Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

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.

Pemetrexed in Recurrent or Progressive Central Nervous System Lymphoma: A Phase I Multicenter Clinical Trial.

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.

Early changes in glioblastoma metabolism measured by MR spectroscopic imaging during combination of anti-angiogenic cediranib and chemoradiation therapy are associated with survival.

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.

Impact of histopathological transformation and overall survival in patients with progressive anaplastic glioma.

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. 10.9years, p=0.0005) and second surgery (1.0 vs. 3.5years, 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. 1.4years, p=0.008) and OS (median 10.0 vs. 4.2years, 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.

Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study.

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.

Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors.

BACKGROUND: 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. METHODS: 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. RESULTS: Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 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. CONCLUSIONS: 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.

A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases.

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 <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.

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.

Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma.

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.

Randomized controlled trial of a video decision support tool for cardiopulmonary resuscitation decision making in advanced cancer.

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.

Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.

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.

Brain metastases.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Initial treatment patterns over time for anaplastic oligodendroglial tumors.

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.

International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors.

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.

The biology of brain metastases-translation to new therapies.

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.

Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide.

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.

EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer.

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.

Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma.

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-1alpha, 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.

Use of video to facilitate end-of-life discussions with patients with cancer: a randomized controlled trial.

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.

Leukodystrophies: classification, diagnosis, and treatment.

BACKGROUND: 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. REVIEW SUMMARY: 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. CONCLUSIONS: 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.