Introduction

Some text in this section has been reproduced from Loan et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

What are brain cavernomas?

Cerebral cavernous malformations (CCMs), also known as brain cavernomas, are intracranial vascular malformations that are diagnosed using histopathological examination or magnetic resonance imaging (MRI). Large brain MRI cohorts have shown that the asymptomatic prevalence of brain cavernomas is 0.16%, currently affecting ≈106,000 people in the UK.2 Some of these people present to medical attention with symptoms such as epileptic seizures or stroke due to either intracranial haemorrhage (ICH) or new non-haemorrhagic progressive or persistent focal neurological deficits (FNDs) anatomically related to the brain cavernoma that do not appear to be due to haemorrhage.3 The incidence of symptomatic brain cavernoma in the UK was 0.24 per 100,000 per year at the turn of the millennium,4 so ≈160 people are newly diagnosed with symptomatic brain cavernoma in the UK annually. The impact of brain cavernoma is disproportionately high in comparison to their frequency, because they are usually diagnosed in children and young adults of working age.4 People with brain cavernoma face a considerable risk of recurrent stroke, which is reliably known over 5 years after diagnosis,5 but is likely to continue for their lifetime. The 5-year risk of ICH ranges from ≈3.8% for people with non-brainstem cavernoma who have presented without a stroke to ≈30.8% for people with brainstem cavernoma who have presented with stroke due to ICH or FND. People with brain cavernoma who present with an epileptic seizure almost inevitably develop epilepsy within 1 year, and only half of the people with brain cavernoma-related epilepsy achieve 2-year seizure freedom.6 These persistent symptoms also cause economic consequences for people with brain cavernoma, carers, the NHS, social services and lost productivity in the UK workforce.7 Although most brain cavernomas are solitary and sporadic, around one-fifth are multiple with autosomal dominant inheritance due to mutations in three genes,8 so there are implications for relatives as well.

Why is this research important?

Recurrent epileptic seizures and persistent symptoms of stroke due to ICH or FND result in disability, handicap and psychological consequences for people with brain cavernoma.9 Therefore, ‘intervention’ as active treatment of cavernoma in usual clinical practice is done with neurosurgical resection for some patients (to try to prevent ICH or epileptic seizures) or stereotactic radiosurgery (which is preferred for different patients because neurosurgery is too risky or patients want a non-invasive treatment).10 However, intervention has complications that can be fatal or disabling,11,12 and there are few reliable data about the benefits and risks of medical management with intervention versus medical management alone.13–15 Consequently, guidelines have been unable to make strong recommendations for clinical practice,14–16 and a James Lind Alliance Priority Setting Partnership found that the top research priority for cavernoma was, ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with brain or spine cavernoma?’17

How does the existing literature support this proposal?

Randomised controlled trials

A search of ClinicalTrials.gov trial register on 19 January 2024 for interventional studies using the terms ‘cavernoma OR cavernous angioma OR cavernous malformation’ revealed five randomised controlled trials (RCTs) of drug therapies for brain cavernoma but no completed, ongoing or planned RCTs of intervention.

Observational cohort studies

In several systematic reviews of observational cohort studies comparing intervention to medical management of brain cavernoma, or one form of intervention to another, we have not found any studies at low risk of bias that demonstrated sufficiently ‘dramatic’ associations between intervention versus medical management of brain cavernoma and clinical outcomes that would make a RCT unnecessary,13,18 based on systematic reviews and meta-analyses, including (1) observational cohort studies that compared active treatment with stereotactic radiosurgery or neurosurgery against conservative management in a concurrent or historical control group and reported clinical outcome;11–13 (2) observational cohort studies without comparison groups reporting clinical outcomes after either conservative management,5 neurosurgery12,19 or stereotactic radiosurgery;11,19 and (3) decision analysis comparing all management strategies using a Markov model with a time horizon of 5 years.20

There are seven observational cohort studies (n = 394 participants) that compared neurosurgical resection and medical management, from which estimates of the relative risk of neurosurgery can be calculated (see Table 1 overleaf).10,21–26 The best available comparative data on an entire incident brain cavernoma population found neurosurgery to be associated with harm over 5 years [hazard ratios (HRs) 2.2–3.6],10 although other comparative studies restricted to brainstem/deep brain cavernomas have suggested both harm [risk ratios (RRs) 1.9–7.8] and benefit (RRs 0.5–0.6) on the risk of ICH over 4–6 years,22–25 but the long-term difference in risk is unknown and might favour neurosurgery.

In the only observational cohort study involving 41 participants comparing stereotactic radiosurgery with medical management at one hospital in Republic of Korea,27 the RR was incalculable because of the paucity of outcomes (Table 1). Indirect comparisons imply that stereotactic radiosurgery might be superior to medical management over 5 years. In our systematic review and meta-analysis of 30 cohort studies of patients undergoing stereotactic radiosurgery for brain cavernoma (median 61%, of whom had brainstem cavernoma; and median 91%, of whom had presented with ICH), during a median follow-up of 48 [interquartile range (IQR) 35–62] months after stereotactic radiosurgery, the annual incidence of the composite of death, ICH or FND was 3.63% [95% confidence interval (CI) 3.17 to 4.16].11 Using these data to estimate the 5-year risk (16.9%) after stereotactic radiosurgery and comparing the risk indirectly to the cumulative 5-year risks of ICH with medical management that range from ≈18 to ≈31% for comparable patient groups5 suggests that stereotactic radiosurgery might be superior to medical management over 5 years. A systematic review of stereotactic radiosurgery restricted to brainstem cavernoma suggested that treatment was beneficial by comparing ICH risks before and after treatment,28 but their findings are unreliable because they may simply reflect the untreated clinical course of brain cavernoma in which ICH risk declines over time.5

Clinical guidelines

These major gaps in the evidence base informing the management of patients with brain cavernomas have prevented clinical guidelines in the UK and USA from making strong recommendations about whether to use treatment with intervention or medical management alone for brain cavernomas.14,15 These uncertainties were confirmed by patients and carers in a James Lind Alliance Priority Setting Partnership in the UK.17

The need for a pilot phase randomised controlled trial

Resolving this therapeutic dilemma was likely to be challenging for several reasons: the incidence of symptomatic brain cavernoma is low despite a high prevalence, interventions are available in everyday clinical practice14,15 and accumulated experience in specialist centres has determined usual clinical practice hitherto despite the lack of high-quality evidence.29 Recruitment was likely to be challenging given the history of RCTs comparing active treatment of intracranial vascular malformations with invasive procedures versus medical management.30,31 A similar RCT comparing active treatment versus medical management for arteriovenous malformations of the brain (ARUBA) revealed strong and polarised views held by different clinical specialties about different therapeutic approaches (neurosurgery, stereotactic radiosurgery and endovascular embolisation), which were barriers to RCT recruitment.31 Slow recruitment to ARUBA seemed to be due to the disengagement of some specialty groups that did not accept the lumping of these different types of active treatment in one intervention arm, that disputed whether the findings were clinically applicable because there was insufficient funding for long-term follow-up to determine whether the early hazards of treatment were offset by gains in the longer term31,32 and that questioned external validity because of the lack of information about patients who were not randomised. Identical problems beset a similar RCT of intracranial aneurysm management.30 However, the reasons for poor recruitment to previous RCTs have not been formally studied. Many RCTs experience recruitment challenges due to difficulties that recruiters have in explaining concepts like uncertainty, equipoise and randomisation.33 Also, patients may have treatment preferences (e.g. for less invasive procedures), and patient/family preferences may affect RCTs involving children in particular.34

Therefore, in late 2018, the NIHR issued a commissioned call for a pilot phase RCT addressing this dilemma (see Report Supplementary Material 1 and Report Supplementary Material 2), and we were awarded a contract for the study.

We aimed to conduct a pilot phase RCT with embedded research to investigate the potential barriers to recruitment and optimise recruitment processes with a Qualitative research integrated within Trials (QuinteT) Recruitment Intervention (QRI),35 which has been integrated into over 50 RCTs, including RCTs comparing surgery and medical management.36 A QRI would allow the identification and understanding of generic and trial-specific recruitment challenges,33,37,38 and the development of tailored plans to address these issues. There is observational evidence of the benefits associated with a QRI in at least five RCTs.39 In our proposed Cavernomas A Randomised Effectiveness (CARE) pilot RCT, knowledge about proportions of patients screened, eligible, approached, consented and randomised, as well as what affects these stages of recruitment and could be influenced, will inform the feasibility of a definitive RCT.