Infusion Of Bevacizumab Research Articles

Bevacizumab-associated intracerebral hemorrhage in patients with CNS malignancy: A single-center retrospective cohort study.

e13509 Background: Gliomas are a known risk factor for the development of spontaneous intracranial hemorrhage (ICH) independent of therapies directed against them, with studies reporting an incidence of 1.9-3.8%. Bevacizumab (BEV) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) FDA approved for recurrent glioblastoma. ICH is commonly considered to be a potential adverse effect of BEV use in patients with glioma, with previous retrospective studies describing incidence of intracerebral hemorrhage ranging from 1.9-3.3%. Methods: We performed a single center (Mayo Clinic, Rochester, MN) retrospective chart review of all patients who received BEV therapy at our institution for a diagnosis of primary CNS malignancy. We used ICD-9 and ICD-10 codes to identify adult patients with primary CNS neoplasms that subsequently developed ICH. Results: We screened 10,507 adult patients with a diagnosis of primary CNS neoplasm treated at our center from 01/31/2008 to 12/31/2018 and found 644 patients treated with bevacizumab. Of these, 23 (3.6%) suffered an ICH within 12 weeks of a BEV infusion (median 9 days post infusion, 1-24 IQR). The dose of BEV in all hemorrhages was either 10 mg/kg every two weeks (n = 21) or 15 mg/kg every three weeks (n = 2). No patients treated with infusions at 7.5 mg/kg every three weeks (n = 79) or 5 mg/kg every two weeks (n = 17) suffered ICH events, however this did not meet significance (P = 0.06) when compared to patients on 10 mg/kg or above. The median ICH score was 1 (0-2 IQR). There was an increase in ECOG scores documented at clinical follow up following the hemorrhage compared to the pre-hemorrhage functional status (ECOG 3.28 versus 1.2, p = < 0.0001), with 13 patients (56%) having developed severe debility or death (ECOG 4 n = 3, ECOG 5 n = 10). Conclusions: In our single-center cohort of patients with a primary diagnosis of CNS neoplasms treated with BEV, ICH occurred in 3.6% of patients. Those who experienced an ICH in proximity to BEV infusion had significant morbidity and mortality with a clear decline in functional status. There was a signal of dose response as far as ICH incidence in our cohort with dosages 10 mg/kg per infusion or above.

A randomized phase II study comparing oral S-1 plus 24-hour infusion of irinotecan (Iri) and bevacizumab (Bev) with FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer (MCRC).

613 Background: FOLFOX or FOLFIRI plus Bev is a first-line treatment for MCRC. Recent studies have confirmed that oral S-1 combined with Iri and Bev is equivalent to FOLFIRI plus Bev. Iri is usually administered as a short-term 90-min. infusion. However, the cytocidal activity is S-phase specific, and carboxylesterases, that convert Iri into SN-38, are less likely to become saturated when Iri is given as a long-term infusion. Therefore, a low dose of Iri given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare this regimen with FOLFIRI plus Bev. Methods: The subjects comprised 120 chemotherapy-naïve patients with MCRC. The study group received 24-hr infusion of Iri at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1 to 14. The FOLFIRI group received Iri at a dose of 150 mg/m2, 5-FU given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2400 mg/m2 as a 46 hr-infusion, 200 mg/m2 of leucovorin on days 1 and 15. Bev was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was the 1 y progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From October 2013 through December 2017, a total of 61 patients assigned to receive IRIS plus Bev (the A group) and 59 patients assigned to receive FOLFIRI plus Bev (the B group) were included in the analysis. The 1y RFS was 37.3% in the A group and 17.0% in the B group (p = 0.0281). The PFS was 10.2 mon in the A group and 10.0 mon in the B group, and the median OS was 27.0 mon and 28.6 mon, respectively (p = 0.26, p = 0.68). RR was significantly higher in the A group (87.0%) than in the B group (61.7%) (p = 0.005). The main grade 3 or 4 AEs were neutropenia (27.8%) and diarrhea (11.1%) in the A group and neutropenia (23.4%) and leukopenia (6.4%) in the B group. Conclusions: Our results showed that Iri, given biweekly as a 24-hour infusion in combination with oral S-1 and Bev, is a highly effective and well-tolerated regimen for the first-line treatment of MCRC. Clinical trial information: UMIN000014664.

Arterial and Venous Thromboembolic Safety of Bevacizumab in Patients with High Grade Gliomas

INTRODUCTIONBevacizumab, an angiogenesis inhibitor targeting vascular endothelial growth factor A, is used for the treatment of recurrent glioblastoma, the most common primary brain malignancy in adults. Multiple studies demonstrate the efficacy of bevacizumab on progression-free and overall survival of patients with recurrent glioblastoma. However, real world safety data of bevacizumab in patients with glioblastoma is limited on serious adverse outcomes including arterial and venous thrombosis. Our study aimed to evaluate the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) in a population-based sample of adult patients with high grade gliomas.METHODWe conducted a nested case-control study within a retrospective cohort of patients receiving treatment for high grade gliomas under the protocol by Stupp, et al. (radiotherapy plus concomitant/adjuvant temezolomide). Patients were sampled from the Truven Health MarketScan® Research Database, containing administrative health claims data of over 40 million commercially insured enrollees and their dependents, between 2009 and 2015. A validated algorithm was used to identify patients with high grade gliomas that underwent craniotomy (index time) with external beam radiation and temozolomide-based treatment occurring within 91 days (cohort entry time). Patients were excluded if they received craniotomy, radiation, temozolomide or bevacizumab during year prior to surgery or had one of our outcomes of interest (ATE or VTE) during the cohort ascertainment period (between index and cohort entry dates). Patients were required to have continuous health plan enrollment during the 12-month baseline and follow up periods (unless died). Surgical procedures and chemotherapy treatments were identified using diagnostic and procedural medical and pharmacy claims data. These data sources were also used to identify VTE risk factors, including medical conditions, procedures and medication use, and to calculate modified Charlson comorbidity index scores at baseline.Cases of ATE and VTE were each identified in the overall cohort using a validated algorithm for administrative claims data. For ATE and VTE separately, each case was matched to up to ten controls on sex, age group, index time and follow-up duration using incidence density sampling with replacement. Exposure to bevacizumab was characterized as any use (yes vs. no) and recent use (last bevacizumab infusion within 30 days prior event or control censoring). We estimated relative risk of ATE and VTE associated with bevacizumab in separate models using conditional logistic regression models to calculate adjusted odds ratios (aOR) and 95% confidence interval (CI). All multivariable models were adjusted for sex, age, and comorbidity index scores; models for risk of VTE were also adjusted for number of baseline VTE risk factors and VTE prophylaxis received.RESULTSOur final study cohort included 2157 patients undergoing treatment for high grade gliomas. We identified 25 ATE cases and 99 VTE cases and matched incidence density-sampled controls (n=170 for ATE; n=819 for VTE) for our nested case-control analysis. A higher proportion of ATE cases received bevacizumab during follow up compared to the controls (28% vs. 17%). In multivariable analyses, no statistically significant increase in ATE risk was observed with bevacizumab overall (aOR 1.51, 95% CI 0.54-4.24), although confidence intervals were wide given the few events observed. Compared to controls in the VTE analysis, cases had a slightly higher proportion of baseline VTE risk factors (2 or more: 17% vs. 13%) and treatment with bevacizumab (13% vs. 9%). However, we found no significant increased risk of VTE associated with bevacizumab overall (aOR 1.40, 95% CI 0.71-2.75) or recent infusion of bevacizumab (aOR 1.40, 95% CI 0.65-3.01).CONCLUSIONSOur findings from this large retrospective cohort of patients undergoing treatment for high grade glioma provide little evidence in support of the increased risk of ATE and VTE reported with use of bevacizumab in other cancer sites. Our study was limited by an overall small number of ATE events observed, and further research is needed to confirm safety of bevacizumab with respect to arterial thrombosis. These population-based estimates show no significant increase in risk of VTE associated with bevacizumab and suggest its safe use in the treatment of high grade gliomas. DisclosuresLee:AbbVie Inc.: Research Funding. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Better efficacy of intrapleural infusion of bevacizumab with pemetrexed for malignant pleural effusion mediated from nonsquamous non-small cell lung cancer.

Background and objectiveSeveral clinical trials have reported that intrapleural infusion of bevacizumab with or without cisplatin exhibits encouraging efficacy in nonsquamous non-small cell lung cancer (NS-NSCLC) patients with malignant serous cavity effusion. However, most of the studies included a number of different types of cancers or different hydrops types rather than focusing on one. In addition, no study reported the efficacy and toxicity of intrapleural infusion of bevacizumab and pemetrexed for advanced NS-NSCLC patients with malignant pleural effusion (MPE).Patients and methodsWe retrospectively collected patients with MPE mediated from NS-NSCLC who underwent intrapleural infusion of bevacizumab between August 2012 and February 2017. According to the different combined agents with bevacizumab, we divide patients into two groups: Group 1 (BP Group) intrapleural infusion of bevacizumab combined with pemetrexed and Group 2 (BD group) intrapleural infusion of bevacizumab combined with cisplatin.ResultsA total of 45 patients were enrolled in this study. Twenty-two of them received intrapleuralinfusion of bevacizumab and pemetrexed every 2 weeks, 23 received bevacizumab and cisplatin after draining effusion as much as possible. The progression-free survival for patients in BP group was significantly higher than BD group (P < 0.05) while the overall survival between the two groups was not significantly different (P > 0.05). In addition, there was no statistical difference in adverse effects between two groups.ConclusionIntrapleural infusion of bevacizumab and pemetrexed is effective and tolerable for patients with MPE mediated from NSCLC.

A Distinct Advantage to Intraarterial Delivery of 89Zr-Bevacizumab in PET Imaging of Mice With and Without Osmotic Opening of the Blood-Brain Barrier.

Glioblastoma multiforme (GBM) is the most aggressive and common type of brain cancer. Five-year survival rates are below 12%, even with the most aggressive trimodal therapies. Poor blood-brain barrier (BBB) permeability of therapeutics is a major obstacle to efficacy. Intravenous administration of bevacizumab is the standard treatment for GBM. It has been recently demonstrated that a single intraarterial infusion of bevacizumab provides superior therapeutic outcomes in patients with recurrent GBM. Further GBM treatment benefits can be achieved through opening of the BBB before intraarterial infusion of bevacizumab. However, a rationale for intraarterial delivery and BBB opening when delivering antibodies is lacking. A method facilitating quantification of intraarterial delivery of bevacizumab is needed for more effective and personalized GBM treatment. Here, we demonstrate such a method using PET imaging of radiolabeled bevacizumab. Methods: Bevacizumab was conjugated with deferoxamine and subsequently radiolabeled with 89Zr. 89Zr-bevacizumab deferoxamine (89Zr-BVDFO) was prepared with a specific radioactivity of 81.4 ± 7.4 MBq/mg (2.2 ± 0.2 μCi/mg). Brain uptake of 89Zr-BVDFO on carotid artery and tail vein infusion with an intact BBB or with BBB opening with mannitol was initially monitored by dynamic PET, followed by whole-body PET/CT at 1 and 24 h after infusion. Th ex vivo biodistribution of 89Zr-BVDFO was also determined. Results: Intraarterial administration of 89Zr-BVDFO resulted in gradual accumulation of radioactivity in the ipsilateral hemisphere, with 9.16 ± 2.13 percentage injected dose/cm3 at the end of infusion. There was negligible signal observed in the contralateral hemisphere. BBB opening with mannitol before intraarterial infusion of 89Zr-BVDFO resulted in faster and higher uptake in the ipsilateral hemisphere (23.58 ± 4.46 percentage injected dose/cm3) and negligible uptake in the contralateral hemisphere. In contrast, intravenous infusion of 89Zr-BVDFO and subsequent BBB opening did not lead to uptake of radiotracer in the brain. The ex vivo biodistribution results validated the PET/CT studies. Conclusion: Our findings demonstrate that intraarterial delivery of bevacizumab into the brain across an osmotically opened BBB is effective, in contrast to the intravenous route.

VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma

BackgroundVascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant.MethodsWe assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients’ clinical outcome.ResultsIn athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively).ConclusionsQuantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

Optimizing intrapleural bevacizumab dosing in non-small-cell lung cancer-mediated malignant pleural effusion: less is more.

Intrapleural infusion of bevacizumab (BEV) is an emerging clinical treatment for malignant pleural effusion, but many details of usage need to be determined, especially for the effective dose. We performed a retrospective study of the records of malignant pleural effusion patients from non-small-cell lung cancer who underwent intrapleural infusion of BEV. According to the BEV dose commonly used in clinical, patients were allocated into either low-dose group or high-dose group. A total of 71patients were enrolled in this study. Administration with intrapleural BEV in low dose has less toxicity. For survival data, low- and high-dose groups have no difference. Lower rates of serious BEV-related toxicities and similar survival date are noted when lower dosages are used without diminishing positive clinical impact.

Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases.

To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases. This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS). Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival. This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.

Adipose-derived stem cells decrease pain in a rat model of oxaliplatin-induced neuropathy: Role of VEGF-A modulation

Oxaliplatin therapy of colorectal cancer induces a dose-dependent neuropathic syndrome in 50% of patients. Pharmacological treatments may offer limited relief; scientific efforts are needed for new therapeutic approaches. Therefore we evaluated in a preclinical setting the pain relieving properties of mesenchymal stem cells and its secretome. Rat adipose stem cells (rASCs) were administered in a rat model of oxaliplatin-induced neuropathy.A single intravenous injection of rASCs reduced oxaliplatin-dependent mechanical hypersensitivity to noxious and non-noxious stimuli taking effect 1 h after administration, peaking 6 h thereafter and lasting 5 days. Cell-conditioned medium was ineffective. Repeated rASCs injections every 5 days relieved pain each time with a comparable effect. Labeled rASCs were detected in the bloodstream 1 and 3 h after administration and found in the liver 24 h thereafter. In oxaliplatin-treated rats, the plasma concentration of vascular endothelial growth factor (pan VEGF-A) was increased while the isoform VEGF165b was upregulated in the spinal cord. Both alterations were reverted by rASCs. The anti-VEGF-A monoclonal antibody bevacizumab (intraperitoneally) reduced oxaliplatin-dependent pain. Studying the peripheral and central role of VEGF165b in pain, we determined that the intraplantar and intrathecal injection of the growth factor induced a pro-algesic effect. In the oxaliplatin neuropathy model, the intrathecal infusion of bevacizumab, anti-rat VEGF165b antibody and rASCs reduced pain.Adult adipose mesenchymal stem cells could represent a novel approach in the treatment of neuropathic pain. The regulation of VEGF-A is suggested as an effective mechanism in the complex response orchestrated by stem cells against neuropathy.

Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis

Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders.Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769-78. ©2017 AACR.

Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors

BackgroundVascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors.MethodsIn this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics.ResultsTwenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion.ConclusionsThe combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination.Trial registrationThe study was retrospectively registered on ClinicalTrials.gov (number NCT01202032) on 2010, Sept 14th.

Apparent diffusion coefficient changes predict survival after intra-arterial bevacizumab treatment in recurrent glioblastoma

Superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) has emerged as a novel therapy in the treatment of recurrent glioblastoma (GB). This study assessed the use of apparent diffusion coefficient (ADC) in predicting length of survival after SIACI BV and overall survival in patients with recurrent GB. Sixty-five patients from a cohort enrolled in a phase I/II trial of SIACI BV for treatment of recurrent GB were retrospectively included in this analysis. MR imaging with a diffusion-weighted (DWI) sequence was performed before and after treatment. ROIs were manually delineated on ADC maps corresponding to the enhancing and non-enhancing portions of the tumor. Cox and logistic regression analyses were performed to determine which ADC values best predicted survival. The change in minimum ADC in the enhancing portion of the tumor after SIACI BV therapy was associated with an increased risk of death (hazard ratio=2.0, 95% confidence interval(CI) [1.04-3.79], p=0.038), adjusting for age, tumor size, BV dose, and prior IV BV treatments. Similarly, the change in ADC after SIACI BV therapy was associated with greater likelihood of surviving less than 1year after therapy (odds ratio=7.0, 95% CI [1.08-45.7], p=0.04). Having previously received IV BV was associated with increased risk of death (OR 18, 95% CI [1.8-180.0], p=0.014). In patients with recurrent GB treated with SIACI BV, the change in ADC value after treatment is predictive of overall survival.

NIMG-42. PENETRATION OF RADIOLABELED TEMOZOLOMIDE CORRELATES WITH CONTRAST ENHANCEMENT IN PATIENTS WITH RECURRENT GBM TREATED WITH BEVACIZUMAB

Anti-angiogenic agents can decrease vascular permeability raising concern that these agents may also decrease blood brain barrier (BBB) penetration of concomitantly administered chemotherapy. We evaluated if the volume of contrast enhancement in recurrent glioblastoma (GBM) patients correlated with the volume of temozolomide penetration using MR-PET. After labeling temozolomide with the positron emitter [11C], we performed MR-PET scans in patients receiving bevacizumab 10mg/kg Q2weeks and temozolomide 50mg/m2 daily. Patients were scanned prior to bevacizumab (but after achieving steady state for oral temozolomide to minimize nonspecific binding), 1 day post first bevazicumab infusion, and prior to the third bevacizumab infusion. Tumor regions of interest were outlined on the T1-post contrast and FLAIR images. Volume of temozolomide delivery within the FLAIR hyperintensity (greatest potential extent of visible tumor) was determined by selecting all voxels above a threshold by using 3D Slicer software on the SUV map. This SUV volume was correlated to the volume of contrast enhancement and also correlated to the volume of FLAIR hyperintensity using Pearson correlation coefficient (PCC). Each visit was considered a separate data point even if it was from the same patient. Eight patients have been accrued to the study. A total of 9 MR-PET visits have been analyzed. The preliminary analysis showed the volume of contrast enhancement correlated with volume of PET uptake (PCC = 0.74) and the volume of FLAIR hyperintensity also correlated with volume of PET update (PCC = 0.86). These indicate that smaller volumes of radiolabeled temozolomide uptake corresponded to smaller contrast enhancing volumes and smaller FLAIR hyperintensity volumes. Volume of penetration of radiolabeled temozolomide correlates with contrast enhancement in patients with recurrent GBM treated with bevacizumab. Contrast enhancement may be a surrogate marker for concomitant drug delivery even with drugs such as temozolomide which penetrate an intact BBB.

18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches

PurposeNitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival.MethodsA total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG.ResultsA 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159–0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively).ConclusionsThe decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

Tolérance du bévacizumab au cours de l’hypertension artérielle pulmonaire associée à la sclérodermie systémique : à propos d’une observation

IntroductionNo data is available regarding the safety of bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, in patients with pulmonary arterial hypertension (PAH), a condition in which VEGF seems to play a significant and probably protective role. Case reportWe report a patient with a history of systemic sclerosis-associated PAH, stable under bosentan therapy. She was diagnosed with metastatic cervical epidermoid carcinoma and treated by two successive cytotoxic chemotherapy regimens. As these treatments failed to control disease progression, she was started on anti-angiogenic therapy: 3 infusions of bevacizumab 15 mg/kg were administered. Over the course of this treatment, no change in the clinical status or echocardiography parameters was noted. ConclusionThis observation suggests that, under careful clinical and echocardiographic follow-up, bevacizumab therapy can be well tolerated in case of stable and moderate PAH. Decision of treatment should be taken cautiously, as the possibility of PAH worsening is not excluded.

Dynamic Susceptibility Contrast-Enhanced MR Perfusion Imaging in Assessing Recurrent Glioblastoma Response to Superselective Intra-Arterial Bevacizumab Therapy

Recurrent glioblastoma currently has no established standard of care. We evaluated the response of recurrent glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab by using dynamic susceptibility contrast-enhanced MR perfusion imaging. We hypothesized that treatment response would be associated with decreased relative CBV and relative CBF. Patients were accrued for this study from larger ongoing serial Phase I/II trials. Twenty-five patients (14 men, 11 women; median age, 55 years) were analyzed. Four distinct ROIs were chosen: 1) normal-appearing white matter on the contralateral side, 2) the location of the highest T1 enhancement in the lesion (maximum enhancing), 3) the location of highest relative CBV in the lesion (maximum relative CBV), and 4) nonenhancing T2 hyperintense signal abnormality surrounding the tumor (nonenhancing T2 hyperintensity). There was a statistically significant median percentage change of -32.34% (P = .001) in relative CBV in areas of maximum relative CBV following intra-arterial bevacizumab therapy. There was also a statistically significant median percentage decrease in relative CBF of -30.67 (P = .001) and -27.25 (P = .037) in areas of maximum relative CBV and maximum tumor enhancement, respectively. Last, a trend toward statistical significance for increasing relative CBV in nonenhancing T2 hyperintense areas (median percent change, 30.04; P = .069) was noted. Dynamic susceptibility contrast-enhanced MR perfusion imaging demonstrated a significant decrease in tumor perfusion metrics within recurrent glioblastomas in response to superselective intra-arterial cerebral infusion of bevacizumab; however, these changes did not correlate with time to progression or overall survival.

Intrapericardial bevacizumab safely and effectively treats malignant pericardial effusion in advanced cancer patients.

We evaluated the safety and efficacy of intrapericardial bevacizumab (BEV) for treating symptomatic malignant pericardiac effusion (MPCE) in seven advanced cancer patients. All patients had previously undergone multiple lines of systemic therapy. Each patient received paracentesis and intrapericardial infusions of 100 or 200 mg of BEV every two weeks. Systemic treatments for primary tumors continued for all patients during BEV treatment. Of the seven patients, three achieved a complete response, two achieved a partial response, and two showed no response with regard to MPCE after BEV infusion. The median overall survival time was 168 days (range, 22-224 days). In six of the seven patients, effusion did not recur before death. Toxicity associated with BEV treatment was mild and manageable in all patients. This study provides preliminary evidence that intrapericardial BEV may be an effective and safe treatment for MPCE in patients with advanced cancers.

MNGO-04PHASE II TRIAL OF BEVACIZUMAB IN PATIENTS WITH SURGERY AND RADIATION REFRACTORY PROGRESSIVE MENINGIOMA

BACKGROUND: Systemic treatment options are limited for meningioma that progress following surgery and radiotherapy. VEGF is associated with neovascularization, tumor growth, and edema in meningioma. This prospective phase II study was undertaken to determine the efficacy of bevacizumab (BEV), a VEGF ligand binding monoclonal antibody in patients with progressive benign (BM), atypical (AM), and malignant meningioma (MM) as measured by 6-month progression free survival (PFS-6). Secondary endpoints included median progression free survival (mPFS), median overall survival (mOS), and radiographic response rate (RR). METHODS: Patients with histologically confirmed BM, AM, or MM with radiographic progression were eligible. There was no limit on prior therapies. BEV was administered 10 mg/kg intravenously every two weeks. After 6 months of therapy, stable patients were eligible to switch to an every 3-week schedule of BEV (15 mg/kg). Clinical examination and imaging were performed every 4 and 8 weeks respectively for the first 6 months then every 6-12 weeks. Responses were graded using the Macdonald criteria. RESULTS: 40 patients were treated: 15 BM, 22 AM, and 13 MM. Median KPS was 80. Median age was 54 (23-81) years. Median number of BEV infusions was 16 (2-62). Best responses were stable disease (BM: 100%; AM: 86%; MM: 82%); partial response (BM: 0%; AM: 5%; MM: 0%), progressive disease (BM: 0%; AM: 5%; MM:18%). PFS-6, mPFS, and mOS were 87%, 22.5 months, 35.6 months for BM; 77%, 15.3 months, not reached for AM, and 46%, 3.7 months, 12.4 months for MM. CONCLUSIONS: Treatment of progressive meningioma with BEV commonly leads to disease stabilization. The results are promising compared to a contemporary meta-analysis, in which PFS6 was 29% and 27% for BM and AM/MM respectively, but require confirmation. Toxicity was minimal and expected for BEV notwithstanding prolonged drug exposure.

NIMG-74ENHANCING LESIONS OUTSIDE THE IRRADIATED FIELD IN ANAPLASTIC OLIGODENDROGLIOMA: TUMOR OR NOT?

In patients with primary brain tumors, any new enhancement outside of the field of radiation is often assumed to be progressive disease and treated as such without confirmatory tissue. Recently we have encountered 3 cases that demonstrate that this cannot be universally assumed. All 3 patients had pathology proven anaplastic oligodendroglioma at initial resection with 1p19q codeletion. 2 patients were male and one was female, and age at presentation ranged from 39 to 50 years old. All were treated with resection and subsequent chemotherapy and focal radiation either up front or at first recurrence. 2 had recurrent tumors confirmed with resection and pathological diagnosis, which was then re-treated and stabilized for over two years in both cases. Months to years after last treatment, all 3 patients developed new enhancing masses outside the field of initial radiation with at least one lesion in the contralateral hemisphere. 2 out of 3 patients underwent biopsy of these new lesions, one demonstrating gliosis and necrosis, the other demonstrating plasma cell infiltrate. For one of these patients, serial MRI has subsequently demonstrated migrating enhancement but no clear progression. The third patient who did not undergo biopsy has undergone intermittent bevacizumab infusions with again waxing and waning enhancement for the last five years that continue to resolve each time bevacizumab is reinstituted. Clinically, all 3 patients are currently not receiving any treatment for their enhancement other than surveillance MRI and all remain neurologically stable with no new symptoms. While the pathophysiology of this phenomenon is not understood, these three cases demonstrate that new enhancing lesions outside the initial radiation treatment field should not be globally assumed to be new tumor foci or treated as such. In some patients, there may be patterns of enhancement that reflect other processes and do not require aggressive tumor management.

Safety of spinal radiotherapy in metastatic cancer patients receiving bevacizumab therapy: a bi-institutional case series.

We retrospectively assessed the outcome of patients receiving emergency spinal radiation therapy (RT) concurrently with bevacizumab. Clinical records of 18 consecutive patients receiving emergency spinal RT for symptomatic vertebral metastases during the course of bevacizumab-based therapy were examined. Patients were receiving biweekly bevacizumab combined with paclitaxel (n=17) or with docetaxel/carboplatin (n=1) or as a single agent (n=1) for advanced metastatic carcinoma. RT was delivered at doses of 30 Gy in 10 fractions (n=8), 20 Gy in five fractions (n=9) or 18 Gy in nine fractions (n=1). In 10 patients (56%), irradiation field encompassed the thoracic vertebrae. The median time interval between the bevacizumab infusion and the RT course was 1.5 days (0-8 days). The median follow-up was 8.3 months (2 days-42 months). A clinical benefit of RT was reported in 13 patients (72%), including four patients with complete pain relief. Two of the three patients with neurological impairment at the time of RT experienced a partial improvement in their symptoms. No pain recrudescence was reported within the irradiated field after RT completion. All toxicities were mild to moderate, with no acute toxicity reported in 13 patients (72%). No RT disruption was necessary because of acute toxicity. No delayed toxicity was reported within RT fields among 11 patients with at least 6 months of follow-up. Spinal RT during the course of bevacizumab-based therapy was not associated with the occurrence of unexpected adverse effects. This suggests that emergency RT should not be contraindicated in these patients, provided that doses and treatment volumes are defined carefully.