Exploring Guolin Qigong (Mind-Body Exercise) for Improving Cancer Related Fatigue in Cancer Survivors: A Mixed Method Randomized Controlled Trial Protocol.

BACKGROUND: Cancer-related fatigue and its associated symptoms of sleep disorder and depression are prevalent in cancer survivors especially among breast, lung, and colorectal cancer survivors. While there is no gold standard for treating cancer-related fatigue currently, studies of mind-body exercises such as Qigong have reported promise in reducing symptoms. This study was designed to evaluate the feasibility and effect of Guolin Qigong on cancer-related fatigue and other symptoms in breast, lung and colorectal cancer survivors while exploring their perceptions and experiences of Guolin Qigong intervention. METHODS: This is an open-label randomized controlled trial with 60 participants divided into 2 study groups in a 1:1 ratio. The intervention group will receive 12 weeks of Guolin Qigong intervention with a 4-week follow-up while control will receive usual care under waitlist. The primary outcome will be feasibility measured based on recruitment and retention rates, class attendance, home practice adherence, nature, and quantum of missing data as well as safety. The secondary subjective outcomes of fatigue, sleep quality and depression will be measured at Week-1 (baseline), Week-6 (mid-intervention), Week-12 (post-intervention), and Week-16 (4 weeks post-intervention) while an objective 24-hour urine cortisol will be measured at Week-1 (baseline) and Week-12 (post-intervention). We will conduct a semi-structured interview individually with participants within 3 months after Week-16 (4 weeks post-intervention) to obtain a more comprehensive view of practice adherence. DISCUSSION: This is the first mixed-method study to investigate the feasibility and effect of Guolin Qigong on breast, lung, and colorectal cancer survivors to provide a comprehensive understanding of Guolin Qigong's intervention impact and participants' perspectives. The interdisciplinary collaboration between Western Medicine and Chinese Medicine expertise of this study ensures robust study design, enhanced participant care, rigorous data analysis, and meaningful interpretation of results. This innovative research contributes to the field of oncology and may guide future evidence-based mind-body interventions to improve cancer survivorship. TRIAL REGISTRATION: This study has been registered with ANZCTR (ACTRN12622000688785p), was approved by Medical Research Ethic Committee of University Malaya Medical Centre (MREC ID NO: 2022323-11092) and recognized by Western Sydney University Human Research Ethics Committee (RH15124).

Unmet needs in people with high-grade glioma: Defining criteria for stepped care intervention.

BACKGROUND: We aimed to define levels of unmet supportive care needs in people with primary brain tumour and reach expert consensus on feasibility of addressing patients' needs in clinical practice. METHODS: We conducted secondary analysis of a prospective cohort study of people diagnosed with high-grade glioma (n = 116) who completed the Supportive Care Needs Survey-SF34 during adjuvant chemoradiation therapy. Participants were allocated to one of three categories: no need ('no need' for help on all items), low need ('low need' for help on at least one item, but no 'moderate' or 'high' need), or moderate/high need (at least one 'moderate' or 'high' need indicated). Clinical capacity to respond to the proportion of patients needing to be prioritised was assessed. RESULTS: Overall, 13% (n = 5) were categorised as no need, 23% (n = 27) low need, and 64% (n = 74) moderate/high need. At least one moderate/high need was reported in the physical and daily living domain (42%), and psychological (34%) domain. In recognition of health system capacity, the moderate/high need category was modified to distinguish between: moderate need ('moderate' need indicated for at least one item but 'high' need was not selected for any item) and high need (at least one 'high' need indicated). Results revealed 24% (n = 28) moderate need and 40% (n = 46) high need. Those categorised as high need indicated needing assistance navigating the health system and information. CONCLUSIONS: Using four step allocations resulted in 40% of patients indicating high need. Categories may facilitate appropriate triaging, and guide stepped models of healthcare delivery.

[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

Background and purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed. Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise. Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TVMR+FET delineation.

Exploring Web-Based Information and Resources That Support Adolescents and Young Adults With Cancer to Resume Study and Work: Environmental Scan Study.

BACKGROUND: Adolescents and young adults (AYAs) diagnosed with cancer experience physical, cognitive, and psychosocial effects from cancer treatment that can negatively affect their ability to remain engaged in education or work through cancer treatment and in the long term. Disengagement from education or work can have lasting implications for AYAs' financial independence, psychosocial well-being, and quality of life. Australian AYAs with cancer lack access to adequate specialist support for their education and work needs and report a preference for web-based support that they can access from anywhere, in their own time. However, it remains unclear what web-based resources exist that are tailored to support AYAs with cancer in reaching their educational or work goals. OBJECTIVE: This study aimed to determine what web-based resources exist for Australian AYAs with cancer to (1) support return to education or work and (2) identify the degree to which existing resources are age-specific, cancer-specific, culturally inclusive, and evidence-based; are co-designed with AYAs; use age-appropriate language; and are easy to find. METHODS: We conducted an environmental scan by searching Google with English search terms in August 2022 to identify information resources about employment and education for AYAs ever diagnosed with cancer. Data extraction was conducted in Microsoft Excel, and the following were assessed: understandability and actionability (using the Patient Education and Materials Tool), readability (using the Sydney Health Literacy Laboratory Health Literacy Editor), and whether the resource was easy to locate, evidence-based, co-designed with AYAs, and culturally inclusive of Aboriginal and Torres Strait Islander peoples. The latter was assessed using 7 criteria previously developed by members of the research team. RESULTS: We identified 24 web-based resources, comprising 22 written text resources and 12 video resources. Most resources (21/24, 88%) were published by nongovernmental organizations in Australia, Canada, the United States, and the United Kingdom. A total of 7 resources focused on education, 8 focused on work, and 9 focused on both education and work. The evaluation of resources demonstrated poor understandability and actionability. Resources were rarely evidence-based or co-designed by AYAs, difficult to locate on the internet, and largely not inclusive of Aboriginal and Torres Strait Islander populations. CONCLUSIONS: Although web-based resources for AYAs with cancer are often available through the websites of hospitals or nongovernmental organizations, this environmental scan suggests they would benefit from more evidence-based and actionable resources that are available in multiple formats (eg, text and audio-visual) and tailored to be age-appropriate and culturally inclusive.

The impact of fluorine-18-fluoroethyltyrosine positron emission tomography scan timing on radiotherapy planning in newly diagnosed patients with glioblastoma.

Background and purpose: Glioblastoma is one of the most common and aggressive primary brain tumours in adults. Though radiation therapy (RT) techniques have progressed significantly in recent decades, patient survival has seen little improvement. However, an area of promise is the use of fluorine-18-fluoroethyltyrosine positron-emission-tomography (18F-FET PET) imaging to assist in RT target delineation. This retrospective study aims to assess the impact of 18F-FET PET scan timing on the resultant RT target volumes and subsequent RT plans in post-operative glioblastoma patients. Materials and Methods: The imaging and RT treatment data of eight patients diagnosed with glioblastoma and treated at a single institution were analysed. Before starting RT, each patient had two 18F-FET-PET scans acquired within seven days of each other. The information from these 18F-FET-PET scans aided in the creation of two novel target volume sets. The new volumes and plans were compared with each other and the originals. Results: The median clinical target volume (CTV) 1 was statistically smaller than CTV 2. The median Dice score for the CTV1/CTV2 was 0.98 and, of the voxels that differ (median 6.5 cc), 99.7% were covered with a 5 mm expansion. Overall organs at risk (OAR) and target dosimetry were similar in the PTV1 and PTV2 plans. Conclusion: Provided the 18F-FET PET scan is acquired within two weeks of the RT planning and a comprehensive approach is taken to CTV delineation, the timing of scan acquisition has minimal impact on the resulting RT plan.

PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group.

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.

From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients.

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3.3-G34R, and H3.1-K27M) primarily linked to childhood brain cancer. We demonstrate the utility of our assays for sensitively detecting these mutations in cell-free DNA released from cultured diffuse intrinsic pontine glioma (DIPG) cells and in the cerebral spinal fluid of a pediatric patient with DIPG. We further screened tumor tissue DNA from 89 adult patients with glioma and 1 with diffuse hemispheric glioma from Southwestern Sydney, Australia, an ethnically diverse region, for these three mutations. No histone mutations were detected in adult glioma tissue, while H3.3-G34R presence was confirmed in the diffuse hemispheric glioma patient.

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.

Management Paradigm of Central Nervous System Metastases in NSCLC: An Australian Perspective.

Life-prolonging central nervous system active systemic therapies for metastatic NSCLC have increased the complexity of managing brain metastases (BMs). Australian medical oncologists, radiation oncologists, and neurosurgeons discussed the evidence guiding the diverse clinical approaches to the management of BM in NSCLC. The Australian context is broadly applicable to other jurisdictions; therefore, we have documented these discussions as principles with broader applications. Patient management was stratified according to clinical and radiologic factors under two broad classifications of newly diagnosed BMs: symptomatic and asymptomatic. Other important considerations include the number and location of metastases, tumor histotypes, molecular subtype, and treatment purpose. Careful consideration of the pace and burden of symptoms, risk of worsening neurologic function at a short interval, and extracranial disease burden should determine whether central nervous system active systemic therapies are used alone or in combination with local therapies (surgery with or without radiation therapy). Most clinical trial evidence currently focuses on historical treatment options or a single treatment modality rather than the optimal sequencing of multiple modern therapies; therefore, an individualized approach is key in a rapidly changing therapeutic landscape.

Exploring the clinical utility of a brief screening measure of unmet supportive care needs in people with high-grade glioma.

Background: People living with high-grade glioma (HGG) have diverse and complex needs. Screening aims to detect patients with some level of unmet need requiring triaging and further assessment. However, most existing measures of unmet need are not suitable for screening in this population due to their length. We aimed to explore the clinical utility of a brief screening tool (SCNS-ST9) in people with HGG in detecting unmet needs. Methods: Secondary analysis of data collected in a prospective cohort study of 116 people with HGG who completed the Supportive Care Needs Survey (SCNS-SF34) and a brain cancer-specific needs survey (BrTSCNS) during chemoradiation (T1) and 6 months later (T2). The SCNS-ST9 contains a subset of 9 items from the SCNS-SF34. Data analysis determined the number of individuals with unmet needs on the SCNS-SF34 and the BrTSCNS, not identified as having some level of need by the SCNS-ST9. Results: Overall, 3 individuals (T1: 2.6% [3/116]; T2: 4.8% [3/63]) at each time point reported other unmet needs on the SCNS-SF34 that were missed by the SCNS-ST9. Domain-specific screening items missed a higher proportion of individuals (3.2%-26%), particularly in the psychological and health systems domains. Only 1 individual with brain cancer-specific needs was missed by SCNS-ST9 overall. Conclusion: Findings demonstrate the sensitivity and clinical utility of a brief screening tool (SCNS-ST9) of unmet needs in people with HGG. Routine use of this screening tool, supported by clinical pathways, may improve access to support services, potentially reducing the burden of disease for these patients.

Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study-TROG 18.06.

PURPOSE: The O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation. METHODS: Sites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]). RESULTS: Data was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00-30.10%), 5.89% (5.01-6.68%), and 5.01% (3.37-6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63-0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement. CONCLUSION: The FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience.

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.

Access to psychosocial support for people with brain tumor and family members: Healthcare professional perspectives.

OBJECTIVES: Ongoing access to psychosocial support is important to maintain the well-being of people with brain tumor (PwBT) and their families; yet, there is limited knowledge of psychosocial care access. This qualitative study aimed to develop an understanding of psychosocial support pathways specific to PwBT from the perspectives of Australian healthcare professionals. METHODS: Semi-structured interviews were conducted with 21 healthcare professionals working in hospital and community services supporting PwBT and their family members. Transcribed interviews were coded and analyzed thematically. RESULTS: The three major themes identified were: (1) Challenges in fitting people into the care system within existing pathways; (2) Benefits of longer-term care coordination and interdisciplinary connections; and (3) Brain tumor affects the whole family. Despite established psychosocial care pathways, service access varied and lacked continuity for individuals with lower-grade glioma and benign tumors across the illness trajectory. CONCLUSIONS: Healthcare professionals recognize the need for improved access to care coordination and multidisciplinary psychosocial care tailored to the varying needs of PwBT and their families.

Clinical Trials in the Brain Tumour Population: Challenges and Strategies for the Future.

PURPOSE OF REVIEW: This review identifies challenges and barriers to successful development of drugs in neuro-oncology trials at the preclinical, clinical and translational stages that we believe has contributed to poor outcomes for patients over the last 30 years. RECENT FINDINGS: Several key strategies have been proposed by leading groups to address these and improve patient outcomes. Better preclinical testing using more sophisticated and clinically relevant models is needed. A greater focus on assessing blood-brain barrier penetrance and targeting key biological processes such as tumour heterogeneity and immune response is vital. Adopting innovative trial designs permitting faster results and addressing key issues (including molecular heterogeneity and combinatorial approaches) is highly desirable. A stronger translational focus is also clearly needed. Implementation of these strategies is already starting to occur. Maintaining and increasing these novel approaches will require coordinated efforts between clinicians, scientists, industry and funding/regulator bodies.

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.

Australian genome-wide association study confirms higher female risk for adult glioma associated with variants in the region of CCDC26.

BACKGROUND: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex. METHODS: We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex. RESULTS: We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05). CONCLUSIONS: Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.

Determining the Research Priorities for Adult Primary Brain Tumours in Australia and New Zealand: A Delphi Study with Consumers, Health Professionals, and Researchers.

The aim of this project was to determine research priorities, barriers, and enablers for adult primary brain tumour research in Australia and New Zealand. Consumers, health professionals, and researchers were invited to participate in a two-phase modified Delphi study. Phase 1 comprised an initial online survey (n = 91) and then focus groups (n = 29) which identified 60 key research topics, 26 barriers, and 32 enablers. Phase 2 comprised two online surveys to (1) reduce the list to 37 research priorities which achieved consensus (>75% 2-point agreement) and had high mean importance ratings (n = 116 participants) and (2) determine the most important priorities, barriers, and enablers (n = 90 participants). The top ten ranked research priorities for the overall sample and sub-groups (consumers, health professionals, and researchers) were identified. Priorities focused on: tumour biology, pre-clinical research, clinical and translational research, and supportive care. Variations were seen between sub-groups. The top ten barriers to conducting brain tumour research related to funding and resources, accessibility and awareness of research, collaboration, and process. The top ten research enablers were funding and resources, collaboration, and workforce. The broad list of research priorities identified by this Delphi study, together with how consumers, health professionals, and researchers prioritised items differently, and provides an evidence-based research agenda for brain tumour research that is needed across a wide range of areas.

Multi-Arm GlioblastoMa Australasia (MAGMA): protocol for a multiarm randomised clinical trial for people affected by glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary central nervous system cancer in adults. The objective of the Multi-Arm GlioblastoMa Australasia (MAGMA) trial is to test hypotheses in real world setting to improve survival of people with GBM. Initial experimental arms are evaluating the effectiveness of interventions in newly diagnosed GBM (ndGBM). This study will compare maximal surgical resection followed by chemoradiotherapy plus adjuvant chemotherapy for 6 months with the addition of (1) 'neoadjuvant' chemotherapy beginning as soon as possible after surgery and/or (2) adjuvant chemotherapy continued until progression within the same study platform. METHODS AND ANALYSIS: MAGMA will establish a platform for open-label, multiarm, multicentre randomised controlled testing of treatments for GBM. The study began recruiting in September 2020 and recruitment to the initial two interventions in MAGMA is expected to continue until September 2023.Adults aged ≥18 years with ndGBM will be given the option of undergoing randomisation to each study intervention separately, thereby giving rise to a partial factorial design, with two separate randomisation time points, one for neoadjuvant therapy and one for extended therapy. Patients will have the option of being randomised at each time point or continuing on with standard treatment.The primary outcome for the study is overall survival from the date of initial surgery until death from any cause. Secondary outcomes include progression-free survival, time to first non-temozolomide treatment, overall survival from each treatment randomisation, clinically significant toxicity as measured by grade 3 or 4 adverse events and health-related quality-of-life measures. Tertiary outcomes are predictive/prognostic biomarkers and health utilities and incremental cost-effectiveness ratio.The primary analysis of overall survival will be performed separately for each study intervention according to the intention to treat principle on all patients randomised to each study intervention. ETHICS AND DISSEMINATION: The study (Protocol version 2.0 dated 23 November 2020) was approved by a lead Human Research Ethics Committee (Sydney Local Health District: 2019/ETH13297). The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBER: ACTRN12620000048987.

An investigation of the conformity, feasibility, and expected clinical benefits of multiparametric MRI-guided dose painting radiotherapy in glioblastoma.

Background: New technologies developed to improve survival outcomes for glioblastoma (GBM) continue to have limited success. Recently, image-guided dose painting (DP) radiotherapy has emerged as a promising strategy to increase local control rates. In this study, we evaluate the practical application of a multiparametric MRI model of glioma infiltration for DP radiotherapy in GBM by measuring its conformity, feasibility, and expected clinical benefits against standard of care treatment. Methods: Maps of tumor probability were generated from perfusion/diffusion MRI data from 17 GBM patients via a previously developed model of GBM infiltration. Prescriptions for DP were linearly derived from tumor probability maps and used to develop dose optimized treatment plans. Conformity of DP plans to dose prescriptions was measured via a quality factor. Feasibility of DP plans was evaluated by dose metrics to target volumes and critical brain structures. Expected clinical benefit of DP plans was assessed by tumor control probability. The DP plans were compared to standard radiotherapy plans. Results: The conformity of the DP plans was >90%. Compared to the standard plans, DP (1) did not affect dose delivered to organs at risk; (2) increased mean and maximum dose and improved minimum dose coverage for the target volumes; (3) reduced minimum dose within the radiotherapy treatment margins; (4) improved local tumor control probability within the target volumes for all patients. Conclusions: A multiparametric MRI model of GBM infiltration can enable conformal, feasible, and potentially beneficial dose painting radiotherapy plans.