Temozolomide-based Chemoradiation Research Articles

719: De Ritis ratio in elderly glioblastoma patients treated with temozolomide-based chemoradiation

719: De Ritis ratio in elderly glioblastoma patients treated with temozolomide-based chemoradiation

Optimizing Recurrent Glioblastoma Salvage Treatment: A Multicenter Study Integrating Genetic Biomarkers From the Korean Radiation Oncology Group (21-02).

Few studies have used real-world patient data to compare overall treatment patterns and survival outcomes for recurrent glioblastoma (rGBM). This study aimed to evaluate postprogression survival (PPS) according to the treatment strategy for rGBM by incorporating biomarker analysis. We assessed 468 adult patients with rGBM who underwent standard temozolomide-based chemoradiation. The impact of predictors on PPS was evaluated in patients with isocitrate dehydrogenase wild-type rGBM (n = 439) using survival probability analysis. We identified patients who would benefit from reirradiation (re-RT) during the first progression. Median PPS was 3.4, 13.8, 6.6, and 10.0 months in the best supportive care (n = 82), surgery (with/without adjuvant therapy, n = 112), chemotherapy alone (n = 170), and re-RT (with/without chemotherapy, n = 75) groups, respectively. After propensity score matching analysis of the cohort, both the surgery and re-RT groups had a significantly better PPS than the chemotherapy-only group; however, no significant difference was observed in PPS between the surgery and re-RT groups. In the surgery subgroup, surgery with chemotherapy ( P = .024) and surgery with radio(chemo)therapy ( P = .039) showed significantly improved PPS compared with surgery alone. In the no-surgery subgroup, radio(chemo)therapy showed significantly improved PPS compared with chemotherapy alone ( P = .047). Homozygous deletion of cyclin-dependent kinase inhibitor 2A/B, along with other clinical factors (performance score and progression-free interval), was significantly associated with the re-RT survival benefit. Surgery combined with radio(chemo)therapy resulted in the best survival outcomes for rGBM. re-RT should also be considered for patients with rGBM at first recurrence. Furthermore, this study identified a specific genetic biomarker and clinical factors that may enhance the survival benefit of re-RT.

CTNI-27. TRIAL IN PROGRESS A PHASE 2 STUDY OF BPM 31510 (AN OXIDIZED COQ10-LIPID CONJUGATE NANODISPERSION) WITH VITAMIN K AND STANDARD CHEMORADIATION IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract INTRODUCTION: BPM 31510 is a novel drug-lipid conjugate nanodispersion that significantly increases the bioavailability of ubidecarenone (oxidized CoQ10). Supraphysiological concentrations of CoQ10 have been shown to have a paradoxical pro-oxidant effect on a variety of malignant cells while not altering the metabolic phenotype in normal cells. Glioblastoma multiforme (GBM) is a metabolically active cancer that is reliant on mechanisms of redox homeostasis to avert reactive oxygen species (ROS)-triggered apoptosis. This trial investigates whether this susceptibility of GBM metabolism may be effectively targeted by the potentially synergistic combination of BPM 31510 and standard-of-care radiotherapy, a known producer of ROS. Early-phase trials of BPM 31510 have shown a favorable safety profile with primarily hepatotoxicity and coagulopathy, the latter of which is mitigated by co-administration of Vitamin K. TRIAL DESIGN: BPM 31510IV-11 (NCT04752813) is a single-arm multicenter phase 2 study of BPM 31510 + Vitamin K1 in combination with standard chemoradiation for newly diagnosed GBM. Eligible patients have GBM with no prior therapy, and those with recent hemorrhage, coagulopathy, or who require anticoagulation are excluded. BPM 31510 starts 2-4 weeks after biopsy or resection initially as monotherapy for 2 weeks followed by an additional 6 weeks in combination with temozolomide-based chemoradiation. To assess safety of BPM 31510 with concomitant chemoradiotherapy, this study begins with a dose confirmation phase and allows for one dose reduction in the event of a DLT. The starting dose of BPM 31510 is 110 mg/kg administered as a continuous infusion over 96-hours weekly. The primary endpoint is 6-month progression-free survival (PFS6) by RANO criteria. Secondary endpoints include overall survival and safety. Approximately 50 patients will be enrolled for 90% power in rejecting the null hypothesis of PFS6 ≤ 30%. The study is enrolling at two US sites with a third opening soon.

P06.08.A CLINICAL OUTCOME AND TRANSLATIONAL INSIGHTS FROM A PHASE I/II TRIAL WITH THE TUMOR-TARGETING ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF FOR PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Cytokine-based therapies are promising cancer immunotherapies that potentially can convert an immunologically “cold” tumor microenvironment into a “hot” one and may trigger potent antitumor immunity. However, the systemic administration of pro-inflammatory cytokines at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising tumor necrosis factor (TNF) fused to the antibody L19 that binds a tumor-specific epitope of fibronectin. This allows targeted delivery of relevant doses of TNF to the tumor while sparing healthy organs. Here, we report the results of a clinical trial with systemically administered L19TNF as monotherapy for patients with recurrent glioblastoma. MATERIAL AND METHODS NCT03779230 was an open-label, non-randomized, multicenter phase I/II clinical trial to investigate the safety and preliminary efficacy of L19TNF monotherapy for patients with IDH-wildtype WHO grade 3/4 glioma at first relapse. L19TNF was administered intravenously in three-week cycles. Tumor responses were assessed by iRANO criteria. Accompanying translational research comprised longitudinal analyses of MRI scans using automated segmentation as well as for five matched paired samples obtained before and after L19TNF tissue immunophenotyping using imaging mass cytometry and mass spectrometry-based proteomics to characterize immunological and molecular effects of the treatment. RESULTS From 2019 - 2020, we enrolled 20 patients (19 WHO Grade 4 and 1 WHO grade 3) from three centers in Switzerland; tumors of 17 patients (85%) had a prognostically unfavorable unmethylated MGMT promoter status. L19TNF could be safely administered at a dose of 13 µg/kg and we did not observe severe adverse events. The median progression-free survival was 2.0 months and the median overall survival was 10.9 months. Using MRI imaging including perfusion maps, we observed that L19TNF led to treatment-associated tumor necrosis within one week of the treatment. Imaging mass cytometry and proteomics from five matched paired samples obtained before and after L19TNF revealed immunophenotypic and molecular changes in tumor tissue, indicating the induction of an anti-tumor immune response and alterations of multiple non-immunological pathways (transcription, translation, cell cycle, proliferation). CONCLUSION The intravenous administration of L19TNF is safe in patients with recurrent glioblastoma and shows pharmacodynamic effects at the tumor site. Ongoing studies investigate L19TNF in combination with temozolomide-based chemoradiation for patients with newly diagnosed glioblastoma (NCT04443010) and in combination with lomustine for patients at first progression (NCT04573192).

Long-term treatment outcomes of temozolomide-based chemoradiation in patients with adult-type diffuse IDH-mutant grade 2 astrocytoma

PurposeTo report the long-term outcomes in adult patients with grade 2 IDH-mutant astrocytoma treated with temozolomide (TMZ)-based chemoradiation. Methods: One hundred and three patients with histologically proven grade 2 astrocytoma received radiation therapy (RT), 50.4–54 Gy in 1.8 Gy fractions, and adjuvant TMZ up to 12 cycles. Fifty-two patients received RT at the time of tumor progression and 51 in the early postoperative period for the presence of at least one high-risk feature (age > 40 years, preoperative tumor size > 5 cm, large postoperative residual tumor, tumor crossing the midline, or presence of neurological symptoms). Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis.ResultsWith a median follow-up time of 9.0 years (range, 1.3–15 years), median PFS and OS times were 9 years (95%CI, 6.6–10.3) and 11.8 years (95%CI, 9.3–13.4), respectively. Median PFS was 10.6 years in the early treatment group and 6 years in delayed treatment group (hazard ratio (HR) 0.30; 95%CI 0.16–0.59; p = 0.0005); however, OS was not significantly different between groups (12.8 vs. 10.4 years; HR 0.64; 95%CI 0.33–1.25; p = 0.23). Extent of resection, KPS, and small residual disease were associated with OS, with postoperative tumor ≤ 1 cc that emerged as the strongest independent predictor (HR: 0.27; 95%CI 0.08–0.87; p = 0.01).ConclusionsTMZ-based chemoradiation is associated with survival benefit in patients with grade 2 IDH-mutant astrocytoma. For this group of patients, chemoradiation can be deferred until time of progression in younger patients receiving extensive resection, while early treatment should be recommended in high-risk patients.

LMAP-04 CHOOSING WISELY BETWEEN RADIOTHERAPY DOSE-FRACTIONATION SCHEDULES: THE MOLECULAR GRADED PROGNOSTIC ASSESSMENT (MOLGPA) FOR ELDERLY GLIOBLASTOMA (EGBM-MOLGPA)

Abstract This study aimed develop a prognostic model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT). Patients aged ≥65 years who underwent radiotherapy for IDH-wildtype eGBM between 2006 and 2021 were included. Patients planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT (334 patients; median, 60 Gy in 30 fractions) or HFRT (239 patients; median, 45 Gy in 15 fractions), respectively. We developed the molecular graded prognostic assessment score for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each prognostic factor for overall survival (OS). Temozolomide-based chemoradiation was applied for 86% of patients. With a median follow-up of 17.4 months, the median OS was 18.7 months for CFRT plus temozolomide group, 15.1 months for HFRT plus temozolomide group, and 10.4 months for RT alone group. The eGBM-molGPAwas established based on prognostic factors from multivariate analysis (performance, extent of resection, temozolomide, methylation of the MGMT promoter, subventricular zone involvement, temporalis muscle thickness, and the mutation status of TERT promoter and TP53 gene) and patients were allocated to three risk groups (high risk, total score 3.0–4.5; intermediate risk, 1.5–2.5; low risk, 0.0–1.0). Patients treated with CFRT plus temozolomide had significantly improved OS compared to those treated with HFRT plus temozolomide or radiotherapy alone in the low and intermediate risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options. CFRT plus temozolomide can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among radiotherapy options.

Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors

BackgroundRadiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution.MethodsThe treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed.ResultsPlan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05).ConclusionIn our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.

Cognitive function after concurrent temozolomide-based chemoradiation therapy in low-grade gliomas.

We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG). We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time. Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40years old at diagnosis and those with an education > 16years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination). Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.

Quality of life following concurrent temozolomide-based chemoradiation therapy or observation in low-grade glioma.

Low-grade glioma (LGG) exhibits longer median survival than high-grade brain tumors, and thus impact of our therapies on patient quality of life remains a crucial consideration. This study evaluated the effects of concurrent temozolomide-based chemoradiation (RT + TMZ) or observation on quality of life (QOL) in patients with low-grade glioma. We completed a retrospective cross-sectional study of adults with LGG who underwent surgery with known molecular classification from 1980 to 2018. Postoperatively, patients were either observed or received adjuvant concurrent temozolomide-based chemoradiation. EQ-5D and PHQ-9 depression screen were completed before outpatient visits every 2-3months. Baseline score was defined as ± 30days within initial operation. Of the 63 patients (mean age 44 ± 17years, 51% female) with baseline EQ-5D or PHQ-9 depression screen data and at least one follow-up measure, 30 (48%) were observed and 33 (52%) received RT + TMZ. No significant decline was seen in EQ-5D or PHQ-9 scores at 3, 6, 9, 12, and 24months compared to baseline scores for all patients. At each time point, there was no significant difference between those who were observed or received adjuvant therapy. The linear mixed model estimating PHQ-9 value or EQ-5D index demonstrated that there was no significant difference in PHQ-9 or EQ-5D index between treatment groups (p = 0.42 and p = 0.54, respectively) or time points (p = 0.24 and p = 0.99, respectively). Our study found no significant decline in patient QOL or depression scores as assessed by patient- reported outcome measures for patients with low-grade glioma up to 2years following surgery. We found no difference between RT + TMZ compared to observation during this time frame. Additional follow-up can help identify the longer-term impact of treatment strategy on patient experience.

MRI-Based Radiomic Signature for PI3K/AKT-Activated Glioblastoma

Prior work has demonstrated that transcriptional signatures and immune cell infiltrates associated with phosphatidylinositol 3-kinase (PI3K) downregulation are able to distinguish glioblastoma patients who respond to immune checkpoint blockade. PI3K/Akt pathway is involved in tumorigenesis, immune microenvironment regulation, and chemo-radiation treatment resistance. We hypothesized that PI3K/Akt-activated glioblastoma may harbor imaging features that would allow for radiomic discrimination.Patients from The Cancer Genome Atlas and the Ivy Glioblastoma Atlas Project who underwent resection and received temozolomide-based chemoradiation from 1996-2003 were included. All tumors underwent RNA-sequencing and had pre-, post-operative and surveillance MRIs. Single sample Gene Set Enrichment Analysis (ssGSEA) was applied to gene expression data to identify samples with PI3K/Akt pathway activation. A programming environment-based machine learning software was used to extract unique quantitative image features from manually segmented pre-operative tumors from post-contrast T1 sequences. Prior to image analysis, all images underwent z-score normalization over all voxels. Extracted features included shape features, first-order statistical, intensity-histogram based, fractal, local intensity, and texture matrix-based features from both unfiltered and filtered images (wavelet decompositions). A threshold of P < 0.05 was used to identify significant radiomic features. Adaptive LASSO-penalized regression was used to develop a radiomic predictor for PI3K-Akt downregulation. Area under the ROC curve (AUC) assessed performance of the model with three-fold internal cross-validation.Twenty-two patients with glioblastoma were included in the analysis. Tumors from 8 of 22 patients (36.4%) had downregulation of PI3K/Akt signaling by ssGSEA. Among tumors with upregulation of PI3K/Akt signaling, 71% had upstream loss or deletion of PTEN. Tumors with downregulated PI3K/AKT signaling were also more likely to have intratumoral B cell lymphocytes identified by ssGSEA. Overall, 2800 radiomic features were extracted from pre-operative, post-contrast MRI images of 22 patients with glioblastoma. 49 features were significantly different between the two groups. Adaptive LASSO regression analysis was performed to develop a 6-feature radiomic signature with an AUC of 0.955 (95% Confidence Interval, 0.862-1.000).We identified a radiomic signature comprised of 6 features that classifies PI3K/Akt-activated glioblastoma, which is associated with increased immune cell infiltration and potential response to immunotherapy. This signature may help in identifying patients who may benefit from immunomodulation in glioblastoma.

Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population.

Temozolomide (TMZ), an alkylating agent with a broad-spectrum antitumor activity, ability to cross blood-brain barrier (BBB), shown to be effective against malignant glioma. This study aims to investigate the effect of 1236C>T (rs1128503) single-nucleotide gene polymorphisms of ABCB1 (MDR1) in north-Indian patients diagnosed with glioma undergoing TMZ-based chemoradiotherapy. Genotyping was performed in 100 patients diagnosed with malignant glioma (50 anaplastic astrocytoma (AA) patients and 50 glioblastoma multiforme (GBM) patients) and 150 age and sex-matched controls by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method, followed by sanger sequencing. TMZ plasma levels were analyzed by reverse phase HPLC method. Glioma patient's survival time was analyzed by Kaplan-Meier's curve. Results of MDR1 gene 1236C>T polymorphism showed significant allelic and genotypic frequency association between glioma patients and controls. The plasma TMZ levels between metabolizers group in Grade III and Grade IV were found to be statistically significant (p < 0.05). The mutant genotype (TT) has less survival benefit compared with other genotypes (CT/CC) and the survival difference between AA and GBM was found to be statistically significant (p < 0.05). Though CT and TT polymorphisms have significant association with lower TMZ levels in both Grade III (AA) and IV (GBM) tumors, the survival difference seems to be mainly among patients with Grade III tumors. Our findings suggest that the MDR1 gene polymorphism plays a role in plasma TMZ levels and in survival time of glioma patients and, hence, TMZ therapy in malignant glioma can be predicted by genotyping MDR1 (1236C>T) gene polymorphism.

Incorporating genomic signatures into surgical and medical decision-making for elderly glioblastoma patients.

Glioblastoma (GBM) is the most common type of malignant primary brain tumor in adults. It is a uniformly fatal disease (median overall survival 16 months) even with aggressive resection and an adjuvant temozolomide-based chemoradiation regimen. Age remains an independent risk factor for a poor prognosis. Several factors contribute to the dismal outcomes in the elderly population with GBM, including poor baseline health status, differences in underlying genomic alterations, and variability in the surgical and medical management of this subpopulation. The latter arises from a lack of adequate representation of elderly patients in clinical trials, resulting in limited data on the response of this subpopulation to standard treatment. Results from retrospective and some prospective studies have indicated that resection of only contrast-enhancing lesions and administration of hypofractionated radiotherapy in combination with temozolomide are effective strategies for optimizing survival while maintaining baseline quality of life in elderly GBM patients; however, survival remains dismal relative to that in a younger cohort. Here, the authors present historical context for the current strategies used for the multimodal management (surgical and medical) of elderly patients with GBM. Furthermore, they provide insights into elderly GBM patient-specific genomic signatures such as isocitrate dehydrogenase 1/2 (IDH1/2) wildtype status, telomerase reverse transcriptase promoter (TERTp) mutations, and somatic copy number alterations including CDK4/MDM2 coamplification, which are becoming better understood and could be utilized in a clinical trial design and patient stratification to guide the development of more effective adjuvant therapies specifically for elderly GBM patients.

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns.

There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. At a median follow-up of 18.6months (95% CI 15.9-21.2), PFS and OS were 7.5 (95% CI 6.7-8.3) and 13.9 (95% CI 10.9-16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7months; p = 0.006) and OS (10.6 vs. 17.9months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma.

Feasibility of hippocampus-sparing VMAT for newly diagnosed glioblastoma treated by chemoradiation: pattern of failure analysis

BackgroundTo identify the pattern of failure and oncological safety of hippocampus (HC)-sparing IMRT (HSRT) in newly diagnosed glioblastoma (GBM) patients.Materials and methodsEighty-two GBM patients treated with temozolomide-based chemoradiation using HSRT between 2014 and 2018 were retrospectively reviewed. HSRT consisted of a sparing of Dmax of the contralateral HC < 17 Gy. Fifteen patients were unable to achieve the dose-constraints for adequate target coverage. The dose to ipsilateral HC was kept as low as possible. The pattern of failure was investigated, focusing on the area in the vicinity of the spared HC (organ and + 1 cm area). The median HSRT dose was 60 Gy in 30 fractions.ResultsThe median follow-up for survivors was 11.7 months. The median progression-free and overall survival were 9.7 and 23.5 months, respectively. Six (7.3%) and eight (9.8%) patients eventually demonstrated progressive disease at the contralateral HC and HC + 1 cm, respectively. The 12-month contralateral HC and HC + 1 cm failure-free rate were 97.2 and 93.4%, respectively. However, no patient (0%) and two patients (2.4%) showed failure at contralateral HC and HC + 1 cm at initial progression, respectively. The dominant pattern of failure at the contralateral HC was by subependymal seeding (66.7%).ConclusionThe incidence of failure at the contralateral HC and HC + 1 cm is very low and mostly accompanied by disseminated disease progression after HSRT. Since HSRT does not compromise oncological outcomes, it could be considered especially for GBM patients who are expected to have favorable survival outcomes.

Chemoradiation in elderly patients with glioblastoma from the multi-institutional GBM-molRPA cohort: is short-course radiotherapy enough or is it a matter of selection?

The optimal radiotherapy regimen in elderly patients with glioblastoma treated by chemoradiation needs to be addressed. We provide the results of a comparison between conventionally fractionated standard radiotherapy (CRT) and short-course radiotherapy (SRT) in those patients treated by temozolomide-based chemoradiation. Patients aged 65years or older from the GBM-molRPA cohort were included. Patients who were planned for a ≥ 6-week or ≤ 4-week radiotherapy were regarded as being treated by CRT or SRT, respectively. The median RT dose in the CRT and SRT group was 60Gy in 30 fractions and 45Gy in 15 fractions, respectively. A total of 260 and 134 patients aged older than 65 and 70years were identified, respectively. CRT- and SRT-based chemoradiation was applied for 192 (73.8%) and 68 (26.2%) patients, respectively. Compared to SRT, CRT significantly improved MS from 13.2 to 17.6months and 13.3 to 16.4months in patients older than 65years (P < 0.001) and 70years (P = 0.002), respectively. Statistical significance remained after adjusting for age, performance status, surgical extent, and MGMT promoter methylation in both age groups. The benefit was clear in all subgroup analyses for patients with Karnofsky performance score 70-100, Karnofsky performance score ≤ 60, gross total resection, biopsy, methylated MGMT promoter, and unmethylated MGMT promoter (all P < 0.05). CRT significantly improved survival compared to SRT in elderly glioblastoma patients treated with chemoradiation in selected patients amenable for chemoradiation. This study is hypothesis-generating and a prospective randomized trial is urgently warranted.

Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424

To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in2015. The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

Sub-Ventricular Zone Contact Influences Survival and Relapse Pattern in Glioblastoma

Several preclinical and retrospective data have described a relationship between glioblastomas (GB) contacting the SVZ and greater aggressiveness with decreased survival rates. We aimed to identify prognostic factors of survival and patterns of recurrence among patients with GB regarding anatomical relation between lesion and SVZ. 133 patients with GB treated between 2010 and 2016 were identified. All patients received surgical resection followed by temozolomide-based chemoradiation. 109 patients (82%) received a normofractionated radiotherapy scheme of 54-60 Gy and 24 (18%) received a hypofractionated scheme of 40,05 Gy (2,67 Gy/fr). Lesions were classified regarding their anatomical relation with SVZ using a dichotomic classification and Lim’s classification considering contact with both SVZ and cerebral cortex (Group I: SVZ+/Cortex+; Group II: SVZ +/Cortex-; Group III: SVZ -/Cortex+ and Group IV: SVZ -/Cortex-). Median follow-up, progression free survival (PFS) and overall survival (OS) were 18.6 months (95%CI 15.9-21.2), 7.5 months (95%CI 6.7 - 8.3) and 13.9 months (95%CI 10.9 - 16.9) respectively. Sixty-eight patients (51,13%) presented with anatomical contact with SVZ. Regarding Lim’s classification, the following rates were registered: SVZ+/Cortex+ (21,81%); SVZ +/Cortex- (29,32%); SVZ -/Cortex+ (33,08%) and SVZ -/Cortex- (15,79%). On univariate analysis, initial contact with SVZ was poor prognostic factor for PFS (6.1 vs. 8.7 months; p=0,006) and for OS (10.6 vs. 17.9 months; p=0,037), remaining statistically significant in multivariate analyses for PFS by both dichotomic and Lim’s classification systems. Contact with SVZ was related with higher proportion of aggressive clinical progressions (30.9% vs. 11.3%; p=0.007) and higher percentage of contralateral relapses (23.4% vs. 9.1%; p=0.048) Our results suggest that contact with SVZ might be an independent poor prognostic factor for PFS and that it is associated with reduced OS and more aggressive and contralateral relapses.

Distribution differences in prognostic copy number alteration profiles in IDH-wild-type glioblastoma cause survival discrepancies across cohorts

The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH-wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR, CDKN2A, and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH-wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies.

Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era

BackgroundImmunotherapy is currently being examined as a treatment modality for glioblastoma. Maintaining an optimal total lymphocyte count (TLC) after radiotherapy (RT) and using temozolomide may be beneficial in optimizing immunotherapy. However, conventional temozolomide-based chemoradiation is known to induce immunosuppressive effects, including lymphopenia. Therefore, this study aimed to identify potential clinical predictors of acute severe lymphopenia (ASL) in patients receiving chemoradiation for glioblastoma.MethodsWe identified patients with glioblastoma treated with RT plus temozolomide from 2006 to 2017. ASL was defined as a TLC of < 500/μL within 3 months after initiating RT. Independent predictors of ASL were determined using logistic regression.ResultsA total of 336 patients were evaluated. Three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) were used in 186 (55.4%) and 150 patients (44.6%), respectively. TLC decreased during RT and remained persistently low during the 1-year follow-up, whereas the levels of other blood cell types recovered. In total, 118 patients (35.1%) developed ASL. During a median follow-up of 19.3 months, patients with ASL showed significantly worse overall survival than did those without ASL (median, 18.2 vs. 22.0 months; P = .028). Multivariable analysis revealed that increased planning target volume (PTV) was independently associated with increased ASL incidence (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00–1.03; P = .042), while IMRT was independently associated with decreased ASL incidence (HR, 0.48; 95% CI, 0.27–0.87; P = .015). A propensity-matched comparison showed that the incidence of ASL was lower with IMRT than with 3D-CRT (20% vs. 37%; P = .005).ConclusionsIMRT and low PTV were significantly associated with decreased ASL incidence after RT plus temozolomide for glioblastoma. An IMRT-based strategy is necessary to enhance treatment outcomes in the immune-oncology era.

Validation of a novel molecular RPA classification in glioblastoma (GBM-molRPA) treated with chemoradiation: A multi-institutional collaborative study

Background and purposeA novel molecular recursive partitioning analysis classification has recently been reported integrating the MGMT promoter methylation (MGMTmeth) and IDH1 mutation (IDH1mut) status for glioblastoma (GBM-molRPA) patients treated with temozolomide-based chemoradiation. The current study was initiated to validate the model in a multi-institutional study. Materials and methodsFour-hundred seventy-one newly diagnosed GBM patients (validation cohort) were allocated to classes I–III of the previously reported GBM-molRPA model. Of the patients, 15.7%, 56.1%, and 28.2% patients were GBM-molRPA class I, II, and III, respectively. MGMTmeth and IDH1mut were observed in 32.3 and 8.8% of patients, respectively. In the training plus validation cohort of 692 patients, 16.2%, 60.8%, and 23.0% patients were class I, II, and III, respectively. ResultsThe median follow-up for survivors and the median survival (MS) of patients was 23.3 and 18.4 months, respectively. The MS for GBM-molRPA class I, II, and III was 49.7 (95% CI, 22.8–76.6), 19.2 (95% CI, 16.2–22.1), and 13.8 months (95% CI, 11.8–15.4) (P < .001 for all comparisons) in the validation cohort. In the training plus validation cohort, the MS was 58.5 (95% CI, 40.7–76.3), 21. (95% CI, 18.6–23.3), and 14.3 months (95% CI, 12.5–16.1) (P < .001 for all comparisons) for class I, II, and III, respectively. ConclusionThe GBM-molRPA is a valid model. This GBM-molRPA classification can be useful in clinics and guiding patient stratification in future clinical trials.