- Email: [email protected]
Retrospective analysis of bevacizumab use in combination with irinotecan for recurrent glioblastoma: a single-institution experience
S48
Abstracts
phosphorylated proteins were quantified by immunoblot analysis. Tumors in animals were labelled with 18 F-fluorodeoxyglucose (FDG), and imaged by animal-PET. Results: We found that NSC-745887 exerted antitumor activities on cell cycle through DNA damage by activating pH2AX, ATM/ATR and CHK1/CHK2 phosphorylation. The cell cycle-related proteins including cyclin A, cyclin D, CDK2, CDK4 and CDK6 were regulated to promote G1 and S phase arrest. The apoptotic-protein such as p53 and caspase-3, were activated after NSC-745887 treatment for 24 hours. However, NSC-745887 also repressed DcR3 expression and encouraged FasL/Fas signaling. In our animal model, administration of NSC-745887 reduced the standard uptake value (SUV) of 18 F-FDG and tumor volume in nude mice bearing with U118MG cells. Conclusions: NSC7–45887 can repress glioblatoma growth and may provide the potential of NSC-745887 to target therapies for human malignant gliomas. No conflict of interest. 328 POSTER Retrospective analysis of bevacizumab use in combination with irinotecan for recurrent glioblastoma: a single-institution experience C. Besson1 , W. Waissi2 , M. Velten3 , L. Nguyen Them4 , R. Schott4 , D. Prebay1 , N. Etienne-Selloum1,5 . 1 Centre Paul Strauss, Pharmacy, Strasbourg, France; 2 Centre Paul Strauss, Radiotherapy, Strasbourg, France; 3 Centre Paul Strauss, Biostatistics, Strasbourg, France; 4 Centre Paul Strauss, Oncology, Strasbourg, France; 5 Faculty of Pharmacy, UMR7213 CNRS, Strasbourg, France Background: In absence of standard treatment for recurrent glioblastoma (rGBM) in Europe, numerous prospective and retrospective studies have evaluated the combination of bevacizumab (BEV) with irinotecan (IRI) in patients with rGBM. We report here our experience with this off-label combination. Material and Methods: We performed a retrospective analysis of consecutive patients treated initially by Stupp protocol and secondly with BEV-IRI for a rGBM between 2007 and 2013. Times to progression and overall survival, as well as toxicities, were investigated. Results: A total of 82 patients were eligible for the analysis. Median age at the diagnosis was 59 years (range, 25−80) and median WHO Performance Status at the recurrence was 1.23 (range, 0−3). Sixty patients (73%) had toxicities, mainly of grade 1 and 2 (92%), such as hypertension, proteinuria, hemorrhage, thrombosis, nausea, diarrhea, fatigue or neutropenia. Most of the grade 3 (n = 9) and grade 4 (n = 1) toxicities were related to BEV treatment. Kaplan–Meier median progression-free survival (PFS) and overall survival at recurrence estimates (calculated from start of BEVIRI) were 6.5 months, 95% CI [5.7−7.8], and 10.7 months, 95% CI [8.5– 12.5], respectively, and were closed to previous results in other prospective and retrospective studies, but observed in older patients than previously (median age ranged from 44.7 to 57 years in previous studies). The median overall survival (calculated from diagnosis) was 23 months, 95% CI [20.5– 24.9]. Multivariate analysis showed that MGMT status (methylated versus unmethylated) had no effect on PFS before the first recurrence (P = 0.925). Similarly, neither age (70 years versus <70 years, P = 0.628) nor WHO performance status (P = 0.463) had significant influence on the overall survival, suggesting than this combination might be also applicable to some frail patients. In the opposite, new surgery of rGBM (n = 18) significantly improve the survival at recurrence (P = 0.029). Conclusions: BEV-IRI Combination is well tolerated and may offer a real clinical benefit for patients with recurrent GBM. Moreover second surgery at recurrence was suggested to be associated with prolonged survival. Our results are in line with previous studies and altogether these findings strengthened the role of these agents for the treatment of recurrent GBM. Conflict of interest: Ownership: No Relationships to Disclose. Advisory Board: Dr Schott has consulting or advisory role for Roche. Board of Directors: No Relationships to Disclose. Corporate-sponsored Research: No Relationships to Disclose. Other Substantive Relationships: Dr Schott was supported by Roche for travel, accommodations and expenses. 329 POSTER Disulfiram − an anti-alcoholism medicine will give cancer patients new hope W. Wang1 . 1 University of Wolverhampton, Research institute in Healthcare Science, Wolverhampton, United Kingdom Background: The medical need for better cancer therapies is urgent while drug development is slow (15 years/drug), risky and costly
Poster Session, Sunday 29 January 2017 ($1.5 billion/drug). This has led to an increasing appreciation of the potential of translation of clinically used old drugs into anticancer application. We have shown that disulfiram (DS), an anti-alcoholism drug used in clinic for over 60 years, demonstrates specific activity against a wide range of cancers. Importantly, we have been able to demonstrate that DS specifically destroys cancer-stem-like cells and enhances the cytotoxicity of conventional first-line anticancer drugs. Although DS shows strong anticancer activity in the lab, its clinical use in anti-cancer indication is limited by its rapid degradation and extensive metabolic conversion in the bloodstream. After administration of currently only available oral version of DS, the drug is enriched in liver where it is promptly methylated, glucuronidated and degraded. Although the metabolites of DS are still effective in antialcoholism, the anticancer activity is completely lost. Therefore, the short half-life of DS in the bloodstream became the bottleneck for repositioning of DS into cancer treatment. In this project, we used a poly lactic-co-glycolic acid (PLGA) nanoparticle to encapsulate disulfiram and examined the anticancer activity of the nanoencapsulated DS in different types of cancers, e.g. brain, breast, liver, lung cancer in vitro and in vivo. Materials and Methods: Nano-encapsulation of DS, hypoxic culture, stable transfection, MTT, CSC culture, lung, liver, breast cancer and glioblastoma mouse models. Results: The newly developed DS-PLGA was characterized. The DSPLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver, lung cancer and glioblastoma stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU, Sorafenib, gemcitabine. DS-PLGA blocked the in vitro migration and invasion of cancer cells at an extremely low concentration (5 nM). It also demonstrated very promising anticancer efficacy in liver, lung cancer and glioblastoma mouse models. DS-PLGA/copper completely blocked the metastasis of liver and lung cancer. We also observed very promising preliminary results from lung cancer patients. Conclusions: Very short half-life in the bloodstream is the bottleneck for translation of DS into cancer treatment. We used nano-technology to extend the half-life of DS and obtained very promising anticancer results from several mouse cancer models. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into cancer treatment. No conflict of interest. 330 POSTER Fotemustine as a third line treatment of high-grade glioma ´ P. Ramirez Daffos1 , G. Blanco Sanchez2 , I. Iglesias Lozano3 , M.J. Gomez 2 Reina1 , A. Salguero Olid2 , M. Dom´ınguez Lopez , A. Quilez Cutillas1 , ´ 2 1 M.J. Mart´ınez Bautista . Hospital Universitario Puerta del Mar, Oncology, Cadiz, Spain; 2 Hospital Universitario Puerta del Mar, Pharmacy, Cadiz, Spain; 3 Hospital Universitario Puerta del Mar, Neurosurgery, Cadiz, Spain Background: Patients with relapse of recurrent high-grade glioma (GAG), don’t usually benefit from a second surgery or reirradiation. In patients pretreated with temozolomide, the prognosis remains poor, with a 9−15% progression-free survival (PFS) at 6 months, a median PFS of 2 months and 6 months of overall survival (OS). With the addition of bevacizumab or fotemustine (MTF), median PFS at 6 months of 40−50% and median OS of 9.2 and 8 months, respectively, were reached. FTM is a third generation nitrosourea with high liposolubility, which allows a high concentration of drug in CNS (central nervous system). There is no currently clinical trial showing a 3rd line treatment benefit in recurrent GAG. The aim of this study is to describe the clinical experience in our hospital with FTM in 3rd line. Material and Methods: An observational, retrospective study was conducted in which all patients who had progressed to temozolomide and irinotecan plus bevacizumab were enrolled and received at least one cycle of fotemustine (TMF) from 2010 to the present. The treatment schedule consisted of: induction doses with 80 mg/m2 intravenously on days 1−15–30–45−60, 4 weeks rest, and then maintenance with 80 mg/m2 every 3 weeks. Demographic, clinical, and pharmacotherapeutic data were collected through the Oncowin® program and the Diraya Digital Specialist Clinical History® . As variables of effectiveness were measured the SLP, SG and survival rate at 3 months. Adverse events grade 3 were recorded according to CTCAE version 4.0. Results: In our center, a total of 7 GAG patients were treated with FTM, 5 women, with a median age of 41 years, who had progressed to temozolomide and irinotecan–bevacizumab (mean of 14 cycles). 42% (n = 3) were anaplastic astrocytomas and 58% (n = 4) multiform glioblastomas. 100% of the patients had PS 0−1 at the beginning of
Abstracts
phosphorylated proteins were quantified by immunoblot analysis. Tumors in animals were labelled with 18 F-fluorodeoxyglucose (FDG), and imaged by animal-PET. Results: We found that NSC-745887 exerted antitumor activities on cell cycle through DNA damage by activating pH2AX, ATM/ATR and CHK1/CHK2 phosphorylation. The cell cycle-related proteins including cyclin A, cyclin D, CDK2, CDK4 and CDK6 were regulated to promote G1 and S phase arrest. The apoptotic-protein such as p53 and caspase-3, were activated after NSC-745887 treatment for 24 hours. However, NSC-745887 also repressed DcR3 expression and encouraged FasL/Fas signaling. In our animal model, administration of NSC-745887 reduced the standard uptake value (SUV) of 18 F-FDG and tumor volume in nude mice bearing with U118MG cells. Conclusions: NSC7–45887 can repress glioblatoma growth and may provide the potential of NSC-745887 to target therapies for human malignant gliomas. No conflict of interest. 328 POSTER Retrospective analysis of bevacizumab use in combination with irinotecan for recurrent glioblastoma: a single-institution experience C. Besson1 , W. Waissi2 , M. Velten3 , L. Nguyen Them4 , R. Schott4 , D. Prebay1 , N. Etienne-Selloum1,5 . 1 Centre Paul Strauss, Pharmacy, Strasbourg, France; 2 Centre Paul Strauss, Radiotherapy, Strasbourg, France; 3 Centre Paul Strauss, Biostatistics, Strasbourg, France; 4 Centre Paul Strauss, Oncology, Strasbourg, France; 5 Faculty of Pharmacy, UMR7213 CNRS, Strasbourg, France Background: In absence of standard treatment for recurrent glioblastoma (rGBM) in Europe, numerous prospective and retrospective studies have evaluated the combination of bevacizumab (BEV) with irinotecan (IRI) in patients with rGBM. We report here our experience with this off-label combination. Material and Methods: We performed a retrospective analysis of consecutive patients treated initially by Stupp protocol and secondly with BEV-IRI for a rGBM between 2007 and 2013. Times to progression and overall survival, as well as toxicities, were investigated. Results: A total of 82 patients were eligible for the analysis. Median age at the diagnosis was 59 years (range, 25−80) and median WHO Performance Status at the recurrence was 1.23 (range, 0−3). Sixty patients (73%) had toxicities, mainly of grade 1 and 2 (92%), such as hypertension, proteinuria, hemorrhage, thrombosis, nausea, diarrhea, fatigue or neutropenia. Most of the grade 3 (n = 9) and grade 4 (n = 1) toxicities were related to BEV treatment. Kaplan–Meier median progression-free survival (PFS) and overall survival at recurrence estimates (calculated from start of BEVIRI) were 6.5 months, 95% CI [5.7−7.8], and 10.7 months, 95% CI [8.5– 12.5], respectively, and were closed to previous results in other prospective and retrospective studies, but observed in older patients than previously (median age ranged from 44.7 to 57 years in previous studies). The median overall survival (calculated from diagnosis) was 23 months, 95% CI [20.5– 24.9]. Multivariate analysis showed that MGMT status (methylated versus unmethylated) had no effect on PFS before the first recurrence (P = 0.925). Similarly, neither age (70 years versus <70 years, P = 0.628) nor WHO performance status (P = 0.463) had significant influence on the overall survival, suggesting than this combination might be also applicable to some frail patients. In the opposite, new surgery of rGBM (n = 18) significantly improve the survival at recurrence (P = 0.029). Conclusions: BEV-IRI Combination is well tolerated and may offer a real clinical benefit for patients with recurrent GBM. Moreover second surgery at recurrence was suggested to be associated with prolonged survival. Our results are in line with previous studies and altogether these findings strengthened the role of these agents for the treatment of recurrent GBM. Conflict of interest: Ownership: No Relationships to Disclose. Advisory Board: Dr Schott has consulting or advisory role for Roche. Board of Directors: No Relationships to Disclose. Corporate-sponsored Research: No Relationships to Disclose. Other Substantive Relationships: Dr Schott was supported by Roche for travel, accommodations and expenses. 329 POSTER Disulfiram − an anti-alcoholism medicine will give cancer patients new hope W. Wang1 . 1 University of Wolverhampton, Research institute in Healthcare Science, Wolverhampton, United Kingdom Background: The medical need for better cancer therapies is urgent while drug development is slow (15 years/drug), risky and costly
Poster Session, Sunday 29 January 2017 ($1.5 billion/drug). This has led to an increasing appreciation of the potential of translation of clinically used old drugs into anticancer application. We have shown that disulfiram (DS), an anti-alcoholism drug used in clinic for over 60 years, demonstrates specific activity against a wide range of cancers. Importantly, we have been able to demonstrate that DS specifically destroys cancer-stem-like cells and enhances the cytotoxicity of conventional first-line anticancer drugs. Although DS shows strong anticancer activity in the lab, its clinical use in anti-cancer indication is limited by its rapid degradation and extensive metabolic conversion in the bloodstream. After administration of currently only available oral version of DS, the drug is enriched in liver where it is promptly methylated, glucuronidated and degraded. Although the metabolites of DS are still effective in antialcoholism, the anticancer activity is completely lost. Therefore, the short half-life of DS in the bloodstream became the bottleneck for repositioning of DS into cancer treatment. In this project, we used a poly lactic-co-glycolic acid (PLGA) nanoparticle to encapsulate disulfiram and examined the anticancer activity of the nanoencapsulated DS in different types of cancers, e.g. brain, breast, liver, lung cancer in vitro and in vivo. Materials and Methods: Nano-encapsulation of DS, hypoxic culture, stable transfection, MTT, CSC culture, lung, liver, breast cancer and glioblastoma mouse models. Results: The newly developed DS-PLGA was characterized. The DSPLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver, lung cancer and glioblastoma stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU, Sorafenib, gemcitabine. DS-PLGA blocked the in vitro migration and invasion of cancer cells at an extremely low concentration (5 nM). It also demonstrated very promising anticancer efficacy in liver, lung cancer and glioblastoma mouse models. DS-PLGA/copper completely blocked the metastasis of liver and lung cancer. We also observed very promising preliminary results from lung cancer patients. Conclusions: Very short half-life in the bloodstream is the bottleneck for translation of DS into cancer treatment. We used nano-technology to extend the half-life of DS and obtained very promising anticancer results from several mouse cancer models. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into cancer treatment. No conflict of interest. 330 POSTER Fotemustine as a third line treatment of high-grade glioma ´ P. Ramirez Daffos1 , G. Blanco Sanchez2 , I. Iglesias Lozano3 , M.J. Gomez 2 Reina1 , A. Salguero Olid2 , M. Dom´ınguez Lopez , A. Quilez Cutillas1 , ´ 2 1 M.J. Mart´ınez Bautista . Hospital Universitario Puerta del Mar, Oncology, Cadiz, Spain; 2 Hospital Universitario Puerta del Mar, Pharmacy, Cadiz, Spain; 3 Hospital Universitario Puerta del Mar, Neurosurgery, Cadiz, Spain Background: Patients with relapse of recurrent high-grade glioma (GAG), don’t usually benefit from a second surgery or reirradiation. In patients pretreated with temozolomide, the prognosis remains poor, with a 9−15% progression-free survival (PFS) at 6 months, a median PFS of 2 months and 6 months of overall survival (OS). With the addition of bevacizumab or fotemustine (MTF), median PFS at 6 months of 40−50% and median OS of 9.2 and 8 months, respectively, were reached. FTM is a third generation nitrosourea with high liposolubility, which allows a high concentration of drug in CNS (central nervous system). There is no currently clinical trial showing a 3rd line treatment benefit in recurrent GAG. The aim of this study is to describe the clinical experience in our hospital with FTM in 3rd line. Material and Methods: An observational, retrospective study was conducted in which all patients who had progressed to temozolomide and irinotecan plus bevacizumab were enrolled and received at least one cycle of fotemustine (TMF) from 2010 to the present. The treatment schedule consisted of: induction doses with 80 mg/m2 intravenously on days 1−15–30–45−60, 4 weeks rest, and then maintenance with 80 mg/m2 every 3 weeks. Demographic, clinical, and pharmacotherapeutic data were collected through the Oncowin® program and the Diraya Digital Specialist Clinical History® . As variables of effectiveness were measured the SLP, SG and survival rate at 3 months. Adverse events grade 3 were recorded according to CTCAE version 4.0. Results: In our center, a total of 7 GAG patients were treated with FTM, 5 women, with a median age of 41 years, who had progressed to temozolomide and irinotecan–bevacizumab (mean of 14 cycles). 42% (n = 3) were anaplastic astrocytomas and 58% (n = 4) multiform glioblastomas. 100% of the patients had PS 0−1 at the beginning of