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INTRODUCTION High-grade meningiomas are associated with significant neuro-cognitive morbidity and a poor prognosis. Systemic therapies, to date, have demonstrated minimal efficacy. We recently found that high-grade meningiomas harbor an immunosuppressive tumor microenvironment and that programmed cell death-ligand 1 (PD-L1) expression may contribute to the aggressive phenotype of these tumors. Therefore, we conducted a single-arm, open-label phase II trial evaluating efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 24 patients with recurrent and progressive grade II and III meningiomas. METHODS The primary endpoint was the rate of progression-free survival at 6 months. The trial distinguished between 6-month PFS (PFS-6) rates of 26% vs. 52%. If at least 10 patients demonstrated a 6-month PFS, among the 24 patients, the agent would be considered worthy of further study. This design has at least 88% power using an exact binomial test with a one-sided significance level of 0.1. RESULTS Between November 2017 to December 2019, twenty-four patients were enrolled. The majority of the patients in our cohort were heavily pre-treated; prior to enrolling to the study, twenty patients underwent more than one surgical resection and twelve patients had received more than one round of radiotherapy. Our study met its primary endpoint and achieved a 6-month progression-free survival rate of 0.50 (90% exact CI: 0.32-0.68) and a median PFS of 8.3 months (90% CI: 4.1-12.9 months). For the twelve patients who achieved the PFS-6 primary endpoint, median PFS from the start of treatment was 17.3 months (90% CI: 9.7 – 24.3 months). Four patients had grade-3 or higher adverse events that were at least possibly treatment-related, including colitis, skin infection, encephalopathy and transaminitis. CONCLUSION Our study achieved its primary endpoint. These results suggest that pembrolizumab exerts promising activity on these tumors and results in prolonged PFS compared to historical controls.

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results., Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31–0.66) and a median PFS of 7.6 months (90% CI: 3.4–12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). Results: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Lessons Learned The findings from this study using monotherapy with pemetrexed in a pretreated patient population are, overall, encouraging. Unlike high-dose methotrexate, which requires several days of inpatient hospitalization, pemetrexed is relatively easy to administer in the outpatient setting and remains a viable treatment option in this patient population. The maximum tolerated dose of pemetrexed administered (900 mg/m2 every 2 weeks) was generally well tolerated and showed activity in patients with relapsed or refractory CNSL. Background There is currently no standard salvage treatment for patients with relapsed/refractory central nervous system (CNS) lymphoma (CNSL). We report the results of a phase I study of pemetrexed, an antifolate drug with broader activity than methotrexate (MTX). We provide the safety, tolerability, and maximum tolerated dose (MTD) of pemetrexed in patients with recurrent CNSL. Methods Through October 2015, 17 patients with relapsed/refractory CNSL received pemetrexed every 2 weeks with the first cohort receiving 600 mg/m2 and dose escalation in increments of 300 mg/m2 to a maximum of 1,200 mg/m2. Three patients were to enroll at each dose level with expansion to six patients in the event of dose-limiting toxicity. Patients with both primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) could be enrolled. Results Seventeen patients were evaluable with a median age of 63.7 years. Main adverse events included fatigue (82.4%), anemia (82.4%), and neutropenia (70.6%). The MTD was established at 900 mg/m2. Dose-limiting toxicities were recorded in one patient in the 600 mg/m2 cohort and in two patients in the 1,200 mg/m2 cohort. Fourteen patients were evaluable for response assessment; 21.4% achieved a complete response, 35.7% had a partial response, 14.3% had stable disease, and 28.6% had progressive disease. The median progression-free survival was 4.2 months. The median overall survival was 44.5 months. In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study. Conclusion Pemetrexed administered at 900 mg/m2 every 2 weeks exhibits single-agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are manageable.

Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood–brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan–Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85, P = 0.006) in Cox proportional hazards model, (3) the largest separation (P = 0.004) in Kaplan–Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma., Metabolic imaging reveals anti-angiogenic (AA) therapy mechanisms in glioblastoma (GBM) GBM is the most common and aggressive type of malignant primary brain tumors (glioma). Patients with GBM have less than 5% survival at 5 years with the best existing treatment and progress is desperately needed to improve patient outcome. Imaging can guide development and clinical translation of new treatments, and can help to understand mechanisms of response and to optimize drug regimens in patients. AA therapy that targets the blood supply of tumors can benefit GBM patients as adjuvant therapy to standard chemoradiation, but the timing of combination therapy may be important to obtain the maximum benefit and minimize negative side effects. Tracking metabolic changes with magnetic resonance spectroscopic imaging (MRSI) during a phase II clinical trial of AA drug cediranib combined with chemoradiation shows that there is a therapeutic window within the first month where there is maximal synergy between the effects of the anti-angiogenesis and chemoradiation. Our data suggest that adjusting the dose of AA therapy during chemoradiation may be beneficial, and MRSI can be used as a precision medicine tool to identify the patients and time for adjusting the combination treatment.

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.

Purpose: GRN1005 is a peptide–drug conjugate with the ability to penetrate the blood–brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor–related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. Methods: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. Results: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m2 every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m2 every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥420 mg/m2 had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥200 mg/m2. Conclusion: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m2 every 3 weeks. Clin Cancer Res; 19(6); 1567–76. ©2013 AACR.

Purpose Decision making regarding cardiopulmonary resuscitation (CPR) is challenging. This study examined the effect of a video decision support tool on CPR preferences among patients with advanced cancer. Patients and Methods We performed a randomized controlled trial of 150 patients with advanced cancer from four oncology centers. Participants in the control arm (n = 80) listened to a verbal narrative describing CPR and the likelihood of successful resuscitation. Participants in the intervention arm (n = 70) listened to the identical narrative and viewed a 3-minute video depicting a patient on a ventilator and CPR being performed on a simulated patient. The primary outcome was participants' preference for or against CPR measured immediately after exposure to either modality. Secondary outcomes were participants' knowledge of CPR (score range of 0 to 4, with higher score indicating more knowledge) and comfort with video. Results The mean age of participants was 62 years (standard deviation, 11 years); 49% were women, 44% were African American or Latino, and 47% had lung or colon cancer. After the verbal narrative, in the control arm, 38 participants (48%) wanted CPR, 41 (51%) wanted no CPR, and one (1%) was uncertain. In contrast, in the intervention arm, 14 participants (20%) wanted CPR, 55 (79%) wanted no CPR, and 1 (1%) was uncertain (unadjusted odds ratio, 3.5; 95% CI, 1.7 to 7.2; P < .001). Mean knowledge scores were higher in the intervention arm than in the control arm (3.3 ± 1.0 v 2.6 ± 1.3, respectively; P < .001), and 65 participants (93%) in the intervention arm were comfortable watching the video. Conclusion Participants with advanced cancer who viewed a video of CPR were less likely to opt for CPR than those who listened to a verbal narrative.

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981–2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980–1984 vs 5% in 2005–2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980–1984 vs 38% in 2005–2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005–2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005–2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.

Brain metastases are the most common neurologic complication related to systemic cancer. With continued improvements in systemic treatment, the incidence is expected to increase. This article reviews the clinical presentation, pathophysiology, prognostic factors, and treatment of metastatic brain tumors.Brain metastases from systemic cancer are up to 10 times more common than primary malignant brain tumors and are a significant burden in the management of patients with advanced cancer. Common presenting symptoms include headache, focal weakness or numbness, mental status change, and seizure. Management and treatment of metastatic brain tumors is complex and dependent on several factors, including age, performance status, number of metastases at presentation, and status of systemic disease. At the time of diagnosis, most patients have more than one brain metastasis, and treatment has traditionally consisted of whole-brain radiation therapy (WBRT). For those patients with single brain metastases, aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT has been shown to improve survival and neurologic outcomes compared with WBRT alone. In patients with a limited number of brain metastases, SRS alone is being increasingly explored as a treatment option that spares the upfront toxicity of WBRT. Currently, the role of chemotherapy is limited to experimental settings and salvage after radiation therapy.Patients with brain metastases have complex needs and require a multidisciplinary approach in order to optimize intracranial disease control while maximizing neurologic function and quality of life. Patients with multiple metastases, uncontrolled systemic disease, and poor functional status are typically treated with WBRT alone, whereas surgery and SRS may be used for additional local control in a subset of patients with fewer tumors and good functional status. The incorporation of neuropsychological outcomes, neurologic function, and quality of life as end points in future studies will offer further guidance for providing comprehensive care to patients with metastatic brain tumors.

Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood–brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood–tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.

Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.

The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter. Symptomatic patients are frequently misdiagnosed and the leukodystrophies are collectively under recognized. However, with ongoing research and increased availability of neuroimaging, our understanding of these diseases is increasing at a steady rate. Recent advances in the diagnosis and treatment of certain forms of leukodystrophy should prompt increased awareness of these diseases in clinical practice.The clinical features, pathophysiology, and therapeutic approach to these diseases are described. Particular emphasis is placed on genetic and pathophysiologic mechanisms, imaging patterns, screening of other family members and, where available, treatment options and resources.With more widespread use of neuroimaging, both pediatric and adult neurologists will increasingly be confronted with white matter disorders. Neurologists should have an approach to the recognition, diagnosis, and management of white matter diseases in general and the leukodystrophies in specific.

Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9 years, p = 0.0005) and second surgery (1.0 vs. 3.5 years, p < 0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4 years, p = 0.008) and OS (median 10.0 vs. 4.2 years, p = 0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population.

Methotrexate (MTX) is a widely used chemotherapeutic agent that can cause acute, subacute, and chronic neurological complications. Subacute MTX neurotoxicity is manifest by abrupt onset of focal cerebral dysfunction occurring days to weeks after MTX administration, usually in children. We describe the neuroimaging features of an adult patient with primary CNS lymphoma who presented with transient aphasia and right hemiparesis 12 days after receiving intravenous high-dose MTX (8 g/m2) chemotherapy. Imaging within 1 h of symptom onset showed bilateral symmetrical restricted diffusion involving white matter of the cerebral hemispheres. CT angiogram and dynamic susceptibility MRI showed no evidence of vasospasm or perfusion defect. MRI five days later showed near-complete resolution of the abnormalities. MRI 3(1/2) months later showed normal diffusion but new hyperintense T2-weighted signal changes in the subcortical white matter corresponding to previous areas of restricted diffusion. The absence of vascular or perfusion abnormalities suggests that transient cytotoxic edema in white matter may explain the syndrome of subacute MTX neurotoxicity.

✓ Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that affects the brain, spinal cord, leptomeninges, and eyes. The clinical presentation and neuroimaging appearance of PCNSL differ in immunocompetent patients and in those with acquired immunodeficiency syndrome (AIDS). A magnetic resonance (MR) image of the brain in immunocompetent patients with PCNSL typically demonstrates one or more homogeneously enhancing lesions located in the periventricular white matter, characteristically spanning the corpus callosum. In patients with AIDS, multiple ring-enhancing lesions are more common. After neuroimages raising the suspicion of PCNSL are obtained, a definitive diagnosis should be established in both immunocompetent and AIDS patients by performing pathological analysis of cerebrospinal fluid (CSF), vitreous fluid, or a biopsy specimen. Brain biopsy sampling remains the gold standard for PCNSL diagnosis in all patients, although the possibility of establishing routine, minimally invasive diagnostic procedures in which Epstein–Barr virus polymerase chain reaction (PCR) analysis of the CSF and nuclear imaging are used is currently under investigation in the population of patients with AIDS. At the time of diagnosis, the patient should undergo further evaluation, which should include a physical examination, ophthalmic evaluation with a slit-lamp examination, serum lactate dehydrogenase levels, human immunodeficiency virus testing, computed tomography scans of the chest/abdomen/pelvis, bone marrow biopsy sampling, contrast-enhanced brain MR imaging, and lumbar puncture (LP). Testicular ultrasonography studies should be considered in men. In patients who cannot undergo LP or in those with evidence of spinal cord dysfunction, contrast-enhanced MR imaging of the entire spine should be considered.

Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.

The GA733-2 gene encodes the epithelial glycoprotein 40, a homophilic cell-cell adhesion molecule, which is expressed on the surface of epithelial cells and associated with a variety of carcinomas, e.g. breast, colorectal and lung carcinomas. To test if it could serve as a tumor marker, we have analysed the expression of GA733-2 in bone marrow (BM) and peripheral blood (PB) from healthy donors, and of patients with haematological malignancies or breast cancer using reverse transcriptase-polymerase chain reaction (RT-PCR). The GA733-2 nested PCR was positive in 100% (8/8) of BM and 40% (16/40) of PB from healthy donors, in 100% (33/33) of BM from patients with breast cancer who had no evidence of distant metastases and also in BM and PB from patients with haematological malignancies. GA733-2 mRNA is not specific as a marker for the detection of breast cancer cells in BM and PB.

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1–8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if

ZusammenfassungGegenstand dieser Arbeit waren tierexperimentelle Untersuchungen zur Biodistribution und Immunszintigraphie der Anti-Muzin-MoAbs 12H12 und BM-7 in thymusaplastischen Nacktmäusen mit xenotransplantierten humanen Mammakarzinomen. Die MoAb waren mit 99mTc markiert; ihre Biodistribution wurde im Tiermodell 24 und 48 h nach i. v. Injektion untersucht. Die 99mTc-Markierungen der MoAbs 12H12 und BM-7 führten zu einer Tumoranreicherung von 20,7% bzw. 8,8% ID/g und zu Tumor/Muskel-Quotienten von 31 bzw. 18 nach 48 h. Im-munszintigraphisch ließ sich mit beiden MoAbs nach 24 h das Mammakarzinom AR gut darstellen. Die beiden MoAbs erfahren im Tiermodell eine schnelle Tumoraufnahme und rasche Blut-Clearance.

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 ( HER2 )–amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2 -amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti–VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2 -amplified breast cancer brain metastases.

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30-0.82), age (HR: 1.03, 95% CI: 1.00-1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70-6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.

Purpose Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Methods Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Conclusion Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.

Purpose To determine whether the use of a goals-of-care video to supplement a verbal description can improve end-of-life decision making for patients with cancer. Methods Fifty participants with malignant glioma were randomly assigned to either a verbal narrative of goals-of-care options at the end of life (control), or a video after the same verbal narrative (intervention) in this randomized controlled trial. The video depicts three levels of medical care: life-prolonging care (cardiopulmonary resuscitation [CPR], ventilation), basic care (hospitalization, no CPR), and comfort care (symptom relief). The primary study outcome was participants' preferences for end-of-life care. The secondary outcome was participants' uncertainty regarding decision making (score range, 3 to 15; higher score indicating less uncertainty). Participants' comfort level with the video was also measured. Results Fifty participants were randomly assigned to either the verbal narrative (n = 27) or video (n = 23). After the verbal description, 25.9% of participants preferred life-prolonging care, 51.9% basic care, and 22.2% comfort care. In the video arm, no participants preferred life-prolonging care, 4.4% preferred basic care, 91.3% preferred comfort care, and 4.4% were uncertain (P < .0001). The mean uncertainty score was higher in the video group than in the verbal group (13.7 v 11.5, respectively; P < .002). In the intervention arm, 82.6% of participants reported being very comfortable watching the video. Conclusion Compared with participants who only heard a verbal description, participants who viewed a goals-of-care video were more likely to prefer comfort care and avoid CPR, and were more certain of their end-of-life decision making. Participants reported feeling comfortable watching the video.

Purpose: Loss of chromosome arms 1p and 19q is a molecular feature of oligodendroglial tumors characterized by responsiveness to chemotherapy and a favorable prognosis. The purpose of this study was to evaluate the prognostic significance of polysomy of chromosomes 1 and 19 in the setting of 1p/19q codeletion.Experimental Design: We analyzed 64 anaplastic oligodendrogliomas with 1p/19q loss or maintenance diagnosed at Massachusetts General Hospital and Brigham and Women's Hospital from 1996 to 2005; fluorescence in situ hybridization for 1p/19q and Ki-67 immunohistochemistry was done. Polysomy was defined as more than two 1q and 19p signals in >30% of the cells with concurrent 1p/19q deletion. Tumors were divided into groups based on their 1p/19q status and compared for progression-free survival, overall survival, and 5-year survival probabilities.Results: Forty-six tumors (72%) in our cohort had 1p/19q loss and 18 (28%) had 1p/19q maintenance. Of those with loss, 19 (41%) had concurrent polysomy and 27 (59%) lacked polysomy. In agreement with previous studies, the group of anaplastic oligodendrogliomas with 1p/19q loss had significantly better progression-free survival and overall survival than anaplastic oligodendrogliomas with 1p/19q maintenance (P = 0.0009 and P < 0.0003, respectively). Among anaplastic oligodendrogliomas with 1p/19q loss, those with polysomy showed shorter progression-free survival than those with 1p/19q loss without polysomy (P = 0.0048). Overall survival was similar in tumors with and without polysomy. The Ki-67 labeling index was not associated with polysomy and did not have prognostic significance.Conclusion: The presence of polysomy in anaplastic oligodendrogliomas with deletion of 1p/19q is a marker of earlier recurrence. (Clin Cancer Res 2009;15(20):6430–7)

In this study, we sought to determine the accuracy with which the International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) diagnosis code for "secondary neoplasm of brain and spinal cord" in health insurance claims measures clinically evident central nervous system (CNS) metastases in patients with non-small cell lung cancer (NSCLC). For 241 consecutive patients with newly diagnosed NSCLC, we compared ICD-9-CM "secondary neoplasm" codes indicating tumor spread to the CNS from institutional billing records to gold-standard chart review to determine: (1) sensitivity, specificity and positive predictive value (PPV) of the site-specific secondary neoplasm code and (2) the accuracy in time of its appearance within billing records compared with the gold standard date of CNS relapse. The occurrence of at least one ICD-9-CM code for brain metastasis (Algorithm 1) had a sensitivity of 100% (95% CI: 100-100%) and PPV of 91% (95% CI: 87-94%). By requiringor= 2 codes (Algorithm 2) oror= 3 codes (Algorithm 3) for the diagnosis of brain metastasis in claims, specificity and PPV improved, while sensitivity did not drop substantially. The claims-based date of diagnosis was also accurate, with 92% of dates falling within 30 days of the gold standard. ICD-9-CM codes in institutional billing claims reliably documented NSCLC metastases to the CNS. These results suggest that Medicare claims data may be used to evaluate clinical and epidemiological issues related to brain metastases in elderly cancer patients.

Metastatic brain tumors are the most common intracranial neoplasm in adults, affecting up to 10% of adults with cancer in the United States. The risk of developing brain metastases varies by primary cancer type, with lung cancer, breast cancer, and melanoma accounting for the majority. The incidence of brain metastases appears to be rising because of several factors, including an aging population, better treatment of systemic disease, and improved cranial imaging techniques. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Many patients are treated with a combination of these, and treatment decisions must take into account clinical prognostic factors in order to maximize survival and neurologic function while avoiding unnecessary treatments. WBRT remains the most widely used treatment for patients with brain metastases. Although many radiation sensitizers have been studied over the years, none has emerged for widespread use. For patients with a limited number of brain metastases and favorable prognostic factors, local therapies such as surgery and SRS improve control rates and may extend survival compared with WBRT alone. SRS can also be used effectively at recurrence in patients with a limited number of lesions. Chemotherapy has traditionally played only a salvage role for brain metastases when all other treatments have failed, but research is likely to increasingly focus on systemic options such as targeted agents and angiogenesis inhibitors, as well as on novel delivery techniques and multidrug resistance pathways specific to brain in order to expand treatment options for this growing population of patients.

BACKGROUND Brain metastases (BM) are the most common intracranial tumors in adults. To the authors' knowledge, established prognostic factors for survival after the diagnosis of BM in breast cancer patients do not take into account HER–2 status, which may have increasing relevance in the trastuzumab therapy era. METHODS The authors identified 83 patients with breast cancer and new parenchymal BM diagnosed between January 1, 2001 and December 31, 2005 who were treated at Massachusetts General Hospital. Survival was estimated using the Kaplan-Meier method and curves were compared using the log-rank test. A Cox proportional hazards model was used to determine independent predictors of survival. RESULTS The median overall survival from the time of BM was 8.3 months. On univariate analysis, HER-2-positive patients were found to have prolonged survival after BM compared with HER-2-negative patients (17.1 months vs 5.2 months). Patients with triple negative disease had a median survival of 4.0 months, compared with 11.2 months for all other patients. Additional predictors of improved survival on univariate analysis included ≤3 BM, controlled or absent systemic disease, and controlled local disease. On multivariate analysis, only HER-2 status, number of BM, and local disease status remained independent predictors of survival. CONCLUSIONS HER-2 status is a strong predictor of survival after the diagnosis of BM. The survival of breast cancer patients with BM appears to be improving, but a better understanding of both the predictors of brain recurrence and the delayed effects of treatment is needed to properly counsel patients regarding the risk-benefit ratio of various treatment modalities. Cancer 2008. © 2008 American Cancer Society.

In Reply to Weltman and Fleury Malheiros: We thank Drs. Weltman and Fleury Malheiros for their comments on our recent article.1 We agree that our analyses were performed on a retrospective dataset, and interpretations are thus subject to limitations and potential biases inherent to any retrospective study. For example, as we discussed in the article, neither central review of pathology nor imaging was performed. Multivariate analyses attempted to control for potential confounding variables, but only a randomized prospective study would definitively address this concern. However, we believe that our conclusions (and cross-comparisons) are supported not only by our own observations but also by recent data and treatment trends in neuro-oncology. For example, in our study, treatment group imbalances did not contribute to differences in outcome in the Cox model. Groups were reasonably well balanced for potential confounders, such as performance status. In addition, Weltman and Fleury Malheiros suggest that standard of care for anaplastic oligoendrogliomas includes radiotherapy as part of the initial treatment regimen. We agree that radiotherapy has well-established efficacy and, for many years, was the standard approach. However, treatment options have evolved since the initial studies during the 1960s–1980s cited by Drs. Weltman and Malheiros. It is now well established that oligodendrogliomas, especially those harboring 1p19q co-deletion, respond to chemotherapy. For example, the recently publicized long-term follow-up of RTOG 9402 demonstrated that chemo-radiotherapy doubled median survival relative to radiotherapy alone in 1p19q co-deleted cases (14.7 vs. 7.3 years).2 Moreover, the German NOA-04 trial of newly diagnosed anaplastic gliomas also suggested that primary chemotherapy is equi-efficacious as primary radiotherapy.3 Furthermore, survival with 1p19q codeleted anaplastic oligodendrogliomas is at least several years. Accordingly, radiotherapy-induced dementia as a late toxicity4 is a real concern. Consequently, many neuro-oncologists advocate for chemotherapy alone and defer radiotherapy until disease progression in 1p19q codeleted cases. The same concern is well established in the controversies surrounding late neuro-cognitive toxicity from early radiotherapy in the treatment of low-grade gliomas, primary central nervous system lymphoma, and resected brain metastases. Therefore, the acknowledged limitations of our retrospective design notwithstanding, our results are concordant with these studies suggesting that overall survival was not compromised by deferring radiotherapy.1 Absent a clear survival advantage, deferred radiotherapy in favor of chemotherapy alone is certainly a reasonable initial strategy. We are not alone. For example, 42% of neuro-oncologists surveyed in 2005 recommended deferring radiotherapy in codeleted cases.5 Similarly, 57% of patients in our retrospective dataset who receive a diagnosis of codeleted tumors since 2005 were treated with chemotherapy alone (almost exclusively temozolomide).6 Therefore, as stated in our publication, “subject to the limitations of study design, our data suggest that initial treatment with chemotherapy alone may be a reasonable option for patients with 1p19q codeleted tumors.”1 Regardless of advised therapy, in our clinical experience, many patients refuse radiotherapy because of perceived concerns about neuro-toxicity. Therefore, although ongoing or future prospective studies may show that deferred radiotherapy adversely affects survival, concerns about cognitive injury are important in determining optimal therapy, and survival may not be the only end point of clinical importance. The CATNON or CODEL phase III trials (for non- or codeleted anaplastic gliomas, respectively) may help to assess quality of life outcomes. Clearly, neuro-oncology is a multidisciplinary field, and treatment requires individualization that depends on discussion among both physicians and patients of risks and benefits of various strategies.

BACKGROUND: (blind field). METHODS: We evaluated MRI markers in 84 GBM patients enrolled in phase 2 trials (NCT00305656, NCT00662506) to investigate the mechanisms of tumor response to anti-VEGF treatment. Forty newly diagnosed GBM (nGBM) patients were treated with the oral pan-VEGFR inhibitor, cediranib, in combination with radiation and temozolomide. Fourteen nGBM patients were treated with radiation and temozolomide alone. Thirty recurrent GBM (rGBM) patients were treated with cediranib alone. All patients underwent serial brain MRI scans at uniform time points. RESULTS: In both the nGBM and rGBM cohorts treated with cediranib, increased tumor perfusion was observed in 20/40 and 7/30 patients, respectively. In contrast, in the nGBM cohort not treated with cediranib increased tumor perfusion was observed in 1/14 patients. Increased tumor perfusion was associated with improved overall survival in nGBM (p = 0.040) and rGBM (p = 0.009) patients. Moreover, increased perfusion was associated with improved tumor oxygenation status in patients the nGBM patients treated with cediranib and chemoradiation. These findings are consistent with a recent report in rGBM patients treated with bevacizumab. CONCLUSIONS: Anti-VEGF therapy confers clinical benefit to GBM patients by normalization of tumor vessels. We hypothesize that the subset of GBM subjects who experience increased perfusion and improved tumor oxygenation status after anti-VEGF therapy will derive optimal benefit from concurrent chemoradiation and innate anti-tumor immune mechanisms. MRI techniques may enable early identification of GBM patients most likely to benefit from this expensive, and potentially toxic, class of anti-cancer drugs. SECONDARY CATEGORY: Imaging.

Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas (GBMs), but tumors invariably recur. Because tumor-associated macrophages (TAMs) have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of TAMs in recurrent glioblastoma (rGBM) patients. We compared autopsy brain specimens from 20 rGBM patients who received antiangiogenic treatment and chemoradiation (AAT+) to 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry (IHC) for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in TAMs in the AAT+ patients. IHC analysis demonstrated an increase in CD68+ TAMs in the tumor bulk (p Citation Format: Christine Lu-Emerson, Matija Snuderl, Nathaniel D. Kirkpatrick, Jermaine Goveia, Jennie Taylor, Christian Davidson, Yuhui Huang, Lars Riedemann, S. Percy Ivy, G. Dan Duda, Marek Ancukiewicz3, Scott R. Plotkin, Andrew Chi, Elizabeth R. Gerstner, April F. Eichler, Jorg Dietrich, Anat O. Stemmer-Rachamimov, Tracy T. Batchelor, Rakesh K. Jain. Increase in tumor-associated macrophages (TAMs) after antiangiogenic therapy is associated with poor survival in recurrent glioblastoma (GBM) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-339. doi:10.1158/1538-7445.AM2013-LB-339

9004 Background: End-of-life decision-making is important to patients, including whether or not to attempt cardiopulmonary resuscitation (CPR). Doctors often rely solely on verbal descriptions to communicate information regarding CPR. Video decision support tools have the potential to improve patients’ understanding of CPR by providing visual images of what this intervention entails. The objective of this study was to examine the effect of a CPR video among patients with advanced cancer on their preferences and knowledge of CPR. Methods: A randomized controlled trial of 150 subjects with diverse advanced cancers (< 1-year prognosis) recruited from 4 cancer centers in the United States. Subjects were randomized to either a verbal narrative describing CPR, or to a video with verbal narrative. The video depicts CPR and reviews the success rate in advanced cancer. Study endpoints were subjects’ CPR preferences, knowledge of CPR (knowledge scores ranged from 0-4, higher score indicating more knowledge), and perceived value of the video. Chi-square tests were used to compare the distributions of categorical outcomes and two-sample t-tests were used to compare the means between the two groups. Results: A total of 150 subjects were randomized to a verbal narrative (n=80) or video with verbal narrative (n=70). Mean age was 62, 49% were women, 47% White, 34% Black, and 47% had lung or colon cancer. Among subjects receiving the verbal narrative, 38 (47.5%) preferred to have CPR attempted; 41 (51.2%) chose not to have CPR; and 1 (1.3%) was uncertain. In the video group, 14 (20%) preferred to have CPR attempted; 55 (78.6%) chose not to have CPR; and 1 (1.4%) was uncertain (P

2009 Background: Anti-angiogenic therapy is hypothesized to synergize with radiation and chemotherapy by improving tumor blood flow. We evaluated the tolerability, efficacy and potential mechanism of action of radiation, temozolomide, and cediranib in newly diagnosed glioblastoma patients. Methods: Newly diagnosed glioblastoma patients were treated with radiation, temozolomide, and cediranib followed by monthly temozolomide for 6 cycles and daily cediranib until tumor progression or toxicity as part of an IRB-approved, Phase Ib/II clinical trial. MRI scans including measurement of cerebral blood flow were performed at baseline, weekly during the 6 weeks of chemoradiation and then monthly. Radiographic response was determined by RANO criteria. Results: Six patients were enrolled in the phase Ib part of the study with cediranib 30 mg daily in combination with temozolomide and radiation. No dose-limiting toxicities were identified. Forty patients were enrolled in the phase II part of the study. Among the entire cohort of 46 patients, median age was 57 (range 35-74), median KPS was 90% (60-100), 36 patients underwent a subtotal resection and 10 underwent biopsy. 26/30 patients taking corticosteroids were able to taper corticosteroids during chemoradiation. Off study reasons included toxicity (14), disease progression (18), and patient preference (2). Five patients remain on study without disease progression and 20 patients have died. Median duration on study was 158 days. Median progression free survival was 288 days (95%CI 240,∞) and median overall survival was 786 days (95%CI 411 ,∞). Best radiographic response in patients who completed chemoradiation was CR in 2 patients, PR in 20 patients, and SD in 15 patients. Patients with increased tumor perfusion during chemoradiation survived nearly 1 year longer (mean OS=611 days) than patients with decreased perfusion (mean OS=269 days). Conclusions: Cediranib was well tolerated and led to improved PFS and OS compared to historical controls, particularly in those with improved perfusion. This combination is being evaluated in an ongoing randomized trial (RTOG 0837).

TPS177 Background: Brain metastases (BM) are common in patients with non-small cell lung cancer (NSCLC), and whole-brain radiation therapy (WBRT) is associated with only modest benefit in many pati...

7542 Background: Non-small cell lung cancer (NSCLC) is the most frequent site of origin for brain metastases (BM), which affect 30%-40% of pts with advanced disease. A small subset of pts with NSCLC harbor mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyroskine kinase inhibitors (TKIs). The characteristics and behavior of BM in this population have not been well described. Methods: From August ‘04 to November ‘08, 373 NSCLC pts underwent EGFR mutation screening at our center; 93 of these developed BM at some time during their course. Clinical and treatment variables were collected by chart review. Survival was estimated using the Kaplan-Meier method and log-rank test. Multivariate predictors were assessed via Cox proportional hazards models. Results: Among the 93 pts with BM, 41 (44%) had an EGFR mutation, including 13 exon 19 del and 12 L858R. Brain was the first site of metastasis in 55/93 pts (59%) and the proportion did not differ by mutation status. ...

2012 Background: TMZ and radiotherapy (RT) improve survival in patients with glioblastoma multiforme. However, DNA repair mechanisms confer resistance to these therapies. Inhibition of PARP1, a cri...

Abstract 1672 Poster Board I-698 Introduction PCNSL is a rare form of non-Hodgkin lymphoma. High-dose methotrexate (HD-MTX) is the backbone of therapy but uncertainty remains about what additional chemotherapies should be added to HD-MTX to improve response rates. Methods After receiving IRB consent, we retrospectively evaluated patients with PCNSL treated at our hospital with combination M/R/T at initial diagnosis or at relapse. Patients were treated in 28-day induction cycles as follows: HD-MTX (8g/m2- dose adjusted based on creatinine clearance) on days 1 and 15; rituximab (375 mg/m2) on days 3, 10, 17, and 24; and temozolomide (150-200 mg/m2) on days 7-11. HD-MTX was given every 2 weeks until complete response (CR) and for 2 additional treatments followed by monthly maintenance treatments for 11 months. Rituximab was given weekly for a total of 8 weeks. Temozolomide was continued for 6 months after CR. Brain MRI was done after every other methotrexate treatment to assess response. Results Sixteen patients were treated between February 2006 and August 2009. Ten patients received MRT as first-line therapy at the time of initial diagnosis and 6 received MRT as salvage therapy at first or second recurrence. The median age of newly diagnosed patients was 58 (range 47-76) and of relapsed patients was 60 (range 46-76). CSF cytology was atypical in 5/15 patients who underwent lumbar puncture (4 first-line, 1 relapse). After first-line therapy, there were 9 CRs (median cycles to CR = 3) and 1 PR (patient still receiving induction treatment). After salvage therapy, there were 4 CRs (median cycles to CR = 4) and 2 PRs (both patients died while receiving treatment- 1 from an unrelated myocardial infarction). With a median follow-up of 10.3 months in the first-line group and 7.2 months in the relapse group, only 3 patients have progressed; one of whom had clinical progression after a PR and a second who relapsed in the skin. Treatment was well tolerated with reversible grade 4 transammonitis in 1 patient and grade 3 hematological toxicities in 8 patients. One patient experienced grade 4 thrombocytopenia related to temozolomide requiring dose reduction for subsequent cycles. Conclusions Combination MRT is well tolerated and resulted in a promising early response rate. The median number of cycles needed to achieve a CR for patients with newly diagnosed PCNSL was less than the 6 cycles we have previously reported for HD-MTX monotherapy suggesting that adding rituximab and temozolomide is beneficial to patients. This combination warrants further evaluation in larger scale, prospective studies. Disclosures Off Label Use: temozolomide and rituximab for PCNSL..

2035 Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs. [Table: see text]

e13010 Background: Pre-clinical evidence suggests antiangiogenic therapy combined with radiation therapy (RT) and chemotherapy may improve tumor control in patients with glioblastoma (GBM). We conducted a phase Ib study to evaluate the safety and maximum tolerated dose (MTD) of the combination of cediranib, a potent pan-VEGF receptor tyrosine kinase inhibitor, standard RT, and temozolomide (TMZ) in patients with newly diagnosed GBM who were not taking enzyme-inducing antiepileptic drugs (EIAED). Methods: After undergoing tumor biopsy or resection, six patients with pathologically confirmed GBM were treated with concurrent TMZ (75mg/m2/day), RT (60 Gy) and cediranib (dose level 1 = 20mg/day; dose level 2 = 30mg/day) followed by post-radiation TMZ (150–200 mg/m2 on days 1–5 of each 28 day cycle) and cediranib (45mg/day) for up to 6 monthly cycles. Cediranib was started concurrently with RT and TMZ 14–21 days after surgery. Results: Six patients were treated (cediranib 20mg = 3 patients; cediranib 30mg = 3 patients). No patients experienced a DLT, establishing the MTD for cediranib in combination with RT and TMZ as 30mg/day in this patient population. Expected toxicities of hypertension, fatigue, and palmar/plantar erythema were observed. During combined cediranib and TMZ therapy in the post-radiation setting, one patient discontinued cediranib because of toxicity (grade 3 transaminase elevation) and one patient required dose reduction to 15mg/day due to grade 3 proteinuria. No intratumoral or intracerebral hemorrhages were observed during the course of cediranib treatment. No cases of wound infection or wound dehiscence were observed. All patients are alive with a median follow-up of 156 days. Conclusions: Cediranib given in combination with standard RT and TMZ for newly diagnosed GBM patients not on EIAEDs is well tolerated and the MTD is 30mg/day. The phase II component of this trial is underway and will include correlative biomarker and MRI studies. [Table: see text]

Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication.We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis.Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age60 y, 1p19q codeleted), class II (age43 y, not codeleted), class III (age 43-59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43-59 y, not codeleted, not frontal lobe tumor or age 60-69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P.0001), with medians ranging from 9.3 years (95% CI: 8.4-16.0) for class I to 0.6 years (95% CI: 0.5-0.9) for class V.These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome.