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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%−81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6–9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

Some patients with metastatic medulloblastoma can be successfully treated with targeted therapy. We report the case of a 42-year-old woman who was diagnosed with sonic hedgehog (SHH)-subgroup medulloblastoma. She was treated with surgery, radiation and chemotherapy. She then developed bone pain. A positron emission tomography (PET) scan confirmed widespread bone metastases from her medulloblastoma. She was started on vismodegib, an oral smoothened inhibitor that targets her tumour type. Her bone pain resolved. A repeat PET scan showed resolution of almost all metastases. Fourteen months after starting vismodegib, her disease recurred and she was transitioned to temozolomide chemotherapy. We document an important case of prolonged response to vismodegib in a patient with systemic SHH-subgroup medulloblastoma metastases.

Ayub Ommaya proposed a surgical technique for subcutaneous reservoir and pump placement in 1963 to allow access to intraventricular cerebrospinal fluid (CSF). Currently, the most common indication for Ommaya reservoir insertion (ORI) in adults is for patients with hematologic or leptomeningeal disorders requiring repeated injection of chemotherapy into the CSF space. Historically, the intraventricular catheter has been inserted blindly based on anatomical landmarks. The purpose of this study was to examine short-term complication rates with ORI with image guidance (IG) and without image guidance (non-IG). We retrospectively evaluated all operative cases of ORI from 2000 to 2014 by the senior author. Patient demographic data, surgical outcomes, and peri-operative complications were collected. Accurate placement and early (30-day) morbidity or mortality were considered primary outcomes. Fifty-five consecutive patients underwent ORI by the senior author over the study period (43.5 ± 16.6 years; 40.0% female). Indications for placement included acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and leptomeningeal carcinomatosis. There were seven (12.7%) total complications: three (37.5%) with no-IG versus four (8.5%) with IG. Catheter malpositions were significantly higher in the non-IG group at 37.5% compared to 2.1%. Catheters were also more likely to require multiple passes with non-IG at 25% compare to 0% with IG. There were no early infections in either group. We demonstrate improved accuracy and decreased complications using an image-guided approach compared with a traditional approach. Our results support routine use of intra-operative image guidance for proximal catheter insertion in elective ORI for intraventricular chemotherapy.

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases.

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.

Introduction: Pseudoprogression (psPD) is a transient post-treatment imaging change that is commonly seen when treating glioma with chemotherapy and radiation. The use of apparent transverse relaxation rate (R *), which is calculated from a contrast-free multi-echo gradient echo Magnetic Resonance Imaging (MRI) sequence, may allow for quantitative identification of patients with suspected psPD. Methods: We acquired a multi-echo gradient echo sequence using a 3T-Siemens Prisma MRI. The signal decay through the echoes was fitted to provide the (R *) coefficient. We segmented the T -gadolinium enhancing the image to provide a contrast enhancing lesion (CEL) and the FLAIR hyperintensity to provide a non-enhancing lesion (NEL). These regions of interest were applied to the multi-echo gradient echo to acquire a mean (R *) within the CEL and NEL. We additionally acquired ADC data to attempt to corroborate our findings. Results: We found that patients who later exhibited PD exhibited a higher (R *) within the CEL as well as a higher ratio of CEL to NEL. Our data correctly distinguished pseudoprogression from treatment effect in 9/9 patients, while ADC corrected identified 7/9 patients using an absolute ADC of 1200 × 10 mm /s. Conclusions: Our method seems promising for the accurate identification of psPD, and the technique is amenable to evaluation in larger, multi-centre patient cohorts. 2 2 1 2 2 −6 2

Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro-Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed.

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine–DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine–DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previously, her mother revealed similar features. Cerebellar liponeurocytoma is a poorly understood entity. This report provides novel evidence of an inheritable predisposition for tumor development. Accurate diagnosis and reporting of clinical outcomes and associated genetic and histopathological changes are necessary for guiding prognosis and developing recommendations for patient care.

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p

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.

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.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 of1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ.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.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%.

INTRODUCTION EGFR-targeted agents can be useful in the treatment of systemic metastatic cancer including that which has spread to the brain. We present the case of a patient with two different EGFR mutations that responded to receptor blockade. CASE REPORT A 38 year old right-handed female presented with a one week history of progressive left-sided weakness and focal seizures. Neuroimaging revealed multiple enhancing brain lesions and a lesion in the left maxillary antrum. Body imaging revealed a right lung mass, hilar and mediastinal nodes and multiple bony lesions. Biopsy of the maxillary antrum lesion showed metastatic poorly differentiated adenocarcinoma, TTF-1 positive, suggesting a lung primary. ALK was not mutated but there was an EGFR mutation (exon 19 deletion). The patient underwent treatment with dexamethasone, levetiracetam, whole brain radiation and afatinib, an oral EGFR-targeted agent. Most of the brain lesions responded completely with only two small residual lesions. Seizures were controlled. There was major partial response from the systemic lesions. Two years later the patient was clinically well but the lung lesion, mediastinal nodes and bony lesions were all enlarging. A new pituitary lesion was identified on brain MRI. A liquid biopsy (blood) revealed a T790M mutation and the patient underwent stereotactic body radiation and EGFR-targeted therapy with osimertinib. All lesions responded to treatment and four years after initial diagnosis the patient is clinically well with stable disease. DISCUSSION Successful treatment of widespread metastatic disease is possible with the use of multiple EGFR-targeted agents in certain patients.

IntroductionThis study aimed to explore the potential for computed tomography (CT) perfusion and 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting sites of future progressive tumour on a voxel-by-voxel basis after radiotherapy and chemotherapy. MethodsTen patients underwent pre-radiotherapy magnetic resonance (MR), FDG-PET and CT perfusion near the end of radiotherapy and repeated post-radiotherapy follow-up MR scans. The relationships between these images and tumour progression were assessed using logistic regression. Cross-validation with receiver operating characteristic (ROC) analysis was used to assess the value of these images in predicting sites of tumour progression. ResultsPre-radiotherapy MR-defined gross tumour; near-end-of-radiotherapy CT-defined enhancing lesion; CT perfusion blood flow (BF), blood volume (BV) and permeability-surface area (PS) product; FDG-PET standard uptake value (SUV); and SUV:BF showed significant associations with tumour progression on follow-up MR imaging (P

The Macdonald criteria and the Response Assessment in Neuro-Oncology (RANO) criteria define radiologic parameters to classify therapeutic outcome among patients with malignant glioma and specify that clinical status must be incorporated and prioritized for overall assessment. But neither provides specific parameters to do so. We hypothesized that a standardized metric to measure neurologic function will permit more effective overall response assessment in neuro-oncology.An international group of physicians including neurologists, medical oncologists, radiation oncologists, and neurosurgeons with expertise in neuro-oncology drafted the Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The scale was subsequently tested in a multicenter study to determine its overall reliability, inter-observer variability, and feasibility.The NANO scale is a quantifiable evaluation of 9 relevant neurologic domains based on direct observation and testing conducted during routine office visits. The score defines overall response criteria. A prospective, multinational study noted a90% inter-observer agreement rate with kappa statistic ranging from 0.35 to 0.83 (fair to almost perfect agreement), and a median assessment time of 4 minutes (interquartile range, 3-5).The NANO scale provides an objective clinician-reported outcome of neurologic function with high inter-observer agreement. It is designed to combine with radiographic assessment to provide an overall assessment of outcome for neuro-oncology patients in clinical trials and in daily practice. Furthermore, it complements existing patient-reported outcomes and cognition testing to combine for a global clinical outcome assessment of well-being among brain tumor patients.

Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O

Introduction: The post-treatment monitoring of glioma patients remains an area of active research and development. Conventional imaging with MRI is a highly sensitive modality for detecting and monitoring primary and secondary brain tumors and includes multi-parametric sequences to better characterize the disease. Standardized schemes for measuring response to treatment are in wide clinical use; however, the introduction of new therapeutics have introduced new patterns of response that can confound interpretation of conventional MRI and can cause uncertainty in the proper management following therapy. Areas covered: A summary of current and evolving techniques for assessing glioma response in this era of new therapies that address these challenges are presented in this review. While this review focuses more on clinical and early clinical methodologies for MRI and nuclear medicine techniques some promising pre-clinical techniques are also presented. Expert commentary: While successful single institution results have been widely reported in the literature, any new methodologies must be undertaken in multi-center settings. Additionally, the need for standardization of protocols in quantitative measured are an important area that must be addressed for new and promising techniques to be implemented to a wide array of patients.

Subependymal giant cell astrocytoma (SEGA) is typically seen in children with tuberous sclerosis (TS), who present with headaches and seizures, and characteristic clinical and cutaneous manifestations of TS. Surgical resection, CSF diversion (for hydrocephalus), radiotherapy, and chemotherapy with a mammalian target of rapamycin (mTOR) inhibitor are treatment options. SEGA can occur in adults without TS, raising diagnostic and therapeutic challenges.

Background The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. Objective To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. Methods The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. Results Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. Conclusion The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice.

Purpose This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Patients and Methods Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m2/day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. Results Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m2/day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. Conclusion A dosage of 10 mg everolimus daily with TMZ 150 mg/m2/day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen.

OBJECTIVE Discordance between HbA1c and fructosamine estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether it is consistent is uncertain. This study aims to coanalyze paired glycosylated hemoglobin (HbA1c)-fructosamine estimations by using fructosamine to determine a predicted HbA1c, to calculate a glycation gap (G-gap) and to determine whether the G-gap is consistent over time. RESEARCH DESIGN AND METHODS We included 2,263 individuals with diabetes who had at least two paired HbA1c-fructosamine estimations that were separated by 10 ± 8 months. Of these, 1,217 individuals had a third pair. The G-gap was calculated as G-gap = HbA1c minus the standardized fructosamine-derived HbA1c equivalent (FHbA1c). The hypothesis that the G-gap would remain consistent in individuals over time was tested. RESULTS The G-gaps were similar in the first, second, and third paired samples (0.0 ± 1.2, 0.0 ± 1.3, and 0.0 ± 1.3, respectively). Despite significant changes in the HbA1c and fructosamine, the G-gap did not differ in absolute or relative terms and showed no significant within-subject variability. The direction of the G-gap remained consistent. CONCLUSIONS The G-gap appears consistent over time; thus, by inference any key underlying mechanisms are likely to be consistent. G-gap calculation may be a method of exploring and evaluating any such underlying mechanisms.

Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo. Neurology (R) 2011;77:1156-1164

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Object Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. Methods Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. Results Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. Conclusions The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA) represent about 5% of primary brain tumors.1 While standard treatment for these tumors has included maximally feasible resection and radiotherapy (RT), there has been long-standing interest in the use of chemotherapy as well. Prior to FDA approval of temozolomide, most gliomas had been treated with resection followed by radiotherapy alone or additional carmustine or a combination regimen that included procarbazine, lomustine, and vincristine (PCV).2,3 Interest in the use of chemotherapy for these tumors was further driven by the discovery of an identifiable subset of tumors that harbor loss of heterozygosity (LOH) of chromosomes 1p and 19q, which render them highly responsive to adjuvant therapies.4,5 The presence of 1p/19q LOH, which is likely the result of a chromosomal translocation,6 has been shown to be associated with radiosensitivity, chemosensitivity, and prolonged survival.4,5,7–10 Those patients who had tumors with deletion of the 1p chromosome had a 100% response rate to adjuvant therapy and a median survival in excess of 10 years.5 The addition of PCV chemotherapy, either before or after RT, has been investigated in two large phase III randomized trials (RTOG 9402 and EORTC 26951).11,12 While neither trial showed an overall survival (OS) advantage with the addition of chemotherapy to RT, subset analysis of patients whose tumors harbored combined 1p and 19q LOH (1p/19q codeletion) showed that these patients had a longer progression-free survival (PFS) with the up-front use of chemotherapy. In addition, patients with 1p/19q codeletion had longer OS and PFS, regardless of treatment arm than did the patients whose tumors had LOH of either one or neither chromosome. However, the use of PCV in these trials was associated with significant levels of toxicity, which limits enthusiasm for the broad application of this regimen, particularly for those patients who are predicted to have lengthened survival. Temozolomide is a cytotoxic alkylating agent that has a less toxic profile than PCV and that has demonstrated clinical antitumor activity against high-grade gliomas, including oligodendrogliomas, both at initial diagnosis and relapse.13–18 Preirradiation or neoadjuvant chemotherapy has several potential advantages. First, in the absence of radiation-induced vascular changes, drug delivery to the tumor is maximized. Second, neoadjuvant chemotherapy allows early treatment of infiltrating tumor cells that may be at or beyond the border of the radiation port. Further, preirradiation chemotherapy allows a true assessment of the efficacy of chemotherapy. Combined chemotherapy with RT with the use of low-dose, daily temozolomide has been used with acceptable levels of toxicity and enhanced clinical benefit in patients with glioblastoma.19 The primary objectives of this phase II study were to evaluate response rate, time to progression, and toxicity of preirradiation chemotherapy with temozolomide followed by concurrent temozolomide and RT in patients with AO and MOA.

Recent trials in glioma have revealed significant limitations in the end points used. This requires a critical and comprehensive review of how brain tumor trials are conducted, particularly of which end points are defined and how response and progression are defined.

Background Haemoglobin A1c (HbA1c) is the only measure of glycaemic control used for many patients with diabetes, but it has limitations and might sometimes be misleading. HbA1c concentrations are influenced by conditions that alter red-cell life and there is evidence that biochemical variation in intracellular glycation rates also influence HbA1c concentrations. This paper is the first to propose a method of using simultaneously measured HbA1c and fructosamine, and error grid analysis, in the clinical setting, to gain a better understanding of glycaemic control. Methods Cross-sectional analytical study using HbA1c and fructosamine measures on the same blood sample from 1744 patients having blood taken for hospital diabetes clinic appointments. No other selection or exclusion criteria were applied. Results The fructosamine results were converted to a HbA1c equivalent which was then compared with the HbA1c. In an Altman-Bland plot, the paired result differences ranged between −6.9% and +5.5% HbA1c with 1139 (65%), 438 (25%), 130 (8%) and 37 (2%) being ≤1%, 1–2%, 2–3% or >3% of HbA1c difference, respectively. In clinical error grid analysis, 864 (50%) results had tight concordance for clinical interpretation, 761 (43%) had one block disunity of probably little clinical significance, but 105 (6%) were two blocks and 14 (1%) were three blocks discordant. Conclusion HbA1c may not accurately reflect glucose control. Our method, utilizing co-assessment with serum fructosamine, evaluates the possible clinical impact of this. We suggest the analysis used in this paper should be used routinely in diabetes practice.

To evaluate the hypothesis that adults with partially resected (PR50% resection) supratentorial low-grade glioma (LGG) benefit from higher doses of radiation.Patients receiving post-operative radiation for WHO grade I-II LGG at the University of Western Ontario between 1979 and 2001 were studied. Patient characteristics evaluated included: age, gender, symptom duration30 days, seizures at presentation, Karnofsky performance status (KPS)70, astrocytoma pathology (AS), and radiation dose. A Cox proportional hazard regression model was constructed to test the influence of radiation dose.One hundred and seven patients were analyzed. Patients who had PR were not significantly different from those with STR (subtotal/total resection) in terms of patient characteristics. Median survival (MST) of PR patients who receivedor=50 Gy was 16.5 months while those who received50 Gy had a MST of 109.2 months. The interaction of radiation dose and extent of resection was tested after controlling for other patient factors by Cox regression model. The interaction was highly significant for both OS and PFS (P=0.013 and P=0.003, respectively). This model remained significant after excluding six patients receiving doses42 Gy (OS, P=0.024, and PFS, P=0.001).The outcome for patients with LGG is dependent on extent of tumor resection and radiation dose. Patients with PR should be considered for higher radiation dose schedules (50 Gy). Future trials on therapeutic strategies for LGG should consider stratification of patients by extent of tumor resection. Our data suggests that one dose does not fit all.

INTRODUCTION: Glioblastoma Multiforme (GBM) is the most common and lethal primary adult brain tumor, with significant variability in therapeutic response due to its underlying molecular and pathological heterogeneity. This study investigated the prognostic and predictive value of an established explant assay of surgical specimens of gliomas in response to the clinically relevant chemotherapy temozolomide (TMZ). METHODS: One hundred and thirty-eight patients with pathologically-verified gliomas and ongoing follow-up of clinical outcomes were included in the study. Tumor specimens at the time of resection were plated onto a collagen matrix with and without TMZ. Using video microscopy, the migratory distance of the cells was quantified over 5 days. RESULTS: One hundred and eleven viable explant assays were collected in glioma patients including 65 GBMs, 19 anaplastic, 13 grade II and 14 recurrent high grade glioma. GBMs showed increased invasiveness compared to anaplastic and grade II gliomas on the assay. Glioma patients whose tumors showed a greater invasive distance on the assay had reduced overall survival. Inhibition of invasion by 20% by TMZ on the explant assay predicted the time to recurrence after TMZ treatment and the overall survival of GBM patients. CONCLUSION: This study demonstrates that an explant assay of surgical specimens of gliomas, by reproducing the in vivo environment, can predict overall survival of gliomas patients and response to temozolomide. Investigations are ongoing to determine whether response on the assay is of predictive value beyond genetic markers including MGMT and IDH1.

The introduction of antiangiogenic therapies for the treatment of malignant glioma and the effect of these agents on standard imaging studies were the stimuli for forming a small group of investigators to critically evaluate the limitations of the Macdonald criteria in assessing response to treatment. The initial goal of this group was to highlight the challenges in accurately determining the efficacy of therapeutic interventions for malignant glioma and to develop new criteria that could be implemented in clinical care as well as in the design and conduct of clinical trials. This initial Response Assessment in Neuro-Oncology (RANO) effort started in 2008 and over the last 7 years, it has expanded to include a critical review of response assessment across several tumor types as well as endpoint selection and trial design to improve outcome criteria for neuro-oncological trials. In this paper, we review the overarching principles of the RANO initiative and the efforts to date. We also highlight the diverse and expanding efforts of the multidisciplinary groups of investigators who have volunteered their time as part of this endeavor.

Dynamic perfusion CT (PCT) is an imaging technique for assessing the vascular supply and hemodynamics of brain tumors by measuring blood flow, blood volume, and permeability-surface area product. These PCT parameters provide information complementary to histopathologic assessments and have been used for grading brain tumors, distinguishing high-grade gliomas from other brain lesions, differentiating true progression from post-treatment effects, and predicting prognosis after treatments. In this review, the basic principles of PCT are described, and applications of PCT of brain tumors are discussed. The advantages and current challenges, along with possible solutions, of PCT are presented.

We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18–67) and a median KPS of 100 (range, 70–100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44–142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.

Since high-grade malignant gliomas can seldom be treated curatively, the main aim of first line therapy is to improve progression free survival (PFS), to reduce morbidity, and to preserve, if not restore neurological functions and the capacity to perform daily activities. Focusing on a single clinical efficacy parameter in clinical trials may provide a potentially biased result, as for patients the overall result of treatment entails a more complex picture of weighing and balancing gains and losses on different outcome measures. In this paper we address different clinical outcomes measures separately and we illustrate the value of multiple outcome measures using the results of a recent clinical trial comparing temozolomide with procarbazine in the treatment of Glioblastoma Multiforme. Compared with procarbazine, temozolomide not only prolonged PFS, but also maintained neurological functioning and performance status for a longer period of time, and also improved health-related quality of life (HRQL). All these statistically significant outcomes demonstrate a remarkable consistency. In addition, temozolomide showed a trend of extending overall survival over procarbazine.

To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma.Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5 mg/m(2) intravenously (i.v.), 30 min dailyx5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated. Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting.Topotecan, delivered in the dailyx5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted.

BACKGROUND Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system in adults. Increased activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway is common. We performed a phase II study using PX-866, an oral PI3K inhibitor, in participants with recurrent GBM. METHODS Patients with histologically confirmed GBM at first recurrence were given oral PX-866 at a dose of 8 mg daily. An MRI and clinical exam were done every 8 weeks. Tissue was analyzed for potential predictive markers. RESULTS Thirty-three participants (12 female) were enrolled. Median age was 56 years (range 35-78y). Eastern Cooperative Oncology Group performance status was 0-1 in 29 participants and 2 in the remainder. Median number of cycles was 1 (range 1-8). All participants have discontinued therapy: 27 for disease progression and 6 for toxicity (5 liver enzymes and 1 allergic reaction). Four participants had treatment-related serious adverse events (1 liver enzyme, 1 diarrhea, 2 venous thromboembolism). Other adverse effects included fatigue, diarrhea, nausea, vomiting, and lymphopenia. Twenty-four participants had a response of progression (73%), 1 had partial response (3%, and 8 (24%) had stable disease (median, 6.3 months; range, 3.1-16.8 months). Median 6-month progression-free survival was 17%. None of the associations between stable disease and PTEN, PIK3CA, PIK3R1, or EGFRvIII status were statistically significant. CONCLUSIONS PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of participants obtained durable stable disease. This study also failed to identify a statistically significant association between clinical outcome and relevant biomarkers in patients with available tissue.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Purpose: A Phase II trial was conducted by the Radiation Therapy Oncology Group (RTOG) to compare the survival of patients with glioblastoma multiforme treated with topotecan combined with standard cranial radiotherapy (RT) for matched patients treated in prior RTOG studies. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and RT. Methods and Materials: Eighty-seven patients with histologically confirmed glioblastoma multiforme received standard cranial RT (60 Gy/30 fractions in 6 weeks) plus topotecan 1.5 mg/m 2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles. Eighty-four patients were evaluated, of whom 60 (71%) were ≥50 years, 44 (52%) were men, and 61 (73%) had a Karnofsky performance status of ≥80. Twenty-nine percent of patients had undergone biopsies, 48% partial resections, and 21% gross total resections. Two resections were unspecified as to the extent of tumor removal. Fourteen percent of patients were recursive partitioning analysis Class III, 46% were Class IV, 35% were Class V, and 5% were Class VI. Results: The median survival was 9.3 months. Sixty-seven patients (80%) had progression. The 1-year survival rate was 32%. One patient remained alive without recurrence. RTOG 9513 patients were matched with patients in an RTOG clinical trial database from previous clinical trials. The matching variables were age, Karnofsky performance status, mental status, and prior surgery. No statistically significant difference was found between the survival of the study patients and that of the matched patients from the RTOG database. Fifty-four percent of patients had Grade IV acute toxicity. The toxicity was primarily hematologic. Four patients had Grade III late central nervous system toxicities. Conclusion: Topotecan administered at a dose of 1.5 mg/m 2 per day i.v. for 5 d/wk every 3 weeks for 3 cycles given concurrently with standard cranial RT for glioblastoma does not produce a statistically significant survival advantage over previously tested therapies. Other methods of administration of topotecan or other camptothecins may provide more effective radiosensitization.

Purpose: Immunohistochemical techniques were used to detect the expression of Ki-67, a nuclear proliferation marker, in 180 low-grade glioma tumor specimens to determine whether Ki-67 is a prognostic predictor of survival or tumor recurrence. Methods and Materials: A clinical database of 180 low-grade glioma patients (35 children aged ≤18 years and 145 adults) was compiled. Eighty patients had received postoperative radiotherapy (RT) and 100 patients had had RT deferred until the time of tumor progression/recurrence. Ki-67 indexes were evaluated retrospectively on tumor specimens from these patients using a semiautomated computer analysis technique. Ten observations were averaged per patient. The maximal Ki-67 value was recorded. Results: The correlation between the Ki-67 index and survival was much higher for the averaged Ki-67 value than for the maximal value. Of the tumor specimens, 29% had a negative Ki-67 index (i.e., zero Ki-67 positive cells) and 7.7% had an average Ki-67 index of ≥5%. An average Ki-67 value of ≥5% was prognostically significant for reduced cause-specific survival (CSS, p = 0.05) and a Ki-67 level ≥10% was strongly significant of a poor survival outcome ( p = 0.009). Ki-67 was not prognostically significant for progression-free survival. Other prognostically significant factors for CSS included age ( p = 0.05), Karnofsky performance status ( p = 0.0001), radiation dose ( p = 0.02), extent of surgical resection (biopsy vs. others, p = 0.004), and timing of radiation ( p = 0.0005). Ki-67 did not remain an independent statistically significant factor for CSS on multivariate analysis. Age and Ki-67 positivity (both maximal and average values) directly correlated (i.e., advancing age was associated with a higher Ki-67 index). When the patient group was further subdivided by age and timing of RT (postoperative vs. deferred), the prognostic significance of Ki-67 for CSS was lost. Within the deferred RT subgroup, a maximal Ki-67 >2% was associated with a worsened CSS. Within the pediatric population, Ki-67-negative patients had a 5-year CSS and progression-free survival of 100%. The 5-year CSS and progression-free survival declined significantly to 84% and 67% for patients with tumors demonstrating any degree of Ki-67 positivity ( p = 0.005 and p = 0.006, respectively). Conclusion: Ki-67 is a useful predictor of CSS in low-grade gliomas; however, it is not independent of other prognostic factors, particularly age. Although Ki-67 was not helpful in predicting which adult patients were likely to benefit from postoperative RT, the results of the present study indicate a possible utility in the selection of pediatric patients for RT and in the selection of poorer prognosis patients for clinical trials.

Orteronel (TAK-700), a selective oral nonsteroidal inhibitor of 17 alpha-monooxygenase (17, 20 lyase), blocks androgen synthesis of both gonadal and adrenal dehydroepiandrosterone sulfate (DHEA) and androstenedione, reduces testosterone levels in men on a GnRH agonist, and is under investigation for the treatment of prostate cancer. Common side effects include fatigue, nausea and vomiting, constipation and headache (30 %), and are usually mild. Cardiovascular side effects are uncommon. Central nervous system toxicities have not been reported. A 60 year old otherwise well man with locally advanced high-risk adenocarcinoma of the prostate (T4, N0, M0; Gleason 9/10) was treated on RTOG study 1115 with biclutamide (androgen receptor inhibitor) 50 mg po daily, leuprolide acetate (GnRH agonist) 22.5 mg sc every 3 months, and orteronel 300 mg po bid. Pelvic radiotherapy (RT) began 2 months later. Near the end of RT he developed intermittent headaches, hypertension and problems with word finding and reading. Amlodipine did not improve his symptoms. A CT scan showed white matter hypodensity in the left temporal and parietal region. A MRI showed T2 and FLAIR hyperintense signal with mass effect in the left posterior temporal, parietal and occipital white matter regions, sparing the cortex, with no restricted diffusion or gadolinium enhancement, and normal MRA and MRV. A diagnosis of posterior reversible encephalopathy syndrome (PRES) was made. The orteronel was stopped and the neurological symptoms improved within days. A repeat MRI done 6 weeks later showed marked reduction in the extent of white matter abnormalities. Two months after stopping orteronel his symptoms have mostly resolved, but he still describes subtle cognitive problems. This is the first case of PRES associated with orteronel. Patients on orteronel who develop hypertension, headache or neurological symptoms are at risk for PRES. Hypertension should be aggressively treated, and orteronel should be stopped if symptoms persist or PRES is identified on MRI.

INTRODUCTION: Usual treatment for glioblastoma is surgical resection, if possible, followed by radiotherapy with adjuvant chemotherapy using temozolomide. However a significant number of patients have a short response to temozolomide and subsequently a poorer prognosis. We investigated the possibility that surgical specimens obtained at the time of surgery might provide valuable information regarding sensitivity to chemotherapies, including temozolomide. In order to do this we used a 3-dimensional matrix assay that mimics brain. We analyzed a subgroup of these patients for O-6-methylguanine-DNA methyltransferase (MGMT) status and correlated this with the response of tumor tissue in the assay to temozolomide. METHODS: Records for patients treated for newly diagnosed or recurrent glioblastoma were analyzed. All patients had undergone surgical resection and tumor specimens at time of surgery were available for culture in a 3-dimensional matrix assay and observed for growth and invasion. Drug effects on mean invasion and growth were expressed as a ratio relative to control conditions. Length of survival was compared between temozolomide treated patients whose screening results had predicted a positive or negative response to temozolomide. The MGMT status of a subgroup of these patients was analyzed and correlated with the response of tumor tissue in the assay to temozolomide. RESULTS: Fifty-eight patients with glioblastoma were assessed. Each patient's tumor displayed a unique invasion and response profile. We looked in particular at the correlation between the outcome of a patient with glioblastoma treated with temozolomide and the response of that patient's tumor tissue to temozolomide in the 3-dimensional assay. Mean survival time for patients whose tumors were not significantly sensitive to temozolomide in the assay was 181.7 +/- 43 days. Mean survival time for patients whose tumors were significantly sensitive to temozolomide in the assay was 290.0 +/- 33 days. Twelve patients underwent MGMT testing. In 10 of the 12 patients there was a correlation between tumor response in the assay and MGMT status. CONCLUSION: The 3-dimensional assay may help predict glioblastoma patients who will show a treatment response to temozolomide. There appears to be a positive correlation between the response profiles in the assay to the MGMT status of the patient's tumor.

BACKGROUND: (blind field). METHODS: Records for patients treated for newly diagnosed or recurrent glioblastoma were analyzed. All patients had undergone surgical resection and tumor specimens at time of surgery were available for culture in a 3-dimensional matrix assay and observed for growth and invasion. Drug effects on mean invasion and growth were expressed as a ratio relative to control conditions. Length of survival was compared between temozolomide treated patients whose screening results had predicted a positive or negative response to temozolomide. The MGMT status of a subgroup of these patients was analyzed and correlated with the response of tumor tissue in the assay to temozolomide. RESULTS: Fifty-eight patients with glioblastoma were assessed. Each patient's tumor displayed a unique invasion and response profile. We looked in particular at the correlation between the outcome of a patient with glioblastoma treated with temozolomide and the response of that patient's tumor tissue to temozolomide in the 3-dimensional assay. Mean survival time for patients whose tumors were not significantly sensitive to temozolomide in the assay was 181.7 +/- 43 days. Mean survival time for patients whose tumors were significantly sensitive to temozolomide in the assay was 290.0 +/- 33 days. Twelve patients underwent MGMT testing. In 10 of the 12 patients there was a correlation between tumor response in the assay and MGMT status. CONCLUSIONS: The 3-dimensional assay may help predict glioblastoma patients who will show a treatment response to temozolomide. There appears to be a positive correlation between the response profiles in the assay to the MGMT status of the patient's tumor. SECONDARY CATEGORY: n/a.

PCV dans le traitement des tumeurs oligodendrogliales: a la recherche de facteurs pronostiques de la reponse et de la survie. Introduction: Nous rapportons des donnees sur la survie et les facteurs pronostiques de survie et de chimiosensibilite avant traitement chez 53 patients porteurs d'oligodendrogliomes traites par chimiotherapie au PCV (procarbazine, lomustine et vincristine). Methodes: 53 patients porteurs d'un oligodendrogliome prouve par anatomopathologie, un oligodendrogliome anaplasique ou un oligo-astrocytome et traites au PCV ont ete identifies dans le registre du London Regional Cancer Center. Une revue retrospective a ete effectuee pour evaluer la survie generale et les facteurs pronostiques de survie et de chimiosensibilite avant traitement. Resultats: La survie mediane a partir du moment du diagnostic etait de 123.6 mois. Le taux de survie general apres 5 et 10 ans etait de 72.7% et 52.7% respectivement. Un âge inferieur a 40 ans, une crise convulsive comme symptome initial, l'absence de deficit cognitif et la presence d'une lesion hypodense homogene sans rehaussement du contraste au CT scan initial avant traitement etaient tous des facteurs associes de facon independante a un bon pronostic. La presence d'une cellularite accrue, de pleomorphisme, de mitoses, de proliferation vasculaire et le fait que la lesion soit classifiee comme anaplasique au moyen de ces marqueurs a l'examen anatomopathologique ont tous ete associes a un pronostic defavorable a l'analyse univariee. A l'analyse multivariee, seule la classification de la lesion comme etant anaplasique et la presence d'une cellularite accrue etaient des determinants significatifs d'une survie defavorable. Le seul facteur associe negativement a la chimiosensibilite etait la presence d'un symptome focal comme mode de presentation. Conclusion: La survie generale est significativement plus longue chez les patients atteints de lesions oligodendrogliales que chez ceux qui ont des tumeurs astrocytaires fibrillaires. Un systeme de classification a deux niveaux base sur les caracteristiques morphologiques standards semble fournir un pronostic precis chez ces patients. La presence d'une composante astrocytaire neoplasique ne semble pas influencer le pronostic. Aucun facteur clinique, radiologique ou anatomopathologique predisant la reponse a la chimiotherapie n'a pu etre identifie.

PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation. PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m2/d to 1.0 mg/m2/d to 1.5 mg/m2/d in different patient groups. RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m2/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m2/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m2/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule. CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m2/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.