Table 4.

Qualitative data in support of findings.

1	Usual care and equipoise “There's a balance of risk, a pattern of morbidity … a spectrum of how likely it is that that morbidity will be realized, that has to be balanced against the perceived effect on the natural history of the disease… I think there's a large grey area where, depending on the previous experience of the surgeon…they might be prepared to operate.” [R196 IM3 p26]
2	Challenges for equipoise in current management of refractory epilepsy “The neurosurgeon may not see the patients early enough in order to make that decision about early intervention, the neurologist will cycle through a whole range of agents with combinations before they refer the patient with epilepsy on to neurosurgeons” [R140, SIV, p5] “In our hospital in [SITE] if we have a symptomatic cavernoma due to a seizure, I tend to refer them early to the surgical clinic rather than trialling two drugs” [Neurologist 236, Neurologist workshop, p44]
3	Patient preferences “So, if I look at it from that perspective…my symptoms without surgery are not strong enough for me to warrant going in to have quite invasive brain surgery. The risk of surgery, it's just not [an option].” [P0407 Int, p5, declined randomisation neurosurgery vs medical management, chose medical management]” “The majority of specialists I've spoken to say ‘Your situation is quite stable, and I don't think you need any kind of treatment at the minute’. And some of them actually, they recommend surgery. But some say ‘No the surgery could be too risky and the gamma knife is the way forward’.” [P0409, Rec cons, p5, declined trial, chose medical management] “[All clinicians] I've spoken to have said to go for [neurosurgery]. Because, if it's not meant to be there, get it out.” [P0422 Rec Cons, declined trial, chose neurosurgery]
4	MDT influence on recruitment “The MDT is not unified in equipoise, that's more clear to me now than it was before we opened. And I would say, the fact that patients come through the MDT provides nothing but the opportunity for me to say, ‘Could I please talk to them about the CARE study?’ But I'll quite often be told ‘no’.” [R196 Int, site screened >30 patients, only 33% of eligible patients approached] “[MDT members] wouldn't outright say ‘not suitable for consideration in CARE’, but they would often have… a preference as to how they think the patient should be managed. There's a reason they don't want to go ahead and approach the patient…. The [neurovascular] MDT is led by a particular consultant, who will have quite a say in how they want things to move forward.” [R189 Int p9, site screened >30 patients, only 18% of eligible patients approached]
5	Exclusion of SRS “We are not big believers in gamma knife for cavernoma. We tend to operate on the cavernomas, including the brainstem ones, provided they've got an appropriate accessible corridor or are subpial. The general view of the MDT is ‘not for gamma knife’” [R125 SIV case discussion]. “I certainly approached other consultants just going back through our screening logs, ‘Did you want to rediscuss this patient [for SRS] at the MDT?’ They've come back and said ‘Actually no…the plan was just to carry on conservative management’.” [R196 Int p6] “I think the other issue is that a lot of people have been practising a certain way for 20 years. So they really believe in their management algorithm. So detaching yourself from your algorithm, which you've had in place for 20 years, you believe in, that is hard.” [R119 Int p8] “Radiosurgery is [seen as] a competitor to the microsurgeon because the microsurgeon sees patients boarding with their feet, going for minimally invasive treatment. The patients don't come for microsurgical resection anymore.” [R215 Int p10]
6	Cavernoma management for children “General feeling in paediatrics… is that 95% of these, if you can do a surgical excision, then most paediatric neurosurgeons would excise them, because they're young they have got 70, 80, 90 years of life left…Children don't usually get referred for radiotherapy for brain tumours unless they are over 5, so that's where… that 5 year old cut-off's come from…we worry about the late effects of radiosurgery, whether it be single or multiple doses.” R153, Int, p5 “I mean I've referred a couple of brainstem cavernomas to [Site offering SRS]… but obviously one of the late effects of brain radiotherapy is cavernoma formation, it's quite paradoxical.” [R235 Int p10] “Unsuitable for trial as unsuitable for surgery or SRS.” Free text screening log report why 5/7 symptomatic cavernoma patients screened at paediatric site were not approached.
7	Challenges of determining eligibility “There are a lot of patients that I've been seeing who are referred as symptomatic cavernoma but...when I see them that's not the case. You have to see quite a lot of patients with cavernoma to identify ones who may actually be suitable for the study. It does take quite a time for the epilepsy work up, perhaps to have more invasive EEG, neuropsychology, perhaps a psychiatry assessment. All of those things are taking much longer, unfortunately, post-pandemic.” [R144 Int p3]
8	Controversy over eligibility criteria “If they're presenting with headaches and they've got a cavernoma, how do you know if the headache is not due to a micro-haemorrhage from cavernoma? You don't but you can see a cavernoma. Therefore, by definition it has bled.” [R205 Int p9]
9	Exclusion of those showing FND with no evidence of haemorrhage from SRS referral “[if] there's no evidence that it’s bled, for example… they screened them out themselves rather than just refer everything to [SRS centre]” [R189, Int, p5]
10	Managing expectations of people (and their clinicians) referred for SRS prior to trial opening “[with] SRS…we are working months behind, because patients would have been referred at a time pre-CARE. Obviously, I can talk to them about it, but then you're in the [SRS] clinic and they've come for [SRS] treatment. It's much, much harder for them to then reverse that decision and decide to go into a trial.” [R178, Int, p22] “So a lot of the referrals to me are referrals for radiosurgery, so they're not being referred to enrol them in a trial. I if I get referred a patient for gamma knife and then and it comes back that I randomise a patient and they end up having conservative management, then I might find [the referring neurosurgeon] says well you know patient, has a bleed, I didn't refer the patient for randomisation, I referred them for gamma knife.” [R119 Int p4 and 5]
11	Length of follow-up “My gut feeling, would be that to remove the cavernoma, to remove that risk of haemorrhage [brings benefit] but whether you'd have a long enough follow-up [within a CARE main phase trial] to determine that. It's almost like the ARUBA trial in that, if you look four or five years later, you're wasting your time. You're looking at the lifetime risk of haemorrhage, not do they have a haemorrhage in the next four years.” [R178 Int p17] “You will of course see all the morbidity of [neurosurgery] very, very early. You may not see some of the benefits for decades. And particularly the seizure benefits, we could argue if you're causing harm early, that. it would take a very long time to balance that out.” [R196 Int p8]
12	Influence of COVID-19 pandemic “I just see the level of anxiety and preparation to come in for an operation at the moment, you know, patients still have to isolate….There's a lot more to put your life on hold for, you know isolate, do pre-OPS, come in. You may be cancelled on the day. All of that's an extra level of stress and anxiety for people compared to, if you're going in for SRS, which is on a more sessional basis, isn't it?” [R189 p 6]
13	Surgeons offering intervention to a broader pool of patients than within usual care “I don't normally use radiosurgery. There are reasons to think it could do something, but til the evidence is out there I wasn't planning on using it. Now there is a trial trying to get that evidence–if you want to try radiosurgery I'm happy organising it through the trial…I really don't operate on very many cavernomas. The vast majority I just wait and see what happens….There is a genuine question whether surgery might change the course of things. If you're somebody who would like to consider surgery, then I believe the way to do it, is to go through the trial.” [R167 Int p8] “According to best current evidence I would proceed with [medical management]. In the context of the trial, as we don't know for sure that medical management is the best, he should go for randomisation.” [R138 SIV case discussion]
14	PI influence over the MDT/MDT equipoise “Because there are just the four of us [in the MDT], I run it usually.” [R138, SIVp2 site recruited >4 patients] “We don't get cavernomas into the MDT unless there is a specific reason for it. If their diagnosis is in doubt or something of that sort. But by and large, there are two of us who do vascular work in [SITE], both of us pretty much sing from the same hymn sheet….We don't discuss every cavernoma through MDT.” [R205 Int, site recruited >4 patients] “The patient is counselled on all the potential options of just taking an observation route, microsurgical resection with its risks depending location, age and suitability, co-morbidities and so the peri-operative risk will be evaluated. Then stereotactic radiosurgery, what it can offer, what we can't guarantee, what we can't prove, like for example the controversy that we will never be able to say, “You are cured,” because it will always be visible on an MRI scan. Then at the end of that decision-making process the patient usually makes an informed decision.” [R215 Int, site recruited >4 patients]
15	Offering SRS based on evidence of lower risk “I think SRS patients, by and large, have already had surgery ruled out, so they have a choice of do absolutely nothing or have the SRS. The dose that we use is relatively small. The risks aren't enormous. Does it work? Does it not work? We don't know, but I just think that that's far more randomisable [than neurosurgery vs medical management].” R178 Int p5 “There can be a willingness on the part of clinicians, and to an extent on the part of patients, to accept treatment that doesn't require general anaesthetic, is done in a day and is unlikely to cause a disability. But whether it's effective or not is a secondary consideration. [p10] If you cannot accept any risk, radiosurgery is probably the way to go. But I cannot guarantee that it's efficacious.” [p26] [R196 Int]
16	Acceptability of intervention with SRS for people with cavernoma “There can be a willingness on the part of clinicians, and to an extent on the part of patients, to accept treatment that doesn't require general anaesthetic, is done in a day and is unlikely to cause a disability. But whether it's effective or not is a secondary consideration. [p10] If you cannot accept any risk, radiosurgery is probably the way to go. But I cannot guarantee that it's efficacious.” [p26] [R196 Int] “The operation I don't want. Not sure about the radiation.” [P1305 Rec cons, p9, accepted randomisation between SRS vs MM]
17	SRS to prevent future bleed, not for seizure control “I would question what benefit SRS would be to seizure outcome. So, we're now moved away from the benefit to the cavernoma outcome, and we're discussing seizure outcome. Again, am I telling patients that their seizures are going to be fewer, that their burden of disease is going to be less, that they'll be able to reduce their medication, etc? The same conversations that you would have if the patient who had a clear focus of epilepsy had that surgically removed? I just don't think that it’s the same thing.” [R178 Int p16]
18	Patients perceiving the CARE trial as an opportunity to access neurosurgery “The general consensus was, unless you're having severe seizures every day and it's disabling you then the cavernoma wouldn't be removed. After that, it was ‘Right, it sucks but I've just got to carry on’. (p8 and 9)The fact that [the trial] gave me the opportunity to go for surgery, it was such a huge relief. Without the CARE trial, I don't think that would have happened” [P1407 Int, p26, 7 year history of seizures, declined trial, chose neurosurgery]

R, Recruiter; IM, Investigator Meeting; SIV, Site initiation visit; P, participant; Int, interview; Rec cons, recruitment consultation.