Robert Reiter: Thank you. It's an honor to be here and I want to thank Silke and Aurelius for the invitation to participate in what so far has been a really great meeting. So my job, my task is to really start this session about oligometastatic disease by providing hopefully some context, some definitions, and concepts.

So what is oligometastatic prostate cancer? So it's actually an intermediate, or at least it's hypothesized to be an intermediate transitional disease state, which is characterized by limited metastatic potential. It was initially proposed in 1995 by Hellman and Weichselbaum. It basically tries to put together two theories of how cancers progress. That is Halsted's Step-wise Theory of Progression and Fisher's Systemic Pattern of Metastasis and tries to bring the two together to argue that cancer metastasis really is a spectrum or cancer is a spectrum that essentially ranges from indolent to widespread metastasis.

The big question is why does this matter? Why does the concept matter? It matters because it has potential clinical or therapeutic implications. The existence of an intermediate or limited metastatic state implies that there's a window of opportunity in which local treatment, that is local treatment both to the primary but also local treatment to all oligometastatic sites can impact outcome meaningfully. This has actually been well established in colon cancer where liver resection can significantly improve survival in men with metastatic colon cancer, but in all honesty, it's not been as well defined or validated in most other cancers.

So now in the case of prostate cancer, what's the evidence that there is such a thing as an oligometastatic disease state? This largely comes from previously performed clinical trials and also observational studies. The one on the upper left is from UCLA, from Isla Garroway, one of my colleagues, who looked at a large group of patients from the Veterans Hospital and essentially categorize them. These were patients who had their prostate in place, and categorize their survival based on the presence of less than five metastases or a greater than five metastases at the time of diagnosis, and showed that those with fewer metastases one to five had a significantly longer survival than those with greater than five. The same thing has been shown in a number of other studies. On the right, there's a study from Piet Ost who's going to be speaking later showing that a single metastasis to bone is associated with a very good prognosis, whereas anything greater than one metastasis is associated with poor survival. So these do suggest that there's an intermediate state characterized by less than five metastasis that could define an oligometastatic state.

What are the potential pathways of metastasis? So I think there are three potential things that could happen. One is oligometastasis could represent a fairly long period of time of a tumor that gets to a metastatic site but has very limited metastatic potential. It's very limited in its potential to metastasize secondarily and form polymetastases. So suggesting that there's really a window of opportunity to treat those oligometastatic sites. The other possibility is that oligometastatic disease in many cases may be a dead end. These may be tumors that are shed into the circulation or into the lymphatic system, go to an end site, form a tumor, but really don't have the capacity, the hallmarks of cancer to be able to metastasize further. Then the final situation, which may be true in many cases, that oligometastasis is really just a, it's a function of when we're actually looking at a tumor. We're simply catching it earlier, but it's destined to metastasize further if we wait simply a little bit of time. So this is one of the reasons there is so much controversy about the concept because we're not really able right now to distinguish between these three different possibilities.

Again, there are a number of biologic models. Ken Pienta came up with an interesting hypothesis about kind of a social science model of metastasis, arguing that oligometastatic disease is a disease where the cancer gets sloughed off. It goes to an inhospitable target organ. The old seed in soil hypothesis where it cannot form tumors efficiently. It cannot metastasize efficiently versus systemic disease where the primary tumors in an inhospitable environment, tumor cells, therefore, shed actively, migrate widely and go to hospitable target sites where they can then grow. It's important to know that at least as of now there's really no genomic classification data, no genomic data to define or classify the oligometastatic state. Gap Six sponsored by Movember is attempting to address this shortfall really in our knowledge of prostate cancer.

So the definitions of oligometastasis, there are really quite many and there's really no consensus, so it requires a number of different parts. So number one is what's the site of disease? Some define it as bone-only disease. Some define it as any site. Others define it as bone and another site. There's really no consistent agreement about what sites of disease constitute oligometastatic disease or not. Number of lesions, generally there's agreement that less than five is oligometastatic disease. The temporal pattern, as we'll hear in the next talk, there is synchronous or de novo. That's when the primary is in place and there are a number of metastases found. Metachronous or recurrent is when the primary has already been treated and there is recurrent disease such as we heard in the last talks and the nodal disease talks earlier. Then there's progressive, which is patients who are actually treated and after treatment with systemic therapy have residual disease kind of like in testicular cancer after primary chemotherapy.

So that's progressive oligometastasis. Then of course castration state. Most studies are focused on hormone-sensitive or naïve prostate cancer, but certainly you can have oligometastatic disease also in the context of castration-resistant disease and it needs to be defined. If you look at trials have been published, they're really all over the map in terms of what definitions have been used and clearly we need to come to some consensus about what definitions and what type of imaging, which I'll get to in a minute, constitute oligometastatic disease, but generally less than five metastases. The site, as I said, can vary depending on the study to include bone or lymph node or both.

Obviously we've got concepts of low metastatic disease and it's really not clear yet whether oligometastatic disease and other low volume as defined by the CHAARTED study or a low risk defined by LATITUDE are equivalent or similar to oligometastasis and this needs to be defined, but certainly trials of CHAARTED, LATITUDE and other studies in this setting and STAMPEDE do suggest that treatment of the primary tumor can impact disease outcome in patients who have low volume or a low-risk disease which could be extrapolated potentially to the oligometastatic setting.

So imaging, we've already heard so much about it but you really can't talk about oligometastatic disease without talking briefly about imaging. As you know, most published studies of oligometastatic disease and trials have been based largely on conventional imaging, MRI, CT, bone scan and first-generation molecular imaging such as sodium fluoride, choline or acetate. The definition and diagnosis of oligometastasis clearly depends on the staging modality and one can expect and when we have seen significant reclassification or upstaging that occurs with modern molecular imaging, PSMA, and axumin, wherein non-metastatic or in zero disease is actually reclassified or recategorized as oligometastatic on newer scans and oligometastatic disease is reclassified as polymetastatic disease. So the problem that we have is extrapolating clinical data based on traditional imaging to that obtained with PSMA imaging may not yet be warranted and we need to essentially think about this prospectively in clinical trials of oligometastatic disease going forward. It's also important to know that even with the best molecular imaging tools such as PSMA PET, we still understage a significant percentage of metastatic disease because PSMA cannot detect very efficiently disease-less nodes or tumors less than five millimeters in size.

There was a very good prospective study published by Yaxley in the Journal of Urology where men with high-risk prostate cancer underwent gallium PSMA scan. All patients underwent surgery with extended pelvic lymph node dissection and the overall sensitivity on a per-patient basis for detection of nodal disease was only about 30 to 40% and on a per-node basis, 24%. Just a few more slides. You've seen this data already about how when you use PSMA PET you upstage patients significantly. The choice of tracer makes a difference. Felix showed this slide showing that a FACBC does not perform as well as PSMA, but obviously the choice of imaging agent tracer is critical to determining the presence of oligometastatic disease.

Here's just a couple of cases. On the upper left is a patient who with traditional imaging has a single site in the rib and a single site in the sacrum. That's certainly oligometastatic disease and that's actually confirmed by PSMA scan on the right. On the other, on the right side is another patient who appears to have oligometastatic disease with traditional imaging by bone scan, but clearly has widespread oligometastatic disease by PSMA PET. So PSMA PET can help to reclassify patients sometimes correctly to really help identify the patient who truly has oligometastatic disease versus the patient who actually has polymetastatic disease.

The final two slides are the clinical trials in this space we're going to hear about. The two central questions are, "do you treat the primary and all metastatic sites and patients who have synchronous disease?" and "do you do metastasis-directed therapy in patients who have metachronous disease?".

The big question is of course, what are the validated endpoints? In STOMP the endpoint was a delay of ADT, but whether this is a valid endpoint is not yet known and we need to really define what valid endpoints are in this subset of patients. So concluding, this is a consensus conference, but clearly there's no consensus yet about the existence of oligometastatic disease as a discreet entity or its definition, no consensus yet on the role of imaging to define or manage. I think we need to include trials. We need to include PSMA imaging and the latest imaging in prospective trials, and we need to define what the appropriate clinical trial endpoints are. Thanks very much.