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doi: 10.1097/01.NT.0000430850.82473.21
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NEWS FROM THE AAN ANNUAL MEETING: Should mTOR Inhibitors Replace Surgery as the First-Line Treatment of Tuberous Sclerosis-SEGA?

Robinson, Richard

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ARTICLE IN BRIEF

Investigators reported that medical treatment — everolimus, a rapamycin analog — was superior to placebo and both more effective and safer than surgery in treating patients with tuberous sclerosis with subependymal giant cell astrocytoma.

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SAN DIEGO—In less than a decade, rapamycin and related compounds have emerged as important alternatives to surgical resection of subependymal giant cell astrocytoma (SEGA) due to tuberous sclerosis complex (TSC). A recent randomized trial demonstrated that everolimus, a rapamycin analog, was superior to placebo in shrinking tumor volume. Should medical therapy now be considered as first-line treatment for SEGA, instead of surgery?

While it is inherently difficult to compare outcomes between medication and surgery, the answer appears to be a tentative but promising “yes,” according to Susanne Yoon, a second-year medical student at the University of Cincinnati College of Medicine, who discussed the results of her study comparing outcomes from the two treatments in a plenary session here at the AAN annual meeting in March.

TSC is attributed to a mutation in one of two genes: tuberous sclerosis complex 1 (TSC1), encoding hamartin; or TSC2, encoding tuberin. Both are tumor growth suppressors, and work together to inhibit a cell proliferation protein called mTOR, which stands for “mammalian target of rapamycin.” Absence of one or the other suppressor leads to the characteristic benign tumors in multiple organs, usually diagnosed in late childhood. About 10 percent of TSC patients develop SEGA along the ventricular wall, which, if left untreated, can cause obstructive hydrocephalus.

Historically, surgery has been the only option available to SEGA patients, but 20 percent of surgery patients experience recurrence, and another 20 percent experience surgery-related complications. And while successful surgery can eliminate the tumor in the brain, tumors elsewhere in the body still cause significant morbidity. “Surgery may be an answer to SEGA but it does not address any other issues that are going on in the patient,” Yoon said.

Trials led by David Franz, MD, and Darcy Krueger, MD, PhD, both of Cincinnati Children's Hospital, established that first rapamycin and then everolimus was an effective treatment for SEGA, based on the combination's ability to significantly reduce, though not eliminate, the tumors in most patients, with reduction below 50 percent of the original volume in about a third. Both drugs inhibit mTOR.

[Some commentators have expressed concerns about the price of mTOR inhibitors, such as everolimus, which can cost as much as $8,000 monthly, depending on the dose.]

“Medical management using mTOR inhibitors is a chronic therapy, however it is non-invasive and it is known to be pretty mild compared to the surgery,” said Yoon. “The goal is not to achieve complete resolution of tumor, but to control the tumor growth or achieve tumor volume reduction in order to avoid surgery.” In addition, mTOR inhibitors have been effective in controlling other comorbidities in TSC patients.

“So the next question was, which one is a better treatment option for TSC SEGA patients?” she said.

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STUDY METHODS, RESULTS

Yoon and her colleagues tried to answer this question first by settling on the meaning of success for each treatment. “In the surgically treated group, we defined complete tumor resection, without any recurrences, as a treatment success,” she explained. “In the medically managed group, we defined a more than 50 percent tumor reduction, without any indication for surgery, as a treatment success.” They then retrospectively reviewed 94 patients treated in Cincinnati Children's Hospital, and at the University of California, Los Angeles Medical Center in collaboration with neurologists and neurosurgeons there.

Twenty-three patients were treated with surgery, and 81 with mTOR inhibitors; patients treated with both were counted in both groups. Mean follow-up was nine years for surgery and three years for medical treatment, a function of the very recent availability of mTOR inhibitors.

Thirty-nine percent of surgery patients achieved a complete cure, but about half of those required more than one surgery to do so. Of those who were not cured, about two-thirds went on to mTOR treatment. About 60 percent of surgery patients experienced adverse events, with intracranial hemorrhage and hydrocephalus being the most frequent complications.

In the medically managed group, 51 percent of the patients achieved more than 50 percent reduction in their tumor, with about equal efficacy for rapamycin and everolimus. Further, they found, “the longer the patients are followed the better they respond to the treatment,” Yoon said. Adverse events occurred in 19 percent of patients, but whether these were all due to treatment was not determined.

In comparison, then, 51 percent of medically treated patients, and 39 percent of surgery patients, had successful outcomes. That difference was not statistically significant. But when the rate of successful medical treatment was compared to the 21 percent success rate after only one surgery, medical treatment was superior (p = 0.026).

Furthermore, she said, “if we expand the definition of medical management efficacy to any volume reduction, medical management was favored over surgery regardless of the number of operations,” since 92 percent of patients had at least some volume reduction with medical treatment, and 67 percent had a reduction of at least 25 percent. Medical treatment was strongly favored on safety grounds as well.

“In conclusion,” Yoon said, despite the limitations of the study, “we think medical treatment offers a better option for TSC SEGA patients, in both efficacy of the treatment and safety.”

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EXPERTS COMMENT

David Viskochil, MD, PhD, said neurosurgeons were likely to be among the most pleased by the results of the study. “At least in our institution, the neurosurgeons never want to go in to perform surgery for individuals with SEGA, though they are forced to by the symptoms.” Dr. Viskochil is professor of pediatrics and a clinical geneticist at the University of Utah in Salt Lake City.

“In symptomatic cases, we're caught in the struggle between surgical and medical management,” he said, and the safety results from Yoon's study helps the decision. “The key thing is that there are many safety issues — prolonged and multiple hospitalizations — for those individuals who underwent surgery. Certainly, a trial of rapamycin is worth considering, except in more extreme cases.”

And for patients who are asymptomatic, but known to be harboring slow-growing tumors? “Now that we have the pathways pretty well dissected, and we have the pharmaceutical firms who are generating compounds that may have fewer side effects, and if we can dose properly, is there a way that we can provide medical preventive care for those who are asymptomatic?” That option remains in the future, but might be considered, Dr. Viskochil said, as more experience is gained with mTOR inhibitors.

BEST PAPER PICK: Lisa DeAngelis, MD, chair of the AAN Science Committee, selected this paper as one of the most “important” papers from this year's AAN Annual Meeting.

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LINK UP FOR MORE INFORMATION:

•. AAN annual meeting abstract: http://bit.ly/XZMQVT.
•. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013 Jan 12;381(9861):125–132. E-pub 2012 Nov 14.
•. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363(19):1801–1811.

•. Neurology Today archive on tuberous sclerosis: http://bit.ly/11v824l.
•. Neurology archive on tuberous sclerosis: http://bit.ly/17dK6Ve.

©2013 American Academy of Neurology

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