Relapsed Glioblastoma Research Articles

462P Regorafenib for relapsed glioblastoma: Retrospective real-world analysis of a single Institution experience

462P Regorafenib for relapsed glioblastoma: Retrospective real-world analysis of a single Institution experience

Second surgery for relapsed glioblastoma: an observational study on criteria for patient selection in real life.

Aim: There is little consensus on salvage management of glioblastoma after recurrence, for lack of evidence.Materials &methods: A retrospective study of treatments in patients with recurrent glioblastoma.Results: Surgery at recurrence was related to better overall survival (OS) and progression-free survival (PFS). Surgery at recurrence, Karnofsky index, MGMT methylation status, younger age at diagnosisand number of chemotherapy cycles were positive factors for OS and PFS. The benefit of OS was relevant for a second surgery performed at least 9months after the first one. Systemic treatments after the second surgery were linked to an improved PFS.Conclusion: Younger age, Karnofsky index, MGMT methylation statusand a median time between surgeries ≥9months may be criteria for eligibility for surgery at recurrence.

Time-resolved, integrated analysis of clonally evolving genomes.

Clonal genome evolution is a key feature of asexually reproducing species and human cancer development. While many studies have described the landscapes of clonal genome evolution in cancer, few determine the underlying evolutionary parameters from molecular data, and even fewer integrate theory with data. We derived theoretical results linking mutation rate, time, expansion dynamics, and biological/clinical parameters. Subsequently, we inferred time-resolved estimates of evolutionary parameters from mutation accumulation, mutational signatures and selection. We then applied this framework to predict the time of speciation of the marbled crayfish, an enigmatic, globally invasive parthenogenetic freshwater crayfish. The results predict that speciation occurred between 1986 and 1990, which is consistent with biological records. We also used our framework to analyze whole-genome sequencing datasets from primary and relapsed glioblastoma, an aggressive brain tumor. The results identified evolutionary subgroups and showed that tumor cell survival could be inferred from genomic data that was generated during the resection of the primary tumor. In conclusion, our framework allowed a time-resolved, integrated analysis of key parameters in clonally evolving genomes, and provided novel insights into the evolutionary age of marbled crayfish and the progression of glioblastoma.

Targeting chromosome 12q amplification in relapsed glioblastoma: the use of computational biological modeling to identify effective therapy—a case report

Relapsed glioblastoma (GBM) is often an imminently fatal condition with limited therapeutic options. Computation biological modeling, i.e., biosimulation, of comprehensive genomic information affords the opportunity to create a disease avatar that can be interrogated in silico with various drug combinations to identify the most effective therapies. We report the outcome of a GBM patient with chromosome 12q amplification who achieved substantial disease remission from a novel therapy using this approach. Following next generation sequencing (NGS) was performed on the tumor specimen. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotype. In silico responses to various drug combinations were biosimulated in the disease network. Efficacy scores representing the computational effect of treatment for each strategy were generated and compared to each other to ascertain the differential benefit in drug response from various regimens. Biosimulation identified CDK4/6 inhibitors, nelfinavir and leflunomide to be effective agents singly and in combination. Upon receiving this treatment, the patient achieved a prompt and clinically meaningful remission lasting 6 months. Biosimulation has utility to identify active treatment combinations, stratify treatment options and identify investigational agents relevant to patients' comprehensive genomic abnormalities. Additionally, the combination of abemaciclib and nelfinavir appear promising for GBM and potentially other cancers harboring chromosome 12q amplification.

Targeting immunoliposomes to EGFR-positive glioblastoma

BackgroundWe assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients.Patients and methodsPatients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained.ResultsThere were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood–brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome.ConclusionsWe clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo—in this case doxorubicin—can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

P14.58 Efficacy and safety of lomustine versus fotemustine as first and second line treament in relapsed glioblastoma patients

Abstract BACKGROUND Glioblastoma (GB) is the most aggressive primary brain tumour. Despite the survival benefit associated with adjuvant therapy, most of patients (pts) relapse after initial therapy. Nitrosoureas (NU) are the standard treatment at relapse in Europe. Both fotemustine (FM) (Addeo schema) and lomustine (LM) (administered orally every 6 weeks) are used in this context. MATERIAL AND METHODS This retrospective cohort study included pts diagnosed with GB treated with NU at relapse in four Catalonia hospitals from 2010 to 2020. Clinical and pathological data were collected from medical records. We analysed 6months-progression-free survival (6m-PFS), progression-free survival (PFS) and overall survival (OS) from the start of NU to progression or death respectively. Differences in toxicity grade using CTCAE v5.0 were analysed globally as ‘non-toxicity’, ‘mild toxicity (grade 1 or 2)’ and ‘high toxicity (grade 3 or 4)’. RESULTS We identified 236 GB pts with a median age of 58 years old. 29% of the pts presented MGMT promotor methylation and only 3%(n=7) had IDH mutation. After a median follow-up of 20 months, 94% of the pts were dead at the time of the analyses. At first line, 83 pts were treated with FM and 18 with LM. Pts treated with FM had better performance status (PS) than those treated with LM (p=.010). Median PFS was 2 months and 6m-PFS was 12% vs 6% in FM and LM group respectively (p=.87). Median OS was 3 months with LM vs 6 months with FM, with no statistically significant differences even adjusted for prognostic factors (p=.79 HR:0.9 CI 95% 0.41–1.96).At second line, 78 were treated with FM and 24 with LM, no differences between groups. Median PFS was 2 months in both groups and median OS was 3 vs 5 months for pts treated with LM vs FM respectively, with no significant differences. 6m-PFS was 13% for LM vs 0% for the FM group (p=.39).Pts received a mean of 1.7 cycles (every 6 weeks) and 4.1 cycles (every 2 weeks) in LM and FM group, respectively. Thrombocytopenia was the most common serious side-effect, with a higher proportion of grade 1–2 toxicity in the FM group (p=.03) that also required more treatment delays (p=.01). CONCLUSION Despite being retrospective study and a few pts were treated with LM, there were no differences neither in PFS nor in OS in pts treated with LM vs FM at first or second line. Higher G1-2 thrombocytopenia was shown in the FM group probably due to a higher number of hematology samples collected.

356P Redo surgery in relapsed glioblastoma multiforme: A comparative cohort analysis of a single institution experience

Glioblastoma multiforme (GBM) is the most common intracranial primary malignant brain tumour. Concurrent chemo-radiation as definitive treatment after maximal debulking is established as first-line treatment standard but recurrences are treated based on institutional experiences with or without surgery before second and susequent line of chemotherapy. In this study we look at our tertiary centre institution experience of recurrent Glioblastoma who underwent redo surgery for first recurrence.

Impact of surgery versus other treatment options in recurrent glioblastoma. Analysis of the Spanish Group of Neurooncology Research (GEINO) RETSINE database.

e14047 Background: Glioblastoma (GBM) is the most common brain primary tumor. Almost all patients have recurrent disease after initial treatment with surgery, radiotherapy and chemotherapy. After disease recurrence, there is no standardized treatment and reoperation is common but there is no proven benefit in randomized trials. Here we retrospectively review the Spanish national database to identify the frequency of reoperations in recurrent GBM and to analyze the impact of surgery on survival in this setting. Methods: We retrospectively reviewed relapsed GBM patients from the Spanish national database RETSINE (Registro Nacional Español de Tumores del Sistema Nervioso Central) supported by the GEINO group. Kaplan-Meier curves and log rank test were used to compare survival. Results: The number of patients with recurrent GBM analyzed was 538, 40% were women and 60% were men. The MGMT status was: methylated 30.9%, unmethylated 33.8%, unknown 35.3%. A total of 89.9% of the patients received radiotherapy and 88.7% received chemotherapy after initial surgery. The median progression-free survival until first recurrence was 7.63 months (IC95% 6.97-8.29). Median overall survival (OS) from GBM diagnosis was 11.96 months (IC95% 10.69- 23.23). At the time of the first progression, surgery was performed in 75 patients, (13.9%), 18 cases were treated with a second radiotherapy (3.3%), second line CT was administered in 268 patients (49.6%), 221 cases received only chemotherapy (40.9%), 47 cases were treated with both surgery and chemotherapy (8.7%); 28 were treated with surgery without chemotherapy (5.2%), 19 cases had a surgery procedure but we have no data about CT, 223 cases did nor receive CT nor surgery (41%). Median overall survival after relapse was 4.06 months (IC95% 3.25-4.87). For those patients without surgery, median OS after relapse was 3.1 m (IC95% 2.84-3.71) and for patients reoperated, median OS was 12.2 m (IC95% 10.8-13.52) p=0.00 Median overall survival after relapse was 1.7 months (IC95% (IC 1.31-2.08) for patients that did not had CT and 7.03 for those with CT(IC95%5.9-8.16) p=0.00 We also compared the results from different treatment options: median OS was 1.6 m (IC95% 1.11-2.08), for patients without treatment; 6.33 m (IC95% 5.34-7.32) for patients treated with chemotherapy; 12.2 m (IC95%11.05-13.34) for patients treated with surgery and CT;12.1 m(IC95% 4.64-19.55) for patients with surgery. Conclusions: Recurrent glioblastoma is a very aggressive disease. In this retrospective study, patients treated with surgery and surgery and CT could have a clinical benefit in terms of survivalin comparison with those not treated with reoperation. Randomized prospective trials are needed to clarify the role of surgery in recurrent GBM.

Targeting chromosome 12q amplification in relapsed glioblastoma: the use of computational biological modeling to identify effective therapy—a case report

Michael P. Castro, Negar Khanlou, Aria Fallah, Anusha Pampana, Aftab Alam, Deepak Anil Lala, Kunal Ghosh Ghosh Roy, Anish Raju R. Amara, Annapoorna Prakash, Divya Singh, Liptimayee Behura, Ansu Kumar, Shweta Kapoor

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients.

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.

Hydrolyzed Rutin Decreases Worsening of Anaplasia in Glioblastoma Relapse.

Gliomas are aggressive and resilient tumors. Progression to advanced stages of malignancy, characterized by cell anaplasia, necrosis, and reduced response to conventional surgery or therapeutic adjuvant, are critical challenges in glioma therapy. Relapse of the disease poses a considerable challenge for management. Hence, new compounds are required to improve therapeutic response. As hydrolyzed rutin (HR), a compound modified via rutin deglycosylation, as well as some flavonoids demonstrated antiproliferative effect for glioblastoma, these are considered potential epigenetic drugs. The purpose of this study was to determine the antitumor activity and evaluate the potential for modifying tumor aggressivity of rutin hydrolysates for treating both primary and relapsed glioblastoma. The glioblastoma cell line, U251, was used for analyzing cell cycle inhibition and apoptosis and for establishing the GBM mouse model. Mice with GBM were treated with HR to verify antitumor activity. Histological analysis was used to evaluate HR interference in aggressive behavior and glioma grade. Immunohistochemistry, comet assay, and thiobarbituric acid reactive substance (TBARS) values were used to evaluate the mechanism of HR action. HR is an antiproliferative and antitumoral compound that inhibits the cell cycle via a p53- independent pathway. HR reduces tumor growth and aggression, mainly by decreasing mitosis and necrosis rates without genotoxicity, which is suggestive of epigenetic modulation. HR possesses antitumor activity and decreases anaplasia in glioblastoma, inhibiting progression to malignant stages of the disease. HR can improve the effectiveness of response to conventional therapy, which has a crucial role in recurrent glioma.

Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients.

2045 Background: REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in relapsed glioblastoma (GBM) patients (pts) with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided). Results: Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The proportion of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.0146). Conclusions: In the REGOMA trial, HRQoL did not change during REG treatment. Pts treated with REG and LOM reported no significant difference in HRQoL. Clinical trial information: NCT02926222. [Table: see text]

Radiosurgery Outcome Related to Chemotherapy Association in Relapsed Glioblastoma Multiforme

Radiosurgery Outcome Related to Chemotherapy Association in Relapsed Glioblastoma Multiforme

Re-irradiation of recurrent glioblastoma as part of a sequential multimodality treatment concept.

The aim of this retrospective study was to evaluate survival outcomes in well-performing, mainly, young patients receiving a sequence of all available therapeutic options for relapsed glioblastoma, including re-irradiation. We performed a retrospective analysis of 27 patients irradiated twice for glioblastoma between 2008 and 2016. In the first line, all had surgical treatment of the tumor followed by radiotherapy with a total dose of 60Gy and temozolomide. All re-irradiated patients were treated with a total dose of 36Gy in 12 fractions. The endpoints were death from glioblastoma or any cause, and toxicity after re-irradiation. The median follow-up of survivors was 35.6months. At the time of analysis, 25 patients had died. The median time between first and second radiotherapy was 18.9months (6.1-58.4). Re-irradiation was performed at different time points of first, second and third progression. The median overall survival after first diagnosis was 39.2months. Five years after first surgery, nearly 20% of the patients were alive. Carefully planned re-irradiation of the brain is a safe therapy for recurrent glioblastoma. Younger and well-performing patients benefit from all available therapy options. Every patient should be discussed in a multidisciplinary setting at each time point of tumor progression. Further prospective studies are needed to define the optimal time, dose and volume of re-irradiation.

OS2.3 Updated results of REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib in relapsed glioblastoma <GBM> patients <PTS>

OS2.3 Updated results of REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib in relapsed glioblastoma <GBM> patients <PTS>

Updated results of REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib in relapsed glioblastoma (GBM) patients (PTS).

2047Background: There is no established treatment regimen for recurrent GBM. GBMs have activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinas...

Response assessment of bevacizumab therapy in GBM with integrated 11C-MET-PET/MRI: a feasibility study.

The objective of this study was to evaluate the potential of integrated 11C-MET PET/MR for response assessment of relapsed glioblastoma (GBM) receiving bevacizumab treatment. Eleven consecutive patients with relapsed GBM were enrolled for an integrated 11C-MET PET/MRI at baseline and at follow-up. Treatment response for MRI was evaluated according to Response Assessment in Neuro-oncology (RANO) criteria and integrated 11C-MET PET was assessed by the T/N ratio. MRI showed no patient with complete response (CR), six of 11 patients with PR, four of 11 patients with SD, and one of 11 patients with progressive disease (PD). PET revealed metabolic response in five of the six patients with partial response (PR) and in two of the four patients with stable disease (SD), whereas metabolic non-response was detected in one of the six patients with PR, in two of the four patients with SD, and in the one patient with PD. Morphological imaging was predictive for PFS and OS when response was defined as CR, PR, SD, and non-response as PD. Metabolic imaging was predictive when using T/N ratio reduction of >25 as discriminator. Based on the morphologic and metabolic findings of this study a proposal for applying integrated PET/MRI for treatment response in relapsed GBM was developed, which was significantly predictive for PFS and OS (P = 0.010 respectively 0,029, log). This study demonstrates the potential of integrated 11C-MET-PET/MRI for response assessment of GBM and the utility of combined assessment of morphologic and metabolic information with the proposal for assessing relapsed GBM.

The earlier the better? Bevacizumab in the treatment of recurrent MGMT-non-methylated glioblastoma.

The adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice. It is an open question whether the delay of BEV to third-line therapy has a negative impact on survival. A total of 61 adult patients (median age 56.9years) with MGMT-non-methylated relapsed GBM treated with BEV (n=45) or nitrosourea (n=16) as second-line therapy were analyzed retrospectively and compared regarding progression-free survival (PFS) and overall survival (OS). Patients treated with second-line BEV had longer median PFS (107days, 95% CI 80.7-133.2days) than patients with second-line nitrosourea (52days, 95% CI 36.3-67.7days, P=0.011, logrank test). However, there was no significant difference in overall survival (BEV median 170days, 95% CI 87.2-252.8days; nitrosourea median 256days, 95% CI 159.9-352.0days, P=0.468). PFS was similar after BEV third-line therapy (median 117days, 95% CI 23.6-210.4days) as compared to second-line BEV therapy (median 107days, 95% CI 80.7-133.3days, P=0.584). Our findings suggest that early treatment with BEV in patients with MGMT-non-methylated relapsed GBM is associated with a better PFS, but not with superior OS, possibly implicating that the early, i.e., second-line, use of BEV is not mandatory and BEV treatment may safely be delayed to third-line therapy in this subgroup of patients.

Sequential immune checkpoint inhibition with concurrent bevacizumab for relapsed glioblastoma: A single centre experience.

e13514Background: Median survival in relapsed glioblastoma is six months, and there are no established second-line therapies. There is increasing interest in the role of immunotherapy in glioblastoma but whilst immune checkpoint inhibitors are now routinely being used in other tumour types, the role of these drugs in glioblastoma is not yet formally evaluated. Methods: We retrospectively identified patients with glioblastoma treated with ipilimumab followed by pembrolizumab at progression, with concurrent bevacizumab and GM-CSF given throughout. Safety, tolerability and treatment responses were reviewed for all patients. Results: Four patients were identified: 3 male and 1 female aged between 23 and 55 years. All patients were treated for relapsed glioblastoma. All patients received 4 cycles of ipilimumab at first relapse, and subsequent pembrolizumab at second relapse (3 patients received 9 cycles, 1 patient received 10 cycles). One patient received concurrent lomustine chemotherapy and all patients rece...

Clinical Impact of Bevacizumab in Patients with Relapsed Glioblastoma: Focus on a Real-Life Monocentric SurVey (SV1 Study)

Objectives: Glioblastoma is one of the most frequent primitive brain tumors. Patients who experience tumor relapse after surgery and concomitant radiochemotherapy have a dismal prognosis. The objective of this study is to analyze efficacy data in terms of overall survival (OS) and progression- free survival (PFS) following combination therapy with bevacizumab (BVZ) and irinotecan among patients with relapsed glioblastoma. Safety data will also be reviewed and all results will be compared with data of the literature. Methods: In this single-center retrospective study, all records of patients treated with BVZ and irinotecan for a relapsed glioblastoma were analyzed. Each chemotherapy cycle was repeated every 15 days until progression. Magnetic resonance imaging and neurologic examination were repeated every 6 weeks during treatment. Results: Forty-five patients were analyzed. The median number of BVZ-irinotecan cycles was 8 (range 1-38). Median PFS was 26 weeks and median OS was 28 weeks. Eighteen of the 45 patients (40% of cases) had an objective response 6 months after initiation of treatment. Two patients had to discontinue treatment due to toxicity. Conclusions: The results of the SV1 study are consistent with those found in phase II studies evaluating the same treatment. The irinotecan-BVZ combination is effective in relapsed glioblastoma with acceptable toxicity. Biomarkers predictive of response to BVZ should help in the selection of patients who could benefit from treatment.