Our next speaker is Matthew Shepard, and Dr. Matthew Shepard will be presenting a late breaking abstract on wholesaler stereotactic radiosurgery for Cushing's disease results from a multicenter international cohort study. Thank you. So, good afternoon. On behalf of all the authors listed here, I would like to thank the tumor section for giving me the opportunity to present our work examining the outcomes of wholesaler stereotactic radiosurgery for Cushing's disease. I don't have any disclosures to make. As we are aware, Cushing's disease results from the excessive secretion of ACTH, usually from a pituitary microadenoma, ultimately leading to pathologically elevated serum levels of cortisol, which not only lead to the development of the classic Cushingoid body habitus, but more importantly, the development of metabolic syndrome, cardiovascular disease, hypertension, and diabetes, which if these patients, and ultimately if these patients do not achieve remission from their Cushing's disease, can ultimately lead to early cause mortality. Surgery is the mainstay treatment for this disorder, and when a pituitary adenoma is identified at the time of surgery, durable remission rates in excess of 90% have been reported in the literature. However, in many instances, a pituitary adenoma is not identified on imaging, nor is an adenoma identified at the time of surgery, and in these patients, even though post-op remission rates between 60 and 80% have been reported with partial or total hypothesectomies, durable remission rates over the long term are much lower, and are estimated in some series to be as low as 25%. Further complicating the management of Cushing's is the fact that the recurrence rate in individuals who do develop remission can be in excess of 50% in studies that have long-term follow-up for their patients on the order of decades. Not surprisingly, as a result, many centers have began using gamma knife radiosurgery as an adjuvant treatment strategy for patients with recurrent or persistent disease, with relatively good outcomes, with remission rates following stereotactic radiosurgery being estimated to be between 50 and 80%. However, there are some issues with radiosurgical planning for patients with Cushing's disease. One is the fact that many patients with Cushing's lack an identifiable adenoma on preoperative MRI, and furthermore, invasion of the adenoma into the adjaining structures, including the cavernous sinus, dura, or even the clivus, is very common, and MRI's ability to detect this microscopic local invasion is relatively poor. So understanding where to target your stereotactic radiosurgery in the cella is not always easy. As a result, some centers have began employing wholesaler stereotactic radiosurgery to get around these issues, however, the outcomes of this approach have not been reported widely in the literature. We therefore sought to define the endocrine outcomes of this approach for patients with Cushing's disease. In order to do this, we performed a multi-center international retrospective cohort design where we identified 294 patients treated with stereotactic radiosurgery for Cushing's disease. We excluded 16 patients with less than six months of endocrine follow-up, leaving us with 278 patients. Of these, the vast majority had discrete adenoma-targeted stereotactic radiosurgery, while 68 patients either had no discernible adenoma on pre-planning MRI, or had concern for local invasion at the time of stereotactic radiosurgery. We defined remission in this series as a normalization of 24-hour urine-free cortisol off-ball pituitary suppressive medications and recurrence as an elevation of the 24-hour urine-free cortisol. This is a representative stereotactic radiosurgical dose planning for a patient receiving whole cell or stereotactic radiosurgery. In general, the plans incorporated not only the contents of the cell lobe, but also in certain cases extended up to the lateral margins of the cavernous sinus, with the dose to the optic apparatus kept below 10 gray. In our series, the median margin dose was, or average margin dose was 22.4 gray, usually prescribed to the 50 percent isodose line, and the average volume treated in our series was 2.6 cubic centimeters. Of the 68 patients receiving whole cell or stereotactic radiosurgery, the vast majority had persistent or recurrent Cushing's disease, and usually these patients had multiple prior treatment strategies in most instances with the average number of attempted adenomectomies approximately being 1.4 per patient. Many patients had prior fractionated radiation and or prior failed medical therapy. As a result of numerous surgeries and prior therapies, about one in three patients in this series already had preexisting hypopituitarism at the time of gamma knife radiosurgery. Prior to stereotactic radiosurgery, the 24-hour urine-free cortisol in this series was 333.6 micrograms per deciliter, and our follow-up was, our endocrine and radiographic follow-up was 5.3 and 4.8 years, respectively. In terms of remission, remission was achievable in 63.2 percent of patients undergoing whole cell or stereotactic radiosurgery with a medium time to remission of 12 months, with a five-year cumulative remission rate at 75 percent. When we looked at univariate analysis, looking at factors associated with remission, we found that the treatment volumes were, increased treatment volumes were associated with Cushing's disease remission in this series. And furthermore, when we stratified patients who received treatment volumes in excess of 1.6 cubic centimeters, we found that these patients also had earlier time to disease remission than their counterparts who did not. In terms of recurrence, out of the 43 patients who did develop remission, the recurrence rate was 21 percent with a median time to disease recurrence of 2.6 years, but nevertheless, the five-year recurrence-free survival rate was quite good at 86.5 percent. Decreased margin dose and decreased maximum doses were prescribed to the cellular associated with disease recurrence on univariate analysis. And when we further examined the rates of new pituitary insufficiency following stereotactic radiosurgery, we found that this occurred in approximately 22 percent of patients with a median time to new endocrinopathy development of one year. And with a vast majority of patients developing their new endocrinopathy within the first five years after treatment. The most common new endocrinopathy was development of hypothyroidism in our series. We then tried to compare the 68 patients receiving whole cellular stereotactic radiosurgery to the 210 patients who received, quote-unquote, discrete adenoma-targeted therapy. And when we did this, what we found, there was no statistical difference in the rates times to initial remission, recurrence-free survival rates over time, and the time to new hormone deficiency. To adjust for different patient characteristics and treatment variables amongst those two populations, we did propensity score matching. And so we found a cohort of 51 patients receiving whole cellular stereotactic radiosurgery versus discrete adenoma gamma knife. And these patients were matched based on age, gender, prior radiation, degree of hypothyroidism, local invasion by the adenoma, treatment volume, and margin dose. And we found that there was no statistical significance difference between those two cohorts with respect to remission rates, time to remission, recurrence rate, recurrence-free survival, or the incidence of new post-procedure endocrinopathies. As a result, our data is consistent with the notion that whole cellular stereotactic radiosurgery is effective at controlling Cushing's disease. And that the rates of endocrinopathy are not necessarily greater than that to patients receiving discrete adenoma therapy in this population. Thus, this treatment strategy should be considered when there's either no adenoma identified on neuroimaging or when there is concern for local invasion by the adenoma. Thank you very much. I'm happy to take any questions. Thank you.

Dr. Matthew Shepard

multicenter international cohort study

wholesaler stereotactic radiosurgery

Cushing's disease

long-term remission