The growth rate and clinical outcomes of radiation induced meningioma undergoing treatment or active monitoring.

INTRODUCTION: Radiation induced meningioma (RIM) incidence is increasing in line with improved childhood cancer survival. No optimal management strategy consensus exists. This study aimed to delineate meningioma growth rates from tumor discovery and correlate with clinical outcomes. METHODS: Retrospective study of patients with a RIM, managed at a specialist tertiary neuroscience center (2007-2019). Tumor volume was measured from diagnosis and at subsequent interval scans. Meningioma growth rate was determined using a linear mixed-effects model. Clinical outcomes were correlated with growth rates accounting for imaging and clinical prognostic factors. RESULTS: Fifty-four patients (110 meningiomas) were included. Median duration of follow-up was 74 months (interquartile range [IQR], 41-102 months). Mean radiation dose was 41 Gy (standard deviation [SD] = 14.9) with a latency period of 34.4 years (SD = 13.7). Median absolute growth rate was 0.62 cm3/year and the median relative growth rate was 72%/year. Forty meningiomas (between 27 patients) underwent surgical intervention after a median follow-up duration of 4 months (IQR 2-35). Operated RIMs were clinically aggressive, likely to be WHO grade 2 at first resection (43.6%) and to progress after surgery (41%). Median time to progression was 28 months (IQR 13-60.5). A larger meningioma at discovery was associated with growth (HR 1.2 [95% CI 1.0-1.5], P = 0.039) but not progression after surgery (HR 2.2 [95% CI 0.7-6.6], P = 0.181). Twenty-seven (50%) patients had multiple meningiomas by the end of the study. CONCLUSION: RIMs exhibit high absolute and relative growth rates after discovery. Surgery is recommended for symptomatic or rapidly growing meningiomas only. Recurrence risk after surgery is high.

Challenges Conveying Clinical Equipoise and Exploring Patient Treatment Preferences in an Oncology Trial Comparing Active Monitoring with Radiotherapy (ROAM/EORTC 1308).

INTRODUCTION: Providing balanced information that emphasizes clinical equipoise (i.e., uncertainty regarding the relative merits of trial interventions) and exploring patient treatment preferences can improve informed consent and trial recruitment. Within a trial comparing adjuvant radiotherapy versus active monitoring following surgical resection for an atypical meningioma (ROAM/EORTC-1308), we explored patterns in communication and reasons why health practitioners may find it challenging to convey equipoise and explore treatment preferences. MATERIALS AND METHODS: Qualitative study embedded within ROAM/EORTC-1308. Data were collected on 40 patients and 18 practitioners from 13 U.K. sites, including audio recordings of 39 patients' trial consultations, 23 patient interviews, and 18 practitioner interviews. Qualitative analysis drew on argumentation theory. RESULTS: Practitioners acknowledged the importance of the research question that the trial aimed to answer. However, they often demonstrated a lack of equipoise in consultations, particularly with eligible patients who practitioners believed to be susceptible to side effects (e.g., cognitive impairment) or inconvenienced by radiotherapy. Practitioners elicited but rarely explored patient treatment preferences, especially if a patient expressed an initial preference for active monitoring. Concerns about coercing patients, loss of practitioner agency, and time constraints influenced communication in ways that were loaded against trial participation. CONCLUSIONS: We identified several challenges that practitioners face in conveying equipoise and exploring patient treatment preferences in oncology, and particularly neuro-oncology, trials with distinct management pathways. The findings informed communication about ROAM/EORTC-1308 and will be relevant to enhancing trial communication in future oncology trials. Qualitative studies embedded within trials can address difficulties with communication, thus improving informed consent and recruitment. ROAM/EORTC-1308 RCT: ISRCTN71502099. IMPLICATIONS FOR PRACTICE: Oncology trials can be challenging to recruit to, especially those that compare treatment versus monitoring. Conveying clinical equipoise and exploring patient treatment preferences can enhance recruitment and patient understanding. This study focused on the challenges that practitioners encounter in trying to use such communication strategies and how practitioners may inadvertently impede patient recruitment and informed decision making. This article provides recommendations to support practitioners in balancing the content and presentation of trial management pathways. The results can inform training to optimize communication, especially for neuro-oncology trials and trials comparing markedly different management pathways.

Atypical meningoma: current management dilemmas and prospective clinical trials.

Atypical meningioma is an intermediate grade tumour with a greater risk of recurrence following surgical resection. Changes to the WHO classification have resulted in an increased reporting of these tumours. The role of early adjuvant radiotherapy after gross total resection has not been clearly defined and the literature evidence is of poor quality providing conflicting information. This review assesses the evidence for current clinical practice, management dilemmas and the need for prospective clinical trials for atypical meningioma.

Treatment Outcomes of Incidental Intracranial Meningiomas: Results from the IMPACT Cohort.

BACKGROUND: Incidental findings such as meningioma are becoming increasingly prevalent. There is no consensus on the optimal management of these patients. The aim of this study was to examine the outcomes of patients diagnosed with an incidental meningioma who were treated with surgery or radiotherapy. METHODS: Single-center retrospective cohort study of adult patients diagnosed with an incidental intracranial meningioma (2007-2015). Outcomes recorded were postintervention morbidity, histopathologic diagnosis, and treatment response. RESULTS: Out of 441 patients, 44 underwent treatment. Median age at intervention was 56.1 years (interquartile range [IQR], 49.6-66.5); patients included 35 women and 9 men. The main indication for imaging was headache (25.9%). Median meningioma volume was 4.55 cm3 (IQR, 1.91-8.61), and the commonest location was convexity (47.7%). Six patients underwent surgery at initial diagnosis. Thirty-eight had intervention (34 with surgery and 4 with radiotherapy) after a median active monitoring duration of 24 months (IQR, 11.8-42.0). Indications for treatment were radiologic progression (n = 26), symptom development (n = 6), and patient preference (n = 12). Pathology revealed World Health Organization (WHO) grade 1 meningioma in 36 patients and WHO grade 2 in 4 patients. The risk of postoperative surgical and medical morbidity requiring treatment was 25%. Early and late moderate adverse events limiting activities of daily living occurred in 28.6% of patients treated with radiotherapy. Recurrence rate after surgery was 2.5%. All meningiomas regressed or remained radiologically stable after radiotherapy. CONCLUSIONS: The morbidity after treatment of incidental intracranial meningioma is not negligible. Considering most operated tumors are WHO grade 1, treatment should be reserved for those manifesting symptoms or demonstrating substantial growth on radiologic surveillance.

A prognostic model to personalize monitoring regimes for patients with incidental asymptomatic meningiomas.

BACKGROUND: Asymptomatic meningioma is a common incidental finding with no consensus on the optimal management strategy. We aimed to develop a prognostic model to guide personalized monitoring of incidental meningioma patients. METHODS: A prognostic model of disease progression was developed in a retrospective cohort (2007-2015), defined as: symptom development, meningioma-specific mortality, meningioma growth or loss of window of curability. Secondary endpoints included non-meningioma-specific mortality and intervention. RESULTS: Included were 441 patients (459 meningiomas). Over a median of 55 months (interquartile range, 37-80), 44 patients had meningioma progression and 57 died (non-meningioma-specific). Forty-four had intervention (at presentation, n = 6; progression, n = 20; nonprogression, n = 18). Model parameters were based on statistical and clinical considerations and included: increasing meningioma volume (hazard ratio [HR] 2.17; 95% CI: 1.53-3.09), meningioma hyperintensity (HR 10.6; 95% CI: 5.39-21.0), peritumoral signal change (HR 1.58; 95% CI: 0.65-3.85), and proximity to critical neurovascular structures (HR 1.38; 95% CI: 0.74-2.56). Patients were stratified based on these imaging parameters into low-, medium- and high-risk groups and 5-year disease progression rates were 3%, 28%, and 75%, respectively. After 5 years of follow-up, the risk of disease progression plateaued in all groups. Patients with an age-adjusted Charlson comorbidity index ≥6 (eg, an 80-year-old with chronic kidney disease) were 15 times more likely to die of other causes than to receive intervention at 5 years following diagnosis, regardless of risk group. CONCLUSIONS: The model shows that there is little benefit to rigorous monitoring in low-risk and older patients with comorbidities. Risk-stratified follow-up has the potential to reduce patient anxiety and associated health care costs.

Cell cycle progression in glioblastoma cells is unaffected by pathophysiological levels of hypoxia.

Hypoxia is associated with the increased malignancy of a broad range of solid tumours. While very severe hypoxia has been widely shown to induce cell cycle arrest, the impact of pathophysiological hypoxia on tumour cell proliferation is poorly understood. The aim of this study was to investigate the effect of different oxygen levels on glioblastoma (GBM) cell proliferation and survival. GBM is an extremely aggressive brain tumour with a heterogeneous oxygenation pattern. The effects of a range of oxygen tensions on GBM cell lines and primary cells were assessed using flow cytometry. Results indicate that cell cycle distribution and viability are unaffected by long term exposure (24-96 h) to pathophysiological levels of oxygen (1-8% O2). Both transient cell cycle arrest and small amounts of cell death could only be detected when cells were exposed to severe hypoxia (0.1% O2). No significant changes in p21 protein expression levels were detected. These findings reinforce the importance of using physiologically relevant oxygen tensions when investigating tumour hypoxia, and help to explain how solid tumours can be both hypoxic and highly proliferative, as is the case with GBM.

The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial.

BACKGROUND: Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN: A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression-free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION: ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION: ISRCTN71502099 on 19 May 2014.