NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Tumor treating fields and maintenance temozolomide for newly-diagnosed glioblastoma: a cost-effectiveness study.

Purpose: The EF-14 trial demonstrated that adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) significantly extends progression-free survival (PFS) and overall survival (OS) for newly-diagnosed glioblastoma (GBM) patients. This study assessed the cost-effectiveness of TTFields and TMZ for newly-diagnosed GBM from the US healthcare system perspective. Methods and materials: Outcomes for newly-diagnosed GBM patients were estimated over a lifetime horizon using an area under the curve model with three states: stable disease, progressive disease, or death. The survival model integrated the 5-year EF-14 trial results with long-term GBM epidemiology data and US background mortality rates. Adverse event rates were derived from the EF-14 trial data. Utility values to determine quality-adjusted life-years, adverse event costs, and supportive care costs were obtained from published literature. A 3% discount rate was applied to future costs and outcomes. One-way and probabilistic sensitivity analyses were performed to assess result uncertainty due to parameter variability. Results: Treatment with TTFields and TMZ was estimated to result in a mean increase in survival of 1.25 life years (95% credible range [CR] = 0.89-1.67) and 0.96 quality-adjusted life years (QALYs) (95% CR = 0.67-1.30) compared to treatment with TMZ alone. The incremental total cost was $188,637 (95% CR = $145,324-$225,330). The incremental cost-effectiveness ratio (ICER) was $150,452 per life year gained and $197,336 per QALY gained. The model was most sensitive to changes in the cost of TTFields treatment. Conclusions: Adding TTFields to maintenance TMZ resulted in a substantial increase in the estimated mean lifetime survival and quality-adjusted survival for newly-diagnosed GBM patients. Treatment with TTFields can be considered cost-effective within the reported range of willingness-to-pay thresholds in the US.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial.

PURPOSE: To determine whether whole-brain radiation therapy (WBRT) is associated with improved overall survival among non-small cell lung cancer (NSCLC) patients with favorable prognoses at diagnosis. METHODS AND MATERIALS: In the N0574 trial, patients with 1 to 3 brain metastases were randomized to receive stereotactic radiosurgery (SRS) or SRS plus WBRT (SRS + WBRT), with a primary endpoint of cognitive deterioration. We calculated diagnosis-specific graded prognostic assessment (DS-GPA) scores for NSCLC patients and evaluated overall survival according to receipt of WBRT and DS-GPA score using 2 separate cut-points (≥2.0 vs <2.0 and ≥2.5 vs <2.5). RESULTS: A total of 126 NSCLC patients were included for analysis, with median follow-up of 14.2 months. Data for DS-GPA calculation were available for 86.3% of all enrolled NSCLC patients. Overall, 50.0% of patients had DS-GPA score ≥2.0, and 23.0% of patients had DS-GPA scores ≥2.5. The SRS and SRS + WBRT groups were well balanced with regard to prognostic factors. The median survival according to receipt of WBRT was 11.3 months (+WBRT) and 17.9 months (-WBRT) for patients with DS-GPA ≥2.0 (favorable prognoses, P=.63; hazard ratio 0.86; 95% confidence interval 0.47-1.59). Median survival was 3.7 months (+WBRT) and 6.6 months (-WBRT) for patients with DS-GPA <2.0 patients (unfavorable prognoses, P=.85; hazard ratio 0.95; 95% confidence interval 0.56-1.62). Outcomes according to the receipt of WBRT and DS-GPA remained similar utilizing DS-GPA ≥2.5 as a cutoff for favorable prognoses. There was no interaction between the continuum of the DS-GPA groups and WBRT on overall survival (P=.53). CONCLUSIONS: We observed no significant differences in survival according to receipt of WBRT in favorable-prognosis NSCLC patients. This study further supports the approach of SRS alone in the majority of patients with limited brain metastases.

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937.

INTRODUCTION: NRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC. METHODS: Patients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required. RESULTS: A total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2-74.7) for PCI and 50.8% (95% CI: 34.0-65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32-0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT. CONCLUSIONS: OS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial.

IMPORTANCE: Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE: To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS: At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS: The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES: The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS: There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04). CONCLUSIONS AND RELEVANCE: Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00377156.

Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial.

PURPOSE: Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. PATIENTS AND METHODS: A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. RESULTS: Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. CONCLUSION: Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.

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.).

A phase II trial of thalidomide and procarbazine in adult patients with recurrent or progressive malignant gliomas.

Thalidomide and procarbazine have demonstrated single agent activity against malignant gliomas (MG). We evaluated the combination of thalidomide and procarbazine with a single arm phase II trial in adults with recurrent or progressive MG. Procarbazine was given at a dose of 250 mg/m(2)/d × 5day q 28 days. Thalidomide was administered at a dose of 200 mg/day continuously. Intrapatient dose escalation of thalidomide was attempted (increase by 100 mg/day weekly as tolerated) to a maximum of 800 mg/day. The primary outcome was tumor response, assessed by MRI and CT. Secondary outcomes were progression free survival (PFS), overall survival (OS) and toxicity. In addition, quality of life questionnaires were performed at baseline and prior to each odd cycle in all treated patients. Eighteen patients (median age of 50) were accrued and received a total of 36 cycles (median 2) of therapy. The median maximum thalidomide dose achieved was 400 mg (range 0-800). No complete or partial responses were seen. One patient (6%) experienced stable disease, fourteen (78%) progressed as best response and three (17%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5-2.5). Seventeen patients have died (one patient lost to follow-up after progression); median survival from enrollment was 7.6 months (95% CI, 3.5-9.4). Grade 3/4 drug related toxicity was minimal. Quality of life diminished over time. The combination of thalidomide and procarbazine demonstrated no efficacy in this trial.

Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases.

PURPOSE: To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three hepatic metastases. PATIENTS AND METHODS: Patients with one to three hepatic lesions and maximum individual tumor diameters less than 6 cm were enrolled and treated on a multi-institutional, phase I/II clinical trial in which they received SBRT delivered in three fractions. During phase I, the total dose was safely escalated from 36 Gy to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points were toxicity and survival. RESULTS: Forty-seven patients with 63 lesions were treated with SBRT. Among them, 69% had received at least one prior systemic therapy regimen for metastatic disease (range, 0 to 5 regimens), and 45% had extrahepatic disease at study entry. Only one patient experienced grade 3 or higher toxicity (2%). Forty-nine discrete lesions were assessable for local control. Median follow-up for assessable lesions was 16 months (range, 6 to 54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4 to 5.8 cm). Local progression occurred in only three lesions at a median of 7.5 months (range, 7 to 13 months) after SBRT. Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively. Among lesions with maximal diameter of 3 cm or less, 2-year local control was 100%. Median survival was 20.5 months. CONCLUSION: This multi-institutional, phase I/II trial demonstrates that high-dose liver SBRT is safe and effective for the treatment of patients with one to three hepatic metastases.

Clinical experience with radiation therapy in the management of neurofibromatosis-associated central nervous system tumors.

PURPOSE: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. METHODS AND MATERIALS: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. RESULTS: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3-64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000-2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. CONCLUSIONS: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors.

Radiation therapy for visual pathway tumors.

The multimodality management of visual pathway tumors frequently involves radiation. Most commonly, photons are delivered via multiple focused beams aimed at the tumor while sparing adjacent tissues. The dose can be delivered in multiple treatments (radiation therapy) or in a single treatment (radiosurgery). Children with visual pathway gliomas should be treated with chemotherapy alone, delaying the use of radiation therapy until progression. Definitive radiation therapy of optic nerve sheath meningiomas results in stable vision in most patients. Radiation therapy or radiosurgery for pituitary tumors can result in control of both tumor growth and hormone hypersecretion. Postoperative radiation therapy or radiosurgery of craniopharyngiomas significantly improves local control rates compared with surgery alone. Radiation therapy is highly effective for eradicating orbital pseudolymphoma and lymphoma. The risk of complications from radiation treatment is dependent on the organ at risk, the cumulative dose it receives, and the dose delivered per fraction.

Radiation safety issues with positron-emission/computed tomography simulation for stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) simulations using a Stereotactic Body Frame (SBF: Elekta, Stockholm, Sweden) were expanded to include 18F-deoxyglucosone positron-emission tomography (FDG PET) for treatment planning. Because of the length of time that staff members are in close proximity to the patient, concerns arose over the radiation safety issues associated with these simulations. The present study examines the radiation exposures of the staff performing SBRT simulations, and provides some guidance on limiting staff exposure during these simulations. Fifteen patients were simulated with PET/CT using the SBF. Patients were immobilized in the SBF before the FDG was administered. The patients were removed from the frame, injected with FDG, and allowed to uptake for approximately 45 minutes. After uptake, the patients were repositioned in the SBF. During the repositioning, exposure rates were recorded at the patient's surface, at the SBF surface, and at 15 cm, 30 cm, and 1 m from the SBF. Administered dose and the approximate time spent on patient repositioning were also recorded. The estimated dose to staff was compared with the dose to staff performing conventional diagnostic PET studies. The average length of time spent in close proximity (<50 cm) to the patient after injection was 11.7 minutes, or more than twice the length of time reported for diagnostic PET staff. That time yielded an estimated average dose to the staff of 26.5 microSv per simulation. The annual occupational exposure limit is 50 mSv. Based on dose per simulation, staff would have to perform nearly 1900 SBRT simulations annually to exceed the occupational limit. Therefore, at the current rate of 50-100 simulations annually, the addition of PET studies to SBRT simulations is safe for our staff. However, ALARA ("as low as reasonably achievable") principles still require some radiation safety considerations during SBRT simulations. The PET/CT-based SBRT simulations are safe and important for treatment planning that optimizes biologic dose distribution with highly accurate and reproducible target definition.

Advances in radiation therapy for brain tumors.

Radiation therapy is used postoperatively as adjunctive therapy to decrease local failure; to delay tumor progression and prolong survival; as a curative treatment; as a therapy that halts further tumor growth; to alter function; and for palliation. Registration of MRI scan data sets with the treatment-planning CT scan is essential for accurate definition of the tumor and surrounding organs at risk. Integrating additional imaging studies that reflect the biologic characteristics of central nervous system tumors is an area of active research. Conformal treatment delivery is used to spare adjacent normal tissue from receiving unnecessary dose. In the dose range used when treating these tumors, the probability of causing serious late toxicity is relatively low and secondary malignancies are rare.

Reducing set-up uncertainty in the Elekta Stereotactic Body Frame using Stealthstation software.

The Elekta Stereotactic Body Frame (SBF) is a device which allows extracranial targets to be localized and irradiated in a stereotactic coordinate system. Errors of positioning of the body relative to the frame are indirectly estimated by image fusion of multiple CT scans. A novel repositioning methodology, based on neurosurgical Stealth technology, is presented whereby accurate patient repositioning is directly confirmed before treatment delivery. Repositioning was performed on four extracranial stereotactic radiosurgery patients and a radiotherapy simulation phantom. The setup error was quantitatively measured by fiducial localization. A confirmatory CT scan was performed and the resulting image set registered to the initial scan to quantify shifts in the GTV isocenter. Alignment confirmation using Stealth took between 5 and 10 minutes. For the phantom studies, a reproducibly of 0.6 mm accuracy of phantom-to-SBF alignment was measured. The results on four actual patients showed setup errors of 1.5 mm or less. Using the Stealth Station process, rapid confirmation of alignment on the treatment table is possible.

Optically guided linac radiosurgery with a Leksell head frame as an adjunct to Gamma Knife treatment.

Because of geometrical limitations in the helmet of the Leksell Gamma Knife(Elekta Corp., Atlanta, GA, USA) certain regions within the cranium cannot be targeted for treatment. We describe a method by which lesions in these regions can be treated with the Varian-Zmed stereotactic radiosurgery system utilizing an infrared optical positioning system attached to a Leksell head frame. We have measured the accuracy of the optical tracking system using a phantom attached to a Leksell frame and have determined that the system can target a linear accelerator radiosurgery beam to an accuracy of within 1 millimeter.

Gamma Knife surgery targeting the resection cavity of brain metastasis that has progressed after whole-brain radiotherapy.

OBJECT: Salvage treatment of large, symptomatic brain metastases after failure of whole-brain radiotherapy (WBRT) remains challenging. When these lesions require resection, there are few options to lower expected rates of local recurrence at the resection cavity margin. The authors describe their experience in using Gamma Knife surgery (GKS) to target the resection cavity in patients whose tumors had progressed after WBRT. METHODS: The authors retrospectively identified 143 patients in whom GKS had been used to target a brain metastasis resection cavity between 2000 and 2005. Seventy-nine of these patients had undergone WBRT prior to resection and GKS. The median patient age was 53 years, and the median prescribed dose was 18 Gy (range 8-24 Gy), with resection cavities of relatively larger volume (> 15 cm3). The GKS dose was prescribed at the 40 to 95% isodose contour (mode 50%). Local recurrence within 1 cm of the treatment volume occurred in four (5.1%) of 79 cases. The median duration of time to local recurrence was 6.1 months (range 2-13 months). The median duration of time to occurrence of distant metastases following GKS of the resection cavity was 10.8 months (range 2-86 months). Carcinomatous meningitis developed in four (5.1%) of 79 cases. Symptomatic radionecrosis requiring surgical treatment occurred in three (3.8%) of 79 cases. The median duration of survival following GKS of the resection cavity was 69.6 weeks. The median 2- and 5-year survival rates were 20.2 and 6.3%, respectively. CONCLUSIONS: When metastases progress after WBRT and require resection, GKS targeting the resection cavity is a viable strategy. In 75 (94.9%) of 79 cases, GKS of the resection cavity in patients in whom WBRT had failed appears to have achieved its goal of local disease control.

Does dose rate affect efficacy? The outcomes of 256 gamma knife surgery procedures for trigeminal neuralgia and other types of facial pain as they relate to the half-life of cobalt.

OBJECT: Gamma Knife surgery (GKS) is a treatment option for patients with refractory typical trigeminal neuralgia (TN), TN with atypical features, and atypical types of facial pain. The Gamma Knife's 201 60Co sources decay with a half-life of 5.26 years. The authors examined whether the decrease in dose rate over 4.6 years between Co source replacements affected the control rates of facial pain in patients undergoing GKS. METHODS: The authors collected complete follow-up data on 239 of 326 GKS procedures performed in patients with facial pain. Patients were classified by their type of pain. The isocenter of a 4-mm collimator helmet was targeted at the proximal trigeminal nerve root, and the dose (80-90 Gy) was prescribed at the 100% isodose line. Patients reported the amount of pain control following radiosurgery by answering a standardized questionnaire. Eighty percent of patients experienced greater than 50% pain relief, and 56% of patients experienced complete pain relief after GKS. Neither dose rate nor treatment time was significantly associated with either the control rate or degree of pain relief. A significant association between the type of facial pain and the pain control rate after GKS was observed (p < 0.001; Pearson chi-square test). In their statistical analysis, the authors accounted for changes in prescription dose over time to prevent the dose rate from being a confounding variable. There was no observable effect of the dose rate or of the treatment duration within the typical period to source replacement. CONCLUSIONS: Patients with facial pain appear to receive consistent treatment with GKS at any time during the first half-life of the Co sources.