Charles Ryan: Hello from APCCC 2019. I'm delighted to be joined by Professor Noel Clarke, who is a Consultant Neurologist at Salford Royal Hospital and the Christie Manchester and current Director of the Manchester University GU Cancer Research Group in the UK. Noel gave a great talk really trying to integrate a lot of what is on our minds now about high versus low volume hormone-sensitive disease, when should we treat the primary, when is it not useful to treat the primary? Tell us about your talk and your perspective on this issue.

Noel Clarke: Yes, thanks Chuck. We've been lucky enough within the UK and the STAMPEDE trial to be able to put together large volumes of data in relation to treatments, outcomes, and we've been correlating and collecting all of the imaging. What we've done is sub analyzed that and we've used the various volume and risk criteria which are used worldwide for the treatments related to docetaxel, abiraterone, and so on to see whether there's any truth in the notion that there is a low volume and high volume effect in these settings.

And that's been really instructive for us. So the essence of my talk was really two fold, one is the threshold effect for treatment of the primary and the second is whether docetaxel or abiraterone have a high low volume effect. Dealing with the first part, what we found was that in a large scale trial there was a subgroup who got benefit when they had the primary treated. If we took, we had something like 2200 patients in STAMPEDE, what we call the M1RT part of STAMPEDE. In other words, does the treatment to the primary radiotherapy improves survival? Overall it doesn't, we found though that if we applied CHAARTED criteria using bone scan, standard bone scan to the patient group, those patients who had four or fewer metastasis on bone scan simply by account actually got the benefit and above that and it's very clear there's a very clear cutoff of five and more, they don't get benefits so there is a threshold effect which gives us an insight into the biology we all know that bone scanning is an imperfect tool but it is predictive and one of the few predictive markers we have.

Charles Ryan: It's logically consistent and in ways it reminds me of the story of kidney cancer where if most of the diseases in the kidney we think, well taking the kidneys out are good idea even in the face of metastatic disease, and what I wonder is if you have four bone metastasis and are intact and a primary in place, that primary is a substantial proportion of the disease burden. Whereas if you have 15 bone metastasis with a small primary, it's a relatively small proportion of the disease burden and I think that it's interesting to see that playing out.

Noel Clarke: Yeah, exactly. And we only showed a little bit of our analysis, we have a whole lot more data which we will subsequently publish and what that shows is that the location and combinations of metastatic disease give us an illustration of biology. So lymph node only behaves differently, lymph node and bone behaves differently, bone only behaves differently. And there are certain thresholds beyond which specific treatments will not work and what we think is that the primary is driving elements of the disease in the early stages that so-called oligometastasis space defined as fewer than four on bone mets and that the poly-metastatic disease starts to drive the process there are.

Charles Ryan: Right because in the poly-metastatic disease, you have more metastasis to metastasis spread, right?

Noel Clarke: Yeah.

Charles Ryan: Are there plans or I don't know of any data currently which would look at sequencing the primaries in patients with versus without sorry... With poly-metastatic disease versus oligometastatic disease for example, versus non-metastatic disease and one wonders there are likely to be some biologic differences in those entities in terms of metastasis promotion or cell cycle regulation. These types of things.

Noel Clarke: I think that's absolutely correct and we've got two translational subgroups within STAMPEDE. One is what I sort of oversee, which is the big group, we're the biomedical imaging group and Gert Attard who is a medical oncologist in London oversees a whole group of translational scientists, myself included, in the biomedical research group.

The biomedical research group is collecting the tissue and the fluids and that will, I hope address some of the questions such as sequencing, biochemistry and so on and we'll cross-correlate that with the imaging and outcome, so we're looking forward to that.

Charles Ryan: Yeah no, I think it's great work and congratulations on that and your presentation. I think we are all looking forward to a day when we will maybe do more than just count lesions although what you're also suggesting is that counting lesions actually tells us a lot. it's just that we need to figure out what that biology is, so.

Noel Clarke: Yeah exactly. And I think we've got the whole volume calculations to work out for lymph flows and [inaudible 00:05:13].

Charles Ryan: Yeah. Well thank you again for joining us always a pleasure to talk with you and we'll let you get back to your sessions.

Noel Clarke: Thanks, Chuck.