Pituitary Radiotherapy for Cushings Disease

Background: The treatment of choice for Cushing’s disease is pituitary surgery. Second-line treatments include repeat pituitary surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. The most used modalities to irradiate patients with Cushing’s disease include fractionated radiotherapy and single-dose Gamma Knife. We aim to review the efficacy and safety of radiotherapy in patients with persistent or recurring Cushing’s disease. Results: Remission of Cushing’s disease after radiotherapy ranges from 42 to 83%. There seems to be no clear difference according to the technique of radiation used. Most patients experience remission of disease within 3 years from treatment, with only few cases reaching normal cortisol secretion after a longer follow-up. Control of tumor growth varies from 93 to 100%. Severe side effects of radiotherapy, such as optic neuropathy and radionecrosis, are uncommon. New-onset hypopituitarism is the most frequent side effect of radiation, occurring in 30–50% of patients treated by fractionated radiotherapy while it has been reported in 11–22% of patients after Gamma Knife. Conclusion: Radiotherapy is an effective second-line treatment in patients with Cushing’s disease not cured by surgery. Consideration of the advantages and disadvantages of Published online: September 10, 2010 Marco Losa Department of Neurosurgery, Istituto Scientifico San Raffaele Via Olgettina, 60 IT–20132 Milano (Italy) Tel. +39 02 264 32396, Fax +39 02 264 37302, E-Mail losa.marco @ hsr.it © 2010 S. Karger AG, Basel 0028–3835/10/0925–0107$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 2/ 20 17 7 :1 2: 39 P M Losa/Picozzi/Redaelli/Laurenzi/Mortini Neuroendocrinology 2010;92(suppl 1):107–110 108 single high dose of radiation is biologically more effective than the same dose delivered in fractions. Thus, a single dose of 20 Gy is biologically equivalent to a fractionated dose of 50 to 110 Gy [5] . However, a single high dose of radiation is also more toxic to normal tissue, particularly to the optic pathway. Therefore, only patients with small tumors that are not in contact with the optic nerves or chiasma are suitable for Gamma Knife treatment. By contrast, conventional radiotherapy can be delivered even to large tumors because fractionation of the total dose lowers the toxicity of radiation to the normal tissue. Results of Radiotherapy in Cushing’s Disease Efficacy The most widely accepted criterion to define remission of hypercortisolism after radiotherapy is normalization of the 24-hour urinary free cortisol concentration. Additional criteria, such as normal basal ACTH and/or cortisol levels and suppression of cortisol secretion after the low-dose dexamethasone test, are variably used. It must be stressed that normalization of hormone secretion after radiation is time-dependent and an adequate follow-up is necessary before evaluating the outcome. The results of radiotherapy in recent series [6–15] plus our unpublished data are summarized in table 1 . Most patients included in these series had previously undergone unsuccessful pituitary surgery or had recurrence of disease, confirming that radiotherapy is almost exclusively used as a second rather than primary choice therapy in Cushing’s disease. The remission rates of hypercortisolism are reasonably homogeneous among the different studies, ranging from 42 to 83%. There seems to be no clear difference according to the type of radiation used. Figure 1 shows our unpublished experience in 49 patients treated by Gamma Knife for Cushing’s disease. The estimated rate of remission at 5 years is 65.9% (95% CI, 48.9–82.9%), but visual inspection of figure 1 shows that most patients experience remission of disease within 3 years from treatment, with only few cases reaching normal cortisol secretion after a longer follow-up. A similar time-course of remission after raTable 1. R esults of selected series of radiotherapy in Cushing’s disease First author, year Type of radiotherapy Number of patients Mean follow-up, years Dose Gy Remission rate, % Murayama, 1992 Conventional 20 12 54 55 Sonino, 1996 Conventional 23 7 50 65 Tsang, 1996 Conventional 29 7 50 56 Estrada, 1997 Conventional 30 3.5 50 83 Nagesser, 2000 Conventional 86 18 50 64 Hoybye, 2001 Gamma Knife 18 17 NR 83 Castinetti, 2007 Gamma Knife 40 5 29.5 42 Jagannathan, 2007 Gamma Knife 90 4 23 54 Minniti, 2007 Conventional 40 9 45 78 Petit, 2008 Proton stereotactic 33 5 20 52 Our series, 2009 Gamma Knife 49 4 25 53