Our next discussant is a recipient of the American Brain Tumor Association Young Investigator Award. Dr. Mehta is presenting Repeat Stereotactic Radiosurgery for Cushing's Disease, Outcomes of an International Multi-Center Study. All right, so thank you for having me out to speak, and thank you to the tumor section for the award. I'll be presenting the results of the outcomes of our International Multi-Center Study on Repeat Stereotactic Radiosurgery for Cushing's Disease. This is the only disclosure we have to report. So as you all know, Cushing's Disease is due to ACTH production from pituitary adenomas that then acts on the adrenal glands, causing cortisol hypersecretion. This disease has an incidence or prevalence of 1 in 20,000 patients and affects women more than men. The symptoms caused by this disease lead to an increased mortality in this population. The cornerstone of Cushing's Disease management, of course, is transfronatal surgery. And this can be very effective in affecting cures in 60% to 90% of patients with the disease. However, due to the small size of these lesions and the propensity for cavernous sinus invasion, sometimes alternate therapies are required, such as radiation therapy, medical therapy, and bilateral adrenalectomy. We recently reviewed the history of management for Cushing's Disease. And Harvey Cushing himself had treated a couple of patients of his initial series with external radiation therapy and reported some success. The first pituitary surgery for Cushing's Disease was not performed until 1933 by one of his trainees, Alfred Pattison. And in these surgeries in two patients, he implanted radioactive seeds in the cell of these patients and reported a clinical improvement in both cases. Modern radiotherapy took a while to gain popularity for Cushing's Disease. However, after the publication in the mid-'90s by Estrada and colleagues in the New England Journal, they showed that in 30 patients who received conventional radiotherapy, 25 had remission. And the median time to remission in this cohort was 18 months. They did not report much follow-up after the remission, and they reported hypopituitarism in over half the patients. More recently, we reported results of a multicenter study on the use of stereotactic radiosurgery for Cushing's Disease in a cohort of 278 patients. We found that the durable cumulative remission in this group was 64% at 10 years. However, 25% of patients had hypopituitarism after treatment, and an additional 3% had cranial neuropathy. These findings led to some reappraisal of the use of radiosurgery specifically for Cushing's Disease, which was highlighted in this Nature Reviews paper recently. There have been many centers that have not previously used radiosurgery as a second-line option, but this hopefully may change. So what do we do when radiosurgery fails? So different options we have. One is medical therapy. Medical therapy requires lifelong therapy and does not work for all patients. Bilateral adrenalectomy can be very effective, but the procedure itself is morbid and can lead to an increased risk of developing Nelson syndrome. So one option that has not been described previously is the use of repeat radiosurgery. And the outcomes of this treatment as a potential salvage therapy are unknown to date. So we sought out to better define the outcomes of repeat radiosurgery using a multicenter international cohort and specifically focus on the endocrine remission rates, but also analyze the rates of adverse radiation effects because this is re-irradiation. So we included patients with an endocrine diagnosis of Cushing's Disease who had prior gamma knife radiosurgery. We excluded any patients with less than six months follow-up. And gamma knife radiosurgery was used for the second treatment, but we tried to keep optic apparatus doses generally below 8 to 10 gray based on the Quantec data. And then finally, our primary outcome was normalization of urine-free cortisol off of all meds to control hypercortisolism. So a total of five sites submitted patients for analysis, and there were 36 patients who were initially included in this cohort. We excluded four due to the fact that they were treated instead for Nelson syndrome, and we excluded 12 patients who had less than six months follow-up. This left 20 patients available for analysis, and up note, the interval between the first and second treatments was a median of three years. And the margin dose in this cohort was 20 gray, which differed a little bit from our initial radiosurgery cohort, which was 25 gray. So we first looked at the initial cumulative remission rate in this cohort. And again, this is off all medications to control hypercortisolism. And this reached nearly two-thirds of the population at 10 years. The time to remission was slightly earlier in this cohort and was only six months. So among the patients who had a remission, two eventually recurred. And so this led to a durable cumulative remission at 10 years of 53%. We weren't able to perform any statistical analyses on the factors that led to remission because of the paucity of cases and just the sheer number. But when we looked at adverse radiation effects, we also had some difficulty because it was hard to differentiate the effect of the initial radiosurgery on factors such as endocrinopathy. Because some of these adverse radiation effects can occur many months or years after the initial treatment, as we heard earlier. So of the 20 patients, six patients had no endocrinopathy after the first radiosurgery. But of those six, two developed a new endocrinopathy after the second radiosurgery. Two patients among the 20 developed some form of cranial neuropathy. And one developed a permanent oculomotor nerve palsy 15 months after the second treatment. And another patient developed just a temporary visual field deficit one week after radiosurgery. But this resolved after eight weeks. So in conclusion, repeat radiosurgery can achieve durable endocrine remission in about half of patients with persistent Cushing's disease. And this is potentially a novel treatment that we can offer these patients who have very treatment-resistant disease. Repeat radiosurgery in this cohort was generally safe and well-tolerated, but it was very hard to assess what the effect was on the normal pituitary gland and new endocrinopathies. And then finally, because initial SRS can take over a year to affect remission, we highly recommend that repeat SRS should be reserved for patients who have had demonstrated hypercortisolemia for at least one year after the initial treatment. And I'd just like to thank our collaborators at these five sites for their help with this work. Thank you.

repeat stereotactic radiosurgery

Cushing's Disease

pituitary adenomas

endocrine remission

hypercortisolemia