Faculty Bibliography

Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as >/=15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

Object Pituitary adenomas are fairly common intracranial neoplasms, and nonfunctioning ones constitute a large subgroup of these adenomas. Complete resection is often difficult and may pose undue risk to neurological and endocrine function. Stereotactic radiosurgery has come to play an important role in the management of patients with nonfunctioning pituitary adenomas. This study examines the outcomes after radiosurgery in a large, multicenter patient population. Methods Under the auspices of the North American Gamma Knife Consortium, 9 Gamma Knife surgery (GKS) centers retrospectively combined their outcome data obtained in 512 patients with nonfunctional pituitary adenomas. Prior resection was performed in 479 patients (93.6%) and prior fractionated external-beam radiotherapy was performed in 34 patients (6.6%). The median age at the time of radiosurgery was 53 years. Fifty-eight percent of patients had some degree of hypopituitarism prior to radiosurgery. Patients received a median dose of 16 Gy to the tumor margin. The median follow-up was 36 months (range 1-223 months). Results Overall tumor control was achieved in 93.4% of patients at last follow-up; actuarial tumor control was 98%, 95%, 91%, and 85% at 3, 5, 8, and 10 years postradiosurgery, respectively. Smaller adenoma volume (OR 1.08 [95% CI 1.02-1.13], p = 0.006) and absence of suprasellar extension (OR 2.10 [95% CI 0.96-4.61], p = 0.064) were associated with progression-free tumor survival. New or worsened hypopituitarism after radiosurgery was noted in 21% of patients, with thyroid and cortisol deficiencies reported as the most common postradiosurgery endocrinopathies. History of prior radiation therapy and greater tumor margin doses were predictive of new or worsening endocrinopathy after GKS. New or progressive cranial nerve deficits were noted in 9% of patients; 6.6% had worsening or new onset optic nerve dysfunction. In multivariate analysis, decreasing age, increasing volume, history of prior radiation therapy, and history of prior pituitary axis deficiency were predictive of new or worsening cranial nerve dysfunction. No patient died as a result of tumor progression. Favorable outcomes of tumor control and neurological preservation were reflected in a 4-point radiosurgical pituitary score. Conclusions Gamma Knife surgery is an effective and well-tolerated management strategy for the vast majority of patients with recurrent or residual nonfunctional pituitary adenomas. Delayed hypopituitarism is the most common complication after radiosurgery. Neurological and cranial nerve function were preserved in more than 90% of patients after radiosurgery. The radiosurgical pituitary score may predict outcomes for future patients who undergo GKS for a nonfunctioning adenoma.

Brain metastases in malignant melanoma carries a poor prognosis with minimal response to any therapy. The purpose of this pilot analysis was to find the effectiveness of vemurafenib, an oral BRAF inhibitor, and radiation therapy in V600 mutated melanoma with brain metastases. BRAF mutation status of the melanoma patients was determined by real-time PCR assay. Retrospective analysis was performed on twelve patients who had the mutation and were treated with either stereotactic radiosurgery or whole brain radiation therapy prior to or along with vemurafenib at a dose of 960 mg orally twice a day. Clinical and radiological responses, development of new brain metastases, overall survival and toxicity were assessed. Improvement in neurological symptoms was seen in 7/11 (64 %) following therapy. Radiographic responses were noted in 36/48 (75 %) of index lesions with 23 (48 %) complete responses and 13 (27 %) partial responses. Six month local control, freedom from new brain metastases and overall survival were 75, 57 and 92 %. Four patients had intra-tumoral bleed prior to therapy and two patients developed steroid dependence. One patient experienced radiation necrosis. This retrospective study suggests that melanoma patients with brain metastases harboring BRAF mutation appear to be a distinct sub-group with a favorable response to vemurafenib and radiation therapy and acceptable morbidity.

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.

Background: Invasion is a dominant escape mechanism following angiogenic blockade in glioblastomas (GBM). Lithium has shown anti-invasive activity in glioma cells by inhibiting Glycogen Synthetase Kinase -3. This phase II study evaluated the safety and efficacy of using lithium and bevacizumab (BEV) in newly diagnosed GBM. Methods: From 2010 through 2012, 20 GBM patients with residual disease after surgery were treated with involved-field radiation therapy to 5940 cGy and concomitant temozolomide (TMZ) (75 mg/m2 daily for 42 days) along with BEV (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by six 28-day cycles of TMZ (150 mg/m2 on days 1-7, BEV (10 mg/kg) on days 8 and 22, and lithium 300 mg BID. Lithium was increased every 7 days up to 600 mg BID with a serum lithium goal level of 0.8 to 1.2 mEq/L. Results: The median follow-up was 9.9 months (range 1.9-24.5). Fourteen patients (70.0%) received at least one dose of lithium and three patients completed the entire course of therapy. The median number of BEV infusion was 9 (range 2-19). Five patients discontinued trial due to skin sensitivity (n = 2), pulmonary embolism (n = 1), infection (n = 1), and hematological toxicity (n=1). Two patients experienced dose limiting lithium toxicity which included drowsiness (n = 1) and tremor (n = 1). No patients experienced grade 3/4 intra-cranial hemorrhage. The median progression free survival (PFS) was 9.3 months. The 12-month PFS and OS were 31.9% and 59.3% respectively. For the 14 patients who received lithium, the 12-month PFS and OS were 42.9% and 69.2% respectively. Conclusions: The strategy of targeting angiogenesis and invasion simultaneously in newly diagnosed GBM is effective and feasible

Background Whole brain radiation therapy (WBRT) reduces local recurrence in patients after surgical resection of brain metastases without improving overall survival. Involved field radiation therapy (IFRT) has been used at our center to avoid delayed neurotoxicity associated with WBRT in well-selected patients with surgically resected single brain metastases. The purpose of this study was to evaluate the long-term outcomes of these patients. Methods Thirty-three consecutive patients with single brain metastases from a known primary tumor were treated with gross total resection followed by IFRT between 2006 and 2011. The postoperative surgical bed was treated to 40.05 Gy in 15 fractions of 2.67 Gy with conformal radiation therapy. Patients received serial MRIs and neurological exams in follow-up. Surgery, WBRT, or stereotactic radiosurgery was performed as salvage treatment when necessary. Results The median follow-up was 16 months (range: 2-65 months). Local control, distant brain recurrence-free survival, and overall survival at 12 and 24 months were 90.3% and 85.8%, 60.7% and 51.4%, and 65.6% and 61.5%, respectively. Overall, 5 (15%) patients developed recurrence at the resection cavity, and 13 (39%) patients experienced recurrence at a new intracranial site. Two patients received WBRT, 8 stereotactic radiosurgery, 2 surgery, and 2 both chemotherapy and IFRT as salvage. Four patients died from CNS disease progression. Conclusion For patients with newly diagnosed single brain metastases treated with surgical resection, postoperative IFRT to the resection cavity achieves reasonable rates of local control and is an excellent alternative to WBRT.