Long-term Outcomes in Primary CNS Lymphoma After R-MVP and High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplant.

BACKGROUND AND OBJECTIVES: Primary CNS lymphoma (PCNSL), a rare CNS malignancy, is usually treated with high-dose methotrexate in the first-line setting, typically followed by consolidation therapy. Due to the broad range of currently available treatments for PCNSL, comparability in long-term follow-up studies is limited, and data are scattered across small studies. METHODS: In this study, we report the long-term survival of patients with newly diagnosed immunocompetent PCNSL, enrolled in a phase II trial from June 2005 to September 2011. Patients were treated using rituximab, methotrexate, vincristine, and procarbazine (R-MVP) chemotherapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in those with partial or complete response to R-MVP. In a post hoc analysis, clinical and imaging features were evaluated in those still alive. RESULTS: 26 of 32 patients underwent HDC-ASCT consolidation. Of them, 3 patients died of treatment-related toxicity and 2 due to disease progression within 1 year of ASCT. None of the remaining 21 patients had disease progression with a median follow-up of 12.1 years and were included in the analysis. Compared with the post-HDC-ASCT assessment, at the last follow-up, there was no significant difference in the median Karnofsky Performance Status (80 [range: 60-100] vs 90 [range: 70-100]), the median Neurologic Assessment in Neuro-Oncology score (1 [range: 0-4] vs 1 [range: 0-5]), and leukoencephalopathy score (1 [range: 0-3] vs 1 [range: 1-4]). DISCUSSION: Long-term follow-up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.

Top advances of the year: Neuro-oncology.

Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction. This review focuses on recent developments in the field, with an emphasis on clinical management. The growing clinical trials landscape reflects advanced insights into cancer immunology and genomics and the need to address molecular and clinical heterogeneity. Recent phase 3 trials investigating anti-PD-1 immunotherapies, particularly nivolumab, have failed to demonstrate improved survival in glioblastoma, underscoring the need to better understand the complexity of CNS immunologic surveillance. Conversely, targeted therapies have accounted for several US Food and Drug Administration approvals extended to brain tumors, particularly therapies directed to BRAF V600E mutations and TRAK fusions, underscoring a need to routinely screen patients for these rare molecular abnormalities. In primary CNS lymphoma, attention has turned to long-term outcomes of consolidation therapies, and recent studies have highlighted the excellent disease control afforded by high-dose chemotherapy and stem cell transplantation. Meningiomas remain a focus of investigations, with preliminary promising results observed with octreotide combined with mTOR inhibition, and immunotherapy with single-agent pembrolizumab. Finally, proton radiotherapy has emerged as a novel alternative for leptomeningeal metastases from solid tumors, which can now be treated more safely with craniospinal irradiation and monitored by the enumeration of circulating tumor cells in the cerebrospinal fluid as a biomarker. Taken together, these incremental advances have improved outcomes in select brain tumor patient populations, whereas ongoing clinical trials hold the promise of meaningful advances and breakthroughs for larger proportions of patients with brain tumors.

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial.

PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma.

The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine.

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

Overall survival in patients with glioblastoma before and after bevacizumab approval.

OBJECTIVE: Glioblastoma (GBM) is an aggressive disease with limited therapeutic options. While bevacizumab was approved in 2009 for the treatment of patients with progressive GBM, its impact on overall survival (OS) remains unclear. Using US population-based cancer registry data (SEER), this study compared OS of patients diagnosed with GBM before and after bevacizumab approval. METHODS: Adult patients from SEER with a GBM diagnosis were divided into two cohorts: patients diagnosed in 2006-2008 (pre-bevacizumab cohort, n = 6,120) and patients diagnosed in 2010-2012 (post-bevacizumab cohort, n = 6,753). Patients were included irrespective of the treatments received. OS post-diagnosis was compared between the study cohorts utilizing Kaplan-Meier analyses and multivariate Cox proportional hazards regression. RESULTS: Among 12,873 patients with GBM, the median age was 62 years, 41% were women, 31% underwent gross total resection, and 75% received radiation therapy. Survival was stable within the 2006-2008 period (median survival = 9 months for each year), but increased after year 2009 (median survival = 10 and 11 months for years 2010/2011 and 2012, respectively). The adjusted hazard of death was significantly lower in the post-bevacizumab approval cohort (hazard ratio = 0.91, p < .01). CONCLUSIONS: The results of this large population-based study suggested an improvement in OS among patients with a GBM diagnosis in 2010-2012 compared to 2006-2008. While the cause of this improvement cannot be proven in a retrospective analysis, the timing of the survival increase coincides with the approval of bevacizumab for the treatment of patients with progressive GBM, indicating a possible benefit of bevacizumab in this population.

Dynamic contrast-enhanced MRI perfusion for differentiating between melanoma and lung cancer brain metastases.

Brain metastases originating from different primary sites overlap in appearance and are difficult to differentiate with conventional MRI. Dynamic contrast-enhanced (DCE)-MRI can assess tumor microvasculature and has demonstrated utility in characterizing primary brain tumors. Our aim was to evaluate the performance of plasma volume (Vp) and volume transfer coefficient (Ktrans ) derived from DCE-MRI in distinguishing between melanoma and nonsmall cell lung cancer (NSCLC) brain metastases. Forty-seven NSCLC and 23 melanoma brain metastases were retrospectively assessed with DCE-MRI. Regions of interest were manually drawn around the metastases to calculate Vpmean and Kmeantrans. The Mann-Whitney U test and receiver operating characteristic analysis (ROC) were performed to compare perfusion parameters between the two groups. The Vpmean of melanoma brain metastases (4.35, standard deviation [SD] = 1.31) was significantly higher (P = 0.03) than Vpmean of NSCLC brain metastases (2.27, SD = 0.96). The Kmeantrans values were higher in melanoma brain metastases, but the difference between the two groups was not significant (P = 0.12). Based on ROC analysis, a cut-off value of 3.02 for Vpmean (area under curve = 0.659 with SD = 0.074) distinguished between melanoma brain metastases and NSCLC brain metastases (P < 0.01) with 72% specificity. Our data show the DCE-MRI parameter Vpmean can differentiate between melanoma and NSCLC brain metastases. The ability to noninvasively predict tumor histology of brain metastases in patients with multiple malignancies can have important clinical implications.

A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning.

High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

Second-opinion interpretations of neuroimaging studies by oncologic neuroradiologists can help reduce errors in cancer care.

BACKGROUND: The purpose of this study was to investigate the utility and clinical impact of second-opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute-designated cancer center. METHODS: We performed a retrospective analysis of initial outside and second-opinion radiology reports from 300 computed tomography and magnetic resonance imaging studies and identified cases with discrepancies between the two reports. An adult neuro-oncologist, pediatric neuro-oncologist, and head and neck surgeon reviewed each pair of discrepant reports based on their area of expertise, patient age, and the type of study performed. The clinicians were blinded to the origin of each report and recorded whether the differences in the reports would have led to a change in patient management and/or disease staging. Histopathologic analysis, clinical assessment, and/or minimum 3-month imaging follow-up served as the reference standards to establish which of the 2 reports was correct. RESULTS: Among the 283 cases that met our study criteria, there were 55 neuroimaging studies with disagreements (19%) between the initial outside report and second-opinion interpretation. Patient management and/or disease stage would have been altered in 42 of 283 cases (15%) based on report differences as determined by the 2 neuro-oncologists and the surgeon participating in the study. Sufficient follow-up was available in 35 of 42 cases (83%). The second-opinion interpretation was correct 100% of the time (35/35). CONCLUSION: Second-opinion interpretations of neuroimaging studies by subspecialized oncologic neuroradiologists provide added value by reducing error and optimizing the care of cancer patients. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2708-2714. © 2016 American Cancer Society.

Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study.

BACKGROUND: The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development. METHODS: We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue. RESULTS: A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values. CONCLUSION: PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo.

Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.

Autologous stem cell transplant in recurrent or refractory primary or secondary central nervous system lymphoma using thiotepa, busulfan and cyclophosphamide.

The prognosis for patients with central nervous system (CNS) involvement by recurrent or refractory diffuse large B-cell lymphoma is poor, with overall survival (OS) of 4-10 months. High-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) is a potential treatment alternative. We reviewed patients with recurrent primary (PCNSL) or secondary (SCNSL) CNS lymphoma referred for consolidation HDC-ASCT utilizing thiotepa, busulfan and cyclophosphamide (TBC). Among the 17 patients included, all had achieved a complete remission after salvage induction chemotherapy, which incorporated methotrexate in 82% of patients. Two patients failed stem-cell harvesting and 15 (88%) underwent transplant. The estimated 3-year progression-free survival (PFS) and OS were both 93% (95% confidence interval 61-99%). Median PFS and OS were not reached. There was no transplant-related mortality. These results confirm the benefit of TBC followed by ASCT in select patients with recurrent PCNSL and suggest a potential role for the regimen in those with SCNSL. Further investigation is warranted.

Emerging therapies for glioblastoma.

IMPORTANCE: Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed. EVIDENCE REVIEW: Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors' files. Clinical trials were identified in the Clinicaltrials.gov registry. FINDINGS: Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed. CONCLUSIONS AND RELEVANCE: Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.

MRI perfusion in determining pseudoprogression in patients with glioblastoma.

We examine the role of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion in differentiating pseudoprogression from progression in 20 consecutive patients with treated glioblastoma. MRI perfusion was performed, and relative cerebral blood volume (rCBV), relative peak height (rPH), and percent signal recovery (PSR) were measured. Pseudoprogression demonstrated lower median rCBV (P=.009) and rPH (P<.001), and higher PSR (P=.039) than progression. DSC MRI perfusion successfully identified pseudoprogression in patients who did not require a change in treatment despite radiographic worsening following chemoradiotherapy.

Cognitive functions in primary CNS lymphoma after single or combined modality regimens.

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.

Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy.

INTRODUCTION: Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging. A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes. METHODS: Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed. Survival was assessed by Kaplan-Meier and landmark analyses by administered treatment to minimize selection bias. RESULTS: We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0). No differences in survival were seen between patients who were treated with WBRT (n =46) and those who were not (n =59, p =0.84) in a landmark analysis. In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis. The median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months). CONCLUSIONS: This retrospective study, the largest published series, demonstrates the poor survival of LM from NSCLC. In this study, survival was not improved by WBRT. The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.

Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer.

Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received accelerated FDA approval for progressive glioblastoma, a primary brain tumor, because of high response rates and low incidence of intracranial hemorrhage. We retrospectively identified patients treated with bevacizumab for active (treatment naïve or progressive) central nervous system (CNS) metastases from NSCLC. MRI scans performed at least 6 weeks after initiating bevacizumab were assessed for response. There were six patients, four women and two men with a median age of 60 years (range 59-77) at initiation of bevacizumab. Five patients had progressive CNS metastases despite prior treatment including surgery, radiotherapy, and/or chemotherapy; one patient had treatment-naïve brain metastases. Two patients had leptomeningeal metastases, isolated or coexistent with parenchymal brain metastases in one patient each. Bevacizumab was administered alone to one patient and in combination with various cytotoxic chemotherapies in the others. Toxicity included an asymptomatic (Grade 1) intra-tumoral hemorrhage which occurred in one of three patients receiving concurrent anticoagulation with bevacizumab. There was no recurrent CNS bleeding in two patients with a prior history of such hemorrhage. Best CNS response (RECIST) was partial in two, stable disease in three, and progression in one. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 14.1 months following initiation of bevacizumab. Clinical benefit was also observed in the form of improved symptoms and reduced corticosteroid requirements. Bevacizumab should be used with caution in patients with active CNS metastases pending additional safety data. This series suggests bevacizumab may be safe and effective for progressive brain metastases from NSCLC and deserves further study.