Therapeutic drug monitoring of osimertinib in EGFR mutant non-small cell lung cancer by dried blood spot and plasma collection: A pilot study.

AIMS: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting. METHODS: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation. RESULTS: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints. CONCLUSIONS: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies.

Hypofractionated re-irradiation with bevacizumab for relapsed chemorefractory glioblastoma after prior high dose radiotherapy: a feasible option for patients with large-volume relapse.

PURPOSE: There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). METHODS AND MATERIALS: A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60 Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. RESULTS: 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. CONCLUSION: Patients with recurrent glioblastoma who have been previously treated with 60 Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.

CA9, CYFIP2 and LGALS3BP-A Novel Biomarker Panel to Aid Prognostication in Glioma.

Brain cancer is a devastating and life-changing disease. Biomarkers are becoming increasingly important in addressing clinical issues, including in monitoring tumour progression and assessing survival and treatment response. The goal of this study was to identify prognostic biomarkers associated with glioma progression. Discovery proteomic analysis was performed on a small cohort of astrocytomas that were diagnosed as low-grade and recurred at a higher grade. Six proteins were chosen to be validated further in a larger cohort. Three proteins, CA9, CYFIP2, and LGALS3BP, were found to be associated with glioma progression and, in univariate analysis, could be used as prognostic markers. However, according to the results of multivariate analysis, these did not remain significant. These three proteins were then combined into a three-protein panel. This panel had a specificity and sensitivity of 0.7459 for distinguishing between long and short survival. In silico data confirmed the prognostic significance of this panel.

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.

A Validated Assay to Quantify Osimertinib and Its Metabolites, AZ5104 and AZ7550, from Microsampled Dried Blood Spots and Plasma.

BACKGROUND: Osimertinib is an oral small-molecule tyrosine kinase receptor inhibitor used to treat non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor mutation. Patients may experience drug toxicity and require dose deescalation. The study aimed to quantitate osimertinib and its 2 active metabolites, AZ5104 and AZ7550, in microsampled dried blood spots (DBS) collected from patients with NSCLC using a hemaPEN device and compare them with plasma drug levels. METHODS: A 6-min ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated using plasma and DBS. The accuracy, selectivity, matrix effect, recovery, and stability were assessed using bioanalytical validation criteria. The hematocrit effect was investigated in DBS. Drug levels were measured in 15 patients with NSCLC, and the Bland-Altman method was used to compare measurements between plasma and DBS. RESULTS: The validated assay determined accurate and precise quantities, respectively, for osimertinib in both plasma (93.2%-99.3%; 0.2%-2.3%) and DBS (96.7%-99.6%; 0.5%-10.3%) over a concentration of 1-729 ng/mL. The osimertinib metabolites, AZ5104 and AZ7550, were similarly validated in accordance with bioanalytical guidelines. For 30%-60% patient hematocrit, no hematocrit bias was observed with DBS for all analytes. The Bland-Altman method showed high concordance between plasma and DBS analyte levels. Stability experiments revealed that osimertinib and its metabolites were poorly stable in plasma at room temperature, whereas all analytes were stable in DBS for 10 days at room temperature. CONCLUSIONS: The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.

NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.

Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm. Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events. Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.

Leptomeningeal neuraxis relapse in glioblastoma is an uncommon but not rare event associated with poor outcome.

BACKGROUND: Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence, associated factors, and outcome of LM relapse in patients with glioblastoma managed with radical intent. METHODS: Patients managed for glioblastoma using the EORTC-NCIC (Stupp) Protocol from 2007 to 2019 were entered into a prospective ethics-approved database. Follow-up included routine cranial MRI surveillance with further imaging as clinically indicated. LM relapse was determined by MRI findings and/or cerebrospinal fluid analysis. The chi-square test of independence was used to evaluate clinico-pathologic factors associated with increased risk of subsequent LM relapse. Median survival post-LM relapse was calculated using Kaplan-Meier technique. RESULTS: Four-hundred-and-seven patients were eligible, with median follow-up of 60 months for surviving patients. Eleven (2.7%) had LM at first relapse and in total 21 (5.1%) experienced LM in the entire follow-up period. Sites of LM relapse were 8 (38%) focal spinal, 2 (10%) focal brainstem medulla and 11 (52%) diffuse spinal. Median overall survival from initial diagnosis for the entire cohort was 17.6 months (95% CI 16.7-19.0). Median survival from LM relapse to death was 39 days (95% CI: 19-107). Factors associated with LM relapse were age less than 50 years (p < 0.01), initial disease located in the temporal lobe (p < 0.01) and tumours lacking MGMT promoter methylation (p < 0.01). CONCLUSIONS: LM relapse is an uncommon but not rare event in patients managed radically for glioblastoma. It is associated with poor outcome with the majority of patients deceased within two months of recognition.

CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review.

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

PSMA Expression Correlates with Improved Overall Survival and VEGF Expression in Glioblastoma.

BACKGROUND: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. METHODS: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0-2+) groups. The association between PSMA and VEGF expression was evaluated using Chi2 analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. RESULTS: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009-2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups-16.1 and 10.8 months, respectively (p = 0.02). CONCLUSION: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival.

Acetazolamide versus placebo for cerebral oedema requiring dexamethasone in recurrent and/or progressive high-grade glioma: phase II randomised placebo-controlled double-blind study.

OBJECTIVES: Symptoms of raised intracranial pressure (ICP) in recurrent high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on ICP symptoms. Acetazolamide reduces ICP when used in other clinical non-cancer settings. The aim of the study was to explore whether the addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent HGG. METHODS: Participants had recurrent HGG with any of dexamethasone recommencement, dose increase or dependency; prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide or placebo for 8 weeks. Standardised protocols were used for dexamethasone dosing, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stable Karnofsky Performance Status Secondary endpoints included toxicity and feasibility. RESULTS: Thirty participants (15 per group) were enrolled (mean age 58 years) from seven Australian sites. The mean baseline dexamethasone dose was 6.2 mg. Mean duration on study treatment was 38 days (placebo group) and 31 days (acetazolamide group) with nine participants (30%) completing all study treatments (six placebo, three acetazolamide). Study withdrawal was due to adverse events (n=6; one placebo, five acetazolamide) and disease progression (n=6 (three per arm)). Four participants (13%) (two per arm) were stable responders. Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: five participants (33%), six events, two related). CONCLUSIONS: The study closed early due to poor accrual and increasing availability of bevacizumab. The addition of acetazolamide did not facilitate dexamethasone reduction. TRIAL REGISTRATION NUMBER: ACTRN12615001072505.

Carer preparedness improved by providing a supportive educational intervention for carers of patients with high-grade glioma: RCT results.

BACKGROUND: High-grade glioma (HGG) is a rapidly progressing and debilitating disease. Family carers take on multiple responsibilities and experience high levels of distress. We aimed to deliver a nurse-led intervention (Care-IS) to carers to improve their preparedness to care and reduce distress. METHODS: We conducted a randomised controlled trial (ACTRN:12612001147875). Carers of HGG patients were recruited during patients' combined chemoradiation treatment. The complex intervention comprised four components: (1) initial telephone assessment of carer unmet needs; (2) tailored hard-copy resource folder; (3) home visit; and, (4) monthly telephone support for up to 12 months. Primary outcomes included preparedness for caregiving and distress at 2, 4, 6 and 12 months. Intervention effects were estimated using linear mixed models which included a time by group interaction. Secondary outcomes included anxiety, depression, quality of life, carer competence and strain. RESULTS: We randomised 188 carers (n = 98 intervention, n = 90 control). The intervention group reported significantly higher preparedness for caregiving at 4 months (model ß = 2.85, 95% CI 0.76-4.93) and all follow-up timepoints including 12 months (model ß = 4.35, 95% CI 2.08-6.62), compared to the control group. However, there was no difference between groups in carer distress or any secondary outcomes. CONCLUSIONS: This intervention was effective in improving carer preparedness. However, carer distress was not reduced, potentially due to the debilitating/progressive nature of HGG and ongoing caring responsibilities. Future research must explore whether carer interventions can improve carer adjustment, self-efficacy and coping and how we support carers after bereavement. Additionally, research is needed to determine how to implement carer support into practice.

Patterns of care in adult histone mutant gliomas: Results of an international survey.

Background: Histone mutant gliomas (HMG) with histone H3 K27 and G34 mutations are recognized as biologically discrete entities with distinct anatomical locations, younger age at presentation (in comparison to the most common high-grade gliomas, IDH wildtype glioblastoma), and poor prognosis. There is a paucity of data regarding the management of adult HMG patients and no consensus on management. This study aims to identify current patterns of Australian and US neuro-oncology clinical practice for this entity. Methods: Following institutional approvals, patterns of care questionnaire designed to capture relevant clinical variables was circulated through the Cooperative Trials Group for Neuro-Oncology (COGNO) in Australia and the Caris Precision Oncology Alliance in the United States (US). Results: Between 4/2021 and 10/2021, 43 responses were collected. 33% (n = 14) of responders tested all patients for HMGs routinely; 40.92% (n = 18) tested in select patients 26% (n = 11) did not test for HMGs. The common indications for testing selected patients were midline anatomic location (n = 18) and age (n = 11) (<50 years). 23 used molecular sequencing, 22 used IHC at their centers. Nine participants stated knowledge of histone H3 mutations did not affect their management of these gliomas, 11 said it affected their management at the time of recurrence, 23 stated it affected the management of midline K27M patients, 11 participants stated it affected the management of K27M mutant gliomas in other locations, and 3 felt it affected the management of G34R/V mutant gliomas. Conclusion: Here we present a description of how the discovery of a new molecular subtype of primary glial tumors, histone mutated gliomas in adults, is being introduced into clinical practice.

Implications of Concurrent IDH1 and IDH2 Mutations on Survival in Glioma-A Case Report and Systematic Review.

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated.

The use of Sonidegib in the adjuvant and advanced phases of Sonic Hedge Hog Mutant Medulloblastomas.

Medulloblastomas are rare embryonal primary brain tumours originating in the cerebellum. Most medulloblastomas arising in adults are associated with mutations in the Sonic Hedge Hog (SHH) pathway. Patient 1 was prescribed Sonidegib for recurrent metastatic SHH mutated medulloblastoma multiple lines of treatment. His leptomeningeal disease responded after 3 months of therapy. The drug was continued for a further 3 months until progressive central nervous system (CNS) and leptomeningeal disease arose. Progression free survival (PFS) from initiation of Sonidegib of 3 months was observed (overall survival 8.8 years). Patient 2 presented with un-resectable SHH mutated meduloblastoma with high risk of relapse who received 14 months of adjuvant Sonidegib. Following biopsy she was treated with chemotherapy and cranio-spinal radiotherapy, followed by 14 months of adjuvant Sonigedib. She remains free of disease over 51 months later. Both clinical scenarios are poorly described in the literature or evaluated in clinical trials with Sonidegib.

Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial.

PURPOSE: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. PATIENTS AND METHODS: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. RESULTS: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. CONCLUSIONS: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region following radiotherapy.

BACKGROUND: The impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. METHODS AND MATERIALS: Patients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. RESULTS: Thirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume. CONCLUSION: IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

Differential effects of radiation fractionation regimens on glioblastoma.

BACKGROUND: Radiotherapy (RT) is a mainstay of treatment for patients with glioblastoma (GB). Early clinical trials show that short course hypofractionation showed no survival benefit compared to conventional regimens with or without temozolomide chemotherapy (TMZ) but reduces the number of doses required. Concerns around delayed neurological deficits and reduced cognition from short course hypofractionated RT remain a concern. The aim of this study was to evaluate the effect of increased interfractional time using two different radiation fractionation regimens on GB. METHODS: The radiobiological effect of increasing doses 0-20 Gy x-ray photon RT on Gl261 and CT2A GB cell lines was compared by colony forming assay, DNA damage by alkaline comet assay, oxidative stress, DNA damage, cell cycle, and caspase-3/7 by MUSE® flow cytometric analyses, and protein expression by western blot analyses. Conventional (20 Gy/10 fractions) and hypofractionated (20 Gy/4 fractions spaced 72 h apart) RT regimens with and without TMZ (200 mg/kg/day) were performed in syngeneic Gl261 and CT2A intracranial mouse models using the Small Animal Radiation Research Platform (Xstrahl Inc.). RESULTS: X-ray photon radiation dose-dependently increased reactive oxygen species, DNA damage, autophagy, and caspase 3/7-mediated apoptotic cell death. While the conventional fractionated dose regimen of 20 Gy/10 f was effective at inducing cell death via the above mechanism, this was exceeded by a 20 Gy/4 f regimen which improved median survival and histopathology in Gl261-tumor bearing mice, and eradicated tumors in CT2A tumors with no additional toxicity. CONCLUSIONS: Spacing of hypofractionated RT doses 72 h apart showed increased median survival and tumor control via increased activation of RT-mediated cell death, with no observed increased in radiotoxicity. This supports further exploration of differential RT fractionated regimens in GB clinical trials to reduce delayed neurological radiotoxicity.

Redo craniotomy or bevacizumab for symptomatic steroid-refractory true or pseudoprogression following IMRT for glioblastoma.

BACKGROUND: There is minimal evidence to support decision making for symptomatic steroid-refractory pseudoprogression or true progression occurring after intensity-modulated radiation therapy (IMRT) for glioblastoma (GBM). This study audited the survival outcome of patients managed with redo craniotomy (RedoSx) or bevacizumab (BEV) for steroid-refractory mass effect after IMRT for GBM. METHODS: Patients with GBM managed between 2008 and 2019 with the EORTC-NCIC Protocol were entered into a prospective database. Patients with symptomatic steroid-refractory mass effect within 6 months of IMRT managed with either RedoSx or BEV were identified for analysis. For the primary endpoint of median overall survival (OS) postintervention, outcome was analyzed in regards to potential prognostic factors, and differences between groups were assessed by log-rank analyses. RESULTS: Of the 399 patients managed with the EORTC-NCIC Protocol, 78 required an intervention within 6 months of IMRT completion for either true or pseudoprogression (49 with RedoSx and 29 with BEV). Subsequently, 20 of the 43 patients managed with RedoSx when BEV was clinically available, required salvage with BEV within 6 months after RedoSx. Median OS postintervention was 8.7 months (95% CI: 7.84-11.61) for the total group; and 8.7 months (95% CI: 6.8-13.1) for RedoSx and 9.4 months (95% CI: 7.8-13.6) for BEV (P = .38). Subsequent use of BEV in RedoSx patients was not associated with improved survival compared with RedoSx alone (P = .10). Age, time from IMRT, and ECOG performance status were not associated with OS. In the RedoSx patients, immunohistochemical features such as Ki-67% reduction correlated with survival. The presence of pure necrosis and residual tumor cells only had improved survival compared with the presence of gross tumor (P < .001). CONCLUSIONS: At time of symptomatic steroid-refractory true or pseudoprogression following IMRT for GBM, BEV was equivalent to RedoSx in terms of OS. Pseudoprogression with residual cells at RedoSx was not associated with worse outcome compared to pure necrosis.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.

A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

BACKGROUND: Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide. METHODS: VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm. RESULTS: A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals. CONCLUSION: The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.