A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial.

BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. METHODS: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. DISCUSSION: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. TRIAL REGISTRATION: ISRCTN: 11460478. CLINICALTRIALS: Gov: NCT05629702.

Models of acute mucosal tolerance to radiotherapy alone applied to synchronous chemoradiation schedules in head and neck cancer.

Three models defining mucosal tolerance when radiotherapy alone is delivered have been published. Modelling studies have converted the contribution of synchronous chemotherapy to the rate of grade 3 mucositis to biologically effective dose (BED). The purpose of this study was to apply radiotherapy mucosal tolerance models to studies of synchronous chemoradiation. Trials of synchronous cisplatin and radiotherapy were identified. The BED for cell kill for each regime was calculated. Initially, this was done using the protocol parameters and a global value for the contribution of chemotherapy of 5.1 Gy10. These values were then compared with the BED cell kill ceiling values from each of the models calculated using the intended overall treatment time. These steps were then repeated using the delivered radiotherapy parameters and a value for the contribution from chemotherapy calculated to take into account dose intensity. Eight eligible treatment arms were identified. When using the intended radiotherapy parameters, six of these appeared to be tolerable when compared with the ceiling values for two of the models. All were found intolerable by one model. When using the actual delivered radiotherapy doses and overall treatment times and correcting for chemotherapy dose intensity, one treatment arm remained intolerable by all three models, a further treatment arm by two models and four treatment arms by one model. Two current models of mucosal tolerance derived from radiotherapy data predict a majority of previously reported chemoradiation study arms to be tolerable particularly when the delivered parameters are used for calculation.

The Utility of Multiparametric Magnetic Resonance Imaging in Reducing Diagnostic Uncertainty for Primary Central Nervous System Lymphoma.

BACKGROUND: A key limitation in treatment initiation in primary central nervous system lymphoma (PCNSL) is the diagnostic delay caused by lack of recognition of a lesion as a possible lymphoma, steroid initiation, and lesion involution, often resulting in an inconclusive biopsy result. We highlight the importance of multiparametric magnetic resonance imaging (MRI), which incorporates diffusion-weighted imaging, dynamic susceptibility contrast-enhanced perfusion-weighted imaging, and proton magnetic resonance spectroscopy in addition to standard MRI sequences in resolving diagnostic uncertainty for PCNSL. METHODS: At our center, a consecutive series of 10 patients with histology-proven PCNSL (specifically, diffuse large B-cell lymphoma of the central nervous system) underwent multiparametric MRI. We retrospectively analyzed qualitative and semiquantitative parameters and assessed their radiological concordance for this diagnosis. RESULTS: We noted overall low apparent diffusion coefficient on diffusion-weighted imaging (mean minimum apparent diffusion coefficient of 0.74), high percentage signal recovery on perfusion-weighted imaging (mean 170%), a high choline-to-creatine ratio, and a high-grade lipid peak on proton magnetic resonance spectroscopy giving an appearance of twin towers. Of 10 patients, 9 had MRI findings concordant for PCNSL, defined as at least 3 of 4 parameters being consistent for PCNSL. CONCLUSIONS: Concordance between these imaging multiparametric modalities could be used as a radiological predictor of PCNSL, reducing diagnostic delays, providing a more accurate biopsy target, and resulting in quicker treatment initiation.

Reconfiguration from emergency to urgent elective neurosurgery for glioblastoma patients improves length of stay, surgical adjunct use, and extent of resective surgery.

Background: Glioblastoma (GB) is the most common intrinsic brain cancer and is notorious for its aggressive nature. Despite widespread research and optimization of clinical management, the improvement in overall survival has been limited. The aim of this study was to characterize the impact of service reconfiguration on GB outcomes in a single centre. Methods: Patients with a histopathological confirmation of a diagnosis of GB between 01/01/2014 and 31/12/2019 were retrospectively identified. Demographic and tumour characteristics, survival, treatment (surgical and oncological), admission status, use of surgical adjunct (5-aminolevulinic acid, intra-operative neuro-monitoring), the length of stay, extent of resection, and surgical complications were recorded from the hospital databases. Results: From August 2018 the neurosurgical oncology service was reconfigured to manage high-grade tumours on an urgent outpatient basis by surgeons specializing in oncology. We demonstrate that these changes resulted in an increase in elective admissions, greater use of intra-operative adjuncts resulting in the improved extent of tumour resection, and a reduction in median length of stay and associated cost-savings. Conclusions: Optimizing neuro-oncology patient management through service reconfiguration resulted in increased use of intra-operative adjuncts, improved surgical outcomes, and reduced hospital costs. These changes also have the potential to improve survival and disease-free progression for patients with GB.

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance.

BACKGROUND: Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls. METHODS: In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls. FINDINGS: Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years. INTERPRETATION: Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. FUNDING: Pfizer.

Metastatic Colon Cancer in the Pituitary: A Case Report with Review of Literature.

We report a rare case of metastatic colonic adenocarcinoma to the pituitary gland in a 58-year-old who presented with visual decline and panhypopituitarism. He underwent urgent transsphenoidal endoscopic surgery with significant improvement of his vision, followed by adjuvant fractionated radiotherapy to the resection cavity. He made a satisfactory recovery, but regrettably died from COVID-19 9 weeks after completion of radiotherapy. A multidisciplinary approach is essential for optimal management of this condition due to its rarity and complexity.

The Expanding Role of Radiosurgery for Brain Metastases.

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole-brain radiotherapy (WBRT) improved local control rates compared with WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to a greater use of SRS alone, including for patients with multiple metastases and following surgical resection. Molecular information, targeted agents, and immunotherapy have also altered the landscape for the management of brain metastases. This review summarises current and emerging data on the role of SRS in the management of brain metastases.

Revised radiobiological modelling of the contribution of synchronous chemotherapy to the rate of grades 3-4 mucositis in head and neck cancer.

INTRODUCTION: Biological effective dose (BED) calculations modelled on reduced accelerated repopulation when synchronous chemotherapy is delivered significantly correlate with observed differences in local control in randomised trials of platinum-based chemoradiation. The purpose of this study was to examine whether a similar relationship existed in the context of grades 3-4 mucositis. METHODS: Biological effective dose from radiotherapy and synchronous chemotherapy was calculated using three different models: AB using the additional BED attributable to chemotherapy and standard repopulation parameters; zero repopulation (ZRP) using zero correction for repopulation; and variable t(p) (Vt(p)) using a variable doubling time for mucosal stem cell repopulation. The correlation between the percentage change in biological effective dose between trial arms, and the observed percentage change in the rate of grades 3-4 mucositis was examined by using the Pearson product-moment correlation. RESULTS: With the AB model, there were no significant correlations with observed differences in rates of grades 3-4 mucositis. With either the ZRP or Vt(p) models, significant correlations were observed. A value of 5 days for the doubling time during repopulation (T(p)) was associated with the most significant correlation (P = 0.002). CONCLUSION: Models where the dose lost due to accelerated repopulation is reduced imply a therapeutic loss from the use of synchronous chemotherapy when only local control and the rate of acute grades 3-4 mucositis are considered.

Revising the radiobiological model of synchronous chemotherapy in head-and-neck cancer: a new analysis examining reduced weighting of accelerated repopulation.

PURPOSE: Previous studies of synchronous chemoradiation therapy have modeled the additional effect of chemotherapy as additional radiation therapy biologically effective dose (BED). Recent trials of accelerated versus conventional fractionation chemoradiation have cast doubt on such modeling. The purpose of this study was to identify alternative models. METHODS AND MATERIALS: Nine trials of platinum-based chemoradiation were identified. In radiation therapy-alone arms, the radiation therapy BED for tumor was calculated using standard parameters. In chemoradiation arms, 3 methods were used to calculate tumor BED (tBED): additional BED, addition of 9.3 Gy BED for tumor to the radiation therapy BED; zero repopulation, BED with no correction for repopulation; variable t(p) (the average doubling time during accelerated repopulation), values of t(p) 3-10 were used to examine a partial suppression of repopulation. The correlations between the calculated percentage change in tBED for each method and observed percentage change in local control were assessed using the Pearson product moment correlation. RESULTS: Significant correlations were obtained for all 3 methods but were stronger with zero repopulation (P=.0002) and variable tp (t(p) = 10) (P=.0005) than additional BED (P=.02). CONCLUSIONS: Radiobiological models using modified parameters for accelerated repopulation seem to correlate strongly with outcome in chemoradiation studies. The variable tp method shows strong correlation for outcome in local control and is potentially a more suitable model in the chemoradiation setting. However, a lack of trials with an overall treatment time of more than 46 days inhibits further differentiation of the optimal model.