A/Prof Shankar Siva

Joseph Ischia: Next we’re going to give you the highlights of the point counterpoint discussion we had regarding the role of systemic therapy in oligometastatic. I was actually arguing the case of early systemic therapy and I’m joined by Shankar Siva who is a radiation oncologist at Peter Mac in Melbourne and he was given the task of arguing the case for metastasis-directed therapy.

So, I was given the task of going first and I looked at this from the perspective of I know we can delay ADT if we give metastasis-directed therapy and I know that either by surgery or radiation we get very good local control certainly at the doses that are appropriate in radiation, which you can go to a pretty high dose, but we’re looking over 99% local control and certainly with surgery we see very few infield recurrences. But the argument that I made was we can do that and you do delay ADT, but inevitably most of these people will have an out-of-field recurrence. My discussion focused around, “Are we doing these patients a disservice by not treating them early while their disease volume is low?” It’s because we know that disease volume is important. It is a surrogate marker for how it’s going to respond to androgen deprivation whether that be when we look at charted, they do the low volume versus high volume, it’s an important distinction where they do a lot better where upfront chemo is only useful in the high-volume disease. Low-volume doesn’t seem to receive as much benefit because of the advantages of the androgen sensitivity of the cancer. It’s already optimally treated.

Looking at the early ADT treatments we’ve got several meta-analyses looking at relatively old data that it’s arguable whether there’s a benefit in overall survival, but certainly benefits in complications and disease progression and we’ve even got the Messing trial. While it was underpowered, you don’t need a large trial to show a large effect. Men lived longer, in fact 84% chance of being alive, greater chance of being alive at any time point if they’d had early ADT rather than delaying.

So, this has really formed the basis my argument, is that we can do metastasis-directed therapy but are we missing an opportunity to cure micrometastatic disease some might say but at least knock it on the head. I think one of the key things to realize is that there is no evidence in this oligometastatic disease comparing metastasis-directed therapy to early ADT, and in light of that, we’re desperately in need of a trial in this space because we spend a lot of our MDMs discussing this exact topic.

So, Shankar you took the counterpoint argument, what were the highlights of your talk?

A/Prof Shankar Siva: I mean, thanks for debating with me. I found it was a really quite stimulating debate. From my perspective, I suppose I was doing the case for metastasis-directed therapy and in a lot of ways, our arguments are synergistic in a sense because we do recognize a lot of patients will actually recur. The majority of patients will recur and majority of them will recur within two years. But from my perspective, going through with androgen deprivation and early systemic therapy is a medical rollercoaster. Once you start on this, the patient is pretty much committed to this for the remainder of their lifespan and switching between different agents. But I think the role of metastasis directed therapy is the potential to add an extra line of therapy and potentially have a localized therapy that can be used in conjunction with the systemic therapy at a later time point. And so far, you’re right, it’s about patient selection and is low-volume oligometastatic disease is the key. The evidence that we have in my interpretation of the data so far is that they’re used of systemic therapies is most beneficial for a high-volume disease and in the biochemical recurrence setting we still have level 1 evidence to support the use of early initiation of immediate androgen deprivation. So, we’re talking about a patient population that may potentially benefit locally-directed therapies whether that be surgical from a lymph node dissection stereotactic radiotherapy or a whole pelvis radiotherapy, whichever approach. The question is about balancing the toxicities of each approach and selecting the appropriate treatment approach for those patients. You’re right though, these kinds of opinions are largely not evidence-based. We have run a couple of clinical trials so far particularly in Melbourne and these are due to report relatively soon and one of the studies I was involved with which is POPSTAR will hopefully have some results in only a handful of months’ time. So, in the absence of this kind of high-level evidence, we really should get involved in clinical trials. I think there is a new study being led from Piet Ost over in Belgium from Ghent University which is PEACE V, a study that’s been run through Movember and hopefully it’s an opportunity as clinicians in Australia and New Zealand to join in such a study.

Joseph: Fantastic. I do hope that we join that study. I think the number of cases every week that we just uh and ah over what to do with these oligometastases and PSMA has just not helped because it’s detecting all these cancers and we just don’t know what to do with them, though it’ll be very interesting to see. Thanks a lot Shankar, I really appreciate you joining us.

Shankar: Thanks.