ASCO 2016: Accuracy of multi-parametric MRI to predict further investigational biopsy

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Published: 6 Jun 2016
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Prof Nick James and Prof Charles Ryan

Prof Nick James (Warwick medical School Cancer Research, University of Warwick, UK) and Prof Charles Ryan (UCSF School of Medicine, San Francisco, USA) look at some of the ASCO highlights around the accuracy of multi-parametric MRI to predict which patients require further investigational biopsy.

They also discussed the Phase II IMAAGEN trial - Effect of abiraterone acetate and low-dose prednisone on prostate-specific antigen and radiographic disease progression in patients with non-metastatic castration-resistant prostate cancer.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

 

ASCO 2016

ASCO 2016: Accuracy of multi-parametric MRI to predict further investigational biopsy

Prof Charles Ryan – UCSF School of Medicine, San Francisco, USA
Prof Nick James – Warwick Medical School Cancer Research, University of Warwick, UK

 

NJ: Hi, I’m Nick James. I’m joined here again by Charles Ryan from UCSF in San Francisco talking about presentations at the prostate oral session at the Chicago ASCO meeting. Charles, we were going to have a discussion about…


CR: Well, I wanted to get your thoughts on both the hypofractionation data as a clinical oncologist, I thought that was very interesting and I wonder about the practical implications of that. Then the MRI data on replacing biopsy.


NJ: Yes, so to deal with the hypofractionation thing, this is something where we’ve recently paused a very large UK trial with a very similar design. We had two hypofractionation arms and one standard fractionation arm and that study showed that the higher of the two hypofractionation arms, which actually was exactly the same dose as the dose presented today by Charles Catton, was basically non-inferior to the standard fractionation and there were no significant differences in toxicity in the UK trial and that was very much replicated in the Canadian and North America trial presented by Charles Catton today. So, certainly within the UK, the feeling was that we were completely convinced by this data, quite literally. When we presented the UK data at ECC last autumn our group got off the plane at home, went to the radiotherapy prescription rules and changed the prescriptions for the patients who hadn’t started, we were that convinced. We’d recruited a hundred or so patients to the trial so we had extensive experience with it already, all our planning algorithms were set up, it’s actually very easy to change the dose on a plan because you don’t change the plan. It’s very popular with the patients.


CR: And when you’re talking about quality of life, one of the things that the patients want to avoid doing is making several trips into the hospital. This is reducing this by fourfold or something like that.


NJ: It is. In our trial it was 37 down to 20 fractions so it almost halves it. They didn’t have quite the same toxicity data presentation as we did but what we found was that essentially you get slightly more toxicity but it’s over quicker. So the area under the toxicity curve, this is acutely, was differently distributed, as you’d expect, if you’ve got your treatment concentrated into four weeks instead of just under eight. But if you look at all the late toxicity measures there were no differences at all. That was exactly the same, confirmed today. So we’re convinced, and obviously from the resources point of view prostate cancer radiotherapy is one of the biggest single things in our department so it had a huge impact on our availability to do more interesting stuff.


CR: Right, you can treat more patients.


NJ: Yes, it frees up more time for all sorts of things like doing fancier IMRT, IGRT type things, nodal treatments, all sorts of things. So it’s had a very beneficial impact. The saving to the National Health Service per year is millions, it’s a really positive impact.


CR: Is the MRI data going to save the National Health Service millions by not doing biopsies?


NJ: The MRI data is very interesting. Although we weren’t participating in the study the economics of the NHS are very different from the economics in North America. So MR scans are relatively cheap in the UK and they are cheaper than a trus-guided biopsy. So although there are issues if you start MRIing all your prostates in that you clog up your MR machines, the economics are reasonably clear. And there are all sorts of other advantages, so if you do an MR then you can decide not to biopsy people and what Hashim Ahmed’s study showed, I think very convincingly, was that it’s perfectly safe and reasonable to not biopsy people who have got a borderline raised PSA and a benign looking prostate on MR.


CR: Yes, I think there are huge implications for that.


NJ: I think the data were very clear, they did a very elegant study where they’d done the biopsies both ways, they blinded everybody to everything and then interpreted all the data at the end. But the other consequence of it which he didn’t discuss today but which is very important is that we do, as everybody does now, a lot of active monitoring for low risk disease. So a) you’ve got more confidence that your low risk disease really is low risk, and b) if you’ve done your MR before your biopsy you’ve got an MR that is completely clean. Because we know that the biopsy artefacts, in fact that group, the UCL group, has shown it takes between three and six months for the biopsy artefact to go away. So you’ve got a lot of problems interpreting whether something does or does not use it as a capsule if you’ve stuck twelve needles through it before you do your scan. Whereas, if you’ve done nothing to it and you then want to go down the active monitoring, six months, twelve months later you’re comparing a clean scan with a clean scan with no artefact on it. So it greatly facilitates active monitoring for low risk patients. And also you don’t lumber them with a diagnosis of a cancer that isn’t really a cancer. So I think there are lots of pluses. To a degree, practice is already quite rapidly transiting that way in the UK really restricted only by access to MR, the economics don’t restrict it in the NHS, MR time does to a degree.


CR: Did you want to comment on the quality of life data from the CHAARTED data that was presented? I’d like to hear your comments on that.


NJ: I did, yes. So that data is very interesting. The data they presented very much mirrors the toxicity data we have from STAMPEDE which is that there is, of course, a hit from having chemotherapy to your quality of life and nobody is surprised by that. But the thing that was pleasing from that data was that the quality of life appears to recover either to the same or possibly even to a better level once the chemotoxicity has cleared out of the system. That may well be because you’re preventing or delaying relapses. One of the things we saw in STAMPEDE, for example, was that the rate of symptomatic skeletal events was reduced by 40% and the lady presenting the data didn’t disentangle what was disease related from what was treatment related in the downstream things. But I’m assuming that some of the impact on the quality of life beyond twelve months must have been things like symptomatic skeletal events which have got to mess your quality of life up.


CR: Yes, there’s no way to improve quality of life better than to have the disease under control and not to be worrying about it. When I treat patients with chemotherapy in that setting I refer to it as an investment in their time and I talk to them about a potential hit in quality of life and with the hope and the assumption that it will be better later. So this data really validates the way I’ve been speaking to patients about it.


NJ: It does. In many ways it’s quite an easy sell to patients, isn’t it, because if you’re looking in the palliative setting, this is slightly caricaturing, you’re looking at ten lots of treatment for a relatively modest survival gain in your last year or two of life. Whereas in this you’ve got fifteen weeks and if you have six cycles from dose 1 to dose 6 for a much bigger gain in survival later when you’re much less keen on having chemo. I find it a very easy discussion, I have to say.


CR: The CHAARTED data, one of the big debates of course is the low volume story and whether you think this quality of life would be measured… the quality of life is different by high versus low volume and if we want to keep talking I’d be delighted to hear your thoughts on node-only disease and STAMPEDE and things like that.


NJ: So within STAMPEDE the headline statistic for STAMPEDE was for the whole population which included high risk, non-metastatic, node positive and metastatic and the whole trial is positive. The trial is very underpowered for the M0 so we only had 35 deaths on the docetaxel arm in the M0 so we really can’t say too much about it. But the failure free survival effect is exactly the same in the M0, it’s a hazard ratio of 0.6. So you could argue, particularly because the duration of the hormone therapy is limited for those as well to 2-3 years, that actually delaying your relapse by 40% may be a sufficient justification on its own, it certainly is in breast cancer. So the recommendations we’ve made to our investigators are that they can give docetaxel if they wish to the patients who are going to…


CR: To the high risk M0.


NJ: Yes, so basically STAMPEDE is still recruiting. We’ve moved on to different questions, we’re just opening a randomisation to metformin as a disease modifying agent. We have a randomisation to radiotherapy for the metastatic patients to the prostate just closing out recruitment and we’ve just closed recruitment to a combination of abiraterone and enzalutamide. Now, we amended the protocol so that investigators and clinicians and patients can decide whether or not they want to give docetaxel to patients. So we’re obviously collecting that data. What we’re finding is that 75% of the metastatic patients going into STAMPEDE in the last month or so are receiving docetaxel as part of their standard care. Of the non-metastatic ones, 30% of those are also receiving docetaxel.


CR: And what about node only?


NJ: That will include the node only and I haven’t got the breakdown between node negative and node positive non-metastatic. So we’re counting pelvic nodes as non-metastatic in this context. I’m suspecting that most of those will be the node positive M0 patients.


CR: So you’re saying that the node positive M0 patients in STAMPEDE, there’s a failure free survival advantage and the overall survival data is not mature enough to conclude anything at this point.


NJ: Exactly. So they’re only 15% of the total in the trial so they will never be powered up on their own. So within the trial patients with, say, bulky pelvic nodes, no metastases, they’re likely to die of prostate cancer. In fact, we know they are dying of prostate cancer, most of the deaths in the trial are from prostate cancer because we’ve excluded patients with significant cardiovascular disease, for example. So we’re not seeing a lot of deaths from other causes.


CR: This has been a debate at our centre on where to draw the line in terms of the volume of disease that would or would not benefit from chemotherapy.


NJ: I think it may well be the case. If you’ve got a whole load of bulky pelvic nodes… we give them radiotherapy as well because with IMRT you can easily give them a tidy dose of radiotherapy and we’ve separately published, because we didn’t randomise node positive patients to radiotherapy or not, we just let clinicians decide, it turned out that it was almost a 50-50 split and it was a split by institution, it didn’t appear to be a clinically driven split. So every patient in our centre gets radiotherapy to their nodes; in the centre down the road in Coventry nobody does because the institution decided there wasn’t any evidence. So we’ve done a multivariable analysis and essentially whether or not you’ve got radiotherapy is a significant factor once you’ve corrected for the case mix differences. So we think there’s strong evidence you should give them radiotherapy but they still die of prostate cancer in large numbers, just a bit later than the metastatics. They may have bulkier disease than the low volume metastatics, to be honest. So I think it’s entirely plausible and reasonable to give them the treatment.


CR: I do too, actually.


NJ: So the M0 patients, it’s an interesting question, so within STAMPEDE we’ll be reporting our abiraterone data in castrate sensitive patients getting abiraterone up front. So these will be M0 and M1s and obviously you had a poster on a variant of that topic.


CR: Well M0 CRPC is an area that is uncharted territory, pardon the pun. It’s uncharted territory from the standpoint of there are no standard options, there’s no regulatory approvals in this space. There are a number of trials underway which have as the goal to see if metastasis can be prevented or delayed and whether or not early integration of AR targeted drugs is going to lead to an improvement in survival. So our study that we presented was actually a phase II study, so not randomised, it was with abiraterone and asked two important questions. One is if abiraterone can be given with 5mg of prednisone as opposed to 10mg, a pretty straightforward question, the answer to that is yes, absolutely. In this setting at least there were very few hypokalaemia events, very few oedema events, no different than what we saw in the 302 study. So I would conclude that in this setting it’s perfectly safe to do 5mg of prednisone. The second question is the efficacy question and the short answer is it’s highly efficacious - 90% of patients had a 50% decline in PSA, the median time to PSA progression was about 28 or 29 months and the median time to metastasis had not yet been reached. This was a study of 140-some patients. So this definitely suggests, confirms, what you would have assumed is that abiraterone has activity in CRPC even when there aren’t visible metastases. It just doesn’t answer the question of whether we’re justified in doing it in terms of cost and toxicity. So that will remain unanswered but there are certainly patients out there with M0 CRPC, picking up on your previous point, who are destined to die of prostate cancer. We know that even within the spectrum of the 302 study of the metastatic patients, it looks like those patients with a lower volume of disease may have leveraged a greater benefit over placebo in that study. So it’s just reasonable to consider that we might want to consider in certain cases treating M0 CRPC with abiraterone or other drugs, I just don’t think that we should say that that’s the case in all patients. I should point out finally that the PSA doubling time in that group of patients, the median was 3.4 months. If you look at curves, those patients are destined to have metastasis relatively quickly. So the fact that we don’t have a median time to metastasis after three years of follow up is pretty significant.


NJ: Absolutely, it’s entirely plausible. One of the things that’s happened, quite a strong trend in the UK now, is that we’re tending to not put our rising PSA patients on hormone therapy any time early, we’re doing much more imaging and much less treatment of rising PSA. The other thing that we’ve got is increasingly good access to things like choline PET, we’re just setting up PSMA PET in our centre. You find oligometastatic patients very easily with PET that you don’t pick up on CT and then we’re treating them radically. I can’t imagine the same trend isn’t emerging in America.


CR: It is emerging, it is. It’s PSMA PET, choline PET and the growth of SBRT is something that’s also coming along which is increasing enthusiasm for radical treatment of oligometastatic disease. I just gave a talk on this the other day and I said it’s a different disease state, there’s the rising PSA, there’s metastatic and there’s oligometastatic. We don’t know, perhaps even in the oligometastatic setting, cure is possible. I have patients who have radiated their metastases and we’ve had the primary radiated and they come off of therapy and are followed.


NJ: Absolutely, I have the same.


CR: So we have to figure out a way to prove this or put this up to a test that tells us it should be considered as standard approach.


NJ: Yes, there are trials going on of SBRT in these sorts of settings so I think it will be very interesting. Right, I think our time is up and it’s been a real pleasure.


CR: OK, very good. A pleasure.