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Comprehensive geriatric assessment (CGA) can categorize elderly glioblastoma (GBM) patients into three groups predicting survival: A monoinstitutional study
abstracts
Annals of Oncology
420P
Comprehensive geriatric assessment (CGA) can categorize elderly glioblastoma (GBM) patients into three groups predicting survival: A monoinstitutional study
treatment strategy against GBM. We investigated whether photoimmunotherapy (PIT) targeting epidermal growth factor receptor (EGFR) can promoteT cell activation, whilst overcoming the immunologically cold status of GBM. Methods: The phthalocyanine dye (IR700) was conjugated to affibody molecule (ZEGFR:03115). Cell viability, reactive oxygen species (ROS) production and major damage associated molecular patterns (calreticulin (CRT), heat shock protein 70 (Hsp70), high mobility group box 1 (HMGB1), and ATP) were studied in human and murine glioma cell lines post-ZEGFR:03115–IR700 PIT using flow cytometry (FC), Western blot and ELISA. Maturation of dendritic cells (DCs) stimulated by ZEGFR:03115-IR700 PIT was verified by FC. Xenografts and syngeneic murine tumour models (subcutaneous and orthotopic) were used to determine therapeutic and tumour-specific immune response following PIT. Post-treatment tumours were evaluated ex vivo. Results: Cells treated with ZEGFR:03115–IR700 PIT showed a significant decrease in cell viability. Generation of ROS post-PIT resulted in translocation of CRT to the cell membrane and the release of HMGB1, Hsp70 and ATP. FC analysis showed significant increase in the surface expression of CD86 and HLA-DR molecules on DCs stimulated by ZEGFR:03115–IR700 PIT compared to the negative controls. In vivo, PIT led to a significant delay in subcutaneous tumour growth. A therapeutic efficacy of the conjugate was observed in brain tumours as early as 24 h post-irradiation. Ki-67, CD31, H&E staining of tumour sections showed a reduced cell proliferation index, distinct differences in vessel density, extensive tumour necrosis and microhaemorrhage on the margins of the treated tumours. In addition, tumour-infiltrating lymphocytes were elevated in the treated mice compared with the controls. Conclusions: EGFR-targeted PIT is an attractive therapeutic strategy that boosts the anti-tumour T cell response which might influence the suppressed immune microenvironment in GBM patients. Legal entity responsible for the study: The authors. Funding: The Institute of Cancer Research; The National Science Centre (NCNOPUS13#2017/25/B/NZ5/00039); and CRUK Convergence Science Centre Fund. Disclosure: All authors have declared no conflicts of interest.
E. Bergo1, M. Caccese1, M. Padovan1, L. Bellu2, A. Brunello1, V. Zagonel1, G. Lombardi1 Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy, 2Radiation Therapy and Nuclear Medicine Unit, Veneto Institute of Oncology, IOV – IRCCS, Padua, Italy
1
Background: Treatment for GBM elderly patients (pts) is a challenge in neuro-oncology. The CGA is currently used for assessing elderly pts and its score correlates with outcome in many types of tumors. We have reported some general outcomes of CGA in GBM pts. Here we performed a large retrospective analysis for identifying specific CGA category correlations with PFS and OS Methods: Pts aged 65 years, with histological diagnosis of GBM and availability of CGA result were enrolled. The CGA was administered before starting radio/chemotherapy (RT/CH) or palliative care Results: we enrolled 113 pts; median age was 71.7 years. Radical surgery was performed in 33% of cases; 80% of pts were treated with RT/CH combination; median number of maintenance temozolomide (TMZ) cycles was 3.9. Most pts had a high Karnofsky Perfrmance Score (80%). According to CGA score, 35% of pts were categorized as “fit”, 30% as “vulnerable” and 35% were “frail”, and median overall survival was 16.5 vs 12.1 vs 10.3 months (p ¼ 0.1). On multivariate analysis, CGA score proved an independent predictor of survival: vulnerable and frail pts reported an HR of 1.5 and 2.2, respectively, compared to fit pts (p ¼ 0.04). Moreover, we demonstrated a statistical association between CGA and type of treatment, fit pts being more frequently treated with RT/ CT (98% vs 90% and 52% of vulnerable and frail pts, respectively, p < 0.001); yet, frail pts received fewer cycles of maintenance TMZ than vulnerable and fit (2.8 vs 5 and 5.2, respectively; p < 0.001). No association between CGA and PFS was demonstrated. Conclusions: CGA score was shown to be a significant predictor of mortality in elderly GBM pts. The score can classify pts into three categories statistically correlating with survival. It could be a useful treatment decision tool suggesting the more appropriate treatment. However, a prospective study is warranted. Legal entity responsible for the study: Veneto Institute of Oncology IOV IRCCS. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
421P
Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy
G. Kramer-Marek1, J. Maczynska1, F. Raes1, K. Malarz2, C. Da Pieve1, M. de Mezer3, M. Niedbala4, K.J. Harrington1, W. Kaspera4 1 Radiotherapy And Imaging, The Institute of Cancer Research, Sutton, UK, 2Silesian Centre for Education and Interdisciplinary Research, University of Silesia, Chorzow, Poland, 3Center for Advanced Technology, Adam Mickiewicz University, Poznan, Poland, 4Department of Neurosurgery, Regional Hospital, Medical University of Silesia, Sosnowiec, Poland
422P
Upregulation of sFRP3 circulating expression levels correlates survival outcomes in glioblastoma
G. Bruixola1, S. Dolz2, E. Sanmartın2, T. Fleitas3, J. Font de Mora2, G. Reyne´s4 Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain, 2 Laboratory of Cellular and Molecular Biology, Instituto de Investigaci on Sanitaria La Fe, Valencia, Spain, 3Medical oncology, Hospital Clinico Universitario de Valencia, 4 on Sanitaria La Fe, Valencia, Valencia, Spain, Medical Oncology, Instituto de Investigaci Spain
1
Background: Glioblastoma (GBM) is characterized by invasion, heterogeneity and high angiogenesis, conferring a poor prognosis. The aim of our study was to assess serum proteins related to these hallmarks with potential prognostic value in GBM. Methods: Serum samples from GBM patients (N ¼ 57 pts) were collected before Stupp regimen. We defined as “LT survivors” (LTS) those pts above 36-months survival, and as “ST survivors” (STS) those below 6-months survival. In the discovery cohort (N ¼ 25 pts), 4 pts were identified in each group. A pooled analysis from serum samples of each group was performed by a protein profiling platform based on antibody array technology. Expressed proteins were assessed for differential expression between the two groups. In silico validation by using data obtained from French glioma study at R2 was performed. In situ expression levels from selected proteins involved in tumor progression (TP), cell proliferation (CP), invasion (Inv) and cell death (CD) that significantly correlate (p < 0.05) with OS in gliomas were studied. ELISA analysis against an independent sample set from the validation cohort (n ¼ 32 pts, LTS n ¼ 4, STS n ¼ 7) was used to verify expression levels of the target proteins. Results: A total of 1000 proteins were analyzed by the array. 214 proteins showed differences in fluorescence intensity more than 10-fold between LTS vs STS. Among them, SMAD4, SMAD5, TWEAK, VEGFR2, WISP1, FGF21, NEUROD1, SFRP3, SFPR4 and Bax were selected since obtained the highest differences in fluorescence intensity and correlated with differential OS outcomes in silico. ELISA validation demonstrated SFRP3 to be upregulated in the STS group (media expression (pg/ml) STS¼1849;LTS¼1039) (p ¼ 0.018). No statistically significant differences were observed in the expression levels for the other proteins between LTS and STS. In validation cohort, median overall survival according to SFRP3 expression (low/high) was 19.7 months (CI 95% 10.7-28.61) vs 9.42 months (CI 95% 3.11-15.72) respectively, although did not reach statistical significance (p ¼ 0.073). Conclusions: Higher circulating SFRP3 level has been associated with STS in GBM. Overexpression of serum SFPR3 in GBM may be a surrogate indicator of poorer prognosis. Further studies are warranted. Legal entity responsible for the study: The authors. Funding: GEINO. Disclosure: All authors have declared no conflicts of interest.
Background: Glioblastoma (GBM) employs a variety of mechanisms to suppress the tumour immune microenvironment. A therapeutic approach aiming to abolish immunosuppressive cells and activate anti-GBM immunity would provide a powerful
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz243 | v153
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz243.030/5577856 by guest on 26 October 2019
Methods: Retrospective analysis of adult patients with HGG diagnosis, proposed to systemic treatment between 2009 and 2018. Exclusion criteria was anticoagulation previous to diagnosis. VTE was defined as radiographic-confirmed thrombus in venous system. Risk factors for VTE and ICH were analyzed by chi-squared test and multivariate logistic regression; survival analysis by Kaplan-Meier method. Results: Of 410 patients, 31 (7,8%) developed a VTE, including 22 deep, 6 pulmonary and 3 central vein thrombosis. Twenty-nine patients with VTE had WHO grade 4 glioma and 2 patients had grade 3 (anaplastic astrocytoma and oligodendroglioma). In 22 cases, the VTE occurred during systemic treatment, more frequently during Temozolomide (n ¼ 15), followed by IrinotecanþBevacizumab (n ¼ 6). The median time to VTE was 10,11 months. Khorana score, age, ECOG performance status, smoking and obesity did not significantly differ in the VTE population. All VTE were initially treated with low molecular weight heparin (LMWH), of which 64.5% maintained LMWH, and the remainder switched to warfarin (19.4%) or to direct oral anticoagulant (16.1%). Six patients (19,4%) had spontaneous ICH under anticoagulation. Patients with grade 3 glioma (p ¼ 0,032) had significantly higher rates of ICH. Patients with higher ECOG had significantly higher risk of ICH (OR 3,23 (95CI 1,18-8,81), p ¼ 0,022). HAS-BLED and ACCP bleeding scores were not associated with ICH. There was no significant difference in overall survival for TVE or ICH. Conclusions: According to our data, ICH occurred in nearly 20% anticoagulated patients with HGG, as described in literature, and did not correlate with poorer prognosis. High ECOG performance status was an independent risk factor for ICH. Further effort towards better prediction models for VTE and ICH in HGG is warranted. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
420P
Comprehensive geriatric assessment (CGA) can categorize elderly glioblastoma (GBM) patients into three groups predicting survival: A monoinstitutional study
treatment strategy against GBM. We investigated whether photoimmunotherapy (PIT) targeting epidermal growth factor receptor (EGFR) can promoteT cell activation, whilst overcoming the immunologically cold status of GBM. Methods: The phthalocyanine dye (IR700) was conjugated to affibody molecule (ZEGFR:03115). Cell viability, reactive oxygen species (ROS) production and major damage associated molecular patterns (calreticulin (CRT), heat shock protein 70 (Hsp70), high mobility group box 1 (HMGB1), and ATP) were studied in human and murine glioma cell lines post-ZEGFR:03115–IR700 PIT using flow cytometry (FC), Western blot and ELISA. Maturation of dendritic cells (DCs) stimulated by ZEGFR:03115-IR700 PIT was verified by FC. Xenografts and syngeneic murine tumour models (subcutaneous and orthotopic) were used to determine therapeutic and tumour-specific immune response following PIT. Post-treatment tumours were evaluated ex vivo. Results: Cells treated with ZEGFR:03115–IR700 PIT showed a significant decrease in cell viability. Generation of ROS post-PIT resulted in translocation of CRT to the cell membrane and the release of HMGB1, Hsp70 and ATP. FC analysis showed significant increase in the surface expression of CD86 and HLA-DR molecules on DCs stimulated by ZEGFR:03115–IR700 PIT compared to the negative controls. In vivo, PIT led to a significant delay in subcutaneous tumour growth. A therapeutic efficacy of the conjugate was observed in brain tumours as early as 24 h post-irradiation. Ki-67, CD31, H&E staining of tumour sections showed a reduced cell proliferation index, distinct differences in vessel density, extensive tumour necrosis and microhaemorrhage on the margins of the treated tumours. In addition, tumour-infiltrating lymphocytes were elevated in the treated mice compared with the controls. Conclusions: EGFR-targeted PIT is an attractive therapeutic strategy that boosts the anti-tumour T cell response which might influence the suppressed immune microenvironment in GBM patients. Legal entity responsible for the study: The authors. Funding: The Institute of Cancer Research; The National Science Centre (NCNOPUS13#2017/25/B/NZ5/00039); and CRUK Convergence Science Centre Fund. Disclosure: All authors have declared no conflicts of interest.
E. Bergo1, M. Caccese1, M. Padovan1, L. Bellu2, A. Brunello1, V. Zagonel1, G. Lombardi1 Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy, 2Radiation Therapy and Nuclear Medicine Unit, Veneto Institute of Oncology, IOV – IRCCS, Padua, Italy
1
Background: Treatment for GBM elderly patients (pts) is a challenge in neuro-oncology. The CGA is currently used for assessing elderly pts and its score correlates with outcome in many types of tumors. We have reported some general outcomes of CGA in GBM pts. Here we performed a large retrospective analysis for identifying specific CGA category correlations with PFS and OS Methods: Pts aged 65 years, with histological diagnosis of GBM and availability of CGA result were enrolled. The CGA was administered before starting radio/chemotherapy (RT/CH) or palliative care Results: we enrolled 113 pts; median age was 71.7 years. Radical surgery was performed in 33% of cases; 80% of pts were treated with RT/CH combination; median number of maintenance temozolomide (TMZ) cycles was 3.9. Most pts had a high Karnofsky Perfrmance Score (80%). According to CGA score, 35% of pts were categorized as “fit”, 30% as “vulnerable” and 35% were “frail”, and median overall survival was 16.5 vs 12.1 vs 10.3 months (p ¼ 0.1). On multivariate analysis, CGA score proved an independent predictor of survival: vulnerable and frail pts reported an HR of 1.5 and 2.2, respectively, compared to fit pts (p ¼ 0.04). Moreover, we demonstrated a statistical association between CGA and type of treatment, fit pts being more frequently treated with RT/ CT (98% vs 90% and 52% of vulnerable and frail pts, respectively, p < 0.001); yet, frail pts received fewer cycles of maintenance TMZ than vulnerable and fit (2.8 vs 5 and 5.2, respectively; p < 0.001). No association between CGA and PFS was demonstrated. Conclusions: CGA score was shown to be a significant predictor of mortality in elderly GBM pts. The score can classify pts into three categories statistically correlating with survival. It could be a useful treatment decision tool suggesting the more appropriate treatment. However, a prospective study is warranted. Legal entity responsible for the study: Veneto Institute of Oncology IOV IRCCS. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
421P
Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy
G. Kramer-Marek1, J. Maczynska1, F. Raes1, K. Malarz2, C. Da Pieve1, M. de Mezer3, M. Niedbala4, K.J. Harrington1, W. Kaspera4 1 Radiotherapy And Imaging, The Institute of Cancer Research, Sutton, UK, 2Silesian Centre for Education and Interdisciplinary Research, University of Silesia, Chorzow, Poland, 3Center for Advanced Technology, Adam Mickiewicz University, Poznan, Poland, 4Department of Neurosurgery, Regional Hospital, Medical University of Silesia, Sosnowiec, Poland
422P
Upregulation of sFRP3 circulating expression levels correlates survival outcomes in glioblastoma
G. Bruixola1, S. Dolz2, E. Sanmartın2, T. Fleitas3, J. Font de Mora2, G. Reyne´s4 Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain, 2 Laboratory of Cellular and Molecular Biology, Instituto de Investigaci on Sanitaria La Fe, Valencia, Spain, 3Medical oncology, Hospital Clinico Universitario de Valencia, 4 on Sanitaria La Fe, Valencia, Valencia, Spain, Medical Oncology, Instituto de Investigaci Spain
1
Background: Glioblastoma (GBM) is characterized by invasion, heterogeneity and high angiogenesis, conferring a poor prognosis. The aim of our study was to assess serum proteins related to these hallmarks with potential prognostic value in GBM. Methods: Serum samples from GBM patients (N ¼ 57 pts) were collected before Stupp regimen. We defined as “LT survivors” (LTS) those pts above 36-months survival, and as “ST survivors” (STS) those below 6-months survival. In the discovery cohort (N ¼ 25 pts), 4 pts were identified in each group. A pooled analysis from serum samples of each group was performed by a protein profiling platform based on antibody array technology. Expressed proteins were assessed for differential expression between the two groups. In silico validation by using data obtained from French glioma study at R2 was performed. In situ expression levels from selected proteins involved in tumor progression (TP), cell proliferation (CP), invasion (Inv) and cell death (CD) that significantly correlate (p < 0.05) with OS in gliomas were studied. ELISA analysis against an independent sample set from the validation cohort (n ¼ 32 pts, LTS n ¼ 4, STS n ¼ 7) was used to verify expression levels of the target proteins. Results: A total of 1000 proteins were analyzed by the array. 214 proteins showed differences in fluorescence intensity more than 10-fold between LTS vs STS. Among them, SMAD4, SMAD5, TWEAK, VEGFR2, WISP1, FGF21, NEUROD1, SFRP3, SFPR4 and Bax were selected since obtained the highest differences in fluorescence intensity and correlated with differential OS outcomes in silico. ELISA validation demonstrated SFRP3 to be upregulated in the STS group (media expression (pg/ml) STS¼1849;LTS¼1039) (p ¼ 0.018). No statistically significant differences were observed in the expression levels for the other proteins between LTS and STS. In validation cohort, median overall survival according to SFRP3 expression (low/high) was 19.7 months (CI 95% 10.7-28.61) vs 9.42 months (CI 95% 3.11-15.72) respectively, although did not reach statistical significance (p ¼ 0.073). Conclusions: Higher circulating SFRP3 level has been associated with STS in GBM. Overexpression of serum SFPR3 in GBM may be a surrogate indicator of poorer prognosis. Further studies are warranted. Legal entity responsible for the study: The authors. Funding: GEINO. Disclosure: All authors have declared no conflicts of interest.
Background: Glioblastoma (GBM) employs a variety of mechanisms to suppress the tumour immune microenvironment. A therapeutic approach aiming to abolish immunosuppressive cells and activate anti-GBM immunity would provide a powerful
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz243 | v153
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz243.030/5577856 by guest on 26 October 2019
Methods: Retrospective analysis of adult patients with HGG diagnosis, proposed to systemic treatment between 2009 and 2018. Exclusion criteria was anticoagulation previous to diagnosis. VTE was defined as radiographic-confirmed thrombus in venous system. Risk factors for VTE and ICH were analyzed by chi-squared test and multivariate logistic regression; survival analysis by Kaplan-Meier method. Results: Of 410 patients, 31 (7,8%) developed a VTE, including 22 deep, 6 pulmonary and 3 central vein thrombosis. Twenty-nine patients with VTE had WHO grade 4 glioma and 2 patients had grade 3 (anaplastic astrocytoma and oligodendroglioma). In 22 cases, the VTE occurred during systemic treatment, more frequently during Temozolomide (n ¼ 15), followed by IrinotecanþBevacizumab (n ¼ 6). The median time to VTE was 10,11 months. Khorana score, age, ECOG performance status, smoking and obesity did not significantly differ in the VTE population. All VTE were initially treated with low molecular weight heparin (LMWH), of which 64.5% maintained LMWH, and the remainder switched to warfarin (19.4%) or to direct oral anticoagulant (16.1%). Six patients (19,4%) had spontaneous ICH under anticoagulation. Patients with grade 3 glioma (p ¼ 0,032) had significantly higher rates of ICH. Patients with higher ECOG had significantly higher risk of ICH (OR 3,23 (95CI 1,18-8,81), p ¼ 0,022). HAS-BLED and ACCP bleeding scores were not associated with ICH. There was no significant difference in overall survival for TVE or ICH. Conclusions: According to our data, ICH occurred in nearly 20% anticoagulated patients with HGG, as described in literature, and did not correlate with poorer prognosis. High ECOG performance status was an independent risk factor for ICH. Further effort towards better prediction models for VTE and ICH in HGG is warranted. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.