Treatment, healthcare utilization and outcomes in patients with glioblastoma in Ontario: a 10-year cohort study.

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Receipt of adjuvant therapies has been shown to exert a significant positive effect on patient survival. Little is known however about how changes in standards of care and healthcare system factors, such as access, affect real-world outcomes. In this study, we provide an overview of GBM in Ontario and examine elements of care, including treatment patterns, healthcare utilization, and overall survival, from 2010 to 2019, to interpret the impact of the changes in practice standards and expansion of the care network within this period. METHODS: Using linked health-administrative databases from Ontario, Canada, we conducted a population-based cohort study to examine the clinical and biological characteristics, treatment, and healthcare utilization patterns of adult GBM patients diagnosed between 2010 and 2019. The primary outcomes were enrollment in adjuvant chemoradiation treatment and 1-, 2-, and 5-year survival. All analyses were performed using the Statistical Analysis Software (SAS). RESULTS: 5392 patients were diagnosed with GBM in Ontario from 2010 to 2019 (58% male, 42% female). The median age at diagnosis was 64. Receipt of adjuvant chemoradiation within one year of diagnosis increased from 51% in 2010 to 63% in 2019. 1-year, 2-year, and 5-year overall survival for all patients remained stable, ranging between 40 and 43%, 15-19%, and 5-7%, respectively. For patients above the age of 65, however, 1-year survival increased from 19% in 2010 to 26% in 2019. INTERPRETATION: Regionalization enabled access to treatment closer to home for many patients. Over the last decade, receipt of adjuvant chemoradiation increased among elderly patients, but the improvement in 1-year overall survival over time was accounted for by sociodemographic and clinical covariates. Our findings support the efforts for regionalization of services to improve accessibility. CONCLUSION: This Ontario-based study provides insight into the effect of practice evolution and healthcare utilization on the overall survival of patients with GBM. Overall survival for most patients with glioblastoma has remained stagnant over the past decade. Changes in treatment standards and expansion of access to treating centres have been associated with prolonged survival in elderly glioblastoma patients.

A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase.

Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance.

Patterns of T2-FLAIR discordance across a cohort of adult-type diffuse gliomas and deviations from the classic T2-FLAIR mismatch sign.

PURPOSE: T2-FLAIR mismatch serves as a highly specific but insensitive marker for IDH-mutant (IDHm) astrocytoma with potential limitations in real-world application. We aimed to assess the utility of a broader definition of T2-FLAIR discordance across a cohort of adult-type diffuse lower-grade gliomas (LrGG) to see if specific patterns emerge and additionally examine factors determining deviation from the classic T2-FLAIR mismatch sign. METHODS: Preoperative MRIs of non-enhancing adult-type diffuse LrGGs were reviewed. Relevant demographic, molecular, and MRI data were compared across tumor subgroups. RESULTS: Eighty cases satisfied the inclusion criteria. Highest discordance prevalence and > 50% T2-FLAIR discordance volume were noted with IDHm astrocytomas (P < 0.001), while < 25% discordance volume was associated with oligodendrogliomas (P = 0.03) and IDH-wildtype (IDHw) LrGG (P = 0.004). "T2-FLAIR matched pattern" was associated with IDHw LrGG (P < 0.001) and small or minimal areas of discordance with oligodendrogliomas (P = 0.03). Sensitivity and specificity of classic mismatch sign for IDHm astrocytoma were 25.7% and 100%, respectively (P = 0.06). Retained ATRX expression and/or non-canonical IDH mutation (n = 10) emerged as a significant factor associated with absence of classic T2-FLAIR mismatch sign in IDHm astrocytomas (100%, P = 0.02) and instead had minimal discordance or matched pattern (40%, P = 0.04). CONCLUSION: T2-FLAIR discordance patterns in adult-type diffuse LrGGs exist on a diverging but distinct spectrum of classic mismatch to T2-FLAIR matched patterns. Specific molecular markers may play a role in deviations from classic mismatch sign.

No adults allowed: Adolescents and Medical Decision Making.

The majority of the literature focused on whether consent should be extended to the adolescent population arises from themes adapted from American tort law. In contrast to the USA, Ontario does not delineate an age of consent for medical treatment and relying on American guidelines to guide practice in Ontario is problematic. While the literature is saturated with discussions for and against seeking adolescent consent, there are currently no bioethical guidelines on adolescent consent in the province of Ontario. This paper explores adolescent refusal of care and adolescent request for care in opposition to parental wishes. The paper seeks to answer the following questions: What is the difference between an adolescent and an adult in medical decision-making? What are the barriers to seeking adolescent consent? And, can the neurobiological argument be an accurate guide for obtaining adolescent consent?

Choreographed expansion of services results in decreased patient burden without compromise of outcomes: An assessment of the Ontario experience.

Background: Neuro-oncology care in Ontario, Canada has been historically centralized, at times requiring significant travel on the part of patients. Toward observing the goal of patient-centered care and reducing patient burden, 2 additional regional cancer centres (RCC) capable of neuro-oncology care delivery were introduced in 2016. This study evaluates the impact of increased regionalization of neuro-oncology services, from 11 to 13 oncology centers, on healthcare utilization and travel burden for glioblastoma (GBM) patients in Ontario. Methods: We present a cohort of GBM patients diagnosed between 2010 and 2019. Incidence of GBM and treatment modalities were identified using provincial health administrative databases. A geographic information system and spatial analysis were used to estimate travel time from patient residences to neuro-oncology RCCs. Results: Among the 5242 GBM patients, 79% received radiation as part of treatment. Median travel time to the closest RCC was higher for patients who did not receive radiation as part of treatment than for patients who did (P = .03). After 2016, the volume of patients receiving radiation at their local RCC increased from 62% to 69% and the median travel time to treatment RCCs decreased (P = .0072). The 2 new RCCs treated 35% and 41% of patients within their respective catchment areas. Receipt of standard of care, surgery, and chemoradiation (CRT), increased by 11%. Conclusions: Regionalization resulted in changes in the healthcare utilization patterns in Ontario consistent with decreased patient travel burden for patients with GBM. Focused regionalization did not come at the cost of decreased quality of care, as determined by the delivery of a standard of care.

Human Epidermal Growth Factor Receptor 2-Low Breast Cancer Brain Metastases: An Opportunity for Targeted Systemic Therapies in a High-Need Patient Population.

PURPOSE: Trastuzumab deruxtecan is a new treatment option for patients with advanced human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC). Although HER2-low status has been characterized in early and advanced BC, it has yet to be fully characterized in brain metastases (BrM). METHODS: Patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre and for whom HER2 status was available on resected BrM were studied. Estrogen receptor, progesterone receptor, and HER2 status were assessed on the basis of ASCO/College of American Pathologists (CAP) guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH)-negative status. HER2-positive (HER2+) was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathologic features were recorded. We also assessed the prognostic association between extent of HER2 expression and (1) brain-specific progression-free survival (bsPFS), as well as (2) overall survival (OS). RESULTS: In this retrospective cohort of 102 patients with resected BC BrM, 53% (n = 54) were HER2+, 29.4% (n = 30) were HER2-low, and 17.6% (n = 18) had HER2-zero status. Among BrM that were triple-negative on the basis of ASCO/CAP guidelines, 63.6% (n = 14/22) were reclassified as being HER2-low. Sixty percent (n = 15/25) of BrM that were hormone receptor-positive/HER2-negative (HR+/HER2-) were reclassified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low, and HER2+ were concordant in 82.3% (n = 42/51) of cases (Cohen's kappa, 0.58; P = .07). There was no significant association between HER2-zero, HER2-low, and HER2+ status in BrM and either bsPFS or OS. CONCLUSION: Among patients with surgically resected BrM, a high proportion of those with metastatic triple-negative BC and HR+/HER2- disease have HER2-low BrM with potential to benefit from HER2-targeted therapy.

Brain Metastases in the Setting of Stable Versus Progressing Extracranial Disease Among Patients With Metastatic Breast Cancer.

INTRODUCTION: Women with metastatic breast cancer (BC) are at risk of developing brain metastases (BrM), which may result in significant morbidity and mortality. Given the emergence of systemic therapies with activity in the brain, more breast oncology clinical trials include patients with BrM, but most require extracranial disease progression for trial participation. METHODS: We evaluated the proportion of patients with BC BrM who have intracranial disease progression in the setting of stable extracranial disease in a retrospective cohort study of 751 patients treated between 2008 and 2018 at the Sunnybrook Odette Cancer. Extracranial disease progression was defined as any progression outside of the brain within 4 weeks of a patient's local/regional treatment. Clinical/pathologic characteristics and outcomes were also abstracted from patients' medical records. RESULTS: Of 752 patients in the cohort, 691 were included in our study. Sixty-one patients were excluded due to the presence of a second primary tumor or uncertain tissue origin of the BrM. BC subtype based on the primary tumor was known for 592 (85.6%) patients; 33.1% (n = 196) had HER2+ disease, 40% (n = 237) had HR+/HER2- disease, and 26.9% (n = 159) had triple negative BC. Extracranial disease status was available for 677 patients (98%); 41.1% (n = 284/691) had stable extracranial disease and 56.8% (n = 393/691) had extracranial disease progression within 4 weeks of treatment for BrM. DISCUSSION: A high proportion of patients with BC BrM (41.1%) would be excluded from clinical trials due to stable extracranial disease. Efforts should be made to design trials for this patient population.

Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis.

Background: Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy. Methods: In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466. Findings: Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55-0.63; p < 0.001; n = 56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55-0.65; p < 0.001; n = 78 studies; n = 27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51-0.70; p < 0.001; n = 28 studies; n = 26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2 = 73.6%; 95% CI 68.4%-77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52-1.05; p = 0.08; n = 9 studies; n = 1384 patients). Interpretation: Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic. Funding: No funding.

Sinonasal Malignancy Following Cranial Irradiation: A Scoping Review and Case Report of Sinonasal Teratocarcinosarcoma.

Background Radiation therapy is a mainstay of treatment for brain tumors, but delayed complications include secondary malignancy which may occur months to years after treatment completion. Methods We reviewed the medical records of a 41-year-old female treated with 60 Gy of radiation for a recurrent astrocytoma, who 6 years later developed a locally advanced sinonasal teratocarcinosarcoma. We searched MEDLINE, Embase, and Web of Science to conduct a scoping review of biopsy-proven sinonasal malignancy in patients who previously received cranial irradiation for a brain tumor. Results To our knowledge, this is the first report of a patient to present with a sinonasal teratocarcinosarcoma after receiving irradiation for a brain tumor. Our scoping review of 1,907 studies produced 14 similar cases of secondary sinonasal malignancy. Median age of primary cancer diagnosis was 39.5 years old (standard deviation [SD]: 21.9), and median radiation dose was 54 Gy (SD: 20.3). Median latency time between the primary cancer and secondary sinonasal cancer was 9.5 years (SD: 5.8). Olfactory neuroblastoma was the most common sinonasal cancer ( n = 4). Fifty percent of patients died from their sinonasal cancer within 1.5 years. Conclusion Patients who receive radiation exposure to the sinonasal region for treatment of a primary brain tumor, including low doses or scatter radiation, may be at risk of a secondary sinonasal malignancy later in life. Physicians who monitor at-risk patients must be vigilant of symptoms which may suggest sinonasal malignancy, and surveillance should include radiographic review with careful monitoring for a secondary malignancy throughout the entire irradiated field.

Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.