Matt Williams’s research while affiliated with Imperial College London and other places

Background Brain metastases are the most common intracranial tumours. Variation exists in the use of stereotactic radiosurgery for patients with 10 or more brain metastases. Concerns include an increasing number of brain metastases being associated with poor survival, the lack of prospective, randomised data and an increased risk of toxicity. Methods We performed a systematic review and meta-analysis to assess overall survival of patients with ten or more brain metastases treated with stereotactic radiosurgery as primary therapy. The search strings were applied to MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). Log hazard ratios and standard errors were estimated from each included study. A random-effects meta-analysis using the DerSimonian and Laird method was applied using the derived log hazard ratios and standard errors on studies which included a control group. Results 15 studies were included for systematic review. 12 studies were used for pooled analysis for overall survival at set time points, with a predicted 12 month survival of 20–40%. The random-effects meta-analysis in five studies of overall survival comparing ten or greater metastases against control showed statistically worse overall survival in the 10 + metastases group (1.10, 95% confidence interval 1.03–1.18, p-value = < 0.01, I² = 6%). A funnel plot showed no evidence of bias. There was insufficient information for a meta-analysis of toxicity. Discussion Overall survival outcomes of patients with ten or more brain metastases treated with SRS is acceptable and should not be a deterrent for its use. There is a lack of prospective data and insufficient real-world data to draw conclusions on toxicity. PROSPERO ID CRD42021246115

Background High-grade gliomas (HGG) account for 60–75% of all adult gliomas. The complexity of treatment, recovery and survivorship creates a need for novel monitoring approaches. Accurate assessment of physical function plays a vital role in clinical evaluation. Digital wearable tools could help us address unmet needs by offering unique advantages such as scale, cost and continuous real-world objective data. We present data from 42 patients enrolled into the BrainWear study. Methods An AX3 accelerometer was worn by patients from diagnosis or at recurrence. Age-, sex-matched UK Biobank control groups were chosen for comparison. Results 80% of data were categorised as high-quality demonstrating acceptability. Remote, passive monitoring identifies moderate activity reduces both during a course of radiotherapy (69 to 16 minutes/day) and at the time of progressive disease assessed by MRI (72 to 52 minutes/day). Mean acceleration (mg) and time spent walking daily (h/day) correlated positively with the global health quality of life and physical functioning scores and inversely with the fatigue score. Healthy controls walked on average 2.91h/day compared to 1.32h/day for the HGG group on weekdays and 0.91h/day on the weekend. The HGG cohort slept for longer on weekends (11.6h/day) than weekdays (11.2h/day) compared to healthy controls (8.9h/day). Conclusion Wrist-worn accelerometers are acceptable and longitudinal studies feasible. HGG patients receiving a course of radiotherapy reduce their moderate activity by 4-fold and are at least half as active as healthy controls at baseline. Remote monitoring can provide a more informed and objective understanding of patient activity levels to help optimise health related quality of life (HRQoL) among a patient cohort with an extremely limited lifespan.

AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Despite poor outcomes, there is little work on end of life care in primary brain tumour patients. The majority of patients with cancer prefer to die at home, but most do not. METHOD We identified all patients with a malignant primary brain tumour diagnosed in England between 2013-2018 and who died up until 1st of August 2020. RESULTS 20,684 patients were selected. The median age at diagnosis was 68 years (IQR=19), 42% were female. 55% died within 6 months of diagnosis. 36% of people died at home (compared to 24% of the entire population in England), 25% died in hospital, 15% died in a hospice, 9% died in a nursing home. 15% had an unrecorded or other place of death. 47% (n=9,682) patients had radiotherapy, of which 8.7% (n=1,806) had radiotherapy in the 3 months before death; 29% (n=5,947) patients received chemotherapy (6%(n=1,292) during the last 3 months). 87%(n=18,013) patients had surgery (36%(n=7,370) during the last three months). For all treatments the chance of patients dying at home decreases if the patient has treatment in the last three months of life. CONCLUSION To our knowledge, this is the first work exploring the relationship between anti-cancer treatment near the end of life and the location of death. Further work will focus on building a comprehensive model to predict rates of death in hospital, and examine variation on a national level.

AIMS The GlioCova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018, of which 15,277 patients were diagnosed with a cranial glioblastoma. Here we present data on the direct care costs of treatment, based on secondary care data. METHOD We examined data on inpatient and outpatient care for all cranial glioblastoma patients in the dataset. We used the NHS HRG4+ Reference Costs Grouper 2017-2018 to assign costs standardised to 2017-2018. RESULTS A total of 14,999 patients were admitted to hospital between the last three months of 2012 and up to the end of 2019, of which we were able to assign costs to 14,691 patients. Total inpatient cost was over £321 million (34% of which was attributed to direct costs of spells of neurosurgery, chemotherapy, and radiotherapy). 14,528 patients had outpatient care, of which we were able to assign costs to 14,419 patients. Total outpatient cost was over £92 million (41% of which was attributed to chemotherapy and radiotherapy). CONCLUSION The estimated secondary care costs for adult glioblastoma patients in England were over £414 million for patients diagnosed between 2013-2018, but do not include patient out-of-pocket costs, primary care, social care, or end of life care costs. Future work will examine variation in care and costs and extend it to the wider brain tumour cohort. We also hope these data will help make the economic argument for improvements in care for brain tumour patients. More information on GlioCova: https://blogs.imperial.ac.uk/gliocova/about-gliocova/

AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present detailed analysis of first-line treatments of adult glioblastoma (GBM) patients. METHOD We identified all adults patients diagnosed with a GBM. We focused on the first line of treatment and we defined ‘maximal’ first-line treatment as surgical resection followed by chemo-radiotherapy with 59-60 Gy and with at least one cycle of adjuvant chemotherapy Temozolomide. RESULTS 15,294 patients were diagnosed with a glioblastoma (60% male) with a median age of 66. 79% of patients received some treatment, with younger patients more likely to be treated (>90%, 18 - 59; < 30%, > 80). 54% underwent debulking surgery; 23%, biopsy. 14% received ‘maximal’ treatment and 21%, none. Patients who had no treatment had a median survival of 2 months whereas patients who received ‘maximal’ treatment had a median survival of 16 months. CONCLUSION Most adult patients with a GBM in England have a histological diagnosis, and some oncological treatment. However, only 14% receive ‘maximal’ treatment. Of the 3222 patients who received none, some of these may have had purely private treatment; however, our dataset includes any private sector work undertaken in NHS hospitals. Survival remains poor, but outcomes in those receiving maximal treatment match those from clinical trials. However, most patients do not receive maximal treatment, and so the easiest route to improving outcomes may be optimise delivery of treatment in the 65% of patients who receive sub-maximal treatment. More information on https://blogs.imperial.ac.uk/gliocova

AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.

AIMS Discrepancies exist in the use of stereotactic radiotherapy (SRT) for patients with 10 or more brain metastases. Concerns include multiple metastases being associated with poor survival and the lack of prospective data. We analysed survival outcomes of these patients in a multi-centre cohort. METHOD We performed a retrospective cohort study of 511 consecutive patients from three SRT centres treated for brain metastases between January 2010 - August 2021, censored in January 2022. We assessed survival post-SRT of patients with ≥10 metastases against a matched group of 5-9 and 1-4 metastases using the logrank test for statistical testing. We used a multivariate Cox model to assess the relationship between overall survival and: number of metastases; total volume; primary malignancy; use of systemic anti-cancer therapies with intracranial penetrance; controlled extracranial disease. Results with p-values <0.05 were considered significant. RESULTS Survival data was available for all patients, and for 85-100% of factors in multivariate analysis. 63 patients had ≥10 metastases (median 19). Median survival was 13.3 months, compared with 15.1 and 19.0 months for the 5-9 and 1-4 metastasis groups respectively. Differences were not statistically significant (p-value 0.14). Increasing volume of disease (HR 1.05 [1.01-1.09], p-value: 0.01), non-small cell lung cancer (HR 3.5 [1.35-9.09] p-value: 0.01) and use of systemic anti-cancer therapy with intracranial penetrance (HR 0.239 [0.105-0.547] p-value: <0.01) had a statistically significant effect on survival in multivariate analysis. CONCLUSION Carefully selected patients with multiple metastases have acceptable survival outcomes following SRT and this approach should be more widely considered.

AIMS The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we investigate patient safety and post-operative complications after first surgical intervention. METHOD We identified patients undergoing first surgical intervention (surgical debulking or biopsy) and used a modified Delphi approach to identify diagnosis codes indicating potential post-surgical complications. We calculated Elixhauer Comorbidity Index (ECI) weights based on our data and developed regression models to link patient characteristics and ECI with 30-day mortality, readmission and chance of complication. RESULTS 29,258 out of 51,775 patients underwent a surgical intervention (28,173 surgical debulking; and 1,207 biopsy). 11,959 (40.9\%) patients had at least one comorbidity during first intervention admission. In hospital mortality was 0.99\% (N = 289), 30-day mortality was 2.3\% (N = 677) and 30-day readmission was 12.7\% (N = 3,725). 13,137 patients (44.9\%) had at least one complication code from our defined list, either during their first surgical intervention or during a 30-day readmission. Predictors of 30-day mortality, readmission, and risk of complications included age, ECI score, number of complications, type of intervention (biopsy vs surgical debulking), income quintile, and tumour type (i.e., Glioblastoma versus other types of brain tumours). CONCLUSION To our knowledge this is the first study in England to assess post-surgical complications in a large brain tumour patient cohort. Our further work will focus on variation in outcomes between different centres/ centre volumes/ regions and the cost of complications. More information: https://blogs.imperial.ac.uk/gliocova/about-gliocova/.

Background Glioblastoma is the most common malignant brain tumor in adults and has a poor prognosis. This cohort of patients is diverse and imaging is vital to formulate treatment plans. Despite this, there is relatively little data on patterns of use of imaging and imaging workload in routine practice. Methods We examined imaging patterns for all patients aged 15–99 years resident in England who were diagnosed with a glioblastoma between 1st January 2013 and 31st December 2014. Patients without imaging and death-certificate-only registrations were excluded. Results The analytical cohort contained 4,307 patients. There was no significant variation in pre- or postdiagnostic imaging practice by sex or deprivation quintile. Postdiagnostic imaging practice was varied. In the group of patients who were treated most aggressively (surgical debulking and chemoradiation) and were MRI compatible, only 51% had a postoperative MRI within 72 hours of surgery. In patients undergoing surgery who subsequently received radiotherapy, only 61% had a postsurgery and preradiotherapy MRI. Conclusions Prediagnostic imaging practice is uniform. Postdiagnostic imaging practice was variable. With increasing evidence and clearer recommendations regarding debulking surgery and planning radiotherapy imaging, the reason for this is unclear and will form the basis of further work.

Research on brain metastases kept innovating. We aimed to illustrate what topics the research focused on and how it varied in different periods of all the studies on brain metastases with topic modelling. We used the latent Dirichlet allocation model to analyse the titles and abstracts of 50,176 articles on brain metastases retrieved from Web of Science, Embase and MEDLINE. We further stratified the articles to find out the topic trends of different periods. Our study identified that a rising number of studies on brain metastases were published in recent decades at a higher rate than all cancer articles. Overall, the major themes focused on treatment and histopathology. Radiotherapy took over the first and third places in the top 20 topics. Since the 2010’s, increasing attention concerned about gene mutations. Targeted therapy was a popular topic of brain metastases research after 2020.