Pituitary adenoma: The efficacy of radiotherapy as the sole treatment

ht. J. Rndiarion Onco/ogy ho/ Phys Vol. 17, pp. 165-169 Printed in the U.S.A. All rights reserved.

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036cL3017/89 $3.00 + a0 0 1989 Pergamon Press plc

l Brief Communication

PITUITARY ADENOMA: THE EFFICACY OF RADIOTHERAPY AS THE SOLE TREATMENT STEPHEN C. RUSH, M.D.

AND JOSEPH NEWALL, M.D.

Division of Radiation Oncology, New York University Medical Center, 566 First Ave., New York, NY 10016 The management of patients with pituitary adenomas by radiotherapy alone, using modern techniques of evaluation and current st@dards of treatment, has not been examined. This is a retrospective review of 29 such patients with nonfunctional pr prolactin secreting pituitary macroadenomas. Patients were analyzed by visual fields, hormone levels, and cn’ scans. All hut one patient received a tumor dose of 4500 cGy in 4 to 5 weeks. The tumor was controlled in w of 28 (93%) patients for an observed period of 3 to 14 years. Seventeen of 21 (81%) patients with visual impairqent experienced normalization or improvement, and seven of ten (70%) patients with hyperprolactinemia achieved normalization of their serum proiactin levels. Post-treatment CT scanning revealed persistent tumor in nine of 17 patients despite clinical improvement. We conclude that: (a) radiotherapy is an effective treatment for these tumors; (b) doses need not exceed 4500 cGy in 25 fractions; (c) radiation is effective for improving vision; (d) radiation can normalize hyperprolactinemia; and (e) tumor regression is variable and unrelated to observed symptom regression. Pituitary tumor, Radiation, Visual field, CT scan, Prolactin.

INTRODUCTION

alone in the modern era as measured by visual improvement, response of hyperprolactinemia, and the pattern of tumor regression as analyzed by computerized tomography (CT) scan.

Pituitary adenomas are benign tumors that are of clinical concern because of their strategic location or excess hormone secretion with secondary physiologic derangement or both. The management of these tumors has changed with improvements in diagnostic imaging, refinement of surgical technique, development of assays for growth hormone and prolactin,’ and the introduction of dopamine agonist therapy. The value of radiation alone as a treatment modality in light of the above has not been defined. It is well establishied that transphenoidal surgery is a safe and effective treatment for microadenomas (4, 5, 14, 23), as is bromocriptine for prolactinomas (9, 11,26,27). However, the literature is not clear regarding treatment guidelines for macroadenomas because of: (a) the high recurrence rate in those surgical series with adequate follow-up (3, 17, 18, 201,24); (b) the inability of bromocrip-

METHODS

AND

MATERIALS

Selection Between

tine to shrink tumors and normalize prolactin in about one-third of the patients ( 12); and (c) the paucity of modern literature regarding the value of radiotherapy with specific detail to visual improvement, hypersecretion, and tumor reduction. This report details the results of treatment on 29 patients treated by a uniform plan of radiotherapy (RT)

October 1973 and September 1985, 105 patients with pituitary adenomas were treated in the Division of Radiation Oncology at New York University Medical Center. Of these, 31 patients received radiation therapy alone (this includes one patient with visual changes from a prolactinoma who had no response to bromocriptine for 6 months prior to RT). Patients received primary RT for one of the following reasons: refused surgery; advanced age; inoperable for medical reasons; reservation of surgery as salvage for a macroadenoma that would clearly require planned postop RT. The diagnosis was established by kinetic tangent perimetry, serum hormone testing, and radiographic examination. One patient was lost to followup, and one patient died within 1 year of a cerebrovascular accident (CVA) with no post treatment examination. The remaining 29 patients form the substance of this report.

Presented by Dr. Rush at the 70th Annual Meeting of the American Radium Society, Seattle, Washington, April 16, 1988, as the recipient of the Young Oncologist Essay Award. Reprint requests to: Stephen C. Rush.

Acknowledgement-The authors thank Cristopher Lee for data retrieval and T-L Mahe and Ruth Lebowitz for preparation of this manuscript. Accepted for publication 18 January 1989. 165

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Treatment Patients were treated by 6oCo or 4 million volt (MV) linear accelerator teletherapy. Twenty-seven patients received a tumor dose of 4500 to 4600 centiGray (cGy) in 4 to 5 weeks using one coronal and two lateral fields. Two patients were treated with parallel opposed fields to 4000 cGy and 4500 cGy, respectively. All fraction sizes were 180-200 cGy per fraction. Our general philosophy has been to treat the tumor with a 1 centimeter (cm) margin to the 90% isodose. Hence, the field sizes ranged from 4 cm X 4 cm X 3.5 cm to 8 cm X 8 cm X 7 cm. Most dimensions were 5 cm to 6 cm. Follow-up One patient left the country after 1 year and is included for evaluation of visual response only. The range of followup for the other 28 patients is 3 to 14 years, with a median follow-up of 8 years. All patients or their surviving family members were interviewed by telephone with attention to resolution or recurrence of symptoms, post-treatment studies, and hypopituitarism. Their primary physicians, endocrinologists, or ophthalmologists were then contacted for appropriate information. When possible, patients were examined. Two patients who had gross visual field defects were tested after treatment by confrontation. All other patients underwent tangent perimetry testing by an ophthalmologist to determine visual field response to irradiation. Prolactin levels were primarily basal determinations taken as fasting morning samples. RESULTS

Patient characteristics There were 16 men with a median age of 52 (range 81) and 13 women with a median age of 58 (range 78). Twelve patients had prolactinomas (including with concomitant acromegaly), ten had non-secretory

VI,WAI.

Table 1. Signs and symptoms at presentation Visual field deficit Headache Decreased visual acuity Cranial nerve palsy Decreased libido Incidental discovery Pan hypopituitarism Galactorrhea/amenorrhea Apoplexy Amenorrhea Acromegaly Oligomenorrhea Hypoadrenal Hypothyroid Hypogonadal

18 10 9 5 5 4 3 3 2 1 1 1 1 1 1

enomas, and seven had no prolactin determination. Twenty-one patients had visual problems. Visual field defects were found in 18 patients (the most common symptom at presentation), decreased visual acuity in nine, and diplopia in five (Fig. 1). Diagnosis of pituitary adenoma was made incidentally in four patients. Presenting symptoms are summarized in Table 1. Tumors were demonstrated radiographically by pneumoencephalogram and/ or cerebral angiography in eight patients and CT scan in 21. The extent of the tumors are shown in Table 2. Tumor control The overall control rate (stabilization or regression of tumor and symptoms) among 28 patients was 93% (Table 3). Progression or recurrence of symptoms occurred in two patients. The first had progressive visual deterioration 6 weeks after RT and underwent surgical decompression. There was minimal visual improvement postoperatively. She died of intercurrent disease 5 years later without progression. The second patient required an operation for recurrence of visual symptoms associated with radiographic progression 3 years after radiation and is currently free of disease 10 years postoperatively. Thus, including surgical salvage, all tumors were controlled.

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Fig. 1. Distribution

2222one ad-

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of patients with visual impairment.

Visual response Seventeen of 2 1 (8 1%) patients who had visual disturbance showed improvement after therapy. Of 3 1 eyes in 17 patients with visual field deficits, 28 normalized or improved for an overall response rate of 90% (28/3 1) (Fig. 2). Three eyes with hemianopsias were unchanged or worse. Of 12 eyes in nine patients with decreased visual acuity, 83% (10/l 2) normalized or improved. Table 2. Radiographic extent of tumor in relation to the sella turcica among 29 patients Suprasellar Lateral Sphenoidal Intrasellar only

21 11 3 5

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Pituitary radiation l S. C. RUSH AND J.NEWALL Table 3. Overall control Years

No. at risk

3 16 6 ~10 10 114

28 21 8

Controlled

Failed 2 0 0

26 21 8

Five patients had 3rd or 6th cranial nerve palsies, three were corrected completely and one was unchanged. One patient had resolution of diplopia, despite a mild paresis still present on examination. Hence, 80% (4/5) of cranial nerve palsies improved without recurrence.

Hyperprolactinemia Twelve patients had hyperprolactinemia. Two have been maintained on bromocriptine following RT and are excluded from this analysis (their prolactin levels are normal). The initial and first normal, or last elevated prolactin, values of the other patients are displayed in Figure 3. Levels were obtained intermittently in some patients, so the time to normalization in them probably does not reflect the true history of their tumors. No patient has recurred since normalization. Seven patients achieved normalization over a period of 3 to 8 years. Three patients still have elevated prolactin levels between 4 and 9 years after radiation therapy. Tumor regression Seven patients have had either one unchanged CT scan within 1 year of RT or no post-treatment CT scans. Two patients who were re-operated on and one patient lost to follow-up after 1 year are not evaluated in this section. The other 19 patients had adequate serial CT scans in which a pattern of regression could be determined. Eight patients developed an “empty sella.” That is, the sella was filled with oerebrospinal fluid (CSF), and occasionally a band of tissue lining the floor. Eight patients showed improvement, where at least the extrasellar com-


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Fig. 2. Outcome of therapy in relation to pretreatment of visual field deficit.

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Fig. 3. The response of hyperprolactinemia

to radiation.

ponents regressed, with or without a subsequent decrease in intrasellar mass. Three patients with macroadenomas and extrasellar extension experienced no visible change on CT scans 3 or more years after therapy. Complications Seven of 24 patients at risk for hypopituitarism are on thyroid replacement, and five of 24 are on steroid replacement. Not all of the group at risk have been followed with hormone determinations, but are asymptomatic. The time to begin replacement therapy was from 6 months to 11 years after RT. One patient had a CSF leak repaired 3 years after treatment. One patient developed inappropriate secretion of antidiuretic hormone (SIADH), but the relation to pituitary irradiation is unclear. One patient experienced apoplexy into an asymptomatic, persistent adenoma 12 years after radiotherapy. He underwent transphenoidal surgery and is well 1 year after surgery. A final patient who experienced resolution of visual field defects, became blind 3 years after treatment from optic nerve dysfunction. It is unknown if this was radiation induced. He received 4600 cGy in 23 fractions. Three patients had CVA after RT. One patient, as mentioned, was 82 years old and died of a CVA 1 year after radiation. Another elderly patient died from a CVA 5 years after radiation. A 45year-old man without apparent risk factors suffered a CVA 4 years after RT. DISCUSSION Transphenoidal surgery is generally regarded as the primary modality of therapy for pituitary macroadenomas. Radiation therapy has been used as an adjunct to decrease the recurrence rate from up to 86% to lo-25% (3, 6, 10, 17-2 1,24). Primary radiotherapy has generally been reserved for inoperable patients. The value of RT alone for general control is well documented (6, 10, 16, 21). However, there is a paucity of literature addressing its role in improvement of visual impairment and endocrinopathy by current techniques and standards. Previous reports show the ability of RT to improve

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visual field defects secondary to pituitary macroadenomas (16,2 1,25). These series report improvement rates ranging from 41% to 68%. However, treatment was not uniform. The authors use relatively lower doses (21) and smaller field sizes (16, 25). When reported, visual field defects greater than quadranopsias did not respond well. This latter fact had led to the reluctance of physicians to recommend primary RT. On the contrary, this series reports the improvement and normalization of bitemporal hemianopsias. Until recently, the role of RT in decreasing hyperprolactinemia appeared limited to reducing the serum value without normalization (7, 13, 22). However, Grossman reports a series of 36 young women with prolactinomas who were trying to conceive and were treated with adequate RT and bromocriptine (8). Eight of 26 patients tested after discontinuation of the drug had normal prolactin levels. In a 1987 report, Mehta et al. also shows the long course toward normal prolactin values in six patients of nine following RT ( 15). Our data on ten patients confirm this to be the history of a prolactinoma after RT. The rate of serum prolactin reduction may be similar to that of growth hormone reduction after pituitary irradiation for acromegaly (1). The treatment of prolactinomas has been enhanced by the popularization of dopamine agonist therapy. A review by Jordan and Kohler shows that 87% of 3 1 patients with impaired vision experienced improvement with bromocriptine only (12). Sixty-five percent of 78 macroprolactinomas attained normal prolactin levels. Similar tumors treated by surgery normalize in only 20 to 50% of the cases. Our small series added to the literature suggests that many patients with hyperprolactinemia can eventually be cured by primary radiotherapy. Similar to the long time for normalization of hyperprolactinemia, is the radiographic response. Most tumors did not show a change in the first year and some did not

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appear to change until the third post-treatment year. Our findings that ten of 18 patients showed a residual or unchanged tumor by CT scan a&m the importance of serial scans in documenting either recurrence or progression of disease after RT, in the absence of progressive visual loss. Similar findings are noted by Bruckman et al. among patients who predominantly had combined therapy (2). The development of hypopituitarism after pituitary irradiation was expected. Its incidence is clearly underestimated by our series for reasons mentioned above. The development of blindness in one patient was quite disturbing. However, there were no such cases among 69 patients who received surgery and radiation for pituitary tumors during the same study period. Additionally, only one other elderly patient in the combined therapy population suffered from a CVA. The possibilities of treatment then include surgery, radiotherapy, or bromocriptine alone or in combination. Observation is occasionally a viable option as well. Therefore, in the absence of a clearly defined therapy a decision as to treatment should be based on a number of issues including visual loss (degree and history of onset), short term vs. long term control of tumor mass, hormone elevation with attendant functional derangements, urgency of need for hormone normalization, patient age and condition, patient preference, side effects, and cost must be taken into account. As far as nonfunctional macroadenomas are concerned, the custom in patients with extrasellar extension is to give radiotherapy after surgery. Since RT is effective in restoring vision and controlling tumors, with an efficacy historically similar to combined treatment, many patients could be spared surgery and receive RT alone in the absence of rapid visual loss. The same logic applies to macroprolactinomas if bromocriptine is not tolerated or chosen. We currently recommend primary RT for such patients.

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6. Emmanuel, I. G. Symposium on pituitary tumors-historical aspects of radiotherapy, present technique and results. Clin. Radiol. 17:154-160; 1966. 7. Gomez, F.; Reyes, F. L.; Faiman, C. Nonpuerperal gaIactorrhea and hyperprolactinemia: clinical findings, endocrine features and therapeutic responses in 56 cases. Am. J. Med. 62:648-660; 1977. 8. Grossman, A.; Cohen, B. L.; Charlesworth, M.; Plowman, P. M.; Rees, L. H.; Wass, J. A. H.; Jones, A. E.; Besser, G. M. Treatment of prolactinomas with megavoltage radiotherapy. Br. Med. J. 288: 1105-l 109; 1984. 9. Hammond, C. B.; Haney, A. F.; Land, M. R.; Van der Met-we, J. V.; Ory, S. J.; Wiebe, R. H. The outcome of pregnancy in patients with treated and untreated prolactinsecreting pituitary tumors. Am. J. Obstet. Gynecol. 147: 148-157; 1983. 10. Hayes, T. P.; Davis, R. A.; Raventos, A. The treatment of pituitary chromophobe adenomas. Radiology 98:149-153; 1971. Il. Johnston, D. G.; Prescott, R. W. G.; Kendall-Taylor, D.; Hall, K.; Crombie, A. L.; Hall, R.; McGregor, A.; Watson,

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M. J.; Cook, D. Hyperprolactinemia, long-term effects of bromocriptine. Am. J. Med. 75:868-874; 1983. Jordan, R. M.; Kohler, P. 0. Recent advances in diagnosis and treatment of pituitary tumors. In: Stolerman, G., ed. Advances in internal medicine. Chicago: Yearbook Medical Publishers, Inc.; 32:299-324; 1987. Kleinberg, D. L.; Noel, G. L.; Frantz, A. G. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N. Engl. J. Med. 296:589-600; 1977. Laws, Jr., E. R.; Trautmann, J. C.; Hollenhorst, R. W. Transsphenoidal decompression of the optic nerve and chiasm-visual results in 62 patients. J. Neurosurg. 46:7 17722; 1977. Mehta, A. E.; Reyes, F. L.; Faiman, C. Primary radiotherapy of prolactinomas. Am. J. Med. 83:49-58; 1987. Pistenma, D. A.; Goffinet, D. R.; Bagshaw, M. A. Treatment of chromophobeadenomas with megavoltage irradiation. Cancer 35:1574-1582; 1975. Post, K. D.; Biller, B. J.; Adelman, L. S.; Molitch, M. E.; Wolpert, S. M.; Reichlin, S. Selective transsphenoidal adenomectomy in women with galactorrhea-amenorrha. JAMA 242(Suppl. 2):158-162; 1979. Randall, R. V.; Laws, E. R.; Abboud, C. F.; Ebersold, M. J.; Kao, P. C.; Schetaner, B. W. Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas. Mayo Clin. Pro. 58:108-121; 1983. Ray, B. S.; Patterson, Jr. R. H. Surgical experience with chromophobeadenomas of the pituitary gland. Neurosurg. 34:71-729; 1971.

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20. Serri, 0.; Rasio, E.; Beauregard, H.; Hardy, J.; Somma, M. Recurrence of hyperprolactinemia after transsphenoidal adenomectomy in women with prolactinoma. N. Engl. J. Med. 309:280-283; 1983. 2 1. Sheline, G. E. Treatment of nonfunctioning chromophobe adenomas of the pituitary. Am. J. Roentgenol. 120:553561; 1974. 22. Sheline, G. E.; Grossman, A.; Jones, A. E.; Besser, G. M. Radiation Therapy for Prolactinomas. In: Black, P. M., Zervas, N. T., Ridgway, E. C., Martin, J. B. eds. Secretory tumors of the pituitary gland. New York Raven Press; 1984: 93-108. 23. Stefanis, G. S.; Cavanuagh, H. D.; Tindall, G. T. Ophthalmological Aspects of Pituitary tumors. In: Tindall, G. T., Collins, W. F. eds. Clinical management of pituitary disorders. New York: Raven Press; 1979;239-263. 24. Tindall, G. T.; McLanahan, S.; Christy, J. H. Transsphenoidal microsurgery for pituitary tumors associated with hyperprolactinemia. J. Neurosurg. 48:849-860; 1978. 25. Urdaneta, N.; Chessin, H.; Fischer, J. J. Pituitary adenomas and craniopharyngiomas: analysis of 99 cases treated with radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2:667673; 1977. 26. Vance, M. L.; Evans, W. S.; Thomer, M. 0. Bromocriptine. Ann. Intern. Med. 100:78-91; 1984. 27. Zarate, A.; Canales, E. S.; Cano, C.; Pilonieta, C. J. Followup of patients with prolactinomas after discontinuation of long-term therapy with bromocriptine. Acta. Endocrine. 104:139-142; 1983.