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Mack Roach: Hi, Mack Roach from UCSF. I'm very proud of my radiation oncology colleagues for clarifying the role of radiation. Both of those talks were great, and your talk was great too. Although one clarification: RTOG 94-13 is not a negative trial, and we can talk about that offline.

Neha Vapiwala: Thank you.

Alberto Briganti: Can you please congratulate me also, Mack, please, because I defended surgery.

Mack Roach: Thank you too, Alberto. You're amazing.

Alberto Briganti: Sorry, I feel alone.

Neha Vapiwala: Compliments for all.

Daniel Spratt: We love you.

Francesco Sanguedolce: So I'm Francesco Sanguedolce from Barcelona. Actually, I'm a urologist, and I too congratulate my colleagues there on the panel defending our practice. And so I had two comments, actually, to bring to attention. One is about the data that were shown by Karim in the last Congress. I found it difficult to understand exactly the reason why there was such a result on this outcome in terms of metastasis-free survival based on the fact that the trial wasn't designed for that. So the main outcome was the [inaudible 00:01:19] lapse. And so the issue is it's the first time that we hear that the location of the lymph nodes may have some impact on survival. So my question is whether there might be other factors, for example, intensification treatment that have been added, and maybe we need to wait for the results for this question from the paper.

The second thing is about the actual issue regarding surgery in this setting of patients. I think it should be highlighted—the point that Professor Briganti showed is we are living probably a shift in staging, so we should be careful not in denying patients who might actually benefit not a treatment but a monotherapy with surgery, and be very careful in actually comparing the side effects of these two treatment approaches.

I think in most cases radiotherapy is underestimating the actual impact, especially in the long term. And the only trial that we got, and not the actual Uro data, Peter, is from the ProtecT trial. And the ProtecT trial is showing that after Hamdy last year showed that there's no difference. And actually we know from other evidence in a study in Australia that one of the main reasons of unexpected hospitalization of patients in urology departments is actually radiation therapy, radiation cystitis. So I will be more careful in comparing the side effects of these two treatments. Thank you.

Daniel Spratt: Just to make a quick comment: about 80% of all randomized trials have been done with radiation as the primary therapy, and NRG has proudly—as the data I showed you from the correlative studies—many trials out to 20 years of follow-up. I've tried to find that, and I'd love to see if you could show me the surgical trials that have reported that. That'd be great. But these are very well-done, centrally reviewed studies, and so I realize we all have our anecdotes, but in over 10,000 patients, we don't see this actually beyond three years. There is no difference in the hazard ratio of side effects when you look at eight years, 10 years, 15 years. So the early side effects are really what predict the late side effects. So obviously side effects can happen long-term, but I think this is mythical in terms of at 10 years all of a sudden are falling apart. They can of course happen just like small bowel obstructions, or other adhesions, or things after surgery, but I think these are uncommon events.

Alberto Briganti: Can I make a comment on this? Because I think that we are talking about an extremely heterogeneous patient population, and it's a matter of definition. So it's true, surgery has never been correctly randomized to surgery plus other therapy over the last years as compared to radiation therapy. We need to be very honest on that also, that we don't have any head-to-head comparative trials between surgery and radiation therapy in the setting [inaudible 00:04:32] disease—the only one which is the ProtecT trial honestly included patients with too favorable disease. I mean we cannot extrapolate those data. So we cannot say that radiation therapy is the only standard of treatment in these patients. We cannot say that surgery is the only standard of treatment of these patients until we have head-to-head comparative data.

Regarding the toxicity. Well, we lost all surgeons, and I'm talking about the big data coming from the trials. Let's just be very basic, and honestly all of us in the room being surgeons have removed bladders for severe damages after radiation therapy, and I did one last week. So these data exist and these cases exist. Thank you.

Neha Vapiwala: Question.

Speaker 7: [Inaudible 00:05:22] from American University in Lebanon, and I disclose, I'm a urologist, but I want to underscore the role of surgery in pT3 disease, which we've always done in the Middle East, and we get patients very late. Surgery has really improved a lot in the past 10 years, and I think quality of life is excellent. And many times, as mentioned by the radiation oncologists and Dr. Efstathiou, you are doing a single modality treatment in these patients, especially when downgraded, they're not always being committed to multimodality and radiation after surgery. So a radical prostatectomy with a lymphadenectomy, mostly extended in the high-risk patient, has a big role and especially in view of the data you presented on PSMA, for example, a negative predictive value. If you don't operate, you may lose 30% of these that are really not going to be known in terms of negative lymph node on the PSMA PET.

So I think I vouch for surgery. It's not on everyone; of course, we have to use the overall ECOG status, but whenever possible surgery should be the number one modality in high-risk patients. I wanted the opinion of surgeons and radiation oncologists.

Daniel Spratt: I'd like to ask a question. There's just not data to support what you're saying in the sense that it's proven to be a necessary modality. You can of course make these claims. But in the CALGB trial, one of the very few contemporary randomized trials with surgery, 85% of patients by five years had to receive subsequent therapy or recurred in a contemporary high-risk trial. So it is the vast, vast, vast majority of patients that are having subsequent treatments at just five years.

Piet Ost: I also didn't argue that surgery is bad. I argued that in these high-risk to very high-risk, the probability of the patient requiring multimodal therapy is still very high. I do indicate if you are better at selecting a patient that only would require surgery and no other therapy, that would be great. But I'd love to see that data. And often what we still see nowadays is a patient, if they have a T3b upfront on MRI, they have a high Gleason score, they will end up getting radiation plus hormonal therapy anyway. So why would we give them two local therapies? Because we know that the quality of life will get down. If we add radiation, quality of life goes down. So that to me is the big thing. What are we exposing our patients to? Are we really benefiting them, giving them these multimodal therapies? And there is no data that we do.

So if local control is already that good, and I do admit there are bad cases, but also with surgery, you've got your pulmonary embolisms, you've got your lymphedema, which I didn't hear a lot about lymph node dissection and lymphedema, which can be very, very bad. And everybody can come up with cases you did last week; it's called negative recall bias. Everybody has that. And you see that in the quality of life reports. There are outliers, there are bad patients with surgery, and there are very bad patients as well with radiation. It's with every treatment, but we can't know up front. But if you know up front that the patient will require two treatments, why do that? That's my point.

Neal Shore: I think we're running up on time. No, we're going to have to stop the questions. But a final comment from Dr. Gleave.

Martin Gleave: Oh, it was more of a question to continue this ongoing never-ending debate. But I think that the question is, I think we're quite fortunate to have two modalities that are very effective, for the most part have side effect profiles that are manageable. But the issue of layering therapies, having surgery and subsequent post-operative additional therapies, is a common theme throughout the vast majority of oncology. Whether that's in breast cancer, colorectal cancer, and others where we do add in, as appropriate, radiation therapy and systemic therapies following surgery. So the need for layering of therapies is not a reason to actually discourage the role for surgery. But again, selection, selection, selection is key. And it comes back to—and it wasn't presented by anybody—but perhaps one of our radiation colleagues can just address the issues of 13 out of 14 propensity-weighted studies, thousands, tens of thousands of patients, surgery versus radiation. In the absence of randomized trials—which is an absence of evidence rather than an evidence of absence problem—those propensity-weighted analyses are not... 13 out of 14 show benefit for surgery over radiation.

Daniel Spratt: They did that for low-risk disease as well.

Neal Shore: Final comments by Mr. Matheson, who's going to give perfect clarity, then we'll go to the...

Neha Vapiwala: Yes. Solve it.

Mack Roach: Go to the solve it. Perfect.

David Matheson: Well, in an attempt to give perfect clarity, what I would say is what this highlights very much is the need to supply information to the patient so that the patient, where possible, is enabled to make an authentic choice, knowing the benefits, the merits, the demerits, and so on, of the different modalities, combinations, et cetera. Because after all, it's the patient who's going to live with it. It's not the clinician. So trusting the patient, enabling them, empowering them—to me, from a patient perspective, is absolutely essential. So that they go into these things with their eyes open, and with their eyes open with the authentic choice, finding the work that we've done anecdotally and formally is they're going to find it much easier to live with the consequences.

Neha Vapiwala: Thank you, sir.