The Value of Etoposide for Recurrent Glioma.

BACKGROUND: For multiply recurrent glioma, options are few and choices are very limited. Etoposide in combination with carboplatin and/or bevacizumab has been evaluated in recurrent glioma with modest efficacy. This retrospective study describes the efficacy of etoposide monotherapy in adults with multiply recurrent diffuse glioma. METHODS: In this single center retrospective series, all adult patients with radiographically proven multiply recurrent diffuse glioma (WHO grade 2-4) treated with etoposide between 2016 and 2020 were evaluated. Progression-free survival (PFS) and overall survival (OS) after initiating etoposide were calculated for the total group and for different histologic tumor types. In addition, treatment-related toxicity was recorded. RESULTS: Totally, 48 patients with a median age 43 years-old (range 24-78) were included. Etoposide was given as 3rd line of treatment in 18 patients (37.5%) and as 4th or 5th line of treatment in 30 patients (62.5%). The majority were diagnosed with a glioblastoma, WHO grade 4 (27, 56.3%). The median PFS was 8.6 weeks (95% confidence interval [CI]: 8.3-8.9). The median OS of the total population was 4.0 months (95% CI: 2.4-5.6). Patients with an oligodendroglioma had the best OS (median 13 months), compared to astrocytoma and glioblastoma, but the difference was not statistically significant (p = 0.15). Etoposide was stopped due to progression in the majority of the patients (81.3%). Only 1 patient had a grade 3 toxicity. CONCLUSION: Etoposide is a well-tolerated chemotherapy in heavily pretreated patients with multiply recurrent glioma and could be considered when other options are not available. OS was 4 months after initiating etoposide.

Treatment Patterns and Outcomes of Patients with Grade 4 Glioma Treated with Radiation during the COVID-19 Pandemic.

During the first year of the COVID-19 pandemic there was a global disruption in the provision of healthcare. Grade 4 gliomas are rapidly progressive tumors, and these patients are at risk of poorer outcomes due to delays in diagnosis or treatment. We retrospectively evaluated the impact of the pandemic on treatment patterns and outcomes of patients with grade 4 gliomas in British Columbia. We identified a cohort of 85 patients treated with radiotherapy between March 2020-2021 (COVID era) and compared baseline characteristics, treatments, and outcomes with a control cohort of 79 patients treated between March 2018-2019 (pre-COVID era). There were fewer patients treated with radiotherapy over age 65 in the COVID era compared to the pre-COVID era (p = 0.037). Significantly more patients were managed with biopsy relative to partial or gross total resection during the COVID era compared to the pre-COVID era (p = 0.04), but there were no other significant differences in time to assessment, time to treatment, or administration of adjuvant therapy. There was no difference in overall survival between eras (p = 0.189). In this assessment of outcomes of grade 4 gliomas during the pandemic, we found that despite less aggressive surgical intervention during the COVID era, outcomes were similar between eras.

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline.

The 2021 World Health Organization (WHO) classification of CNS tumors incorporates molecular signatures with histology and has highlighted differences across pediatric vs adult-type CNS tumors. However, adolescent and young adults (AYA; aged 15-39), can suffer from tumors across this spectrum and is a recognized orphan population that requires multidisciplinary, specialized care, and often through a transition phase. To advocate for a uniform testing strategy in AYAs, pediatric and adult specialists from neuro-oncology, radiation oncology, neuropathology, and neurosurgery helped develop this review and testing framework through the Canadian AYA Neuro-Oncology Consortium. We propose a comprehensive approach to molecular testing in this unique population, based on the recent tumor classification and within the clinical framework of the provincial health care systems in Canada. Contributions to the field: While there are guidelines for testing in adult and pediatric CNS tumor populations, there is no consensus testing for AYA patients whose care occur in both pediatric and adult hospitals. Our review of the literature and guideline adopts a resource-effective and clinically-oriented approach to improve diagnosis and prognostication of brain tumors in the AYA population, as part of a nation-wide initiative to improve care for AYA patients.

Treatment of Older Adult Patients with Glioblastoma: Moving towards the Inclusion of a Comprehensive Geriatric Assessment for Guiding Management.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, and over half of patients with newly diagnosed GBM are over the age of 65. Management of glioblastoma in older patients includes maximal safe resection followed by either radiation, chemotherapy, or combined modality treatment. Despite recent advances in the treatment of older patients with GBM, survival is still only approximately 9 months compared to approximately 15 months for the general adult population, suggesting that further research is required to optimize management in the older population. The Comprehensive Geriatric Assessment (CGA) has been shown to have a prognostic and predictive role in the management of older patients with other cancers, and domains of the CGA have demonstrated an association with outcomes in GBM in retrospective studies. Furthermore, the CGA and other geriatric assessment tools are now starting to be prospectively investigated in older GBM populations. This review aims to outline current treatment strategies for older patients with GBM, explore the rationale for inclusion of geriatric assessment in GBM management, and highlight recent data investigating its implementation into practice.

Personalized oncogenomic analysis of metastatic adenoid cystic carcinoma: using whole-genome sequencing to inform clinical decision-making.

Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets. We report five cases of metastatic ACC, not originating in the salivary glands, in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Genomic workup included whole-genome and transcriptome sequencing, detailed analysis of tumor alterations, and integration with existing knowledge of drug-target combinations to identify potential therapeutic targets. Analysis reveals low mutational burden in these five ACC cases, and mutation signatures that are commonly observed in multiple cancer types. Notably, the only recurrent structural aberration identified was the well-described MYB-NFIB fusion that was present in four of five cases, and one case exhibited a closely related MYBL1-NFIB fusion. Recurrent mutations were also identified in BAP1 and BCOR, with additional mutations in individual samples affecting NOTCH1 and the epigenetic regulators ARID2, SMARCA2, and SMARCB1. Copy changes were rare, and they included amplification of MYC and homozygous loss of CDKN2A in individual samples. Genomic analysis revealed therapeutic targets in all five cases and served to inform a therapeutic choice in three of the cases to date.

O6-Methylguanine-DNA methyltransferase is a novel negative effector of invasion in glioblastoma multiforme.

The dismal prognosis of glioblastoma multiforme (GBM) is mostly due to the high propensity of GBM tumor cells to invade. We reported an inverse relationship between GBM angiogenicity and expression of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT), which has been extensively characterized for its role in resistance to alkylating agents used in GBM treatment. In the present study, given the major role of angiogenesis and invasion in GBM aggressiveness, we aimed to investigate the relationship between MGMT expression and GBM invasion. Stable overexpression of MGMT in the U87MG cell line significantly decreased invasion, altered expression of invasion-related genes, decreased expression of α(5)ß(1) integrin and focal adhesion kinase, and reduced their spindle-shaped morphology and migration compared with the empty vector control. Conversely, short hairpin RNA-mediated stable knockdown of MGMT or its pharmacologic depletion in the MGMT-positive T98G cell line were required for increased invasion. The inverse relationship between MGMT and invasion was further validated in primary GBM patient-derived cell lines. Using paraffin-embedded tumors from patients with newly diagnosed GBM (n = 59), tumor MGMT promoter hypermethylation (MGMT gene silencing) was significantly associated with increased immunohistochemical expression of the proinvasive matricellular protein secreted protein acidic and rich in cysteine (SPARC; P = 0.039, χ(2) test). Taken together, our findings highlight for the first time the role of MGMT as a negative effector of GBM invasion. Future studies are warranted to elucidate the role of SPARC in the molecular mechanisms underlying the inverse relationship between MGMT and GBM invasion and the potential use of MGMT and SPARC as biomarkers of GBM invasion.

Off-trial access to experimental cancer agents for the terminally ill: balancing the needs of individuals and society.

The development of cancer therapies is a long and arduous process. Because it can take several years for a cancer agent to pass clinical testing and be approved for use, terminal cancer patients rarely have the time to see these experimental therapies become widely available. For most terminal cancer patients the only opportunity they have to access an experimental drug that could potentially improve their prognosis is by joining a clinical trial. Unfortunately, several aspects of clinical trial methodology that are set in place in order to optimise drug development for the benefit of future generations of cancer patients, pose significant limitations to current patient participation. Therefore, several terminal cancer patients believe that they should have the right to access experimental agents that have passed initial safety testing without having to participate in clinical trials. However, granting off-trial access to patients could be detrimental to the scientific process of drug development, and thus could pose significant risks to the health of future patients relying on sound research. Examining this matter through two divergent ethical lenses, rights-based ethics and communitarian ethics, may provide new insight into the issues surrounding the balance between the autonomous rights of current terminal cancer patients, and the needs of future patients and the values of society.

MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib.

Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O(6)-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT-positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O(6)-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors.