Adjuvant Temozolomide Therapy Research Articles

P07.03.A COMPLETE LONG-LASTING RESPONSE TO MULTIMODAL THIRD LINE TREATMENT WITH NEUROSURGICAL RESECTION, CARMUSTINE WAFER IMPLANTATION AND DABRAFENIB PLUS TRAMETINIB IN A BRAFV600E MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND BRAF mutations are drivers of oncogenesis in a variety of tumors and they can be successfully targeted with small molecule inhibitors. In primary central nervous system tumors, BRAFV600E mutations are most frequently found in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma and epithelioid glioblastoma. Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that was approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harboring BRAFV600E mutation. MATERIAL AND METHODS In February 2016, a 21-year-old female was admitted to our Unit for seizures. A brain magnetic resonance imaging (MRI) revealed a frontal contrast enhanced lesion. Neurosurgical resection was performed. The histological analysis diagnosed anaplastic pleomorphic xanthoastrocytoma (PXA) WHO grade III. A volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp protocol). In October 2017, a brain MRI showed relapsing disease. Six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered, and then neurosurgical partial removal and carmustine wafer implantation were performed. The histological analysis confirmed BRAF V600E mutated anaplastic PXA. RESULTS In April 2019 the 24-year-old female patient with BRAF mutated anaplastic PXA started her third-line therapy with dabrafenib. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness and the best control of the side effects, in August 2020 the patient was put on combined treatment with dabrafenib plus trametinib. Since December 2021 the residual tumor has not been longer visible. Last MRI evaluation, performed on January 26th 2023, showed no recurrence of the disease, four years after BRAF inhibitor treatment beginning. CONCLUSION Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients in third-line therapy, showing complete response and for such a long time. The emergence of optimized sequencing strategies and targeted agents, including multimodal treatment and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG and to improve patient outcomes.

Impact of Extended Adjuvant Temozolamide Beyond 6 Months in the Management of Glioblastoma Patients.

Our study aimed to assess the benefit of prolonging adjuvant temozolomide (TMZ) therapy beyond 6 cycles in glioblastoma multiform patients. The medical records of 329 patients in 2 cancer centers in Egypt were reviewed from January 2008 to December 2018 who were diagnosed with diffuse gliomas. Data were collected on patient demographics, presenting complaints, tumor size, treatment modalities (extent of surgery, radiotherapy dose and technique, concomitant TMZ, and the number of adjuvant TMZ cycles), and reported adverse events. In the studied cohort, 105 patients were treated with adjuvant TMZ, 33 patients received <6 cycles (TMZL), 41 patients received the standard 6 cycles (TMZS), and 31 patients received >6 cycles (TMZE). Our results showed the median overall survival in the TMZL arm was 8.47 months compared with 15.83 months in the TMZS arm and 27.33 months in the TMZE arm ( P < 0.001). Furthermore, a median progression-free survival of 6.35 months was reported in the TMZL group versus, 12.7 and 22.90 months in (TMZS) and (TMZE) groups, respectively( P < 0.001). In the multivariate analysis, the extended adjuvant TMZ with a hazard ratio of 3.106 (95% CI: 2.43-14.46; P < 0.001) was statistically significantly associated with a better outcome. Extended adjuvant TMZ therapy beyond 6 cycles may significantly improve the progression-free survival and overall survival in patients with glioblastoma multiform.

BIOM-21. THE EFFECTIVENESS OF CIRCULATING MICRO RNAS DERIVED FROM GLIOBLASTOMA AS A BIOMARKER FOR EARLY DIAGNOSIS AND PROGNOSIS

Abstract BACKGROUND Glioblastoma is the most common primary intracranial malignancy in adults. In cases where biopsy is not feasible due to tumors in inoperable locations including the brainstem, biomarkers such as micro RNA-21 (miR-21) extracted from blood samples could be utilized for diagnostic or prognostic purposes. In this study, we examined the role of miR-21 as a diagnostic factor in patients with glioblastoma. METHODS Inclusion criteria included patients with age greater than 20 years and with histologic confirmation of diagnosis. The blood samples were collected prior to surgery, after surgical resection, after concurrent chemoradiotherapy, and after 3 cycles of adjuvant temozolomide therapy. Using TaqMan assay, we extracted miR-21 from blood samples and compared its level with tumor volume on brain magnetic resonance imaging (MRI) scans. miR-21 levels before and after treatments were compared within each subject. RESULTS Eleven newly diagnosed glioblastoma patients were enrolled in this study, and final analyses were performed for eight patients with complete follow up serum samples. Two patients with stable disease after treatment displayed a decrease in miR-21 levels. Three out of four subjects with increase in miR-21 showed progressive disease on MRI scans. One patient with stable disease and an increased miR-21 level experienced postoperative intracranial hemorrhage and ischemic event. The two patients with unchanged miR-21 levels showed stable disease. CONCLUSION miR-21 levels were associated with progressive disease in glioblastoma patients. miR-21 has potential be utilized as a diagnostic marker in patients with glioblastoma, and further studies are needed to elucidate its role as a prognostic marker.

Volumetric Analysis of Glioblastoma for Determining Which CpG Sites Should Be Tested by Pyrosequencing to Predict Temozolomide Efficacy.

The aim of the present study was to determine which individual or combined CpG sites among O6-methylguanine DNA methyltransferase CpG 74–89 in glioblastoma mainly affects the response to temozolomide resulting from CpG methylation using statistical analyses focused on the tumor volume ratio (TVR). We retrospectively examined 44 patients who had postoperative volumetrically measurable residual tumor tissue and received adjuvant temozolomide therapy for at least 6 months after initial chemoradiotherapy. TVR was defined as the tumor volume 6 months after the initial chemoradiotherapy divided by that before the start of chemoradiotherapy. Predictive values for TVR as a response to adjuvant therapy were compared among the averaged methylation percentages of individual or combined CpGs using the receiver operating characteristic curve. Our data revealed that combined CpG 78 and 79 showed a high area under the curve (AUC) and a positive likelihood ratio and that combined CpG 76–79 showed the highest AUC among all combinations. AUCs of consecutive CpG combinations tended to be higher for CpG 74–82 in exon 1 than for CpG 83–89 in intron 1. In conclusion, the methylation status at CpG sites in exon 1 was strongly associated with TVR reduction in glioblastoma.

Randomized phase II/III trial of veliparib or placebo in combination with adjuvant temozolomide in newly diagnosed glioblastoma (GBM) patients with MGMT promoter hypermethylation (Alliance A071102).

2001 Background: PolyADP-ribose polymerase (PARP) is an important modulator of DNA repair following temozolomide (TMZ) therapy. Pre-clinical testing demonstrated significant survival benefit for the combination of TMZ and PARP inhibitor veliparib in a subset of GBM pt-derived xenografts with MGMT promoter hypermethylation. Methods: After central pathology review and MGMT testing, patients (pts) with newly diagnosed, MGMT promoter hypermethylated GBM who had completed concurrent radiation and TMZ were randomized to adjuvant therapy with TMZ (Days 1-5 q28 days) combined with either placebo or veliparib (Days 1-7 q28 days). Veliparib/placebo+TMZ treatment was continued for up to 6 cycles. Pts accrued on the phase II and III portions of the trial were included in the primary endpoint analysis of overall survival (OS), with 90% power to detect a hazard ratio of 0.71 using a one-sided log-rank test with type I error rate of 0.05. The planned phase III sample size was 400 pts with data maturity after 302 deaths. Results: The phase II and III portions of the trial were open to accrual from 12/15/2014 to 2/6/2017 and 11/8/2017 to 10/15/2018, respectively; 447 pts were accrued to the trial and used in this intention to treat analysis. The two treatment groups were well balanced for prognostic factors, 421 pts initiated treatment, median follow-up was 57.8 months (mos), 380 pts had disease progression and 335 pts have died. There was no difference in OS (p = 0.15; HR 0.89 (0.71-1.11), median OS 28.1 vs. 24.8 mo. for TMZ+veliparib vs. TMZ+placebo, respectively) and no difference in secondary endpoint progression free survival (PFS, p = 0.31; HR 1.05 (0.86-1.30), median 13.2 vs. 12.1 mo, respectively). There was a notable trend for extended OS with TMZ+veliparib treatment at intermediate time-points between 24 and 42 mos (3-year OS 36.6% vs. 28.9% with TMZ+placebo, p = 0.09). In an unplanned exploratory analysis, treatment with TMZ at the time of first recurrence was associated with extended post-recurrence OS (p = 0.03) for pts treated on the experimental arm; median post-recurrence OS with TMZ salvage was 17.0 mo in the TMZ+veliparib arm and 12.6 mo in the TMZ+placebo arm, as compared to 9.6 mo in either arm if TMZ salvage was not used. These data are consistent with a possible effect of veliparib limiting the emergence of TMZ resistance in a subset of GBM pts. Conclusions: Veliparib combined with adjuvant TMZ therapy was not associated with significant extension in OS or PFS in newly diagnosed, MGMT hypermethylated GBM pts. However, a subset of pts treated with TMZ+veliparib may have an extended survival following re-treatment with TMZ at first recurrence. Clinical trial information: NCT02152982.

Chasing a\xa0rarity: a\xa0retrospective single-center evaluation of prognostic factors in primary gliosarcoma

Background and purposePrimary gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma multiforme. We performed a single-center analysis to identify prognostic factors.Patients and methodsWe analyzed the records of 26 patients newly diagnosed with primary WHO grade IV GS. Factors of interest were clinical and treatment data, as well as molecular markers, time to recurrence, and time to death.ResultsMedian follow-up was 9 months (range 5–21 months). Gross total resection did not lead to improved survival, most likely due to the relatively small sample size. Low symptom burden at the time of diagnosis was associated with longer PFS (P = 0.023) and OS (P = 0.018). Median OS in the entire cohort was 12 months. Neither MGMT promoter hypermethylation nor adjuvant temozolomide therapy influenced survival, consistent with some previous reports.ConclusionIn this retrospective study, patients exhibiting low symptom burden at diagnosis showed improved survival. None of the other factors analyzed were associated with an altered outcome.

Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival

ObjectiveGlioblastoma multiforme (GBM) is the most common primary malignant central nervous system (CNS) tumor. The Stupp regimen is the standard treatment, although the optimal number of temozolomide (TMZ) treatment cycles remains controversial. We compared the effects of standard 6 cycles versus > 6 cycles of TMZ chemotherapy post-surgery with concurrent chemoradiotherapy on primary GBM patient survival.Patients and methodsWe performed a single center retrospective study of GBM patients that underwent total resection, concurrent chemoradiotherapy, and at least 6 cycles of adjuvant TMZ chemotherapy from June 2011 to August 2018. Patients were divided into 2 groups based on adjuvant TMZ treatment plan: Group A(n = 27): standard 6-cycle adjuvant TMZ therapy and Group B(n = 26): > 6 cycles of adjuvant TMZ therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Continuous variables were analyzed by ANOVA, and the Kaplan-Meier method was used to evaluate PFS and OS. Univariate and multivariate COX analyses determined correlation between survival rates and covariates. We used The Mini Mental State Examination (MMSE) and Karnofsky Performance Status (KPS) to assess patients’ neurocognitive function and quality of life.ResultsAfter follow-up, median PFS was 15 months in in Group A (95%CI 9.5–20.5) and 20.1 months in Group B (95%CI 15.9–24.4). Group A median OS was 19.4 months (95%CI 15.5–23.2), compared to 25.6 months in Group B (95%CI 20.4–30.8). The 2-year survival rate of Groups A and B was 36% was 66%, respectively (P = 0.02). and 5-year survival was 7% in both. Multivariate COX regression analysis showed association between patient PFS and long-period adjuvant chemotherapy, but not OS. There were no significant difference in disability or quality of life during treatment with Stupp protocol, but differences in MMSE and KPS were in favour of the Groups B after year 1 of the treatment (P < 0.05).ConclusionsLong-term adjuvant TMZ chemotherapy was beneficial for PFS and 2-year survival rate in GBM patients, and improved their quality of life contemporarily. But OS was not significantly improved.

RTID-03. A PHASE I CLINICAL TRIAL TO EVALUATE MTD OF PERAMPANEL AND MEMANTINE IN COMBINATION WITH STANDARD CHEMORADIOTHERAPY FOR THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM –A STUDY DESIGN

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated cross-talk between neuron and glioma through neuro-transmitter glutamate receptors (AMPA and NMDA receptors) promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential strategy to prevent and treat GBM progression, particularly given the fact that the two blockers act through different anti-glioma mechanism. OBJECTIVE/ HYPOTHESIS We hypothesize that adding Perampanel (an AMPA receptor blocker) and Memantine (a NMDA receptor antagonist) to standard temozolomide plus radiation therapy for the treatment of newly diagnosed GBM patients may be well tolerated and have a safe profile to prevent tumor progression, seizure recurrence or cognition impairment from radiation. STUDY DESIGN 3 + 3 DESIGN: Maximum Tolerated Dose (MTD) is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. MTD will not be more than FDA approved maximized doses for Perampanel (12 mg daily) and Memantine (20 mg bid) for the treatment of neurological diseases. Once the MTD is found, the patient will continue at MTD for the completion of concurrent chemoradiation therapy plus completion of 6 cycles of adjuvant temozolomide therapy. SUMMARY A Phase I trial to study the safety and toxicity of combined Perampanel and Memantine with standard chemo-radiation therapy to treat patients with newly diagnosed glioblastoma (GBM). To find Maximum Tolerated Dose (MTD) Levels of Perampanel and Memantine at concurrent chemoradiation therapy phase and adjuvant chemotherapy phase to prepare for future phase II or III trial.

Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular-Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation.

The ventricular–subventricular zone (V‐SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V‐SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V‐SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard‐of‐care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ), and X‐irradiation (XRT), followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V‐SVZ in C57BL/6 mice. We found that chemoradiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of caspase 3, but not in NSCs, and that A cells within the V‐SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess the repair of DNA double‐strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of antiapoptotic proteins compared with type A cells. This preclinical research, demonstrating that murine NSCs residing in the V‐SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. stem cells 2019;37:1629–1639

Dendritic cell vaccines for high-grade gliomas

Glioblastoma (GBM) is the most common and fatal primary adult brain tumor. To date, various promising chemotherapeutic regimens have been trialed for use in GBM; however, temozolomide (TMZ) therapy remains the only US Food and Drug Administration-approved first-line chemotherapeutic option for newly diagnosed GBM. Despite maximal therapy with surgery and combined concurrent chemoradiation and adjuvant TMZ therapy, the median overall survival remains approximately 14 months. Given the failure of conventional chemotherapeutic strategies in GBM, there has been renewed interest in the role of immunotherapy in GBM. Dendritic cells are immune antigen-presenting cells that play a role in both the innate and adaptive immune system, thereby making them prime vehicles for immunotherapy via dendritic cell vaccinations (DCVs) in various cancers. There is great enthusiasm surrounding the use of DCVs for GBM with multiple ongoing trials. In this review, we comprehensively summarize the safety, efficacy, and quality of life results from 33 trials reporting on DCV for high-grade gliomas.

Prediction of survival in patients affected by glioblastoma: histogram analysis of perfusion MRI.

The identification of prognostic biomarkers plays a pivotal role in the management of glioblastoma. The aim of this study was to assess the role of magnetic resonance dynamic susceptibility contrast imaging (DSC-MRI) with histogram analysis in the prognostic evaluation of patients suffering from glioblastoma. Sixty-eight patients with newly diagnosed pathologically verified GBM were retrospectively evaluated. All patients underwent MRI investigations, including DSC-MRI, surgical procedure and received postoperative focal radiotherapy plus daily temozolomide (TMZ), followed by adjuvant TMZ therapy. Relative cerebral blood volume (rCBV) histograms were generated from a volume of interest covering the solid portions of the tumor and statistically evaluated for kurtosis, skewness, mean, median and maximum value of rCBV. To verify if histogram parameters could predict survival at 1 and 2years, receiver operating characteristic (ROC) curves were obtained. Kaplan-Meier method was used to calculate patient's overall survival. rCBV kurtosis and rCBV skewness showed significant differences between subjects surviving > 1and > 2years, According to ROC analysis, the rCBV kurtosis showed the best statistic performance compared to the other parameters; respectively, values of 1 and 2.45 represented an optimised cut-off point to distinguish subjects surviving over 1 or 2years. Kaplan-Meier curves showed a significant difference between subjects with rCBV kurtosis values higher or lower than 1 (respectively 1021 and 576 days; Log-rank test: p = 0.007), and between subjects with rCBV kurtosis values higher or lower than 2.45 (respectively 802 and 408 days; Log-rank test: p = 0.001). The histogram analysis of perfusion MRI proved to be a valid method to predict survival in patients affected by glioblastoma.

Shadow study: randomized comparison of clinic with video follow-up in glioma undergoing adjuvant temozolomide therapy

Aim:This study was designed with a primary objective to study the rate of agreement in treatment plan and decisions between video follow-up (VF) and conventional clinic follow-up (CF).Patients & methods:Adult patients with intermediate- to high-grade glioma on adjuvant temozolomide (TMZ) with facilities for live video call were invited to participate in the study.Results:The concurrence in decision of administering TMZ between VF and CF was 100% (p < 0.00). The median cost incurred in VF was US$58.15 while that incurred in CF was US$131.23 (p < 0.00).Conclusion:VF can substitute CF during adjuvant TMZ administration (CTRI/2017/01/007626).

Impact of subventricular zone irradiation on outcome of patients with glioblastoma.

Glioblastoma (GBM) is characterized by early relapse and mortality. Treatment resistance could be a characteristic exhibited by pro-genitor neoplastic cells that reside in the subventricular zone (SVZ). This retrospective study was conducted to assess the correlation of SVZ doses and survival in patients with GBM. Forty-seven patients with GBM treated with radiotherapy, concurrent and adjuvant temozolomide therapy, and whose dosimetry data were available were included. The ipsilateral and contralateral SVZs were delineated on co-registered magnetic resonance imaging-computed tomography images as a 5-mm margin along the lateral wall of the lateral ventricles. Median radiotherapy dose prescribed was 59.4 Gy. The mean ipsilateral, contralateral, and bilateral SVZ doses were 56.3 Gy (range 33-63 Gy), 50.4 Gy (range 23-79 Gy), and 52 Gy (28-69 Gy). The progression-free survival (PFS) and overall survival (OS) were calculated from the date of surgery to the date of radiologic and/or clinical progression and death/last follow-up, respectively. Survival probability was estimated using the Kaplan-Meier method. Log-rank test was used to test the significance between groups. Cox proportional hazards analyses were used to identify prognostic factors. At a median follow-up of 19 months, all patients had relapsed. Most recurrences were infield (n = 39). The median PFS and OS were 17 and 19 months, respectively. The PFS and OS at 2 years were 36.2% and 21.3%, respectively. Patients who received ipsilateral SVZ dose of ≥56 Gy appeared to have better but nonsignificant median PFS and OS. Patients receiving contralateral SVZ doses ≥50 Gy showed a similar trend. Only the number of adjuvant temozolomide (≥6 cycles) showed prognostic impact. This retrospective study indicated a trend toward improved-albeit nonsignificant-survival with higher dose to the ipsilateral and contralateral SVZs. A well-designed prospective randomized study is required to identify patients who would benefit from intentional SVZ targeting.

Long-term follow-up results of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastoma multiforme patients. The importance of MRI information in survival: Single-center experience.

Glioblastoma multiforme (GBM) is the most common malignant primary anomaly of central nervous system. The GBM infiltrates the nearly sturctures from the initial tumor and its metastatic attribution is well known. The aim of our single-centered retrospective study was to introduce the importance of postoperative medical imaging confirmation of total tumor resection for patient with GBM combined concomitant and adjuvant chemoradiotherapy on a 10 year long patient follow up. From January 2006 to April 2015 we registered 59 patients with newly diagnosed GBM at the University of Kaposvár Health Center Institute of Diagnostic Imaging and Radiation Oncology. The histological diagnosis was confirmed by a proficient neuropathologist (World Health Organisation WHO; grade IV astrocytoma). According to histological status if the ECOG performance status of patients allowed it the mutidisciplinary oncoteam recommended adjuvant chemoradiotherapy all features strictly by Stupp protocol. (60 Gy dose on the gross tumor volume and 2-3 cm margin for the clinical target volume with parallel 75 mg/m2 TMZ. Four weeks after monotherapial phase patients had to recieve 6 cycles of TMZ first cycle with 150 mg/m2 up to 200 mg/m2). The irradiation was carried out by a conformal three dimensional planning system. 59 patients with the median age of 63 (range 17-84) year. Our sample counted 34 male patients and 25 woman patients. 14 patients underwent gross total tumor resection while, 39 patients underwent partial resection and the rest from our sample 6 patients passed through biopsy. Statistical analysis showed a lengthier survival among males than females, with a median survival of 13 months for males and females, the OS of 26.209 for males, meanwhile 15.625 for females. However, the difference is not considerable (log-rank p=0.203). Our study found that the estimated survival of patients at least 50 years old is significantly shorter at a median survival of 12 months (log rank p=0.027) than that of patients below 50 years of age at a median survival of 23 months. The longest estimated median survival was calculated with patients of ECOG '0' condition (16 months). However, no significant difference was found in the estimated survival of patients of different ECOG conditions (log-rank p=0.146). Based on the extent of surgery, complete resection resulted in the longest average survival of 36.4 months, followed by 21.5 months among patients with biopsy, and 15.8 months among patients with partial resection. Different surgical procedures, however, did not result in significant differences in survival (log-rank p=0.059). The overal survival of patients who had complete resection confirmed by MRI compared with the overal survival of patients with residual tumor confirmed by MRI as well we can estimate that there is significant difference between these two groups (p=0,004). Despite complex and intense treatment, recurrence is inevitable and causes relatively rapid death. In our analysis complete resection, as defined from the neurosurgeon's report and postoperative MRI, resulted in an independently significant improvement in OS. Our results are the evidences that the treatment of patients with glioblastoma multiforme in Hungary is at least on the same level as any other developed European countries.

Perfusion of surgical cavity wall enhancement in early post-treatment MR imaging may stratify the time-to-progression in glioblastoma.

ObjectiveTo determine if perfusion in surgical cavity wall enhancement (SCWE) obtained in early post-treatment MR imaging can stratify time-to-progression (TTP) in glioblastoma.Materials and methodsThis study enrolled 60 glioblastoma patients with more than 5-mm-thick SCWEs as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL). The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.ResultsThe perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03) and borderline significantly for reader 1 (P = 0.08). A positive perfusion state and (P = 0.02) a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2). The contrast enhancement pattern did not become a TTP predictor.ConclusionAssessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP.

SHADOW study: Comparison of conventional clinical follow-up with clinician led video follow-up in newly diagnosed patients with intermediate and high grade glioma receiving adjuvant temozolomide therapy.

2024 Background: In patients with gliomas, nurse led telephonic follow-up was associated with high satisfaction rates and was a valid alternative approach to conventional hospital based follow-up. However, other alternative forms of follow-up have not been studied in patients on active treatment. Methods: SHADOW was a prospective, randomized trial (CTRI/2017/01/007626). Adult intermediate to high grade glioma patients on adjuvant temozolomide with facilities for live video call were invited. After their consent, patients underwent a video follow-up (VF) 4 days prior to clinical follow-up (CF). The decisions taken during the VF and CF were noted in 5 domains, relating to temozolomide decisions (primary endpoint), concurrent medications, need for imaging, molecular testing and rehabilitation. Clinicians performing VF or CF were randomly assigned and were blinded for the other arm decisions. Patients satisfaction and costs incurred in each type of follow-up was documented. The planned sample size was 65, assuming an alpha of 0.05, a kappa coefficient of 0.9 with a one sided CI for lower limit of 0.6 and assuming a 20% lost to follow up rate. Agreement analysis was performed for calculation of Cohen's kappa coefficient. Results: 112 patients were screened and 65 were accrued. All patients underwent both VF and CCF. The concurrence in decision of administering temozolomide between VF and CCF was 100% (Cohen kappa = 1.0, 95%CI 1.0-1.0, p &lt; 0.00). In concurrent medication domain (k = 0.66,95% CI 0.04 -1, p &lt; 0.00), imaging domain (k = 1.0, 95%CI 1.0-1.0, p &lt; 0.00), rehabilitation domain (k = 1.0, 95%CI 1.0-1.0, p &lt; 0.00) and molecular testing domain (k = 0.65, 95% CI 0.20-1, p &lt; 0.00), the agreement was substantial. The satisfaction rate was 100% post video follow up and was 98.5 % post clinical follow up. The median cost incurred in VF was 58.15 USD (IQR 43.38-91.69) while that incurred in CCF was 131.23 USD (IQR 68.8-256 (p &lt; 0.00)). Conclusions: The decisions taken regarding administration of adjuvant TMZ were similar between VF and CCF. Hence, it's practical and economical to substitute CCF with VF during adjuvant TMZ administration. Clinical trial information: CTRI/2017/01/007626.

Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy.

Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer.Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy.PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.

Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48months) with 60 deaths over a 12-month accrual period and an additional 18months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. In phase 1, 24 patients were enrolled. The MTD established was 5mg/kg, given intravenously 5days a week for the first 10 RT fractions, then 3 times a weekfor the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6months (95% confidence interval [CI]: 12.9-17.6months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6months (95% CI: 5.7-9.6months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Prognosis prediction of measurable enhancing lesion after completion of standard concomitant chemoradiotherapy and adjuvant temozolomide in glioblastoma patients: application of dynamic susceptibility contrast perfusion and diffusion-weighted imaging.

PurposeTo assess the prognosis predictability of a measurable enhancing lesion using histogram parameters produced by the normalized cerebral blood volume (nCBV) and normalized apparent diffusion coefficient (nADC) after completion of standard concomitant chemoradiotherapy (CCRT) and adjuvant temozolomide (TMZ) medication in glioblastoma multiforme (GBM) patients.Materials and MethodsThis study was approved by the institutional review board (IRB), and the requirement for informed consent was waived. A total of 59 patients with newly diagnosed GBM who received standard CCRT with TMZ and adjuvant TMZ for six cycles underwent perfusion-weighted and diffusion-weighted imaging. Twenty-seven patients had a measurable enhancing lesion and 32 patients lacked a measurable enhancing lesion based on the Response Assessment in Neuro-Oncology (RANO) criteria in the follow-up MRI, which was performed within 3 months after adjuvant TMZ therapy was completed. We measured the nCBV and nADC histogram parameters based on the measurable enhancing lesion. The progression free survival (PFS) was analyzed by the Kaplan-Meier method with the use of the log-rank test.ResultsThe median PFS of patients lacking measurable enhancing lesion was longer than for those with measurable enhancing lesions (17.6 vs 3.3 months, P<.0001). There was a significant, positive correlation between the 99th percentile nCBV value of a measurable enhancing lesion and the PFS (P = .044, R2 = .152). In addition, the median PFS was longer in patients with a 99th percentile nCBV value ≧4.5 than it was in those with a value <4.5 (4.4 vs 3.1 months, P = .036).ConclusionWe found that the nCBV value can be used for the prognosis prediction of a measurable enhancing lesion after the completion of standard treatment for GBM, wherein a high 99th percentile nCBV value (≧4.5) suggests a better PFS for GBM patients.

P17.48 * SURVIVAL BENEFIT OF LEVETIRACETAM IN GLIOBLASTOMA: A PROSPECTIVE SINGLE-CENTER STUDY

OBJECTIVE: A chemo-sensitizing effect of levetiracetam (LEV) has been suggested because LEV inhibits O-6-methylguanine-DNA methyltransferase (MGMT). However, the survival benefit of LEV has not been clinically documented. This study was performed to assess the survival benefit of LEV as a chemo-sensitizer of temozolomide for glioblastoma patients compared to other anti-epileptic drugs (AEDs). METHODS: A total of 46 consecutive patients with primary supratentorial glioblastoma who were treated with concomitant chemoradiotherapy and adjuvant temozolomide therapy with LEV were prospectively enrolled. Forty-four consecutive patients with the same condition who had not taken LEV during identical chemoradiotherapy were selected as the control group. Gender, age, extent of lesion, the Karnofsky performance scale (KPS) score, extent of removal, and methylation status of the MGMT promoter were not significantly different between the LEV group and the control group. RESULTS: The median progression-free and overall survival (PFS and OS, respectively) of the LEV group (10.8 months [95% CI, 8.3-13.3] and 25.7 months [95% CI, 21.0-30.4], respectively) were significantly longer than those of the control group (6.6 months [95% CI, 5.2-8.0] and 16.8 [95% CI, 12.2-21.4], respectively) (p = 0.017 and 0.035, respectively). Significant prognostic factors for OS of all 90 patients were the preoperative KPS score (p = 0.027; HR = 0.360), methylation status of the MGMT promoter (p = 0.002; HR = 0.203), and LEV (p = 0.004; HR = 0.244) in multivariate analysis. CONCLUSIONS: LEV may provide a survival benefit in glioblastoma patients who receive temozolomide-based chemotherapy compared with other AEDs. A prospective randomized study may be indicated.