Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma

OBJECTIVES/SPECIFIC AIMS: In patients with recurrent glioblastoma (GBM) who undergo a second surgery following standard chemoradiotherapy, histopathologic examination of the resected tissue often reveals a combination of viable tumor and treatment-related inflammatory changes. However, it remains unclear whether the degree of viable tumor Versus “treatment effect” in these specimens impacts prognosis. We sought to determine whether the percentage of viable tumor Versus “treatment effect” in recurrent GBM surgical samples, as assessed by a trained neuropathologist and quantified on a continuous scale, is associated with overall survival. METHODS/STUDY POPULATION: We reviewed the records of 47 patients with histopathologically confirmed GBM who underwent surgical resection as the first therapeutic modality for suspected radiographic progression following standard radiation therapy and temozolomide. The percentage of viable tumor Versus “treatment effect” in each specimen was estimated by one neuropathologist who was blinded to patient outcomes. RESULTS/ANTICIPATED RESULTS: After adjusting for other known prognostic factors in a multivariate Cox proportional hazards model, there was no association between the degree of viable tumor and overall survival (HR 0.83; 95% CI, 0.20–3.4; p=0.20). DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that, in patients who undergo resection for recurrent GBM following standard first-line chemoradiotherapy, histopathologic quantification of the degree of viable tumor Versus “treatment effect” present in the surgical specimen has limited prognostic influence and clinical utility.

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CTIM-14. RANDOMIZED PHASE II OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM). NIVOLUMAB BENEFITS OLDER POPULATION

Neuro-Oncology ◽

10.1093/neuonc/noab196.206 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi52-vi52

Author(s):

Manmeet Ahluwalia ◽

David Peereboom ◽

Yasmeen Rauf ◽

Patrick Wen ◽

David Reardon

Keyword(s):

Overall Survival ◽

Low Dose ◽

Standard Dose ◽

Performance Status ◽

Methylation Status ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Dose Effect ◽

Open Label ◽

Anti Vegf

Abstract BACKGROUND Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. VEGF is upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. RESULTS 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall Survival was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p=0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P=0.90). Most frequent toxicities ( >20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. CONCLUSIONS Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.

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Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma

Journal of Neuro-Oncology ◽

10.1007/s11060-018-03050-6 ◽

2018 ◽

Vol 141 (2) ◽

pp. 421-429 ◽

Cited By ~ 4

Author(s):

Stephen J. Bagley ◽

Robert D. Schwab ◽

Ernest Nelson ◽

Angela N. Viaene ◽

Zev A. Binder ◽

...

Keyword(s):

Treatment Effect ◽

Recurrent Glioblastoma ◽

Viable Tumor ◽

Versus Treatment

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Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden

Neurosurgery ◽

10.1093/neuros/nyaa135 ◽

2020 ◽

Vol 87 (5) ◽

pp. 931-938 ◽

Cited By ~ 1

Author(s):

Kunal S Patel ◽

Richard G Everson ◽

Jingwen Yao ◽

Catalina Raymond ◽

Jodi Goldman ◽

...

Keyword(s):

Overall Survival ◽

Magnetic Resonance ◽

Large Volume ◽

Survival Benefit ◽

Tumor Burden ◽

Recurrent Glioblastoma ◽

Large Tumor ◽

Diffusion Mr ◽

Large Tumor Burden ◽

Mr Characteristics

Abstract Background Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. Objective To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. Methods A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. Results In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69). Conclusion Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

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ATIM-15. A PHASE 1 STUDY OF Ad-RTS-hIL-12 + VELEDIMEX IN ADULTS WITH RECURRENT GLIOBLASTOMA: DOSE DETERMINATION WITH UPDATED OVERALL SURVIVAL

Neuro-Oncology ◽

10.1093/neuonc/noy148.010 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi3-vi4

Author(s):

E Antonio Chiocca ◽

Rimas Lukas ◽

John Yu ◽

Nancy Ann Oberheim Bush ◽

Jill Buck ◽

...

Keyword(s):

Overall Survival ◽

Phase 1 ◽

Recurrent Glioblastoma ◽

Phase 1 Study ◽

Dose Determination

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P14.56 Recurrent Glioblastomas: Should we operate a second and even a third time

Neuro-Oncology ◽

10.1093/neuonc/noz126.291 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii80-iii80

Author(s):

M Yahia-Cherif ◽

O De Witte ◽

C Mélot ◽

F Lefranc

Keyword(s):

Overall Survival ◽

Survival Benefit ◽

Standard Of Care ◽

Recurrent Glioblastoma ◽

Kaplan Meier ◽

Significant Survival ◽

Significant Difference ◽

Second Surgery ◽

Second Resection ◽

Initial Resection

Abstract BACKGROUND The aim of this study was i) to analyse the effect of repeat surgeries on the survival of patients with focally recurrent glioblastoma who have benefited from temozolomide treatment and ii) to identify potential prognostic factors for survival. MATERIAL AND METHODS Cases from 2005 to 2014 in the glioblastoma database of our department were retrospectively reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) as a function of time after one, two and three surgical resections. All patients received the standard of care after the first surgery (temozolomide during and after radiotherapy) and adjuvant treatment after repeat surgeries. RESULTS One hundred-thirty-two glioblastoma patients (median age: 57 years) were included in the study. Among them, 68, 53 and 11 patients underwent one, two and three surgical resections, respectively. The median OS was 11, 16 and 18 months, respectively, for patients who underwent one, two and three surgical resections. Patients who underwent two (p<0.001) or three (p<0.01) surgeries survived significantly longer than patients who underwent only one. No significant difference was observed between patients who underwent two versus three surgeries (p=0.76). A second resection performed more than 6 months after the initial resection was the only factor associated with prolonged survival (p=0.008). CONCLUSION Glioblastoma patients who benefited from temozolomide treatment and underwent surgery for recurrent glioblastoma exhibited a significant increase in survival compared with patients who did not undergo a second surgery. By contrast, a third surgery for a second recurrence did not contribute to any significant survival benefit.

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Impact of resection on overall survival of recurrent Glioblastoma in elderly patients

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2018.08.033 ◽

2018 ◽

Vol 174 ◽

pp. 21-25 ◽

Cited By ~ 6

Author(s):

Jasmin Hager ◽

Eva Herrmann ◽

Sarah Kammerer ◽

Nazife Dinc ◽

Sae-Yeon Won ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Recurrent Glioblastoma

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ACTR-68. FEASIBILITY STUDY OF THE EMULATE THERAPEUTICS™ VOYAGER SYSTEM IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)

Neuro-Oncology ◽

10.1093/neuonc/noz175.109 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi29-vi29

Author(s):

Garni Barkhoudarian ◽

Michael Badruddoja ◽

Nicholas Blondin ◽

Ricky Chen ◽

Sajeel Chowdhary ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Skin Irritation ◽

Recurrent Glioblastoma ◽

Secondary Outcome ◽

Open Label ◽

Serious Adverse Events ◽

Radio Frequency Energy ◽

Long Term Treatment ◽

Recurrent Gbm

Abstract BACKGROUND The EMulate Therapeutics Voyager system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of brain cancer. METHODS This ongoing, open-label, multi-center study (NAT-101) is being conducted in the US and Australia in patients with recurrent GBM. There are 3 treatment groups: 32 patients treated with Voyager alone, 43 patients treated with Voyager + Investigator’s choice of anti-cancer therapy, and 21 patients treated with Voyager+lomustine+/-bevacizumab. The objective of the study is to assess if the Voyager is a safe and feasible treatment for recurrent GBM. The primary outcome measure is safety, assessed by the incidence and evaluation of adverse events (AEs) associated with the Voyager. The secondary outcome measures are progression-free survival and overall survival. RESULTS Enrollment is closed, and long-term treatment and follow-up is ongoing. 96 patients were enrolled and treated. 82 patients reported at least one AE, and 18 AEs were assessed as device-related (mild-moderate; 12 headache, 2 vomiting, 1 nausea, 1 confusion, 1 insomnia, and 1 skin irritation). 31 patients reported at least one serious AE, and none were assessed as device-related. 33% of patients treated with Voyager alone and 36% of patients treated with Voyager + chemotherapy were progression-free after 6 months. 58% of patients treated with Voyager alone and 60% of patients treated with Voyager + chemotherapy remained alive after 6 months; median overall survival is 7 months (95% CI=4.4±14.3) in patients treated with Voyager alone and 10 months (95% CI=6.7±11.5) in patients treated with Voyager + chemotherapy. CONCLUSIONS The Voyager system appears to be safe and feasible for the treatment of recurrent GBM. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is planned.

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Performance of adjuvant treatment correlates with survival in reoperated glioblastomas

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20160144 ◽

2016 ◽

Vol 74 (11) ◽

pp. 887-894 ◽

Cited By ~ 2

Author(s):

Willey Gonçalves Zanovello ◽

Suzana M. F. Malheiros ◽

João Norberto Stavale ◽

Orestes P. Lanzoni ◽

Miguel M. Canteras ◽

...

Keyword(s):

Overall Survival ◽

Adjuvant Treatment ◽

Healthcare Service ◽

Median Overall Survival ◽

Therapeutic Option ◽

Sao Paulo ◽

Recurrent Glioblastoma ◽

Public Healthcare ◽

São Paulo ◽

Single Factor

ABSTRACT Objective To analyze cases of recurrent glioblastoma subjected to reoperation at a Brazilian public healthcare service. Methods A total of 39 patients subjected to reoperation for recurrent glioblastoma at the Department of Neurosurgery, São Paulo Hospital, Federal University of São Paulo, from January 2000 to December 2013 were retrospectively analyzed. Results The median overall survival was 20 months (95% confidence interval – CI = 14.9–25.2), and the median survival after reoperation was 9.1 months (95%CI: 2.8–15.4). The performance of adjuvant treatment after the first operation was the single factor associated with overall survival on multivariate analysis (relative risk – RR = 0.3; 95%CI = 0.2–0.7); p = 0.005). Conclusion The length of survival of patients subjected to reoperation for glioblastoma at a Brazilian public healthcare service was similar to the length reported in the literature. Reoperation should be considered as a therapeutic option for selected patients.

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