The role of GammaTile in the treatment of brain tumors: a technical and clinical overview.

Malignant and benign brain tumors with a propensity to recur continue to be a clinical challenge despite decades-long efforts to develop systemic and more advanced local therapies. GammaTile (GT Medical Technologies Inc., Tempe AZ) has emerged as a novel brain brachytherapy device placed during surgery, which starts adjuvant radiotherapy immediately after resection. GammaTile received FDA clearance in 2018 for any recurrent brain tumor and expanded clearance in 2020 to include upfront use in any malignant brain tumor. More than 1,000 patients have been treated with GammaTile to date, and several publications have described technical aspects of the device, workflow, and clinical outcome data. Herein, we review the technical aspects of this brachytherapy treatment, including practical physics principles, discuss the available literature with an emphasis on clinical outcome data in the setting of brain metastases, glioblastoma, and meningioma, and provide an overview of the open and pending clinical trials that are further defining the efficacy and safety of GammaTile.

Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study.

BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD.

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.).

Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: long term results of RTOG BR0131.

We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma. Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range 1.1-10.1), median progression-free survival (PFS) is 5.8 years (95 % CI 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78 % (95 % CI 61-95 %) and 83 % (95 % CI 67-98 %), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67 %, 95 % CI 55-79 %). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs.

The impact of concurrent granulocyte-macrophage colony-stimulating factor on quality of life in head and neck cancer patients: results of the randomized, placebo-controlled Radiation Therapy Oncology Group 9901 trial.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer. METHODS: Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation. RESULTS: Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean -18.4 GM-CSF, -20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05). CONCLUSION: GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden.

Dosimetric Impacts of Source Migration, Radioisotope Type, and Decay with Permanent Implantable Collagen Tile Brachytherapy for Brain Tumors.

Introduction: Brachytherapy using permanently implantable collagen tiles containing cesium-131 (Cs-131) is indicated for treatment of malignant intracranial neoplasms. We quantified Cs-131 source migration and modeled the resulting dosimetric impact for Cs-131, iodine-125 (I-125), and palladium-103 (Pd-103). Methods and Materials: This was a retrospective analysis of a subgroup of patients enrolled in a prospective, single-center, nonrandomized, clinical trial (NCT03088579) of Cs-131 collagen tile brachytherapy. Postimplant Cs-131 plans and hypothetical I-125 and Pd-103 calculations were compared for 20 glioblastoma patients for a set seed geometry. Dosimetric impact of decay and seed migration was calculated for 2 hypothetical scenarios: Scenario 1, assuming seed positions on a given image set were unchanged until acquisition of the subsequent set; Scenario 2, assuming any change in seed positions occurred the day following acquisition of the prior images. Seed migration over time was quantified for a subset of 7 patients who underwent subsequent image-guided radiotherapy. Results: Mean seed migration was 1.7 mm (range: 0.7-3.1); maximum seed migration was 4.3 mm. Mean dose to the 60 Gy volume differed by 0.4 Gy (0.6%, range 0.1-1.0) and 0.9 Gy (1.5%, range 0.2-1.7) for Cs-131, 1.2 Gy (2.0%, range 0.1-2.1) and 1.6 Gy (2.6%, range 1.2-2.6) for I-125, and 0.8 Gy (1.3%, range 0.2-1.5) and 1.4 Gy (2.3%, range 0.3-1.9) for Pd-103, for Scenarios 1 and 2, respectively, compared with the postimplant plan. For a set seed geometry mean implant dose was higher for Pd-103 (1.3 times) and I-125 (1.1 times) versus Cs-131. Dose fall-off was steepest for Pd-103: gradient index 1.88 versus 2.23 (I-125) and 2.40 (Cs-131). Conclusions: Dose differences due to source migration were relatively small, suggesting robust prevention of seed migration from Cs-131-containing collagen tiles. Intratarget heterogeneity was greater with Pd-103 and I-125 than Cs-131. Dose fall-off was fastest with Pd-103 followed by I-125 and then Cs-131.

Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825).

BACKGROUND: Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. METHODS: NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. RESULTS: A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. CONCLUSION: The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

PURPOSE: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Influence of Residual Disease Following Surgical Resection in Newly Diagnosed Glioblastoma on Clinical, Neurocognitive, and Patient Reported Outcomes.

BACKGROUND: The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. OBJECTIVE: To examine these uncertainties. METHODS: NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method. RESULTS: A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test-Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. CONCLUSION: STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.

A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118).

PURPOSE: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. PATIENTS AND METHODS: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints included overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. RESULTS: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. CONCLUSION: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.

Prospective evaluation of quality of life and neurocognitive effects in patients with multiple brain metastases receiving whole-brain radiotherapy with or without thalidomide on Radiation Therapy Oncology Group (RTOG) trial 0118.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 0118 randomized patients with multiple brain metastases to whole-brain radiotherapy (WBRT) +/- thalidomide. This secondary analysis of 156 patients examined neurocognitive and quality of life (QOL) outcomes. METHODS AND MATERIALS: Quality of life was determined with the Spitzer Quality of Life Index (SQLI). The Folstein Mini-Mental Status Exam (MMSE) assessed neurocognitive function. SQLI and MMSE were administered at baseline and at 2-month intervals. MMSE was scored with a threshold value associated with neurocognitive functioning (absolute cutoff level of 23) and with the use of corrections for age and educational level. RESULTS: Baseline SQLI predicted survival. Patients with SQLI of 7-10 vs. <7 had median survival time (MST) of 4.8 vs. 3.1 months, p = 0.05. Both arms showed steady neurocognitive declines, but SQLI scores remained stable. Higher levels of neurocognitive decline were observed with age and education-level corrections. Of patients considered baseline age/educational level neurocognitive failures, 32% died of intracranial progression. CONCLUSIONS: Quality of life and neuropsychological testing can be prospectively administered on a Phase III cooperative group trial. The MMSE should be evaluated with adjustments for age and educational level. Baseline SQLI is predictive of survival. Despite neurocognitive declines, QOL remained stable during treatment and follow-up. Poor neurocognitive function may predict clinical deterioration. Lack of an untreated control arm makes it difficult to determine the contribution of the respective interventions (i.e., WBRT, thalidomide) to neurocognitive decline. The RTOG has developed a trial to study the role of preventative strategies aimed at forestalling neurocognitive decline in this population.

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 > 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.

Multicenter Trial of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer: Survival and Toxicity Endpoints.

PURPOSE: The radiobiology of prostate cancer may favor the extreme hypofractionation inherent in stereotactic body radiation therapy (SBRT); however, data from a large multicenter study are lacking. We therefore examined the hypothesis that dose-escalated SBRT can be safely administered across multiple institutions, with favorable 5-year disease-free survival (DFS) rates compared with historical controls. METHODS AND MATERIALS: Twenty-one centers enrolled 309 patients with prostate adenocarcinoma: 172 with low-risk (LR) and 137 with intermediate-risk (IR) disease. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. The prostate was prescribed 40 Gy in 5 fractions of 8 Gy. We assessed toxicities using Common Terminology Criteria for Adverse Events (CTCAE) version 3 and biochemical failure using the "nadir + 2" definition. The study population yielded 90% power to identify excessive (>10%) rates of grade ≥3 genitourinary (GU) or gastrointestinal toxicities and, in the LR group, 80% power to show superiority in DFS over a 93% historical comparison rate. RESULTS: At a median follow-up of 61 months, 2 LR patients (1.2%) and 2 IR patients (1.5%) experienced grade 3 GU toxicities, far below the 10% toxicity rate deemed excessive (upper limits of 95% confidence interval, 3.5% and 4.3%, respectively). No grade 4 or 5 toxicities occurred. All grade 3 toxicities were GU, occurring 11 to 51 months after treatment. For the entire group, the actuarial 5-year overall survival rate was 95.6% and the DFS rate was 97.1%. The 5-year DFS rate was 97.3% for LR patients (superior to the 93% DFS rate for historical controls; P = .0008; lower limit of 95% confidence interval, 94.6%) and 97.1% for IR patients. CONCLUSIONS: Dose-escalated prostate SBRT was administered with minimal toxicity in this multi-institutional study. Relapse rates compared favorably with historical controls. SBRT is a suitable option for LR and IR prostate cancer.

Resection and permanent intracranial brachytherapy using modular, biocompatible cesium-131 implants: results in 20 recurrent, previously irradiated meningiomas.

OBJECTIVE: Effective treatments for recurrent, previously irradiated intracranial meningiomas are limited, and resection alone is not usually curative. Thus, the authors studied the combination of maximum safe resection and adjuvant radiation using permanent intracranial brachytherapy (R+BT) in patients with recurrent, previously irradiated aggressive meningiomas. METHODS: Patients with recurrent, previously irradiated meningiomas were treated between June 2013 and October 2016 in a prospective single-arm trial of R+BT. Cesium-131 (Cs-131) radiation sources were embedded in modular collagen carriers positioned in the operative bed on completion of resection. The Cox proportional hazards model with this treatment as a predictive term was used to model its effect on time to local tumor progression. RESULTS: Nineteen patients (median age 64.5 years, range 50-78 years) with 20 recurrent, previously irradiated tumors were treated. The WHO grade at R+BT was I in 4 (20%), II in 14 (70%), and III in 2 (10%) cases. The median number of prior same-site radiation courses and same-site surgeries were 1 (range 1-3) and 2 (range 1-4), respectively; the median preoperative tumor volume was 11.3 cm3 (range 0.9-92.0 cm3). The median radiation dose from BT was 63 Gy (range 54-80 Gy). At a median radiographic follow-up of 15.4 months (range 0.03-47.5 months), local failure (within 1.5 cm of the implant bed) occurred in 2 cases (10%). The median treatment-site time to progression after R+BT has not been reached; that after the most recent prior therapy was 18.3 months (range 3.9-321.9 months; HR 0.17, p = 0.02, log-rank test). The median overall survival after R+BT was 26 months, with 9 patient deaths (47% of patients). Treatment was well tolerated; 2 patients required surgery for complications, and 2 experienced radiation necrosis, which was managed medically. CONCLUSIONS: R+BT utilizing Cs-131 sources in modular carriers represents a potentially safe and effective treatment option for recurrent, previously irradiated aggressive meningiomas.

Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database.

Background: We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods: Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results: Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions: We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021.

Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.

Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513.

PURPOSE: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. METHODS AND MATERIALS: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. RESULTS: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. CONCLUSIONS: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power. METHODS AND MATERIALS: Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ. RESULTS: From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P<.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis. CONCLUSIONS: The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%.

Ectopic intracavernous sinus adrenocorticotropic hormone-secreting microadenoma: could this be a common cause of failed transsphenoidal surgery in Cushing disease? Case report.

Despite diagnostic advances, it remains difficult to identify intrasellar and ectopic parasellar adrenocorticotropic hormone (ACTH)-secreting microadenomas. The authors present the case of a 61-year-old woman with Cushing disease in whom a significant central-to-peripheral and lateralized right-sided ACTH gradient was demonstrated on inferior petrosal sinus sampling; no discernible abnormality was seen on magnetic resonance imaging. She underwent transnasal transsphenoidal surgery. No tumor was found on sellar exploration and a total hypophysectomy was performed, yet her hypercortisolemia persisted. The patient died of cardiac events 17 days postsurgery. Autopsy revealed an isolated, right-sided, intracavernous ACTH-secreting adenoma with no intrasellar communication. This case represents the first failed transsphenoidal surgery for Cushing disease in which there is postmortem confirmation of a suspected intracavernous sinus lesion. It supports the hypothesis that Cushing disease associated with nondiagnostic imaging studies, a strong ACTH gradient on venography, and negative findings on sellar exploration may be caused by an ectopic intracavernous ACTH-secreting adenoma. There are no premortem means of confirming the presence of such lesions, but these tumors could underlie similar cases of failed surgery. Radiation therapy targeting the sella turcica and both cavernous sinuses, possibly supplemented with medical treatment, is suggested for similar patients in whom transsphenoidal hypophysectomy has failed. Adrenalectomy may also be appropriate if a rapid reduction in ACTH is necessary.

Effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: secondary analysis of RTOG 98-02.

PURPOSE: The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. PATIENTS AND METHODS: A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini-Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. RESULTS: Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. CONCLUSION: The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.