegaly is the subject of much controversy. Serum GH levels do not reflect disease status because their concentra tion fluctuates daily. It has been reported that remis sion is defined by parameters such as serum IGF lev els, serum GH levels, nadir GH levels during 75 g OGTT, or the disappearance of clinical symptoms. The authors should evaluate the surgical results o f acromegaly according to these strict standards in a further study. Nobuo HASHIMOTO, M.D. Kyoto University Graduate School of Medicine Kyoto, Japan Suprasellar extension of the pituitary tumor is one of the difficulties which neurosurgeons must overcome in pituitary surgery. If preoperative short-term ad ministration of octreotide is useful to reduce the tumor bulk, as is demonstrated in this communica tion, it will be of benefit to the patients with GH producing adenomas. Our limited experiences have also indicated this benefit without making the tumor fibrous in 4 cases in which preoperative octreotide was administered over various periods. But in another case, after long-term (2 months) use of oc treotide, operative findings revealed strong fibrosis. Probably, some tumor will become fibrotic and others will not. Further study will be required to elucidate the optimum method of preoperative use of octreo tide. This paper clearly defined the benefits of use of octreotide in cases of suprasellar extended tumor. Cavernous extension of the tumor will be treated by radiosurgery if the tumor persists in that area after surgery. Tomokatsu HoRI, M.D. Neurological Institute Tokyo Women's Medical University Tokyo, Japan This paper addresses the issue of preoperative treat ment of growth hormone secreting tumors with oc treotide. The rationale for doing this is that some tumors shrink, and that may in fact make the surgical removal more thorough when it is finally accom plished. The authors present three illustrative patients showing a significant but incomplete degree of shrinkage after treatment with octreotide at a lower than usual dose, namely 100,ug twice a day. Follow ing surgery the results were satisfactory, however, using modern stringent criteria for cure (that is, undetectable growth hormone after administration of an oral glucose tolerance test) none of the patients showed evidence that they actually were in complete remission or were protected against the negative aspects of elevated growth hormone. In such circum stances, octreotide therapy, dopamine agonist ther apy, or radiation therapy particularly in the form of gamma knife radiosurgery, have been useful. Reviewing the literature with regard to preoperative treatment of growth hormone secreting tumors with octreotide, there are mixed results. Perhaps the most compelling fact is that very few pituitary surgeons utilize preoperative octreotide therapy on a routine basis. Edward R. LAWS, Jr., M.D., F.A.C.S. University of Virginia Health Sciences Center Virginia, U.S.A. The authors report a 3-case observation testing the use of octreotide in GH-secreting invasive adenomas. This somatostatin analog was able to shrink the ade nomas by 50% of their volume, with disappearance of the suprasellar extension in two of them, allowing for a better dissection by the transsphenoidal route after two-weeks o f the analog administration. Residual tumor, however, was found in the cavernous sinus in those patients, confirming a near-total surgical resec tion that had to be managed with bromocriptine. The percentage of cure (< 5 ng/ml), even using BCR, is higher than expected from the literature and deserves further trials. Raul MARINO, Jr., M.D. Division of Neurosurgery University of Sao Paulo Medical School Sao Paulo, Brazil The authors have proposed that short-term pretreat ment with octreotide may increase the chance o f complete surgical resection of invasive growth hor mone secreting tumors. However, they have not demonstrated that at all. They have shown that there can be rapid shrinkage of the suprasellar component of the tumor, but none of these patients have been cured, and it has not been shown that identical sur gical results would not have been achieved without pretreatment. The growth hormone has not been normalized in any of these patients with surgery alone. The criteria o f cure should be at the very least a growth hormone less than 2 ng/ml and a normal IGF-1. The more accurate definition of cure is proba bly a growth hormone of less than 1 ng/ml with a normal response to glucose and a normal IGF-1.

6 While pretreatment may make the perioperative period safer by reversing some o f the acral changes in the airway, I do not believe pretreatment has been proven to improve the surgical results. However, it is clear that acromegaly is a disease which often re auires multimodalitv treatment. Kalmon D. POST, M.D. Mount Sinai Medical Center New York, U.S.A. Lucas-Morante and his co-workers reported that tumor shrinkage in acromegalic patients was sig nificant by day 14 and no further shrinkage was achieved by longer administration o f octreotide (ref. 6 of this article). Although this result has been believed as a golden rule, significant tumor shrinkage can be obtained even after two weeks administration in some cases. We have experienced a couple of cases in which a marked size reduction was observed in the third or fourth week. One of the purposes of preoperative administration of octreotide is the size reduction of large tumors. Since most GH secreting adenomas are soft in nature, it is usually easy to remove them totally by suction and/or curettage. However, i f a tumor shows large suprasellar or irregular extension, it cannot be re moved by one staged transsphenoidal surgery. Therefore, we think that preoperative octreotide is not always necessary for a tumor with mild to moderate suprasellar extension. The second purpose is the improvement of the patient's status, such as cardiac failure or diabetes mellitus, by lowering serum GH levels before surgery. The endocrinologists often stress the importance of this indication. In conclusion, we think that the preoperative oc treotide should be given to patients with large suprasellar tumor or with poor risk. If the effect is present but insufficient after two weeks, it is o f value to extend the administration for an additional two weeks. Akira TERAMOTO, M.D., D.M.Sc. Nippon Medical School Tokyo, Japan