A Patient-Reported Outcome Instrument to Assess Symptom Burden and Predict Survival in Patients with Advanced Cancer: Flipping the Paradigm to Improve Timing of Palliative and End-of-Life Discussions and Reduce Unwanted Health Care Costs.

BACKGROUND: Discussions regarding palliative care and end-of-life care issues are frequently delayed past the time of usefulness, resulting in unwanted medical care. We sought to develop a patient-reported outcome (PRO) instrument that allows patients to voice their symptom burdens and facilitate timing of discussions. SUBJECTS, MATERIALS, AND METHODS: A seven-item PRO instrument (Cota Patient Assessed Symptom Score-7 item [CPASS-7]) covering physical performance status, pain, burden, and depression was administered (September 2015 through October 2016) with correlation to overall survival, correcting for time to complete survey since diagnosis. RESULTS: A total of 1,191 patients completed CPASS-7 at a median of 560 days following the diagnosis of advanced cancer. Of these patients, 49% were concerned that they could not do the things they wanted; 35% reported decreased performance status. Financial toxicity was reported by 39% of patients, with family burdens noted in 25%. Although depression was reported by 15%, 43% reported lack of pleasure. Pain was reported by 33%. The median CPASS-7 total symptom burden score was 16 (possible 0-112). With a median follow-up of 15 months from initial survey, 46% had died. Patients with symptom burden scores <29 and ≥29 had a 6-month overall survival rate of 87% and 67%, respectively, and 12-month survival rates of 72% and 50%. A one-point score increase resulted in a 1.8% increase in expected hazard. CONCLUSION: Patients with advanced cancer with higher levels of symptom burden, as self-reported on the CPASS-7, had inferior survival. The PRO facilitates identification of patients appropriate for reassessment of treatment goals and potentially palliative and end-of-life care in response to symptom burden concerns. IMPLICATIONS FOR PRACTICE: A seven-item patient-reported outcome (PRO) instrument was administered to 1,191 patients with advanced cancers. Patients self-reporting higher levels of physical and psychological symptom burden had inferior overall survival rates. High individual item symptom PRO responses should serve as a useful trigger to initiate supportive interventions, but when scores indicate global problems, discussions regarding end-of-life care might be appropriate.

Salvage re-irradiation for recurrent high-grade glioma and comparison to bevacizumab alone.

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18-20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1-2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4-23.1; p < .001) were associated with OS; dose/fractionation was not. Compared with bevacizumab alone, re-irradiated patients had a non-significant increase in OS (HR 0.80; 95% CI, 0.53-1.23; P = .31). Among patients with a local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; p = .12). Survival after re-irradiation for recurrent HGG appears independent of dose/fractionation and compares favorably with bevacizumab alone.

Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma.

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity-modulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.

Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48).

BACKGROUND AND PURPOSE: Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. RESULTS: Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). CONCLUSIONS: Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Central nervous system involvement by Waldenström macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study.

Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 10(9) /l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.

Extent of resection and overall survival for patients with atypical and malignant meningioma.

BACKGROUND: The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival-based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all-cause mortality in patients with atypical and malignant meningioma. METHODS: The Surveillance, Epidemiology, and End Results program was used to identify 575 and 64 patients betweens the ages of 18 and 70 years who were diagnosed with atypical and malignant meningioma, respectively, between 2004 and 2009. Multivariate Cox proportional hazards regression was used to assess the adjusted impact of GTR versus subtotal resection on all-cause mortality. RESULTS: Baseline patient characteristics were similar for patients who did undergo GTR and patients who did not undergo GTR. The 5-year overall survival rates were 91.3% (95% confidence interval [CI], 86.2%-94.5%) and 78.2% (95% CI, 70.0%-84.3%) for patients with atypical meningioma who did and did not undergo GTR, respectively, and 64.5% (95% CI, 45.9%-78.1%) and 41.1% (95% CI, 17.9%-63.1%) for patients with malignant meningioma who did and did not undergo GTR, respectively. After adjustments for available, pertinent confounding variables, GTR was associated with lower all-cause mortality in patients with atypical (hazard ratio, 0.39; 95% CI, 0.23-0.67; P < .001) and malignant meningioma (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .01). CONCLUSIONS: The extent of resection is a powerful predictor of outcome for patients with atypical and malignant meningioma. These data highlight the hazard associated with the presence of gross tumor bulk after surgery and suggest a value for more extensive resections that should be balanced against the additional potential morbidity.

Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma.

Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.

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.

Incidence, risk factors, and reasons for hospitalization among glioblastoma patients receiving chemoradiation.

Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.

Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas.

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/ß, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.

Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab.

While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3-6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC(L)/ADC(M) within nonenhancing T2/FLAIR volume (> or ≤0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC(H) within enhancing T1+C volume (> or ≤25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC(H) within T1+C volume alone (1.3) or ADC(L)/ADC(M) within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma.

Recurrent glioblastoma: volumetric assessment and stratification of patient survival with early posttreatment magnetic resonance imaging in patients treated with bevacizumab.

BACKGROUND: Despite a high radiographic response rate in patients with recurrent glioblastoma following bevacizumab therapy, survival benefit has been relatively modest. We assess whether tumor volume measurements based on baseline and early posttreatment MRI can stratify patients in terms of progression-free survival (PFS) and overall survival (OS). METHODS: Baseline (-4 +/- 4 days) and posttreatment (30 +/- 6 days) MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated for volume of enhancing tumor as well as volume of the T2/FLAIR hyperintensity. Overall survival (OS) and progression-free survival (PFS) were assessed using volume parameters in a Cox regression model adjusted for significant clinical parameters. RESULTS: In univariable analysis, residual tumor volume, percentage change in tumor volume, steroid change from baseline to posttreatment scan, and number of recurrences were associated with both OS and PFS. With dichotomization by sample median of 52% change of enhancing volume can stratify OS (52 weeks vs. 31 weeks, P = .013) and PFS (21 weeks vs. 12 weeks, P = .009). Residual enhancing volume, dichotomized by sample median of 7.8 cm(3) , can also stratify for OS (64 weeks vs. 28 weeks, P < .001) and PFS (21 weeks vs. 12 weeks, P = .036). CONCLUSIONS: Volumetric percentage change and absolute early posttreatment volume of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy.

Update on bevacizumab and other angiogenesis inhibitors for brain cancer.

INTRODUCTION: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. AREAS COVERED: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. EXPERT OPINION: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.

Recurrent high-grade glioma treated with bevacizumab: prognostic value of MGMT methylation, EGFR status and pretreatment MRI in determining response and survival.

Although bevacizumab represented an important advance in treatment of recurrent high-grade gliomas (HGG), responses occur in fewer than half of patients. There are no validated biomarkers for anti-angiogenic therapy that are available for routine clinical use. We assessed the prognostic values of imaging and molecular markers in this patient population. MRI scans from 191 patients with recurrent HGG obtained prior to initiating bevacizumab were reviewed for areas of enhancement, necrosis, T2/FLAIR abnormality, and ADC values. Serial MRI scans following the initiation of bevacizumab were evaluated for response and progression. Non-radiographic markers including EGFR and MGMT status were also assessed with respect to response and patient survival. 65 of 191 patients (34 %) showed complete or partial response at the time of their best response MRI and demonstrated longer progression free survival (PFS) and overall survival (OS) compared to the group without response (PFS: 6.9 vs 3.5 months, OS: 10.9 vs 6.1 months). Minimum ADC values within enhancing and non-enhancing regions were lower in responders compared to those of non-responders (1,099 vs 984 × 10(-6) mm(2)/s, p = 0.006). Smaller enhancing area was associated with longer OS (HR = 1.99, p = 0.017). The ratio of T2/FLAIR to enhancing area was prognostic of OS for only the Grade III HGG subgroup (HR = 0.14, p = 0.004). Area of enhancing tumor at baseline can stratify survival in patients with recurrent HGG treated with bevacizumab. The extent of edema relative to enhancing area may have a prognostic role specific to Grade III HGG.

Retrospective study of pemetrexed as salvage therapy for central nervous system lymphoma.

There is currently no standard therapy for recurrent or chemotherapy-refractory central nervous system lymphoma (CNSL). Pemetrexed has been reported to have activity in patients with primary CNSL (PCNSL). The use of pemetrexed in secondary CNS lymphoma (SCNSL) has not previously been reported. Here we retrospectively review the outcomes and toxicities of standard and modified doses of pemetrexed as salvage therapy in 18 PCNSL and 12 SCNSL patients. The overall response rate for PCNSL patients was 64.7 %, all of whom achieved a complete response (CR). The median progression-free survival (PFS) was 5.8 months. For the SCNSL patients, RR was 58.3 % with 2 CR (16.7 %); the median PFS was 2.5 months. Grade ≥3 adverse events included leukopenia in 5 patients (16.7 %), neutropenia in 1 patient (3.3 %), and fatigue in 3 patients (10.0 %). 3 patients died while on treatment, 2 due to infections and 1 due to pulmonary embolism. Our results indicate that pemetrexed has activity as salvage therapy in recurrent PCNSL, even with modified dosing, but outcomes trend towards less favorable in SCNSL.

Atypical and anaplastic meningiomas treated with bevacizumab.

Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.

Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients.

Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher's exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) experienced hemorrhage, of which four hemorrhages (6%) were serious (grade ≥ 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Discontinuing bevacizumab in patients with glioblastoma: an ethical analysis.

Glioblastoma (GBM) is a highly lethal malignant brain tumor that expresses proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA), a monoclonal antibody against VEGF, is routinely used in the U.S. to treat GBM patients whose tumors have progressed following initial therapy. The Ethics Advisory Committee at the Dana-Farber Cancer Institute was asked to provide consultation on two cases involving patients with recurrent GBM who were receiving bevacizumab. Despite evidence of disease progression, family members advocated for the continued use of bevacizumab because of its mild toxicity profile and concern that discontinuation would impair quality of life. However, continuing bevacizumab in this setting posed physical and financial risks to the patients and raised ethical concerns about resource allocation and justice. We analyze the ethical questions regarding bevacizumab discontinuation in the setting of progressive GBM. We articulate the potential benefits and harms of continuing the drug and identify guiding principles for drug discontinuation that should be made transparent to patients and families. With the increasing availability of new, modestly toxic, expensive drugs for patients with advanced cancer, questions of when to stop these drugs will become increasingly relevant.

Survival among patients with primary central nervous system lymphoma, 1973-2004.

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma that occurs in immunocompetent and human immunodeficiency virus (HIV) patients. Despite treatment advances, previous reports have produced conflicting information about survival trends over time. Using the Surveillance, Epidemiology, and End Results (SEER) data, 2,557 patients diagnosed with PCNSL between 1973 and 2004 were identified and classified by HIV status. Potential predictors of survival were evaluated using log-rank tests. Hazard ratios and 95% confidence intervals (CIs) were computed using a Cox proportional hazards regression model. The cohort included 1,732 (67.7%) HIV-negative patients and 825 (32.3%) HIV-positive patients. Median overall survival was 12 months (95% CI 10, 13) among HIV-negative patients. In this group, median survival increased over time, from 7.5 months (95% CI 6, 14) for patients diagnosed in the 1970s, to 14 months (95% CI 11, 20) for patients diagnosed in the 2000s. Independent predictors of mortality included older age (hazard ratio [HR] 1.03 [95% CI 1.02, 1.03]), earlier year of diagnosis (HR 0.98 [95% CI 0.98, 0.99]), male sex (HR 1.20 [95% CI 1.08, 1.34), married status (HR 0.70 [95% CI 0.63, 0.78]), and receipt of radiation therapy (HR 0.69 [95% CI 0.61, 0.77]). HIV positivity was a powerful adverse prognostic factor in the overall cohort (HR 4.55 [95% CI 4.01, 5.16]). Despite treatment advances, survival among PCNSL patients in the United States remains poor. However, in the subset of PCNSL patients who are HIV-negative, survival has improved over time.