Summary Background Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce ...irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. Methods We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1–4, N0–3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. Findings 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0–59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 74%; 95% CI 56–87 of 34 patients given conventional radiotherapy vs 15 38%; 23–55 of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 41%; 99% CI 23–61 of 44 patients given conventional radiotherapy vs 35 74%; 55–89 of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 83%; 95% CI 63–95 of 24 patients given conventional radiotherapy vs nine 29%; 14–48 of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. Interpretation Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. Funding Cancer Research UK (CRUK/03/005).
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP ...inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.
Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.
Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.
Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.
The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the ...progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients.
In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson’s grade. Patients with atypical meningioma (WHO grade II) and Simpson’s grade 1–3 Arm 1 entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4–5 Arm 2 and Grade III Simpson grade 1–3 or 4–5 Arm 3&4 in which few patients were expected.
Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson’s grade 1–3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%.
These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I–III) is superior to 70% when treated with high-dose (60 Gy) RT.
Summary Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity ...of life. Until now, treatment options have been restricted to surgery and radiotherapy, although neither modality has been well studied in clinical trials. However, the new immune checkpoint inhibitors and molecularly targeted agents that have been introduced for treatment of metastatic melanoma are active against brain metastases and offer new opportunities to improve disease outcomes. New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research.
Summary Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of paediatric brain tumours. Radiotherapy is one of the main contributors to neurocognitive ...sequelae. Current approaches for prevention and reduction of neurocognitive dysfunction include avoidance of radiotherapy in young children and reduction of the radiotherapy dose and volume of brain irradiated. Substantial advances have been made in brain imaging, especially with functional imaging and fibre tracking with the use of diffusion tensor imaging. Radiotherapy techniques for photon therapy have also evolved, with widespread use of techniques such as image-guided radiotherapy, volumetric modulated arc therapy, helical tomotherapy, and adaptive radiotherapy. The number of proton beam and heavy ion therapy facilities is increasing worldwide and there is great enthusiasm for clinical use of advanced MRI-guided radiotherapy systems. Here, we review the potential role of modern imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae in children with brain tumours, and discuss various strategies to integrate these advances to drive further research.
New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate ...649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, R
of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.
Since the first wave of coronavirus disease in March 2020, citizens and permanent residents returning to New Zealand have been required to undergo managed isolation and quarantine (MIQ) for 14 days ...and mandatory testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of October 20, 2020, of 62,698 arrivals, testing of persons in MIQ had identified 215 cases of SARS-CoV-2 infection. Among 86 passengers on a flight from Dubai, United Arab Emirates, that arrived in New Zealand on September 29, test results were positive for 7 persons in MIQ. These passengers originated from 5 different countries before a layover in Dubai; 5 had negative predeparture SARS-CoV-2 test results. To assess possible points of infection, we analyzed information about their journeys, disease progression, and virus genomic data. All 7 SARS-CoV-2 genomes were genetically identical, except for a single mutation in 1 sample. Despite predeparture testing, multiple instances of in-flight SARS-CoV-2 transmission are likely.
To develop an image analysis technique that distinguishes pseudoprogression from true progression by analyzing tumour heterogeneity in T2-weighted images using topological descriptors of image ...heterogeneity called Minkowski functionals (MFs).
Using a retrospective patient cohort (n = 50), and blinded to treatment response outcome, unsupervised feature estimation was performed to investigate MFs for the presence of outliers, potential confounders, and sensitivity to treatment response. The progression and pseudoprogression groups were then unblinded and supervised feature selection was performed using MFs, size and signal intensity features. A support vector machine model was obtained and evaluated using a prospective test cohort.
The model gave a classification accuracy, using a combination of MFs and size features, of more than 85% in both retrospective and prospective datasets. A different feature selection method (Random Forest) and classifier (Lasso) gave the same results. Although not apparent to the reporting radiologist, the T2-weighted hyperintensity phenotype of those patients with progression was heterogeneous, large and frond-like when compared to those with pseudoprogression.
Analysis of heterogeneity, in T2-weighted MR images, which are acquired routinely in the clinic, has the potential to detect an earlier treatment response allowing an early change in treatment strategy. Prospective validation of this technique in larger datasets is required.
Real-time genomic sequencing has played a major role in tracking the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contributing greatly to disease mitigation ...strategies. In August 2020, after having eliminated the virus, New Zealand experienced a second outbreak. During that outbreak, New Zealand used genomic sequencing in a primary role, leading to a second elimination of the virus. We generated genomes from 78% of the laboratory-confirmed samples of SARS-CoV-2 from the second outbreak and compared them with the available global genomic data. Genomic sequencing rapidly identified that virus causing the second outbreak in New Zealand belonged to a single cluster, thus resulting from a single introduction. However, successful identification of the origin of this outbreak was impeded by substantial biases and gaps in global sequencing data. Access to a broader and more heterogenous sample of global genomic data would strengthen efforts to locate the source of any new outbreaks.
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