Episode 35: In the Clinic - Overview of prostate radiotherapy with Dr Alison Tree, 37 to 5 treatments

Join us as we discuss all things prostate radiotherapy with Dr Alison Tree. 
Alison is synonymous with all things prostate radiotherapy and is superb at setting the scene for prostate cancer.

Based at The Royal Marsden Hospital, and The Institute of Cancer Research, Dr Tree has played a key role in several major prostate radiotherapy trials. These include working alongside Professor Nicholas Van As in the PACE trial portfolio and also working on the PIVOTAL Boost trial.

She has special interest in MR-guided prostate radiotherapy (the PRISM trial), boosting dominant intra-prostatic lesions (the DELINEATE trial) and hypofractionation in prostate cancer.

Alison Tree is an amazing speaker on the subject of prostate radiotherapy and we are sure this will be of of interest to anyone interested in prostate cancer or radiotherapy.

This episode contains everything we could want to know about the current position of prostate radiotherapy and future directions of travel.

Enjoy

Transcript

Alison Tree Simply Podcast Recording-20250106_103518-Meeting Recording

 Hello. I'm doctor John McGrane and I'm doctor Michael Rowe. And today we've got a real treat. What we're looking at today is we're going to look at prostate radiotherapy and how that has changed over recent years and how the number of treatments that we're giving in a course of radiotherapy has come down. And we're delighted to have with us one of the big players in that conversation who has been heavily involved with a lot of the trials. And that's Doctor Alison Tree from the Royal Marsden Hospital. 
Hello, Allison. 
Welcome.

 Alison Tree   0:37
 Hello to both of you. Thanks for having me on the show.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   0:40
 And do you want to kind of give us almost like your credentials? Like, who are you and why are you talking to us about prostate radiotherapy?
Alison Tree   0:49
 Yeah, right. Well, yes, I'm a listener. I'm an oncologist from the Royal Marsden Hospital in London. Sutton and I've been involved. Really. The paste trial since 2011. So I guess that's my main credential for being on the show today. And over the last 13 years have been lucky enough to be involved with a sequence. Now, of trials, exploring the limits or maybe not quite even yet. They're reaching the limits of prostate hyper fractionation.
 So that's, I guess why you've invited me on.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   1:14
 Absolutely. And we're going to delve right into that as we go through. And of course that was a joke opening because Alison Tree needs no introduction.
Alison Tree   1:23
 Could be a bad thing or a good thing.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   1:25
 Now, Alison, John alluded to the fact that we're going to talk about fractions reducing over the course of time. Could you set the scene for the changes? Where did we start and where are we today?
Alison Tree   1:38
 Yeah, I'm going to go back 100 years because there was a guy called Claude Rigot, who was one of the forefathers of radiation oncology who did the experiments that set us on a path to fractionation. And he irradiated some Rams testicles in 1927.
 And found that if you give one big dose of radiation to the poor Rams testicle, then it gets very sore and the sperm still get produced to use that as a model of cancer growth. Whereas if you fractionate the dose to the poor RAM, then the skin's not quite so sore and from that.
 The fractionation of radiotherapy was born and for decades we carried on fractionating radiotherapy in all cancers, assuming that that minimised toxicity. But thankfully we've now we're writing the course now because lots of lab experiments started to show that in prostate cancer specifically and now we now know other cancers giving big doses of radiation just a few times is just as effective and may even spare some of those toxicities. We thought we were saving by fractionating, so.
 We've kind of we're kind of doing a course correction from those early days of radiation, radiation oncology.
 And that's how we end up in maybe the 60s, seventies, 80s, giving too great perf fraction and we've had to work our way back from there for a series of trials which we can talk about.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   2:54
 Right. And you are certainly your predecessors at the Marsden have been heavily involved in a lot of those trials and if we think whenever I started as prostate oncologist, we were giving 7 1/2 weeks of radiotherapy and that came about from a trial that was led by David Turnley.
Alison Tree   3:10
 Yep.
 Mm hmm.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   3:16
 That compared 32 treatments with 37. Do you want to just take us from there onwards on where the trials have gone from? Because actually I feel this is one of those occasions.
Alison Tree   3:22
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   3:26
 Well, the UK has the right to kind of beat its own drum and say, you know, we have actually kind of really driven a lot of these fractionation regimes for prostate cancer.
Alison Tree   3:37
 Yeah. And I think that's true for breast and prostate, but obviously today we're focusing on prostate. And you're right, this is one of the big success stories of radiation oncology research over the last few decades. So you started us there with RT01, which is where I normally start the story. And that was a trial that showed that dose escalation giving a bit more dose over a bit longer, which ended up with 74 grey and 37 fractions, improved biochemical control. Now that did come at a price of higher toxicity, which sometimes we forget.
 But it became our standard of care in the UK.
 And then we move on to the chip trial, which is the largest ever global study of localised prostate cancer radiotherapy. Over 3000 patients recruited largely from the UK. So it's good to bang our own drum there. It's deserved. And what chip showed us was that you can drop from a 7 1/2 weeks down to four weeks without any significant penalty and long term toxicity and maintaining very good rates of biochemical control. In fact, when you look at the 10 year data from CHIP.
 60 and 20 is nearly better than 74 and 37 didn't quite reach statistical significance.
 But the graph this the line is significantly consistently above 74 and 37, so 1620 is therefore become our standard in the UK.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   4:50
 So you alluded to the start of this being involved with the pace trial portfolio since 2011 and there's multiple sections to the pace trial portfolio supposed to say alongside this the pace trial portfolio has come about also matching quite significant technological advances in the way we deliver radiotherapy which is allowing us to deliver hypofractionation in a safer way as you say.
Alison Tree   4:57
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   5:16
 Trying to avoid that normal tissue toxicity as well. Can you tell us, give us an overview of?
Alison Tree   5:18
 Yep.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   5:22
 The PACE trial portfolio, what questions are you trying to answer in each of those separate arms?
Alison Tree   5:26
 Yeah. So you're exactly right that we couldn't have asked these questions in the previous era of 3D conformal without image guidance. That's just wouldn't have been safe, I don't think. But when in 2011, the sort of precipitant, was that the cyber knife came to the Royal Marsden. So there was data coming out of the state showing you could cure prostate cancer in five days. So we wanted to set up a trial that compared this new treatment with whatever would have been that man's standard option be that either surgery in pace A or standardly fractionated radiotherapy and pace B. So that's how it started.
 And obviously PACE has now had multiple babies since then, so Pacey came along then pace nodes. So we're now thinking about where to go with pace post op. Perhaps in the future.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   6:08
 We're never happy, are we? So we dropped from 37 treatment days down to 20 and now we're down to five and people are either given those everyday or they're giving them an alternate days. And if we just think about so we recent times there's been a series of big you know high profile publications from the Pierce Trial group. Can we look at PSA so just remind us PSA.
Alison Tree   6:21
 Mm hmm.
 Yeah.
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   6:36
 Was comparing standard. Will you tell me actually, why have you on?
Alison Tree   6:42
 All right. So pace A was randomising men one to one between SBRT SO5 fraction stereotactic body radiotherapy with a dose of 36.25 grey in five fractions and coming with that dose you give 40 grey and five fractions to the prostate with no margin. So it's kind of A2 level dose strategy. So that was the radiotherapy arm and the other patients that were randomised had surgery, so had to be laparoscopic or robotic assisted prostatectomy in a centre doing.
 To 25 cases, so not the kind of low really low volume centres. It's the best we've got to QA for surgery I guess is the metric of workload and so men were recruited to that trial. Initially we had quite a bit of buy in from surgeons, they seemed enthusiastic. We thought we had a shot at a biochemical study needing 800 patients, but sadly it became apparent over the years that it was difficult to recruit. And so we re programmed the study if you like to be a quality of life comparison because I think we're in this group.
 We're expecting big differences in cure rates, so we wanted to see what the differences were in quality of life.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   7:47
 And these were in a relatively low risk group of patients.
Alison Tree   7:52
 Correct. That's right. So we picked the group that we're largely being treated in the states. So there were some low risk patients in pace A and pace B and those patients probably now would be given surveillance. We prefer surveillance where it's safe to do so, but the majority in pace A and pace B were intermediate risk and most of those we've still treat today.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   8:13
 And the results from that were quite reassuring, weren't they?
Alison Tree   8:17
 So they were reassuring. If you're a radiation oncologist.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   8:20
 Well I am.
Alison Tree   8:23
 So I think it showed what we probably suspected. So when we designed the study, the surgeon said that they estimated that 15% of men would be wearing an incontinence pad at two years. So we powered the study based on that. And as you'll know from the results, unfortunately for those men, we found that 1/2 of them were still wearing a pad. So 50% wearing an incontinence pad at two years, so much higher than we'd expected, both us and the surgeon and the patient probably sadly.
 And so much worse urinary incontinence than we'd expected, as you would also expect, the bowel side effects were a bit more common in the radiotherapy arm compared to the surgery arm. But the number of men affected was pretty small as we've seen all of our other studies and the third parameter we looked at was sexual function and other important thing for many men starting prostate treatment and we showed as you once again might expect that the radiotherapy preserved sexual function much, much better than surgery did. So most men in the surgical arm ended up.
 Erectile dysfunction?
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   9:19
 It's always really difficult to do any study comparing radiotherapy versus surgery because people often have their kind of they come in with a predetermined view on what they want. And we've seen many bladder cancer trials fall flat in their face because they the randomization is too big a step.
Alison Tree   9:25
 
 Yeah, yeah, yeah, no, I go, I agree. And I think that was ultimately the difficult thing. I think you have to have echo the person speaking to the patient first has to have the equipoise. And none of us are unbiased. So whether they see the surgeon or the radiation oncology, they we always intuit sort of subconsciously give them a bias. And so that I think made it very difficult. And also if you're, you know, thank fair play to these men who went into a study and could have been randomly assigned surgery or radiotherapy, that's a big thing to ask anyone.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   10:04
 And then what is? Yeah, well, we should have equipoise. We then move into PSB. And this is where we're starting to see the PS trial. Really, in my opinion, starting to change radiation practise.
Alison Tree   10:18
 Yeah. Yeah, that's right. So it's the same group of patients as pace a essentially so low and intermediate risk, but once again 90% intermediate risk. And when we analyse them, you're probably familiar with the unfavourable, unfavourable way of characterising intermediate risk. So there were 3/4 unfavourable intermediate risk in pace B. So that means once again most of these patients, we would still treat in 2024. So these men with early prostate cancer were randomised between standard radiotherapy and that changed over the course of the trial.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   10:19
 Do you want to just give us a little overview on that?
Alison Tree   10:48
 Initially was 78, grey and 39, so he started from what was the European standard because it was an international trial and then over the course of the trial is chip published. We changed the dose on the standard arm to 62 grey in 20 fractions and then the SBRT almost the same doses. So 36.25 grey in five fractions could be given daily or alternate daily. And we recruited 874 men into pace B.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   11:14
 I think importantly in that pace B trial, you weren't using hormone therapy.
Alison Tree   11:18
 Yeah. Yeah. So ironically, that's probably ended up being my favourite bit of the trial. So we did it at the time because we wanted to make it similar between pace A and pace B, and this was a group where some people were starting to suggest the men didn't need hormones. I think in the UK we've been a heavier user than of ADT than most of the rest of Europe. And so we, I guess, maybe partly wanted to address that. But I think one of the important things is we'll come on to a minute in is the biochemical outcomes without ADT. So this was a pure trial of radiation alone.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   11:23
 None.
 And just to remind listeners, you know very often we would give six months of testosterone suppressing ADT alongside the radiotherapy. So actually and you know that can come with cardiovascular and all sorts of other side effects. So actually being able to remove that is a big, big step for a lot of patients.
Alison Tree   11:55
 Yeah, yeah.
 Yeah. And I bet we I don't know if we'll get on to PC today, but we when you look at the quality of life detriment in acute toxicity, the GI and Gu is tiny and then the hormones is the thing that most men are complaining about. As you probably see in clinic. So if we can remove the ADT from men who don't need it, that is a wonderful thing to do.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   12:19
 Mm hmm mm hmm.
 And so obviously it pays to be has sort of reported. Can you give us the sort of the summary of the outcomes that we found in that trial?
Alison Tree   12:31
 Yeah.
 Yeah. So that, yeah, the headline, I guess from the five year outcomes is that the biochemical control was much better than we'd even dreamed of. So 95% biochemical control for standard fractionation, 96 for SBRT. So very few men failing after treatments with radiation alone in the absence of hormone. So really wonderful outcomes and that's great for patients.
 The other side of the coin, of course, is toxicity, so we want to cure patients with no toxicity and we've already seen in the two year publication from Pace B that there's a little flare.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   13:00
 Mm hmm.
Alison Tree   13:05
 Toxicity at about a year ish after treatment from SBRT. Bit like you do. See. Occasionally after Brachy we don't really know why, but there does seem to be maybe 15% of men that get this little flare of annoying symptoms and because of that the toxicity cumulative rates are different between the two arms. So you get more Geo toxicity after S BRT than after longer fractionations, but no significant difference in bowel toxicity which was very low in both arms and for both GI and Gu. Almost no Grade 3 events.
 It's also very rare, which is great.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   13:39
 And that's that, that data that updated data with modern radiotherapy techniques has actually been really helpful in sort of colouring those conversations with patients about whether they want treatment or not. You know the balance, the pros and cons of having upfront radiotherapy, you can actually give updated figures with modern radiotherapy techniques of Gu and GI toxicity. And again, I think that as you said that the your favourite part of the pace beef trial being no ADT think that's been a huge driver as well.
Alison Tree   13:53
 Yeah.
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   14:10
 In this is, you know, patients come. Oh, well, I can have five fractions and no hormones. Then I will probably that might push them more towards having treatment for their prostate cancer, whereas previously they might have had those various barriers, 4 weeks ADT barriers to having, you know, therapy six months of six months is, you know barriers to actually having the treatment that is so effective and can I can I pin Allison down on as.
Alison Tree   14:14
 Yeah.
 Yeah. No, I agree. Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   14:37
 Are there any cases in that intermediate group and just as a reminder, so that's a grade group Gleason grade, you know, 3 + 4 PSA up to 20.
 It's still T2 that you would think. I think this person I'm. I'm just I'm going to give them some form of ADT anyway alongside my 5 fractions.
Alison Tree   14:58
 I think there is. So ultimately what we know from all of the hormone studies is that the hazard ratio of benefit is about .6 across all risk groups. So there is a benefit for all patients, but for the favourable ones, it's usually too small to measure in a trial, right? So if your chance of failing is 4% and you drop that by a hazard ratio .6, you may be getting them one or two percent maximum in biochemical control. So there are patients I will discuss that with if I think they would want to know that.
 And then if the mantis actually do want, I want my 1%, then then fine. It's not going to stop the radiotherapy working by adding hormones.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   15:29
 Mm hmm.
Alison Tree   15:32
 So I think we have to be pragmatic about it.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   15:35
 And are there any special there will be people out there that aren't doing SBRT as standard or outside of trials? Are you more rigorous with things like urinary flow testing or you know, certain parameters that you think I'm actually uncomfortable looking at 5 fractions here? I'd rather go 20 and as a follow on to that.
Alison Tree   15:56
 Yes.
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   16:00
 When we're anyone who's done the pace trial, you get the option of doing it every day of the week for five days or alternate days.
 And for no reason I selected that we go alternate days just because I said to the lady. Well, what's everyone else doing?
 And I just wanted to run with the run with the herd. So can I get your thoughts on both of those?
Alison Tree   16:17
 Sounds good. Stick with the crowd.
 Yeah.
 Yeah. So there are definitely men who I will recommend 20 fractions for still in this group. And those are the men with bad bladder function at baseline. So we're lucky enough that all patients have a flow rate and APV, RA post void residual taken as part of their assessment. But if you don't have that ability and not everyone does that an IPS escort is a pretty good surrogate for that. So my one of my PhD students is currently going through all the do symmetric data from pace B and the biggest predictor of Geo toxicity is baseline IPSS.
 So if you don't have anything else sort of for the patients with a severe I PSS or the ones tending towards that, so 20 and above would count as severe on the IPS scale. I would recommend 20 fractions or at least they need to know that they're at high higher risk than pace. So there they would be the extreme ones in pace that they've got the higher risk of bladder side effects. So those ones I think it's perfectly reasonable to recommend 20 fractions. And then the second part of your question was about.
 Timing. So from the pace data, I can't pick out any difference in toxicity between daily and every other day.
 So I can't give you a science based answer on which is better. So I think it's dealer's choice. So I do every other day. That's what we've always done.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   17:32
 So what do you do?
 Yes.
Alison Tree   17:37
 That's what I've always done, so I just stick with that and I don't, you know, if a man said I really want to get my treatment done in a week, I wouldn't have a problem with that. But most of them happy alternatively.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   17:46
 Can I ask another question about treatment delivery? So spaces, rectal spaces and SBRT So obviously in the paste nodes there is sort of the allowance for rectal spaces as long as it's not too close to a posterior lesion, etcetera. Do you use spaces with your SBRT?
Alison Tree   18:00
 Yeah.
 I don't know. I'm not convinced by the data yet, and obviously we've got the Sabre trial running in the UK that will give us some data, although they've taken the PTV to a higher dose than pace. So obviously that's a slightly different question then, but I I'm not convinced by the data, the rectal toxicity is so low that I I'm not convinced the cost benefits ratio to the patient, let alone the NHS is worth it.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   18:25
 And another thing that comes up a question we get asked because a lot of follow up is done now by PSA trackers and by nurse specialists or trained or specialist radiographers. You know we had our Phoenix definition of biochemical failure that we were quite comfortable with in the kind of conventional area you know you had PSA nadir +2 to allow for any bounce.
Alison Tree   18:49
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   18:49
 And then beyond that, you were a failure and then you come back into the system.
 Stress to add that you're not a failure as a patient, but that the actual PSA control from your treatment is defined as failing.
Alison Tree   18:57
 Yeah, the PSA has failed. Yeah, yeah, yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:04
 And then you come back into the system, but we've got different definitions now.
 You know, hormones, so we don't Phoenix doesn't really apply.
Alison Tree   19:10
 Yeah, yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:13
 And do you want to just remind us what they are?
Alison Tree   19:15
 Yeah. So, well, Phoenix does sort of like if you go back to the original Phoenix paper, it's written in a different era. But there was no kind of mention of how the nadir on ADT should be factored into that. So a lot of those patients were treated without ADT. So I've always struggled to know how it defines how it relates to our current population. But you're right that the pattern of PSA after S BRT, it drops very slowly over 18 months. So it will stay above Phoenix +2 if that's even exists for ages. So I take no notice basically for two years unless it's persistently rising.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:19
 Yeah.
 Yeah.
Alison Tree   19:45
 I don't say make any tell the patient it's going to bounce up and down over the next two years. Don't worry about it. It will come down again and I wouldn't take any action. Certainly wouldn't do any scans for the first two years unless it's rising and rising and rising successively. But after that I would still revert to Phoenix +2 in the absence of anything better. I think in the PSMA era, probably that's not the best definition, but the international community hasn't come up with anything else yet. So
 The in your practise, I don't know if your PSMA petting below two. I think that's not unreasonable, but the kind of line in the sand is still too. In fact that's exactly what I say to GPS if it goes above 2, refer them back because the nadir concept, the GP doesn't know what the nadir was anyway. So does that make sense? Yeah.

Thank you so much, Allison for that great overview of the early pace portfolio. Could you give us 3 takeaway points for our listeners for the results and outcomes of pace A and pace B?

 Alison Tree   38:18
 So I think the most important one is that all patients with early prostate cancer should see an oncologist as well as a urologist. Everyone deserves to hear about the radiotherapy options which we know are have improved a lot in the last decade. So patients should hear about that. The 2nd 1:00 we kind of mentioned didn't we that about the ADTI think that's one of the big wins of Pace B is that these patients most of them don't need ADT. So don't overuse ADT where you think you can get a good biochemical control without it.
 And thirdly, pace BSBRT should be offered to patients, particularly those with good bladder function, where they're eligible for pace B and hopefully in a couple of years pace C as well.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   20:32
 
 We've referred to Pace C and pace nodes. We haven't actually talked about them. Obviously pace nodes are still running as an active trial pace C is closed and hopefully we'll be reporting at some point soon.


MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   20:49
 Could you just give us a quick summary of both those trials?
Alison Tree   20:52
 Yeah. So pace C is essentially the group of prostate cancers, a little bit worse than pace B. So it was intermediate and favourable high risk, if that exists. So you're allowed to be T3A. You're allowed a little bit of Gleason, 4 + 4. Your PSA was allowed to be up to 30, and that. So it's the group of patients who we think need hormones and the randomization in pace C was exactly the same in terms of the SBRT arm. So same doses of S BRT.
 Versus 60 and 20 as the standard arm because by that point Chip had reported.
 No one should be giving more than 20 fractions to those group that for those patients who the standard arm was sixty grade and 20 fractions and we recruited 1208 patients to PACE C and we've presented but not yet published the acute toxicity which looks very similar to pace B. That's reassuring because these are higher risk patients. So they potentially have more SVS in the more similar musicals in the field, but we've shown no worse toxicity than we saw in pace B and that's all we know so far.
 You have to wait until 2728 for the five year biochemical outcome.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   21:54
 And I and I think for us that will make a bigger difference in terms of our use of five fraction radiotherapy because a lot of our patients fall into that category.
Alison Tree   21:57
 Yeah.
 Yeah, it's a much bigger group of patients. Yeah, for sure.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   22:06
 And maybe that will change. We might see that dynamic change with this Chris Hoy effect. So Chris Hoy effect with a lot more people presenting. We've certainly seen in RMDTS lot more patients at younger ages presenting with earlier stage prostate cancer even just in the last two months since Chris Hoy kind of came out.
Alison Tree   22:21
 Well, yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   22:24
 And you know, talked about his diagnosis very bravely.
Alison Tree   22:27
 Yes. Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   22:29
 This group of patients does get hormone therapy alongside that.
Alison Tree   22:31
 Yeah.
 That's right. So they're all in pace C we record we mandated 6 months of ADT. We opened the trial just before COVID hits, so a lot of the patients accidentally got more than six months because obviously we had to shut down a lot of research activities. We couldn't treat patients, but in general, it's the group that you would give six months of ADT to.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   22:55
 And I think another thing that we've seen quite a bit and I'd welcome your thought on it, there's this new, like radiological phenomenon of capsular contact you're leading. You know, if there's more than 14 millimetres caption or contact, it's kind of there's no obvious breach of the capsule. But we're getting this T3A or T2/3A subcategory. And where do you sit on that? Like, would that make you kind of think, well, this person's in my PSB group or my PSC group?
Alison Tree   23:05
 Yes.
 That's a really good question and I don't know if I've got any good scientific data to answer that. So the reason that the radiologists say that is that they know if you've got a long capsular contact, you're likely to be microscopic T3. If you take that prostate out, but you and I know that radiation doesn't stop working if the if the cancer's just into the capsule. So I think it becomes a question about the ATTI don't think the radiotherapy. I don't worry too much about the radiotherapy volumes with relation to that.
 I guess if it's high volume T2 then I might have that conversation about ADT anyway, even if it's T2.
 So if you have a big lesion on MRI, you may have more to gain than the average patient for ADT. I guess that's the that's the byte point of that discussion, isn't it?
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   24:06
 There's one other thing we can't talk about. Can't miss out when we're talking about a hypo fractionation, and that is the ultimate hypofractionation, which is brachytherapy, where you put the prostate on the end of a stick and you put some radiation directly into it by use of an isotope. And whenever I started 10 years ago, and we were comparing 7 1/2 weeks of radiotherapy.
Alison Tree   24:17
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   24:30
 The other side of that people went for high dose rate bracket therapy was one insertion of that followed by three weeks of radiotherapy and that was a big sell to patients because you could drop the attendances by nearly a month.
Alison Tree   24:40
 Yeah.
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   24:43
 Now we're entering an era where we're still doing the bracket therapy the same three weeks of standard radiotherapy after a HDR bracket therapy insertion. So roughly 4 weeks that takes.
 But we're giving the radiotherapy in five days now. This is impacting on Rip Bracha therapy numbers. I recently saw the numbers come out and it dipped during COVID as you might expect, but it hasn't really recovered and I wonder if the.
Alison Tree   25:01
 Yep.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   25:13
 Availability of low fraction number external beam radiotherapy is starting to impact on our bracket therapy service numbers.
Alison Tree   25:22
 Yeah, that's a good question. So I think that's inevitable, isn't it? When I talk to patients, we do a lot of patient involvement for our trials. It's remarkable to me how much the number of treatments matters to patients. So even in the early days of pace, I've been doing the really hard sell. I don't know if this treatment works, it might be more toxic, but we can do it in five days and everyone wants the treatment. So I'm sort of having up the risks and people are just like, no, I want to get my treatment done and get back to work. And I think the same is probably applying to brachytherapy. Now in that we can do.
 Almost the same fractionation you could even do HDR monotherapy in a few.
 As well, but still with SBRT, we're offering them a more convenient treatment without an anaesthetic, without any needles. And I think that's very attractive to patients. And so it may be that that trend continues sadly for our bracket colleagues.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   26:10
 But I suppose it's what's right for the patient in the end.
Alison Tree   26:12
 Yeah, not for sure.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   26:16
 Now.
 Well, you we've didn't actually talk about paste nodes, John, so we should probably interrupt. Yeah, you did. You did. So we should probably zoom through paste nodes and then you can carry on talking John.
Alison Tree   26:29
 I'll do it quickly, John. Then you can get back to whatever you're about to say. No, no, it's fine. It's fine.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   26:30
 Sorry, I do apologise my New Year's resolution is to continue to interrupt. Mike, that's great. The brachy therapy was an excellent question. I had to say it was an excellent question.
Alison Tree   26:36
 So I'll just briefly tell you about paste nodes because it's still recruiting, so we don't have any results to tell you. But Pace knows essentially is the next group up, then slightly nastier cancers where we think they might benefit from irradiation, pelvic node. So this is one of the other controversies, controversies in prostate cancer is do you need to treat the pelvic nodes if they look normal on scans and so pace nodes is trying to ask that question but with five fractions in both arms. So the randomization is between.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   26:41
 Yes, please.
Alison Tree   27:05
 Prostate SBRT just the same as we have done in the past trials versus the same with the addition of the pelvic node treated in five fractions. So that's the novel bit because in the UK we've never done 5 fraction pelvic nodal irradiation to date and the trials thanks to the fantastic UK team is recruiting like a bomb. So it will be done by this time next year that'll be over 1000 patients recruited, which is truly extraordinary and you know we should put ourselves on the back because nowhere else in the world can they achieve that.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   27:35
 And again, you know, we are one of those centres when you say to patients, do you want to go into a trial that involves 5 fractions?
Alison Tree   27:43
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   27:44
 As you say, their eyes light up. You know that they want their people want to go into these trials. It's not very often in radiotherapy that you have people coming to you asking about a radiotherapy trial, but the pace trials are that. So it really is you know it's in patients psyche as well as ours.
Alison Tree   27:47
 Yeah.
 Yeah.
 Yeah. No, I think that's really. And I think having a trial that's a winner for patients is just as a delight to be part of and the same with, we might go on to this in due course, but we've got a trial that's just run looking at two fraction SBRT and that equally even going from 5:00 to 2:00. The patients were like, yeah, I want that arm. I want the two fraction arm, which is extraordinary.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   28:22
 Well, you've stolen my next question.
Alison Tree   28:24
 Oh, sorry.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   28:25
 My next question was going to be your I think you might be a greedy person.
 Because you're not. You're never happy. And we're continuing to move. We've gone 37. We've gone 20, we've gone 5, but we now want to go further.
Alison Tree   28:33
 Yeah.
 Yeah.
 Yeah. So that the fairy tale ending to the story is single fraction treatment, but there's a slight problem with that in that the HDR team got there first and they've shown us that single fraction dose, at least at the doses tested, which were like between 19 and 24. Grey doesn't seem to work. I don't know why, but it doesn't seem to work. So we designed, we have designed a series of trials with two fraction S BRT. So going from 5:00 to 2:00.
 With the idea to test whether that's equivalent, whether it's safe.
 Whether it's actually improves anything for patients and so we've completed the Hermes trial, it's just a small single centre study randomising between 5:00 and 2:00 fractions using the Mr Linac 'cause. If you're only going to do the radiotherapy twice, you need to make the plan specific for that anatomy, not the anatomy from three weeks ago and that's recruited and we're just submitted the toxicity data for publication, which looks very encouraging.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   29:37
 Wow, fantastic.
 What a what a run through.
 And that is, you know, to be able to say to somebody you're going to have two fractions of radiotherapy, you'll be finished by Wednesday if you start on Monday, you'll be finished by Wednesday. Your prostate radiotherapy. And let's not forget breast and prostate radiotherapy make up the majority of all radiotherapy that is delivered in radiotherapy centres across the country.
Alison Tree   29:51
 Yeah.
 Yeah.
 Yeah.
 Yeah, yeah, yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   30:13
 Reduced 75% of the fraction numbers or the number 15? No, that's 2 thirds 66%.
 But we're seeing a 75% reduction here from 20 to five. That is a huge workforce free up.
Alison Tree   30:29
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   30:29
 So it's an amazing piece of work.
Alison Tree   30:31
 Yeah. And we know that there are lots of other cancers where it really matters how quickly you can start. So I think that's our job as prostate to get people in, out, cured and make space for the cervix and head and neck cancer and everything else that's more time dependent.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   30:35
 Mm hmm.
 So it's certainly it certainly has made a bit of a difference because usually this clock that people talk about stops when treatment starts and that was you could start that in your clinic because you could put somebody on hormone therapy and the clock stopped. But now with the pace side of things, it's the radiotherapy. So it does kind of it means we have to regain about 3 weeks from the pathway to try and meet that target. Have you have you noticed that or?
Alison Tree   30:50
 Yeah.
 Yeah.
 Yeah.
 So I think I don't want to say anything too politically inflammatory here. I think my job is to look after the patients.
 And in prostate cancer, if you've got intermediate risk disease, it doesn't matter if you wait three weeks, does it? So I think the main thing is to prioritise the patients that need to start sooner and not be tied up in tick box exercises. I hope I'm not about to get fired.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   31:32
 I think it would take more than that for you to get fired, Allison. Where? Where? Streeting is listening right now, is he? He might be the 2nd listener. He might be. Listen.
Alison Tree   31:34
 Yes.
 Yeah, if only.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   31:42
 All right. Could you? Oh, yeah. Well, so that was fantastic, Allison. Thank you. Really good run through of the evolution of prostate cancer radiotherapy to modern day. We're going to wrap up.
 Could you give us 3 takeaway points from today's session?
Alison Tree   32:01
 Yes. So I think my first one is don't give more than 20 fractions. We kind of covered that briefly at the start, but there's still some people getting eight weeks of radiotherapy in the UK and I'm not quite sure why. So I think that's one way to win your department. The 2nd is I think that for all men who are in the SBRT group, the kind of pace B group, they should definitely see an oncologist to discuss fire fraction S BRT and still a lot of those men getting surgery.
 And sometimes I think that's because they don't get a good oncology opinion. They don't get to speak to an oncologist.
 And then the third thing we didn't touch on so much, but I think what's obvious from the pace data is that you can deliver SBRT in any department, you don't need a fancy machine or any special kit at most of pace B, the treatment was delivered on normal LINAC with or without fiducials. So anyone can do it safely.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   32:50
 I would just like to, as a final point, to retract my statement about you being greedy. I meant greedy in terms of knowledge, not as a person, and I formally apologise.
Alison Tree   32:59
 Yeah, that's. No, I didn't. I didn't take it personally. It's fine. But I think it's good to be, not never satisfied, isn't it? That's what drives us forward to test new things. Yeah. Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   33:05
 Yes, absolutely.
 Massive congratulations to you to Nick Van As to David Dearnley and to the whole team involved in PACE because that, as you say, it just keeps growing and growing and growing. And we've heard that pace post up discussion. I think the post OP scenario is fascinating because I don't think we really have ever grasped it or have a proper hand on it. Chris Parker has done an amazing work with radicals, but.
Alison Tree   33:29
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   33:35
 Go to five different oncologists and you'll get 5 different answers.
Alison Tree   33:39
 Yep.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   33:39
 For a lot of things, so I think it's really the more data that goes into that, the better so, but if anyone can, I think you know the PACE team can certainly nail that down. So good luck to you.
Alison Tree   33:49
 It's the whole UK, though, the PACE team is all of us recruiting, so yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   33:51
 Yes, yes. Fantastic. Thank you so much. Thank you so much, Allison.
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 MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   39:54
 So we've talked about the two fraction trying to get even more hyper fractionated looking forward. We've obviously had the pivotal boost trial running kind of in parallel with pace nodes looking at dose escalation to dominant intraprostatic lesions. Is there scope to integrate that into an S BRT?
Alison Tree   40:11
 Yeah.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   40:16
 Treatment or indeed, is there sort of scope to de escalate treatments within the prostate gland as well.
Alison Tree   40:23
 Yeah, I think that's a great question. So a pivotal boost. We're obviously eagerly awaiting the results. It's completed now, but it will take a few years to get the biochemical results from that. And I think I have my minor concern with the SBRT idea of boosting is that we already achieved such high levels of biochemical control. Where do you have to go when you when you've got 96% biochemical control in that group? I don't really think we can justify a boost. There may be patients with high risk disease such as pace nodes that might need a boost. I think that will.
 Some of the data from Pivotal Boost will help us with that and also delineate cohort E where we where we escalated up to 45 grey with S BRT. But I think your de escalation point is well made. The only reason we treat the whole prostate to the whole doses because in the start.
 Was act and you couldn't see the cancer and we've never really revisited that dogma. And I think now that we can see the cancer on MRI, it begs the obvious question, why do we give the macroscopic and the microscopic disease the same dose? Now we know from our urological colleagues that actually focal therapy, just whether that be high food, cryo, nano, whatever, doesn't work as well as radiotherapy to the whole glands. So I think that's suggesting to us that the whole gland needs some dose. But I think we could safely de escalate that dose to the non tumour bearing.
 Region as defined on MRI.
 And that's what we've been testing in a trial called Destination One, which is a collaboration between US Nki and Sunny Brook in Canada, where we've DE escalated the dose to the rest of the prostate to 30 grain, 5 fractions and then focused what was actually a boost dose in that trial to 45 grain. And so that's with the idea that we could reduce toxicity and maintain control by dropping the dose around the organs at risk where there's no significant cancer and we're taking that idea into the next trial called Destination 2, which is the same approach but in two fractions.
 So whole gland, 27 grey and two fractions versus 20 and two with a boost to the tumour of 27 and two. So that will give us some more data about how well we can de escalate and whether indeed that does reduce toxicity because that's the whole point of that.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   42:20
 And that will be really attractive if because if you've got like a more anterior lesion, you can actually end up with a marked reduction in rectal toxicity, if you're, if you're de escalating, but still managing to deliver it in five fractions.
Alison Tree   42:27
 Yeah.
 Yeah, massively. And I think what the missing piece of the jigsaw is the dose to the urethra that we need to keep below to prevent toxicity because at the moment we're struggling to find that number from pace. But this this kind of trial may give us that because we'll get more heterogeneity to urethral doses. And so you can start to pull out the data that's important for protecting patients in the future.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   42:53
 Another part of the PACE portfolio that's coming, it's like a spoiler alert maybe is the post operative setting?
Alison Tree   43:03
 Yeah, that's right. So this is just an idea at the moment. So we're just knocking this around, kicking it around between a few of us, but still a lot of men choose to have a prostatectomy and we know that sadly a lot of those cancers come back mostly in the region of the prostate. So we end up irradiating the prostate bed and at the moment we do that in 20 fractions. But it begs the question after pace, can we do that safely in five fractions? And I think that's an open question because of course the problem with five fractions sometimes is Geo toxicity and patients have already got a.
 That's been stitched back together. That might be worse. So I think the first question is, can we do it safely? And then can we roll it out into a national trial comparing against longer fractionation?
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   43:45
 So lots of stuff happening, even though we've done so much already, there's whole New Horizons of improvements to potentially achieve, so that's fantastic. Thank you, Allison. So when we're looking ahead, we're going to finish up this session now and we're looking specifically at where you see radiotherapy in prostate cancer going. Could you give us 3 takeaway points for that?
Alison Tree   44:10
 Yeah. So I think although dropping from 5 to 2 is not as big a gain as we've made already in the last decade, I think it's still worth asking whether two fractions could become the new standard in the years to come. So I think that's one thing I think secondly, putting the dose where it matters where the actual cancer is and de escalating to the rest of the prostate. I think that's an idea that deserves proper examination in a big trial. And then thirdly, what we haven't discussed yet, but I'm leaving it as a teaser trailer, is that I think the whole idea of simulation of creating a plan based on anatomy from three weeks ago.
 Probably needs to go in the era of adaptive radiotherapy, so that's the next thing to start testing.
MCGRANE, John (ROYAL CORNWALL HOSPITALS NHS TRUST)   44:46
 Wow, I love it. Thank you so much, Allison. That has been amazing.


Alison Tree   44:56
 It's a pleasure. Thanks for having me on.  |
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