A randomized trial of bevacizumab for newly diagnosed glioblastoma.

BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known. METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab. RESULTS: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group. CONCLUSIONS: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.)

Role of Gamma Knife Surgery in the Management of Pineal Region Tumors

OBJECT: Increasingly, radiosurgery is used to treat pineal region tumors, either as a primary treatment or as an adjunct to conventional radiation therapy. The authors report their experience with Gamma Knife surgery (GKS) for the treatment of pineal region tumors. METHODS: The authors retrospectively reviewed the charts of all patients undergoing GKS at their institution between 1997 and 2005. Seventeen patients underwent GKS for nonmetastatic tumors of the pineal region. All patients were treated using Leksell Gamma Plan treatment planning software (versions 4.12::5.34). The mean treatment volume was 7.42 cm(3) (range 1.2-32.5 cm(3)). Prescribed doses ranged from 12 to 18 Gy. All doses were prescribed to the 50% isodose line. Independent neuroradiologists reviewed all follow-up imaging studies for evidence of progression of disease. RESULTS: One patient (Case 10) died 6 days after GKS. Mean clinical and imaging follow-up in the remaining 16 cases was 31 months. Local control was established during a mean neuroimaging follow-up period of 31 months (range 1-95) in 16 patients (100%). In 2 of these 16 patients (one with an anaplastic astrocytoma, the other with a primitive neuroectodermal tumor), leptomeningeal and spinal spread of tumor developed despite control of the pineal lesions. There were no new neurological deficits attributable to GKS. Three patients died (including the one who died 6 days after GKS) during the follow-up period. Conclusions Excellent control of pineal region brain tumors can be obtained with GKS when it is used in conjunction with surgery, conventional radiation therapy, or both. Patient survival and quality of life can be optimized through the use of multimodal treatment, including surgery, conventional radiation therapy and/or radiosurgery, and chemotherapy, when applicable

Prospective Trial of Gross-Total Resection With Gliadel Wafers Followed by Early Postoperative Gamma Knife Radiosurgery and Conformal Fractionated Radiotherapy as the Initial Treatment for Patients With Radiographically Suspected Newly Diagnosed Glioblastoma Multiforme.

OBJECT: The purpose of this study was to determine whether increased local control and improved survival can be achieved in patients with glioblastoma multiformes (GBMs) who undergo aggressive resection, Gliadel wafer implantation, Gamma Knife radiosurgery (GKS), and fractionated radiotherapy (RT) as the initial treatment. METHODS: Thirty patients with radiographically suspected GBMs were screened for enrollment in a Phase I/II prospective clinical trial. Twenty-seven patients were eligible and underwent gross-total resection and Gliadel wafer implantation. Gamma Knife radiosurgery (12 Gy at 50%) was administered to the resection cavity within 2 weeks of surgery. Patients then received standard fractionated RT (total dose 60 Gy over 6 weeks). Temozolomide was prescribed for patients at the time of recurrence. Surveillance MR imaging, neurological examination, and quality-of-life evaluations were performed at 2-month intervals. To estimate the potential effects on the DNA repair mechanism, tumor tissue was analyzed with methylation-specific polymerase chain reaction analysis and immunohistochemical assays for MGMT gene promoter methylation and protein expression. RESULTS: The median survival for all patients was 50 weeks and the 2-year survival rate was 22%. When stratified into standard and high-risk patient groups, the median survivals were 76 and 33 weeks, respectively. Two patients remain alive at the time of this report with no clinical or radiographic evidence of disease at \u3e 189 and 239 weeks posttreatment and excellent performance status. Local tumor control was achieved in 53% of patients, and local failure occurred in 47%. No acute early toxicity was noted; however, delayed symptomatic radionecrosis occurred in 47% of patients, which required repeated operations 9-24 months after the initial treatment. Delayed hydrocephalus requiring ventriculoperitoneal shunt placement occurred in 47% of patients. There was a significant difference in survival between patients whose tumors contained the methylated and unmethylated MGMT promoter, 103 versus 45 weeks, respectively (p = 0.0009, log-rank test). CONCLUSIONS: The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone. Delayed focal radionecrosis was increased to 47% in this series and was managed with steroids and repeated resection. Aggressive local tumor control with these multimodal therapies should be approached judiciously for a select group of high performance patients and the probability of developing symptomatic radionecrosis requiring surgery should be anticipated and fully disclosed to patients who undergo this treatment

Long-term radiosurgical control of subtotally resected adult pineocytomas.

OBJECT: The optimal management of pineocytomas remains controversial. Although the value of complete microsurgical removal is well accepted, gross-total resection is not always feasible. Data regarding the role of postoperative adjuvant stereotactic radiosurgery (SRS) for residual disease is limited and conflicting. Here, the authors review the largest single-institution experience with multimodal pineocytoma management in an effort to quantify the utility of adjuvant radiosurgical treatment of residual disease. METHODS: The medical records and radiographic studies for all patients with histologically confirmed pineocytoma at the Barrow Neurological Institute between 1999 and 2011 were retrospectively reviewed. Clinical and radiographic data, including the volumetric extent of resection, were collected retrospectively, and Kaplan-Meier analysis was used to identify progression-free survival. RESULTS: Fourteen adults with newly diagnosed pineocytomas were surgically treated in the period from 1999 to 2011. The median clinical and radiographic follow-ups were 44 and 53 months, respectively. Twelve patients (86%) underwent microsurgical removal and 2 (14%) underwent endoscopic biopsy. Five patients (36%) had complete resections and 9 (64%) demonstrated residual disease. Three patients (21%) presented with radiographic recurrence at a median interval of 43 months after initial treatment (range 13-83 months). At the time of recurrence, the median preoperative tumor volume was 2.6 cm(3). Adjuvant SRS was used to treat 3 subtotally resected tumors (33%) following initial presentation and 2 (66%) at the time of recurrence. Among patients with subtotally resected tumors, progression-free survival was significantly longer (p \u3c 0.05) for those who did as compared with those who did not undergo adjuvant radiosurgery. To date, no patient who underwent adjuvant radiosurgery has demonstrated radiographic or clinical evidence of disease progression. CONCLUSIONS: Microsurgical removal remains the definitive treatment for pineocytomas, yet residual disease can be effectively controlled using adjuvant SRS

Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results.

OBJECT: Resection and whole-brain radiation therapy (WBRT) have classically been the standard treatment for a single metastasis to the brain. The objective of this study was to evaluate the use of Gamma Knife surgery (GKS) as an alternative to WBRT in patients who had undergone resection and to evaluate patient survival and local tumor control. METHODS: The authors retrospectively reviewed the charts of 150 patients treated with a combination of stereotactic radiosurgery and resection of a cranial metastasis at their institution between April 1997 and September 2009. Patients who had multiple lesions or underwent both WBRT and GKS were excluded, as were patients for whom survival data beyond the initial treatment were not available. Clinical and imaging follow-up was assessed using notes from clinic visits and MR imaging studies when available. Follow-up data beyond the initial treatment and survival data were available for 68 patients. RESULTS: The study included 37 women (54.4%) and 31 men (45.6%) (mean age 60 years, range 28-89 years). In 45 patients (66.2%) there was systemic control of the primary tumor when the cranial metastasis was identified. The median duration between resection and radiosurgery was 15.5 days. The median volume of the treated cavity was 10.35 cm(3) (range 0.9-45.4 cm(3)), and the median dose to the cavity margin was 15 Gy (range 14-30 Gy), delivered to the 50% isodose line (range 50%-76% isodose line). The patients\u27 median preradiosurgery Karnofsky Performance Scale (KPS) score was 90 (range 40-100). During the follow-up period we identified 27 patients (39.7%) with recurrent tumor located either local or distant to the site of treatment. The median time from primary treatment of metastasis to recurrence was 10.6 months. The patients\u27 median length of survival (interval between first treatment of cerebral metastasis and last follow-up) was 13.2 months. For the patient who died during follow-up, the median time from diagnosis of cerebral metastasis to death was 11.5 months. The median duration of survival from diagnosis of the primary cancer to last follow-up was 30.2 months. Patients with a pretreatment KPS score ≥ 90 had a median survival time of 23.2 months, and patients with a pretreatment KPS score \u3c 90 had a median survival time of 10 months (p \u3c 0.008). Systemic control of disease at the time of metastasis was not predictive of increased survival duration, although it did tend to improve survival. CONCLUSIONS: Although the debate about the ideal form of radiation treatment after resection continues, these findings indicate that GKS combined with surgery offers comparable survival duration and local tumor control to WBRT for patients with a diagnosis of a single metastasis

The impact of adjuvant stereotactic radiosurgery on atypical meningioma recurrence following aggressive microsurgical resection.

OBJECT: Patients with atypical meningioma often undergo gross-total resection (GTR) at initial presentation, but the role of adjuvant radiation therapy remains unclear. The increasing prevalence of stereotactic radiosurgery (SRS) in the modern neurosurgical era has led to the use of routine postoperative radiation therapy in the absence of evidence-based guidelines. This study sought to define the long-term recurrence rate of atypical meningiomas and identify the value of SRS in affecting outcome. METHODS: The authors identified 228 patients with microsurgically treated atypical meningiomas who underwent a total of 257 resections at the Barrow Neurological Institute over the last 20 years. Atypical meningiomas were diagnosed according to current WHO criteria. Clinical and radiographic data were collected retrospectively. RESULTS: Median clinical and radiographic follow-up was 52 months. Gross-total resection, defined as Simpson Grade I or II resection, was achieved in 149 patients (58%). The median proliferative index was 6.9% (range 0.4%-20.6%). Overall 51 patients (22%) demonstrated tumor recurrence at a median of 20.2 months postoperatively. Seventy-one patients (31%) underwent adjuvant radiation postoperatively, with 32 patients (14%) receiving adjuvant SRS and 39 patients (17%) receiving adjuvant intensity modulated radiation therapy (IMRT). The recurrence rate for patients receiving SRS was 25% (8/32) and for IMRT was 18% (7/39), which was not significantly different from the overall group. Gross-total resection was predictive of progression-free survival (PFS; relative risk 0.255, p \u3c 0.0001), but postoperative SRS was not associated with improved PFS in all patients or in only those with subtotal resections. CONCLUSIONS: Atypical meningiomas are increasingly irradiated, even after complete or near-complete microsurgical resection. This analysis of the largest patient series to date suggests that close observation remains reasonable in the setting of aggressive microsurgical resection. Although postoperative adjuvant SRS did not significantly affect tumor recurrence rates in this experience, a larger cohort study with longer follow-up may reveal a therapeutic benefit in the future