Results of radiotherapy in the treatment of acromegaly: Lack of ophthalmologic complications

Results of radiotherapy in the treatment of acromegaly: Lack of ophthalmologic complications

In1 J. Radialion Printed Oncology in the U.S.A. Biol Phys Vol 19, pp. 453-459 0360.3016/90 All rights reserved. Copyright 0 $3.00 1990 Per...

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In1 J. Radialion Printed

Oncology

in the U.S.A.

Biol

Phys

Vol

19, pp. 453-459

0360.3016/90

All rights reserved.

Copyright

0

$3.00

1990 Pergamon

t .I0

Press plc

??Brief Communkation

RESULTS OF RADIOTHERAPY IN THE TREATMENT OF ACROMEGALY: LACK OF OPHTHALMOLOGIC COMPLICATIONS ROBERT J. DOWSETT, M.D.,’ BARBARA FOWBLE, M.D.,’ ROBERT C. SERGOTT, M.D.,4 PETER J. SAVINO, M.D.,4 THOMAS M. BOSLEY, M.D.,4 PETER J. SNYDER, M.D.2 AND THOMAS A. GENNARELLI, M.D.3 Departments of ‘Radiation Oncology, ‘Endocrinology, and 3Neurosurgery, University of Pennsylvania School of MLedicine and Neuro-Ophthalmology Service, and 4Wills Eye Hospital, Philadelphia, PA

Between 1956 and 1988, 25 patients were treated with radiotherapy for acromegaly. Acromegalic features were present in 24 (96%), visual field deficits in 4 (16%), and suprasellar extension was present in 7 patients (28%). The median growth horlmone level was 40.2 ng/ml (range: 13.8-105) in 15 patients. Initial therapy consisted of radiotherapy alone (19 patients) or surgery followed at some interval by radiation (6 patients). The radiation therapy was administered with megavoltage equipment in 23 (92%) patients and orthovoltage equipment in 2 patients. The median total dose was 46 Gy (range: 24-53.44 Gy) with 21 patients receiving at least 45 Gy. With a median followup of 53 months (range: 18-205), 2 of the 19 patients treated with radiotherapy alone have required surgery for symptomatic recurrences. Both are alive and in remission at 69 and 158 months following craniotomy. Thus, the success of radiotherapy as a primary modality in this series is 17/19 (89%). None of the six patients treated postoperatively have recurred. At the time of last follow-up the visual fields remained normal and visual acuity stable in the 21 patients with no pre-existing visual deficits. The four patients with prior visual field deficits improved with therapy. There were no cases of radiation optic neuropathy, brain necrosis or second intracranial malignancies. Seven patients (28%) had evidence of hypopituitarism attributed to the radiotherapy. Growth hormone levels after radiotherapy showed a median of 5.4 ng/ml (range: 3.2-40.0) in 15 patients. Eleven of 15 patients (73%) had growth hormone levels < 10 ng/ml. Radiation use in acromegaly remains a safe and effective modality assuming careful altention is paid to technique, total dose, and fraction size. Acromegaly,

Radiotherapy, Complications.

6,8,9, 17,20,26). Reports of radiation optic neuropathy and brain necrosis, attributed to an increased sensitivity of acromegalic patients to radiotherapy, have been published (4,6, 11, 13, 15, 18,24,28,34). These reports have contributed to a feeling among some, both in and out of the radiotherapy community, that radiation is not a safe modality for use in patients with acromegaly. We report the total experience of the Department of Radiation Oncology at the Hospital of the University of Pennsylvania from 1956-1988 in an effort to further investigate this controversy.

INTRODUCIION Acromegaly is an uncommon disorder caused by growth hormone overproduction from a pituitary adenoma. The incidence and prevalence of this condition have been estimated at 3 and 40 cases per million, respectively (1). The systemic effects of growth hormone overproduction often predominate in the form of acromegalic features, coexisting medical conditions, and increased death rate ( 1, 37). Despite the general benign nature of the pituitary adenoma, local symptomatology often occurs in the form of visual field deficits or less commonly, other cranial nerve or temporal lobe abnormalities. Therapy for this disorder includes radiotherapy, surgery, and medical management directed at the source of the growth hormone overproduction. Parasellar radiotherapy has a proven record and a defined role, both as primary therapy, or postoperative for residual tumor (2,

METHODS

AND MATERIALS

Between 1956 and 1988, 25 patients with pituitary macroadenomas and acromegaly were treated in the Department of Radiation Oncology at the University of Pennsylvania. Hospital charts and radiotherapy records Oncology, Hospital of the University of Pennsylvania, Spruce St., Philadelphia, PA 19104. Accepted for publication 22 February 1990.

Presented at the 3 1st Annual Scientific Meeting of the American Society For Therapeutic Radiology and Oncology, San Francisco, CA, l-6 October 1989. Reprint requests to: Dr. Barbara Fowble, Dept. of Radiation 453

3400

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were reviewed for all acromegalic patients receiving ex-

ternal beam radiation during this time interval. All patients were included in the analysis and form the basis of this report. The patients were evaluated at the time of radiotherapy with history and physical examinations, hormone levels, and radiologic studies to confirm the diagnosis. Diagnostic tests included skull X Rays (20 patients), CT-scan ( 10 patients), cerebral arteriography (3 patients), pneumo-encephalogram (2 patients), and MRI-scan (1 patient). Suprasellar extension was identified in seven patients (28%). Visual field testing before radiotherapy identified deficits in four patients, all of whom had suprasellar extension. Two patients had bitemporal hemianopsia and one patient each had a bitemporal quadrantic defect and a unilateral temporal quadrantic defect. Acromegalic features were present in 24 patients and growth hormone levels were elevated in the 15 patients who were tested. Five patients had elevated prolactin levels. No patients had evidence of hypopituitarism or cranial nerve abnormalities before treatment. One patient had primary hypothyroidism (Table I). Initial treatment consisted of radiotherapy alone (19 patients), surgery and immediate post-op radiotherapy (1 patient), and radiotherapy for recurrence following initial surgical resection (5 patients). A craniotomy was performed in three patients and a transphenoidal hypophysectomy was done in the remaining three patients. All of the resections were considered incomplete. Bromocriptine therapy was the only medical management attempted, and was used in five patients. Generally, bromocriptine was given early in a patient’s course or at the time of relapse following initial therapy. Radiotherapy was administered with megavoltage equipment in 23 (92%) of the cases. The radiation was administered in the Department of Radiation Oncology at the Hospital of the University of Pennsylvania. Total dose ranged from 2400-5344 cGy with 21 patients receiving at least 4500 cGy. All patients were treated with a once daily fractionation schedule given 5 days per week. The most common dose and fractionation scheme was 4600 cGy in 200 cGy fractions (16 patients), which is presently the treatment policy of this department. An additional six patients received 180 cGy fractions with the range of daily fractions for all patients being 167-250 cGy. A maximum dose inhomogeneity across the treatment volume of 5% was accepted. Field sizes were determined

August 1990, Volume 19, Number 2 Table 2. Radiation

therapy No. (‘3%)

Energy 6 Mv/2 Mv 250 Kvp Field (sq. cm.) Median Range Technique Arc Rotation Laterals Laterals + Vertex Dose (cGY) Median Range Fractionation (cGy) Median Range

23 (92) 2 (8) 25 16-68 16 3 6

4600 2400-5344 200 167-250

by tumor volume but were also influenced by treatment era and individual radiotherapist discretion. Generally a 1.O-2.0 cm margin was given around tumor (Table 2). The median length of follow-up of patients was 53 months with a range of 18-205 months. Particular attention was paid to complications of therapy as well as tumor response. Determination of response was based on: (a) stabilization or regression of clinical signs or symptomatology including acromegalic features, visual field deficits, hypertension, and diabetes; (b) stabilization or regression of CT/MRI abnormalities; and (c) reduction of growth hormone levels. Detailed clinical information concerning acromegalic features, hypertension, and diabetes was available in all patients. Radiographic follow-up consisted of CT scans in six patients and both CT and MRI scans in eight patients. Growth hormone levels were determined before and after radiotherapy in 15 patients. In obtaining follow-up information, emphasis was placed on possible signs or symptoms of radiation optic neuropathy, focal brain necrosis, and hypopituitarism, which constitute the most common reported complications of parasellar radiotherapy. Evaluation of radiation optic neuropathy was determined by review of visual field, visual acuity, and funduscopic examinations in all patients. Determination of brain necrosis was based on clinical and radiographic (CT/MRI) evidence. Endocrine testing following radiotherapy was variable, and not all patients had provocative testing. Hypopituitarism was thus defined as clinical and biochemical evidence of pituitary dysfunction requiring hormone replacement.

Table 1. Patient characteristics before radiation Total number:

25

Sex Male Female Age (years) Median Range

15 10 38 14-67

Visual deficits:

4

Diabetes (DM)

6 1 3

Hypertension DM and HTN Acromegalic features

RESULTS

Table 3 compares the pre and post radiotherapy parameters for the 25 patients included in this review. Initial therapy: radiotherapy

24

Nineteen patients with acromegaly received radiation as their initial form of therapy. Three patients presented

Radiotherapy and acromegaly 0 R. J. DOWSE-Met al. Table 3. Treatment

Visual field deficits* Radiation optic neuropathy Hypopituitarism Brain Necrosis Second Malignancy Growth hormone levels (ng,/ml)* Median Range < 10.0 ng/ml C5.0 ng/ml

results PreXRT

PostXRT

4125 o/25 0;5

412s O/25 7125 Q/25 Q/25

40.2 13.8-105 -

5.4 3.2-40.0 1 l/15 6/15

* Based on 25 patients with median follow-up of 53 months. + Improvement noted in all patients but stable residual deficits persist. * Fasting levels based on 15 patients tested. The values represent determinations done immediately prior to radiotherapy and at last follow-up. One patient had surgery following radiotherapy, thus the post-XRT value in this patient represents the combined effect ofboth modalities. Ail other patients had either no pituitary surgery, or had surgery that preceded the radio-

therapy. with suprasellar extension, of which two had visual field deficits. Growth hormone levels were available in 1 1 patients pre and post treatment. The median pre and post radiotherapy growth hormone levels in this group of patients were 40.2 and 5.4 ng/ml, respectively. Growth hormone levels at time of last follow-up were less than 10 ng/ml in 8/l 1 (73%) of the patients initially treated with radiotherapy. Follow-up CT scans were done in five patients and both CT and h4RI in an additional five patients. Seventeen of these patients remained in remission with stabilization ( 12 patients) or regression (5 patients) of their acromegalic features, and when tested, with reduction in growth hormone levels. No patients have had complete resolution of their acromegalic features, but there was reduction in the severity of diabetes and hypertension in those with these disorde:rs. The median postradiotherapy growth hormone level in 10 patients was 6.9 ng/ml with a range of 4.2-40.0 ngjml. Three patients with values greater than 10 ng/ml had levels of 40.0, 30.4, and 10.5 ng/ml, which represent reductions in their preradiotherapy levels by a factor of 2.6, 2.3, and 9.5, respectively. They have had stabilization of their acromegalic features with a corresponding follow-up of 58,49, and 98 months. MRI and/or CT scans in these three patients have documented initial regression and then stabilization of the pituitary masses. This is also true in the five other patients in this group having follow-up scans. The one patient with a preexisting visual field defcit has improved with therapy. None of these 17 patients have undergone subsequent pituitary surgery. Two patients had evidence of symptomatic recurrence manifested as a worsening visual field deficit in one patient, progressive elevation in growth hormone in the one patient tested, and worsening of acromegalic features in

455

both. The patient with increasing levels of growth hormone had a level of 35 ng/ml before treatment with coexisting hyperprolactinemia. The second patient with symptomatic recurrence had suprasellar extension and a visual field deficit present before treatment, which both worsened at time of recurrence. No growth hormone determinations were performed on this patient. CT scans revealed progression of pituitary tumor masses in both patients. These patients had surgery at 11 and 22 months following the radiotherapy. They remain in remission at 69 and 158 months after craniotomy with improvement in the visual field deficit in the patient with suprasellar extension and a growth hormone level of 3.2 ng/ml in the patient tested. Both patients have seen regression in their acromegalic features and stable postoperative MRI and/or CT scans showing no residual tumor. None of the 19 patients had deterioration of vision attributable to the radiotherapy and those who presented with visual field deficits improved with therapy. No clinical or MRI/CT scan evidence of focal brain necrosis was noted. The presence of diabetes (5 patients), hypertension (1 patient), or both (2 patients) was not a predisposing factor for the development of visual or brain complications. Four patients developed hypopituitarism following radiotherapy. Thyroid hormone abnormalities were noted in three patients, hypogonadism in two patients, and hypoadrenalism in one patient. There were no cases of second intracranial malignancies. Initial therapy: surgery Six patients with acromegaly received surgery as their

initial form of therapy. At presentation suprasellar extension was present in four patients, of whom two had visual field deficits. All resections were considered subtotal, but only one patient received immediate postoperative radiation. This patient had improvement in his visual field deficit, stabilization of his acromegalic features, and a 5fold reduction in his preradiotherapy growth hormone level from 100 to 20.1 ng/ml at 24 months follow-up. His subsequent CT and MRI scans show reduction in size of the residual pituitary mass. Five patients received radiotherapy at the time of symptomatic recurrence manifested as worsening preexisting visual field deficits in two patients, enlarging pituitary masses on MRI and/or CT scan in the three patients who were studied, progressive acromegalic features in four, and rising growth hormone levels in the three patients tested. One such patient received radiotherapy for a recurrence 15 months after her original surgical procedure. She had received 2400 cGy out of a planned dose of 4600 cGy when hydrocephalus was identified. The patient immediately underwent a second resection and shunt placement and had stabilization of her acromegalic features at 58 months follow-up. No subsequent growth hormone levels or scans are available on this patient. The remaining four patients who received radiotherapy for recurrence are in clinical remission manifested as improvement in

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456

acromegalic features in three and stabilization in one patient. Growth hormone levels tested in three patients show postradiotherapy values of 5.4, 4.7, and 3.7 compared to preradiotherapy values of 32.3, 45.0, and 40.2, respectively. MRI and/or CT scans done in three patients show improved and stable residual pituitary masses and postoperative changes. None of these six patients had deterioration of their vision attributable to the radiotherapy. Patients with preexisting visual field deficits improved following therapy. Again, no clinical or MRI/CT scan evidence of focal brain necrosis was noted. The presence of diabetes in one patient and both diabetes and hypertension in a second patient was not a predisposing factor to visual or brain complications. Two patients have shown evidence of hypopituitarism. One patient had thyroid, gonadal, and adrenal abnormalities and one patient had thyroid and adrenal deficits. No cases of second intracranial malignancies were identified.

Growth hormone determinations Table 3 contains data on growth hormone levels before radiotherapy was initiated and at last follow-up for the 15 patients tested. Table 4 presents growth hormone levels as a function of time from the completion of radiotherapy. DISCUSSION Patients with acromegaly are thought by some to have increased sensitivity of normal parasellar tissue to radiation. A greater risk of radiation optic neuropathy (RON) and brain necrosis has been suggested based on a number of reports describing these complications in acromegalics treated with parasellar radiotherapy (4, 6, 13, 18, 28). However, on closer review, it becomes clear that most of these patients have been treated with either nonstandard technique, excessive total dose and/or high daily fraction size (4, 11, 13, 15, 24, 34). Thus, many of the complications attributed to an increased radiosensitivity in these patients may actually result from suboptimal radiotherapy delivery. However, Bloom and Kramer (6) have reported on 40 patients with acromegaly treated with radiotherapy, of whom five patients had deterioration of vision attributed to RON. These patients were treated with moderate total doses (46-50 Gy) and fraction size (1200 cGy/day

Table 4. Growth

hormone

levels/time

from radiotherapy

Time (years) 0 Patients (number) GH (ngJm1) Median Range < 10.0 &ml ~5.0 &ml

1-3

3-5

15

15

12

I

3

40.2 13.8-105

18.7 4.7-74.8

7.4 4.5-40.0

5.8 3.7-10.5

4.2 3.2-5.0

617 217

313 313

-

4115 l/15

8112 3112

5-10

>I0

August 1990, Volume 19. Number 2

in 4 of 5 patients). No mention was made of possible coexisting medical conditions such as diabetes mellitus or hypertension in these patients. No further occurrences of RON have occurred since the treatment policy was changed to 46 Gy in 180 cGy fractions. No cases of RON were observed in 140 patients with chromophobe adenomas treated in a similar manner at the same institution. This report strengthened the argument that properly administered radiotherapy, given in doses below those typically associated with RON, can cause catastrophic complications in acromegalic patients. Thus, despite the proven efficacy and safety of radiotherapy in a postoperative setting (8, 19, 27, 35, 36) and as a primary modality, (2, 8, 9, 16, 17, 20, 26, 30) the enthusiasm for the use of radiation in acromegaly has declined. The tolerance of the optic nerve and tract is generally considered to be below the doses used in the treatment of pituitary adenomas. Parsons et al. (23) studied patients receiving treatment for neoplasms involving or adjacent to the orbit. There were no instances of RON below 55 Gy and the risk above 60 Gy was found to be fraction size dependent. An 8% incidence was found for fractions I 190 cGy/day compared to a 4 1% risk at rated 2 195 cGy/day. Other authors have identified RON in patients treated to total doses > 60 Gy (2 1, 28) or a nominal standard dose (NSD) > 2000 rets (32). Harris and Levene, ( 13) studying patients who received radiation for pituitary adenomas and craniopharyngiomas over a dose range of 40-70 Gy, identified five cases of RON. These occurred in patients without acromegaly, who received 245 Gy and only in the cases where the fraction size used was 250 cGy/day. Aristizabal et al. (3) studied 122 patients with pituitary adenomas and found RON associated with fraction size 2 200 cGy and time, dose, and fractionation factor (TDF) 2 80. Twenty-five patients in this series had acromegaly, with only one acromegalic developing RON after receiving 50 Gy in 250 cGy fractions (TDF = 90). Radiation optic neuropathy is manifested as visual field deficits usually followed by abrupt deterioration of visual acuity, and is often associated with characteristic funduscopic abnormalities (7). The latency period after radiotherapy is usually between 1-4 years, but occasionally longer (23). However, the visual fields may be severely affected with preservation of relatively normal visual acuity (22). In our series no patients were found to have evidence of RON or brain necrosis with a median follow-up of 53 months. An extensive review of clinical and radiographic records in these patients identified no instances of these complications. This was despite the fact that the doses used in the majority our patient population, were in the range reported by Bloom and Kramer (6) to cause RON. In general, the radiotherapy was administered according to the guidelines proposed for treatment of pituitary adenomas by Aristizabal et al. (3) and Harris and Levene ( 14), and was found to be safe. Only two patients received

Radiotherapy and acromegaly 0 R. J.

radiation in fraction sizes > 200 cGy. In addition, the three patients receiving ai total dose > 46 Gy had daily fraction sizes s 180 cGy/day. These data indicate that our current policy of treating acromegalics with a three field arrangement, to a total dose of 46 Gy in 200 cGy fractions (TDF = 76) with maximum inhomogeneity across the treatment volume of 5%, appears to be safe and below the tolerance of critical adjacent structures. Although increased radiation sensitivity in acromegalics may exist, our data do not support this concept. The high incidence of hypertension and diabetes in the patients reported here is compatible with those seen in large series of acromegalics (37). The microvascular changes associated with these medical conditions has been offered as a possible explanation for the proposed hypersensitivity to radiation in these patients. The presence of diabetes and/or hypertension was not associated with RON or brain necrosis in this series. Unfortunately, the reports documenting complications in acromegalics do not attempt to correlate the presence, severity, and chronicity of the medical conditions and the degree of baseline vascular disease with outcome. Beaney et al. (5) attempted to quantify damage to the microvasculature in brain tissue using positron emission technology. They measured blood flow and oxygen utilization in the brain and found no evidence of microvascular damage in the temporal lobes of a small group acromegalics treated with radiation. Although no serious optic or central nervous system (CNS) complications occurred in this series, a 28% incidence of hypopituitarism was attributed to radiotherapy. Snyder et al. (33), using provocative testing, reported on a group of patients who received radiation for pituitary adenomas and found evidence of hypopituitarism in up to 70%. This complication has been observed in patients receiving parasellar radiation for other head and neck neoplasms as well (12, 25, 29). Radiotherapy dose response information is rather limited in acromegaly. Sheline et al. (30) clearly showed a dramatic increase in response in those patients treated to doses > 35 Gy compared to lower doses. In a separate report, Lamberg et al. (16) reported a less dramatic dose response at doses > 40 Gy. Many reports using doses in the 40-50 Gy range have shown stabilization of acromegalic features, control of the local tumor mass, and reduction of the growth hormone (GH) levels to normal or near normal range in 70-80% of patients (6, 8, 9, 26). Series of patients where doses > 50 Gy were given have shown no clear additional benefit to the higher dose (2, 17, 20, 26). Although reductions in GH levels are often seen within the first year, return of GH to the normal range after radiotherapy may take up to 5 years (9) or longer (8, 10). Similar overall results have been achieved with transsphenoidal surgery but the reductions in GH are almost immediate with this modality (27, 36). As one may predict, the success of radiotherapy is dependent on the initial extent of growth hormone hypersecretion. Pa-

DOWSETT

et al.

451

tients with GH levels < 40 ng/ml respond with GH levels falling to the normal range more frequently than those with more advanced disease (3 1). The response to radiotherapy seen in this series is consistent with that found in previously published reports (2, 8, 9, 16, 17, 26, 30). The success of radiotherapy as a primary modality was 17/ 19 (89%). These 17 patients had regression (5 patients) or stabilization ( 12 patients) of acromegalic features. In all eight patients tested, there was improvement and then stabilization of pituitary masses identified by MRI and/or CT scans. Seven of 10 patients treated only with radiotherapy have growth hormone levels below 10 ng/ml. The remaining three patients had marked elevations in growth hormone before radiotherapy and have shown impressive declines after treatment, They have stable acromegalic features but are otherwise asymptomatic despite persistently elevated growth hormone levels. Two patients with follow-up levels in the 30-40 ng/ml range have been followed for less than 5 years and further declines in hormone levels may be expected. Continued decline in growth hormone levels 5 years after radiotherapy is evident from our data (Table 4) and has been reported by others (8, 10). Overall, the median growth hormone level in patients followed between 3-5 years was 7.4 ng/ml with further reductions noted with longer follow-up. Two symptomatic recurrences occurred in the 19 patients treated with primary radiotherapy. They were both successfully salvaged with surgery. Radiotherapy given in the postoperative setting at the time of recurrence was equally effective in this series based on a smaller number of patients. Four evaluable patients treated after recurrence with radiotherapy have all responded well. The one patient treated immediately postoperatively for residual tumor had an impressive clinical and radiographic response, and a 5-fold reduction in growth hormone level at 24 month follow-up. In the present series, reductions in GH levels correlated well with clinical and radiographic remission of the disease as previously observed by others (3 1). In addition, patients with marked elevations in GH levels did show impressive reductions after radiotherapy. However, the patients with GH levels > 10 ng/ml after radiotherapy all started with pretreatment levels > 70 ng/ml. This illustrates the difficulty in achieving near normal GH levels in patients with extremely high pretreatment values, which was stated earlier in the discussion. One patient in seven with suprasellar extension and one patient in five with hyperprolactinemia had a symptomatic recurrence after radiotherapy. The presence of these factors did not appear to predict response to radiation in this small subgroup of patients. However, Werner et al. (35) have suggested that acromegalics with concomitant hypersecretion of prolactin are particularly sensitive to radiation. We conclude that the use of radiotherapy, given in the described manner to patients with acromegaly, is both

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safe and effective. There were no instances of RON, brain necrosis, or second intracranial malignancies identified. We advocate the use of megavoltage equipment, multiple field arrangements, with a total dose of 46 Gy in fraction sizes not to exceed 200 cGy. Radiotherapy may be considered as a primary modality in patients whose clinical condition permits slow resolution of the tumor mass and/or GH levels. Surgery should be considered in those patients whose visual findings, medical conditions, or physical appearance require a prompt reduction in tumor mass or hormone levels. Patients with marked elevations of GH levels may have an excessively prolonged period of disease activity when

August 1990. Volume 19. Number 2

treated with radiotherapy alone. This should be considered in the management, with radiotherapy reserved for patients with smaller tumors with lower GH levels. Patients with significant hypertension or diabetes and evidence of vascular disease may represent the subpopulation of acromegalics at greater risk for complications, but we could not document this. Radiotherapy appears to be effective in treating recurrences after surgery in our experience. It clearly has a role for use immediately postoperatively in those patients with subtotal resections, although our report contains only one such patient. The impact of recent advances in medical management of acromegaly, including the long-acting somatostatin analogs, is uncertain.

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Radiotherapy and acromegaly 0 R. J.

tion necrosis of the optic nerve. Am. J. Ophthalmol. 76: 683-686; 1973. 29. Samaan, N. A.; Bakdash, M. M.; Caderao, J. B.; Cangir, A.; Jesse, R. H.; Ballantyne, A. J. Hypopituitarism after external 30. 3 1.

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