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5 Radiation optic neuropathy
after external beam radiation therapy
for acromegaly
Alfons C.M. van den Bergh1, Robin P.F. Dullaart2, Marjanke A. Hoving1, Thera P. Links2,
Cees A. ter Weeme3, Ben G. Szabó1, Jan-Willem R. Pott4
1 Department of Radiation Oncology, 2 Endocrinology, 3 Neurosurgery,
4 Ophthalmology, University Hospital Groningen, The Netherlands.
Radiotherapy and Oncology 2003; 68: 95-100 Acromegaly is an uncommon disease, mostly caused by a growth hormone (GH)- secre-ting pituitary adenoma. Its incidence has been estimated at 2.8 - 6 cases per million and its prevalence at 38 - 68 cases per million2,10,64.
A GH-secreting pituitary adenoma does not only lead to clinical signs and symp- toms, like acral enlargement and soft tissue swelling, but may also be accompanied by visual field defects and acuity loss caused by tumour compression on the optic nerves or chiasm, often seen in combination with pituitary hormone insufficiencies.
Surgery, drug therapy with somatostatin analogs and external beam radiation therapy are currently the available treatment options61. External beam radiation therapy is available since the beginning of the 20th century12,35. It became clear, however, that radiation therapy alone often results in insufficient biochemical control, which means a decline but not a normalisation of GH hypersecretion3,4,24,29,56. Consequently, surgery be-came the initial treatment of choice. According to some experts drug therapy may be the first treatment of choice for selected patients61. Postoperative radiation therapy is per-formed in many centres to reduce the postoperative time span of medical treatment, to normalize remaining GH hypersecretion, and to prevent regrowth of residual tumour75.
Radiation Optic Neuropathy (RON) was for the first time reported by Forrest et al. in 195630. They defined RON as a sudden and profound irreversible vision loss due to damage of the optic nerves or damage of the chiasm caused by radiation therapy.
Kline et al. and Parsons et al. defined the following criteria for diagnosing RON49,65: (a) irreversible visual loss with visual field defects, indicating optic nerve or chiasmal dysfunction; (b) absence of visual pathway compression due to recurrence or progres-sion of tumour, radiation-induced neoplasm, arachnoidal adhesions around the chiasm, radiation retinopathy or any other apparent ophthalmological disease; (c) absence of optic disc edema and (d) optic atrophy within 6 - 8 weeks after onset of symptoms.
In the past decades many reports on RON have appeared in the literature. The last review of RON in acromegaly was published by Eastman et al. in 199225. The radiation dose level for the occurrence of RON is not known. Moreover the dose-response relationship for RON has not been firmly established due to the small numbers of events in most se-ries46,65. It has been suggested that the maximal steepness of the sigmoid dose-response curve for RON is between 50 and 60 Gy46,65. The occurrence of RON after doses as low as 45-50 Gy administered in fractions of 1.67 - 2 Gy seems to be a problem unique to patients with pituitary tumours, and probably reflects pre-existing optic nerve and chiasm com-pression and vascular compromise secondary to a mass effect or due to surgery46,65. Some authors propose that the optic system in acromegalic patients might be more sensitive to radiation damage compared to patients irradiated for non-functioning pituitary adenomas5,6,13,39. This may be caused by vascular and hormonal changes in rela-tion to acromegaly5, but this opinion is not uniformly accepted23,25. Radiation optic neuropathy after external beam radiation therapy for acromegaly The purpose of this literature survey is to determine the incidence of RON in acro megaly, and to establish risk factors associated with its occurrence Literature search and data analysis
The literature review was done, using Medline between 1966 and June 2002 and Embase between 1989 and 2002. Key words searched for were RON, acromegaly and radiotherapy as well as pituitary adenoma and radiotherapy. All papers that included acromegalic pa-tients were checked for vision loss due to radiation therapy. The references retrieved by Medline and Embase were screened for other references, not found by using the above-mentioned key words. To estimate the incidence of RON in acromegaly we only included cohort series of patients, in which RON was taken into consideration. In case of a cohort of all kind of pituitary adenomas, it was only included in Table 1 in case of a known number of acro-megalic patients, in which it was clear how many patients suffered RON. To evaluate risk factors for RON development we included RON-patients from series in which radiation treatment data were available, as well as individual case reports. This present survey includes our own series of 63 patients of whom two developed RON11.
Incidence of RON
As shown in Table 1, 25 of 1845 patients developed RON, yielding an incidence of 1.36% (95%CI: 0.94 - 1.89%). This figure is not significantly lower than that reported by Eastman et al., who calculated an incidence of 2.2% (95%CI: 1.53 - 3.17%) (P = 0.10)25. The incidence reported by Eastman et al. is likely to be overestimated, because they included single case reports of RON in their review25. Although the incidence of RON is low, it is considered a serious complication of radiation therapy. It is therefore of interest to identify the severity of visual loss and the radiation treatment characteristics associated with its occurrence.
Table 1 Incidence of RON in reported series of acromegalic patients
na: not available Radiation optic neuropathy after external beam radiation therapy for acromegaly Severity of visual loss and latency of RON occurrence
When reviewing reported cases of RON in acromegalic patients in whom total radiation dose and fraction size are reported (Table 2) –using the abovementioned search method - it appears that in 24 of 32 patients, in whom visual loss was specified, RON was bilateral in 17 patients (71%) and unilateral in seven patients (29%). Visual acuity was less than 2/10 in 35 of 41 RON affected eyes.
It is generally proposed, that most cases of RON occur within 18 months after ra- diation therapy49. However, Table 2 shows that in eight of 30 patients (27%), RON developed more than 18 months after radiation therapy (median 12 months, range 5-120 months). Thus late development of RON can occur, indicating that the clinician should remain alert of this complication, even many years after radiation therapy. RON in relation to radiation treatment characteristics
A radiation fraction size greater than 2 Gy and/or a total radiation dose greater than 50 Gy are suggested to be risk factors for RON in general5,65. As shown in Table 2, it appears that in 16 of 32 cases (50%) radiation fraction size was greater than 2 Gy and/or total radia-tion dose was greater than 50 Gy. Information with respect to minimum and maximum radiation doses according to ICRU 50/62 recommendations80 within the treated target volume, that also encompass the optic system, was not available in most reports. Other risk factors for RON development
Apart from the probable risk attributable to vascular compromise, GH-secreting pituitary adenoma as such may confer an increased risk for RON development as previously sug-gested5,6,13,39. Older age is another possible risk factor for RON65. In 27 of 32 cases, reviewed in Table 2, age was reported. In this series median age was 53 years, which is approxi-mately 10 years older than the age reported at diagnosis of acromegaly42, and than the median age of the presented cohort11. However, in general there is a lack of data in pu b-lished series with respect to age in those patients who did and who did not develop RON. Therefore, it is not possible to draw definite conclusions about age as a risk factor for RON development.
Remarkably, as shown in Table 2, 20 of 23 patients (87, 95%CI: 66 - 97%), in whom gender was reported, were female, our two cases included (P<0.001 from an equal sex distribution). Since the occurrence of acromegaly is not increased in females42 and it is unlikely that females are treated with radiation therapy more frequently than males, this would suggest that females are at an increased risk for the development of RON. To our knowledge a female predisposition for RON has not been reported earlier.
Pathogenesis and treatment
RON is essentially defined as a diagnosis by exclusion49. Although the pathogenesis of RON is unclear, its microscopic appearance would suggest an initial microvascular in-jury that results in perivascular inflammation, hyalinization, and fibrosis of vessel walls and also loss of endothelium and consequently infarction with reactive gliosis49. Using MRI with gadolinium, enhancement of the retro-orbital optic nerves and chiasm usually occurs, probably as a consequence of a disrupted blood brain barrier within the optic nerves14,38. This may be used to differentiate RON from optic neuritis due to demyelina-tion. Therefore, this diagnostic approach is currently proposed to improve the diagnosis of RON14,38. A few months after the onset of RON the gadolinium enhancement of the optic nerves on MRI disappears38.
Until now there is no effective treatment for RON69. The effect of high dose cor- ticosteroids and of anticoagulants is unclear69. Hyperbaric oxygen therapy has also been used to treat RON, but its efficacy is uncertain15,69.
Radiation optic neuropathy after external beam radiation therapy for acromegaly Table 2 RON in acromegalic patients, in whom total radiation dose and radiation fraction size are available
Visual status due to RON OD:reduced vision OS:Bl After external beam: 84 Visual loss not specified Visual loss not specified Visual loss not specified OD:Visual loss not specified OS:Visual loss not specified Visual loss not specified Visual loss not specified Visual loss not specified OD:VA2/7 OS:VA2/3 OD:VA 0.3 OS:VA 0.1 Visual loss not specified OS:Visual loss not specified Visual loss not specified OD:VA 0.5 OS:VA 1/60 na: not available; F: female; M: male; N: normal ;R: reduced; OS: oculus sinistra/ left eye; OD: oculus dextra/ right eye; VA: visual acuity; Bl: blind; LP: light perception; HM: hand movements: FC: fingercounting[ ]* these references are mentioned in Table 1 and Table 2, because an incidence was mentioned and in case of RON treatment characteristics were available.
Table 2 RON in acromegalic patients, in whom total radiation dose and radiation fraction size are available
Visual status due to RON OD:reduced vision OS:Bl After external beam: 84 Visual loss not specified Visual loss not specified Visual loss not specified OD:Visual loss not specified OS:Visual loss not specified Visual loss not specified Visual loss not specified Visual loss not specified OD:VA2/7 OS:VA2/3 OD:VA 0.3 OS:VA 0.1 Visual loss not specified OS:Visual loss not specified Visual loss not specified OD:VA 0.5 OS:VA 1/60 na: not available; F: female; M: male; N: normal ;R: reduced; OS: oculus sinistra/ left eye; OD: oculus dextra/ right eye; VA: visual acuity; Bl: blind; LP: light perception; HM: hand movements: FC: fingercounting[ ]* these references are mentioned in Table 1 and Table 2, because an incidence was mentioned and in case of RON treatment characteristics were available.
Radiation optic neuropathy after external beam radiation therapy for acromegaly Our literature review suggests that RON occurs in 1.36% of patients with GH-secreting
pituitary adenoma, treated with external beam photon radiation therapy. Assuming that
in as much as 50% of reported cases, no risk factors related to radiation therapy were
present, would suggest that other risk factors, including vascular compromise and GH-
secreting pituitary adenoma itself, contribute to RON occurrence. RON may occur after a
considerable latency period. A female preponderance for developing RON is suggested.
The current dose-fractionation policy in our department is 45 Gy in 1.8 Gy frac- tions for all pituitary adenomas if radiation therapy is indicated. To our opinion there is no benefit in applying a higher total dose in pituitary adenoma radiation treatment, because a dose-volume effect above 45 Gy is absent60. Taken into consideration that in 50% of RON cases radiation treatment characteristics are likely to contribute to the development of this complication, our treatment scheme could further decrease RON development.
1. Al-Mefty O, Kersh JE, Routh A and Smith RR. The long-term side effects of radiation therapy for benign brain tumors in adults. J Neurosurg 1990;73:502-512.
2. Alexander L, Appleton D, Hall R, Ross WM and Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol 1980;12:71-79.
3. Aloia JF, Field RA and Kramer S. Treatment of acromegaly. Arch Intern Med 1973;131:509-515.
4. Aloia JF, Roginsky MS and Archambeau JO. Pituitary irradiation in acromegaly. Am J Med Sci 1974;267:81-8 7.
5. Aristizabal S, Caldwell WL and Avila J. The relationship of time-dose fractionation factors to complications in the treatment of pituitary tumors by irradiation. Int J Radiat Oncol Biol 6. Atkinson AB, Allen IV, Gordon DS, et al. Progressive visual failure in acromegaly following external pituirary adenoma. Clin Endocrinol 1979;10:469-479.
7. Baldwin A, Cundy T and Butler J. Progression of cardiovascular disease in acromegalic patients treated by external pituitary irradiation. Acta Endocrinologica 1985;108:26-30.
8. Barceló B, Pérez C, Dávila N, Lucas T, Salto L, Alcañiz J. Valoración endocrinológica de 61 pacientes acromegálicos tratados con cirugía transesfenoidal aislada, o asociada a telecobaltoterapia y/o bromocriptina. Med Clin 1982;80:735-741.
9. Bataini JP, Glinski B. Supervoltage irradiation in the management of pituitary adenomas. In: Derome PJ, Jedyak CP, Peillon F, editors. Pituitary Adenomas. Paris: Asclepios Publishers, 1980. p.203.
10. Bengtsson B, Edén S, Ernest I, Odén A, Sjögren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand 1988;223:327-335.
11. Bergh van den ACM, Hoving MA, Links TP, et al. Radiation optic neuropathy after external beam radiation therapy for acromegaly. Short communication. Radiother Oncol 12. Béclère MA. Radiotherapie, techniques, résultats, indications et contre-indications de la roentgenthérapie des tumeurs hypophysiares. Rev Neurol 1922;808-817.
13. Bloom B, Kramer S. Conventional Radiation Therapy in the Management of Acromegaly. In: McL.Black P.et al., editors. Secretory Tumors of the Pituitary Gland (progress in endocrine research and therapy), 1st ed. New York: Raven Press, 1984;179-190.
14. Borruat F-X, Schatz NJ, Glaser JS. Neuropathie optique retrobulbaire post-actinique. Klin 15. Borruat F-X, Schatz NJ, Glaser JS, Feun LG, Matos L. Visual recovery from radiation-induced optic neuropathy. J Clinical Neuro-opthalmology 1993;13:98-101.
16. Bringer J, Klawatsch D, Jaffiol C, Orsetti A, Robin M, Mirouze J. Comparaison de diverses therapeutiques de l'acromegalie tumorale. Annales d' endocrinologie 1983;44:107-114.
Radiation optic neuropathy after external beam radiation therapy for acromegaly 17. Chang CH. Radiotherapy of secretory and nonsecretory pituitary adenomas. In: Chang CH, Honaspian EM, editors. Tumours of the central nervous system: modern radiotherapy in multidisciplinary management., New York: Mason; 1982. p.201-213.
18. Ciccarelli E, Valetto MR, Vasario E, Avataneo T, Grottoli S, Camanni F. Hormonal and radiological effects of megavoltage radiotherapy in patients with growth hormone- secreting pituitary adenoma. J Endocrinol Invest 1993;16:565-572.
19. Clarke SD, Woo SY, Butler EB, et al. Treatment of secretory pituitary adenoma with radiation therapy. Radiology 1993;188:759-763.
20. Colby MY, Kearns TP. Radiation therapy of pituitary adenomas with associated visual impairment. Staff meetings of the Mayo Clinic 1962;37:15-24.
21. Cozzi R, Barausse M, Asnaghi D, Dallabonzana D, Lodrini S and Attanasio R. Failure of radiotherapy in acromegaly. Eur J Endocrinol 2001;145:717-726.
22. Davis DH, Laws ER, Ilstrup DM, et al. Results of surgical treatment for growth hormone- secreting pituitary adenomas. J Neurosurg 1993;79:70-75.
23. Dowsett RJ, Fowble B, Sergott RC, et al. Results of radiotherapy in the treatment of acromegaly: lack of ophthalmologic complications. Int J Radiat Oncol Biol Phys 24. Eastman RC, Gorden P, Roth J. Conventional supervoltage irradiation is an effective treatment for acromegaly. J Clin Endocrinol Metab 1978;48:931-940.
25. Eastman RC, Gordon P, Glatstein E, Roth J. Radiation therapy of acromegaly. Endocrinol Metab Clin North Am 1992;21:693-712.
26. Effenterre vR, Boch A-L. Radionécrose du chiasma, étude clinique et radiologique. A propos de trois cas. Neurochirurgie 1993;39:75-84.
27. Emmanuel IG. Symposium on Pituitary tumours (3) historical aspects of radiotherapy, present treatment technique and results. Clin Radiol 1966;17:154-160.
28. Epaminonda P, Porretti S, Vincenzo C, Beck-Peccoz P, Faglia G, Arosia, M. Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly. Clin Endocrinol 2001;55:183-189.
29. Feek CM, McLelland J, Seth J, et al. How effective is external pituitary irradiation for growth hormone-secreting pituitary tumours? Clin Endocrinol 1984;20:401-408.
30. Forrest APM, Peebles Brown DA, Morris SR, Illingworth CFW. Pituitary radon implant for advanced cancer. Lancet 1956;270:399-401.
31. Giovanelli MA, Gaini SM, Tomei G, et al. Transsphenoidal microsurgical treatment of acromegaly. In: Lamberts SWJ, Tilders FJH, van der Veen EA, Assies J, editors. Trends in diagnosis and treatment of pituitary adenomas., Amsterdam: Free University Press; 1984. 32. Goffman TE, Dewan R, Arakaki R, Gorden P, Oldfield EH, Glatstein E. Persistent or recurrent acromegaly. Cancer 1992;69:271-275.
33. Gorden P, Glatstein E, Oldfield EH, et al. Conventional supervoltage radiation in the treatment of acromegaly. In: Robbins RJMS, editor. Acromegaly.A century of scientific and clinical progress., New York: Kluwer/Plenum Publishers;1987. p. 211.
34. Gordon DA, Hill FM and Ezrin C. Acromegaly: A Review of 100 cases. Can Med Assoc J 35. Gramegna, A. Un cas d'acromégalie traité par la radiothérapie. Rev Neurol 1909;17:15-17.
36. Grattan-Smith PJ, Morris JG, Langlands AO. Delayed radiation necrosis of the central nervous system in patients irradiated for pituitary tumours. J Neurol Neurosurg Psychiatry 37. Gutt B, Hatzack C, Morrison K, Pollinger Band Schopohl J. Conventional pituitary irradiation is effective in normalising plasma IGF-I in patients with acromegaly. Eur J Endocrinol 38. Guy J, Mancuso A, Beck R, et al. Radiation-induced optic neuropathy: a magnetic resonance imaging study. J Neurosurg 1991;74:426-432.
39. Hammer HM. Optic Chiasmal Radionecrosis. Trans ophthal Soc U K 1983;103:208-211.
40. Hardy J, Somma M, Vezina JL. Treatment of acromegaly: radiation or surgery? In: Morley JP, editor. Current controversies in neurosurgery., New York: W.B.Saunders; 1976. p.377.
41. Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976;120:167-171.
42. Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary 1999;2:29-41.
43. Hughes MN, Llamas KJ, Yelland ME, Obst D, Tripcony LB. Pituitary adenomas: long-term results for radiotherapy alone and post-operative radiotherapy. Int Radiat Oncol Biol Phys 44. Hunter WM, Gillingham FJ, Harris P, et al. Serial assays of plasma growth hormone in treated and untreated acromegaly. J Endocrinol 1974;63:21-34.
45. Jenkins JS, Ash S, Bloom HJG. Endocrine function after external pituitary irradiation in patients with secreting and nonsecreting pituitary tumours. Q J Med, new series 1972; 46. Jiang GL, Tucker SL, Guttenberger R, et al. Radiation-induced injury to the visual pathway. Radiother Oncol 1994;30:17-25.
47. Kanis JA, Gillingham FJ, Harris P, et al. Clinical and laboratory study of acromegaly: assessment before and one year after treatment. Q J Med, new series 1974;XLIII:409-431.
48. Klijn JGM, Lamberts SWJ, Woerkom van-Eijkenboom WMH, et al. Long term follow-up after external pituitary irradiation of pituitary adenomas. In: Lamberts SWJ, Tilders FJH, van der Veen EA, Assies J, editors. Trends in diagnosis and treatment of pituitary adenomas., Amsterdam: Free University Press; 1984:359-372.
49. Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology 1985;92:1118-1126.
50. Kozak GP, Vagnucci AI, Lauler DP, Thorn GW. Acromegaly pre- and postpituitary irradiation. Radiation optic neuropathy after external beam radiation therapy for acromegaly 51. Kramer S. Indications for, and results of, treatment of pituitary tumors by external radiation. In: Kohler PO, Ross GT, editors. Diagnosis and treatment of pituitary tumors, New York: American Elsevier Publishing Co; 1973. p.217-230.
52. Kundra SN, Sharma BS, Banerjee AK, Ayyagari S, Dhir SP, Kak VK. Damage to the anterior visual pathway and brain parenchyma following external pituitary irradiation. Indian J 53. Lam KSL, Wang C, Choi P, Ma JTC, Yeung RTT. Long-term effects of megavoltage radiotherapy. Aust NZ J Med 1989;19:202-206.
54. Lamberg B-A, Kivikangas V, Vartiainen J, Raitta C, Pelkonen R. Conventional pituitary irradiation in acromegaly. Acta Endocrinol 1976;82:267-281.
55. Landolt AM. Hazards of radiotherapy in patients with pituitary adenomas. In: Derome PJ, Jedyak CP, Peillon F, editors. Pituitary Adenomas. Paris: Asclepios Publishers; 1980. p.227-231.
56. Lawrence AM, Pinsky SM, Goldfine ID. Conventional radiation therapy in acromegaly. Arch Intern Med 1971;128:369-377.
57. Littley MD, Shalet SM, Swindell R, Beardwell CG, Sutton ML. Low-dose pituitary irradiation for acromegaly. Clin Endocrinol 1990;32:261-270.
58. Lüdecke DK, Lutz BS, Niedworok G. The choice of treatment after incomplete adenomectomy in acromegaly: proton- versus high voltage radiation. Acta Neurochir (Wien) 59. Macleod AF, Clarke DG, Pambakian H, Lowy C, Sonksen PH, Collins CD. Treatment of acromegaly by external irradiation. Clin Endocrinol 1989;30:303-314.
60. McCollough WM, Marcus RB, Rhoton AL, Ballinger WE, Million RR. Long-term follow-up of radiotherapy for pituitary adenoma: the absence of late recurrence after >4500cGy. Int J Radiat Oncol Biol Phys 1991;21:607-614.
61. Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 1998;83:2646-4652.
62. Millar JL, Spry NA, Lamb DS, Delahunt J. Blindness in patients after external beam irradiation for pituitary adenomas: two cases occurring after small daily fractional doses. Clin Oncol 1991;3:291-294.
63. Movsas B, Movsas TZ, Steinberg SM, Okunieff P. Long-term visual changes following pituitary irradiation. Int J Radiat Oncol Biol Phys 1995;33:599-605.
64. O'Halloran DJ, Shalet SM. Acromegaly: unravelling a complex disease. Growth Regul 65. Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994;30:755-764.
66. Pistenma DA, Goffinet DR, Bagshaw MA, Hanbery JW, Eltringham JR. Treatment of acromegaly with megavoltage radiation therapy. Int J Radiat Oncol Biol Phys 1976;1:885-893.
67. Powell JS, Wardlaw SL, Post KD, Freda PU. Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 68. Rivoal O, Brézin AP, Feldman-Billard S, Luton J-P. Goldmann perimetry in acromegaly. 69. Roden D, Bosley TM, Fowble B, et al. Delayed radiation injury to the retrobulbar optic nerves and chiasm. Ophthalmology 1990;97:346-351.
70. Ross DA, Wilson CB. Results of transsphenoidal microsurgery for growth hormone- secreting pituitary adenoma in a series of 214 patients. J Neurosurg 1988;68:854-867.
71. Salinger DJ, Brady LW, Miyamoto CT. Radiation therapy in the treatment of pituitary adenomas. Am J Clin Oncol 1992;15:467-473.
72. Schatz NJ, Lichtenstein S, Corbett JJ. Delayed radiation necrosis of the optic nerves and chiasm. In: Glaser JS, Smith JL, editors. Neuro Ophthalmology Symposium of the University of Miami and the Bascom Palmer Eye Institute, 8th ed. St. Louis: CV Mosby; 1975. p.131-139.
73. Sheline GE, Goldberg MB, Feldman R. Pituitary irradiation for acromegaly. Radiology 74. Shih T-Y, Wei C-P, Lui C-C, Leung W. Magnetic resonance imaging of radiation necrosis after radiotherapy for acromegaly: report of a case. J Formos Med Assoc 1994;93:78-80.
75. Speirs CJ, Reed PI, Morrison R, Joplin GF. The effectiveness of external beam radiotherapy for acromegaly is not affected by previous pituitary ablative treatments. Acta Endocrinol 76. Thalassinos NC, Tsagarakis S, Ioannides G, Tzavara I, Papavasilou C. Megavoltage pituitary irradiation lowers but seldom leads to safe GH levels in acromegaly: a long term follow-up study. Eur J Endocrinol 1998;138:160-163.
77. Trampe af E, Lundell G, Lax I, Werner S. External irradiation of growth hormone producing pituitary adenomas: prolactin as marker of hypothalamic and pituitary effects. Int J Radiat Oncol Biol Phys 1990;20:655-660.
78. Tran LM, Blount L, Horton D, Sadeghi A, Parker RG. Radiation therapy of pituitary tumors: results in 95 cases. Am J Clin Oncol 1991;14:25-29.
79. Tsang FW, Brierley JD, Panzarella T, Gospodarowicz MK, Sutcliffe SB, Simpson WJ. Role of radiation therapy in clinically hormonally-active pituitary adenomas. Radiother Oncol 80. Wambersie, A. ICRU report 62; prescribing, recording and reporting photon beam therapy (Supplement to ICRU 50); 1999. 81. Wass JAH, Plowman PN, Jones AE. The treatment of acromegaly by external pituitary irradiation and drugs. In: Lüdecke DKTG, editor. Growth hormone growth factors, and acromegaly. New York: Raven Press; 1987. p.199.
Radiation optic neuropathy after external beam radiation therapy for acromegaly 82. Werder vK, Eversmann T, Fahlbusch Real. Endocrine-active pituitary adenomas: long- term results of medical and surgical treatment. In: Camanni F, Müller EE, editors. Pituitary hyperfunction: physiopathology and clinical aspects. New York: Raven Press; 1984.p.385-406.
83. Werner S, Trampe E, Palacios P, Lax I, Hall K. Growth hormone producing pituitary adenomas with concomitant hypersecretion of prolactin are particularly sensitive to photon irradiation. Int J Radiat Oncol Biol Phys 1985;11:1713-1720.
84. Zaugg M, Adaman O, Pescia R, Landolt AM. External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 40-50 Gy. Int J Radiat Oncol Biol Phys

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