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Petros Grivas: Hello. I'm Petros Grivas. I'm a medical oncologist at Seattle Cancer Care Alliance and I'm an associate professor at the University of Washington and Fred Hutchinson Cancer Research Center. I'm very delighted and excited today to host one of the major contributors in the field, Dr. Alison Birtle, who actually is kind enough to join us from England, which is late right now, but she's still awake and she is going to contribute to our meaningful conversations regarding the very important practice-changing POUT trial. And without further ado, Alison would you like to introduce yourself?

Alison Birtle: Hi, thanks ever so much Petros, and thank you for inviting me to chat with you tonight. So I'm Alison Birtle and I am a consultant oncologist, and I'm based at The Rosemere Cancer Center in Preston, which is in the Northwest of England, which is why you see some little mountains behind me, which is actually the southern mountains of the Lake District in the Northwest of England.

Petros Grivas: This is a fantastic background picture there. And I hope we can visit one day, this beautiful area of Northwest England, Alison.

Alison Birtle: You'll be very welcome.

Petros Grivas: Thank you so much. And I would like to congratulate you again for this huge effort, it is a Herculean effort to get this trial up and running and changing practice. Would you take a couple of minutes to tell us about how this trial came about and the level of energy that it takes to mobilize the resources to get a Phase 3 trial done in this setting?

Alison Birtle: I'd be delighted to. See, the idea of the POUT came about because I used to sit in my MDT week after week, where there was a patient with an upper tract tumor, and. he had had a nephroureterectomy and the urologist would say, "We've given him chemotherapy because they've got a higher risk of recurrence." And I'd say, "Well, there's no data." And the actual impetus for a study came because I was fed up with being asked so many times. And then what happened was we thought, should this be neoadjuvant or should it be an adjuvant study? And rather than just doing something that we thought was the right thing, we went into two really important things, because if you want to study in the area of a low-incidence tumor, to be successful, you have to get the design right from the start, don't you, Petros? 

So we went and we did a survey across the UK to look at what the current practice was. So if you had somebody who'd had a nephroureterectomy, would people give them adjuvant chemotherapy or surveillance? And we found that it was split really, probably about two-thirds of people did surveillance, but about a third would do adjuvant chemotherapy on a case-to-case basis. But everybody said, well, we don't know the answer, so we'll put somebody in a study. Then we asked the same question about neoadjuvant versus adjuvant. And we are all fairly simple souls as oncologists. And we like to see something on a piece of paper that says this patient has definitely got cancer before we give them systemic therapy that might be over-treatment and does come with potential risks, occasionally of life-threatening toxicity. And the message we got back from the oncology community was that we didn't really want to do a neoadjuvant study.

So that was the message from the clinicians. But it is really important that you have patient involvement from the outset. So we put together two focus groups that we got from either patients who were patients of some of my colleagues from the protocol development group, or they were patients who came in response to an advertisement that we put out through Macmillan, one of the UK cancer charities. And we spent a day going through what an adjuvant study was, and what a neoadjuvant study was, and asking the patients. And they came back and said... they once said, the adjuvant study. And there were lots of reasons behind that, but mainly again, they wanted to know if they already had a locally advanced cancer before they had any more treatment. So that is how we started with the design. And then academic trials, when you haven't got a big commercial sponsor because how it didn't have sexy drugs, it just had standard chemotherapy because there were no systemic agent trials in that space before.

So I think from the time we first started with the concept, which was back in about 2009 to the time it was funded, which was March 2011 by Cancer Research UK, we've then had to meet certain timelines in terms of recruitment because this was a rare incidence tumor, you had to have within all the networks, the cancer networks in the UK, you had to have somebody that was really championing the study. And saying that every MDT before a patient had a nephroureterectomy, they could be suitable for POUT and then bringing them back in time to that pathology afterward. What we also did was really important. It was doing a qualitative substudy Petros, which was doing audiotaping. So consenting the patients for audiotaping at the first consultation with either the oncologist or the urologist after the surgery. And then those tapes were analyzed by qualitative researchers at the University of Bristol, with Jenny Donovan and Caroline Wilson and their team.

And then we looked for words that were being used that would either give the patient confidence, or that would actually put the patient off going into the study. So we found that if you said to somebody, well, you've had a nice operation, it's all been removed, then that makes the patient not want to go into an adjuvant study. But if you say to them, look, you've had surgery now, it's gone very well, however, this is cancer that does have a higher chance of recurrence. It's what we call T3, that's a 75% chance of recurrence in the next three years. And we know in other cancers, giving chemotherapy at this point may reduce your risk of recurrence, but we don't know the answer to that.

You find that the patients are much more willing to consider that study. So we then had lists of top tips, both for urologists, oncologists, and the specialist nurses that I publicized at all of the major oncology meetings, all of the major urology, nurse specialists meetings, the oncology meetings, and we took it from there. So it really was a labor of love with POUT from before it first opened and then when the first patient went in, in May 2012. So this was my academic baby, but with a huge supporting cast, 75 centers across the UK, and a fantastic team of people at The Institute of Cancer Research, Trials, and Statistics Unit.

Petros Grivas: Alison thank you for saying all these. It's a fascinating story and to me, it's an inspiration even for young oncologists, right? How they can put their energy and effort together because when there is a will, there's a way. And that is exactly the moral of this story, of this Herculean effort.

Alison Birtle: I think it is and I remember when I had the privilege of having the Plenary Abstract session three years ago at ASCO GU, when we had the first data from the study that somebody said, congratulations on doing the undoable. And it was... I think, if you are an investigator on a trial, you can't sit back and wait for other people to motivate the other investigators. So no matter how brilliant the trial's unit is, they can only do so much. So it is about yourself as the chief investigator. If there's an issue with site recruitment, you need to pick up the phone and speak to that person and say, look, I can see things aren't going so well. Can I help with that? What are the barriers to recruitment? And one of the things that we did that was fantastic was we spent a lot of time looking at the screening logs and particularly Rebecca Lewis from the Institute of Cancer Research, Clinical Trials, and Statistics Unit.

She collected all of this data. We looked at it every month and you would see that sometimes it would say patients not approached due to age, and then you'd go back and you would find out, that decision was made on behalf of the patient, not with the patient. So if you've got somebody who is 79 years old, but they are really fit, they're climbing the mountains behind me and that patient's got a T4 upper tract urothelial cancer with a good GFR, that patient has a high risk of living long enough that that cancer is going to recur, be untreatable at that point in time. So why not put them in an adjuvant study?

Petros Grivas: Absolutely. I think it takes really determination as you said, to motivate people, right? Creating a team and working with a team and leading that team, I think are teaching points about building and monitoring leading teams. And I agree with you, I think this had to happen, and it was a big unmet need that now we have the data. Can you comment a little bit on the design and the eligibility criteria and also the main findings of the study?

Alison Birtle: So POUT was a very simple design. It was one-to-one randomization, a Phase 3 study of non-blinded between four cycles of adjuvant chemotherapy or surveillance, because those were the two options at the time and outside of a clinical study with no evidence supporting one or the other in upper tract tumors. Because of course, they are not muscle-invasive bladder tumors. They have very different biological behavior. They have higher rates of microsatellite instability and methylation. So they are not the same just as urothelial cancer elsewhere in the urinary tract. And to be eligible, patients had to have had an unblocked nephroureterectomy, and then within 90 days of surgery, if they were allocated chemotherapy, they started chemotherapy. And they could have either pT2 to T4 disease, and they could be node-positive as long as those nodes, any that were seen before surgery, were microscopically removed at the time of surgery, and then the patient had to have a negative postoperative CT scan.

Now, sometimes people have said, why didn't you do a template lymph node dissection? Well, if I take you back to when we did the original feasibility for the trial, we asked the surgeons across the UK, what they did in terms of managing the lower ends of the ureter, and also how they manage lymph nodes. And there was no level one evidence to say that doing a template dissection improved survival, and indeed still in the upper tract, that is still a very contentious area. So as long as patients had a negative postoperative CT scan, they were eligible to go into the study. And the chemotherapy was gemcitabine, day one, day eight, 1000 milligrams per meter squared. And then the choice of the second drug was either cisplatin or carboplatin, but carboplatin was only allowed for use, Petros, for reasons of poor GFR.

So if the patient had peripheral neuropathy or if they were diabetic or you didn't want to give them cisplatin for any other reason, they couldn't go into the study because we just wanted to see what the difference was with GFR. And obviously, we can treat quite safely with cisplatin down to a GFR of 50 in the real world. So anybody with a GFR of greater than 50 got GemCis. If it was between 30 and 50, they got GemCarbo. And there was a little bit of leeway for centers that used split-dose cisplatin. So that was done on a case-by-case basis in discussion with the trial management group. But they did have to start chemotherapy within 90 days, there were no exceptions. Follow-up was really pragmatic, really straightforward, standard, cystoscopic surveillance of the bladder. And one of the secondary endpoints was bladder recurrence, and that data we haven't presented yet.

And the primary endpoint of the study was three-year disease-free survival. And we chose that really for a number of reasons. First of all, if you try and power an adjuvant study in a rare tumor for overall survival, you'll be waiting decades for that to get the numbers. Secondly, in an adjuvant study, it's either there or it's not, it's not a case of have you got a pseudoprogression as we see potential with immunotherapy, they either have progression and recurred or they haven't. And also that was a key endpoint in the EOTC 3-09-94 study of adjuvant chemotherapy for muscle-invasive bladder cancer. So it seemed a good place to start. The secondary endpoints were overall survival, metastasis-free survival, toxicity, and really importantly, quality of life because we haven't had the quality of life data in a setting either before.

So the study was powered for 345 patients. And what happened was back in November 2017, like any other well-designed study, we had safety monitoring and the governance committees, one of whom was the Independent Data Monitoring Committee. And they met and said the trial had met its primary endpoint, three-year disease-free survival early, it did make it at two years rather than three years. And so because of that, they asked us to shut the trial prematurely. And those were the first data that we presented back in 2018. And at ASCO GU, this time in 2021, in the virtual meeting, I presented the updated and final analysis based on the three and five-year disease-free survival, metastasis-free survival, and the overall survival data. So what we now have from the final analysis is that there is a 21% difference, quite a staggering difference of disease-free survival at three years in favor of chemotherapy with a really strong hazard ratio of not 0.53, when it's adjusted for the minimization factors we had for the study.

So these are pre-planned subgroups looking at pathological stage nodal status, margin positivity, and chemotherapy type. Metastasis-free survival, there's a 19% difference at three and five years, and disease-free survival at five years is also still positive with a 17% difference between the two groups. Overall survival, there was a trend where the 12% difference at three years, but that wasn't statistically significant. Does that matter? Well, the study endpoint was three-year DFS. We met that, we had to shut. At that point, there were 261 patients, not the 345 that we had anticipated, which was what the study was powered on to try and look for overall survival as a secondary endpoint. So it was unethical to carry on with the study because we had met that disease-free survival, which was the primary endpoint of the study. So we obviously haven't got sufficient power to look for that overall survival signal.

So I would say it's still a pretty strong signal with 12%, even though it's not statistically significant. The other thing is let's get back to May 2012 when the first patient was entered into POUT and then five years later when it shut, lots of those patients were in the PreMiO era, so they would not have gotten a second treatment with a checkpoint inhibitor. They would have gotten second-line chemotherapy when they recurred and if they recurred. And so the efficacy for that is far less than if they'd have had access to a checkpoint inhibitor. So had we been able to treat those patients, then it is likely that you would have seen a much stronger overall survival signal and you can see that actually more patients in the surveillance arm went on to chemotherapy than those who were in the chemotherapy arm.

And that is probably because second-line chemotherapy doesn't work very well. We know that it is about 15% to 18% with weak bTAXOL. What I also found brilliant was, we didn't have any unexpected toxicities. There were no deaths on trial because of chemotherapy and the quality of life data was also very strong. So it's chemotherapy, you get chemotherapy toxicities, they are all very manageable, very predictable. They have a little drop at about cycle three of chemotherapy, related to nausea and vomiting, and then it bounces back up at six months. And if you look at 12 and 24 months, Petros, what you see is actually the quality of life is better in the patients in the chemotherapy arm than in those who were on surveillance. And that is probably because some of that group, the surveillance group are going to be recurring within that timeframe.

So I'm really proud of the UK for this. It was a triumph and patients across the land and the breadth of the country went into the trial. But also I did say at ASCO GU this year as well, this is a triumph of patients for patients because we had patients from the beginning who helped in the design of the study and all the patient literature, the patient information sheets, and all the consent forms. And I have to say thank you to two men who both died. And that is Chris Harris, he was part of my first focus group. He died the year before last and Andrew Winterbottom, who was on the trial management group and who was the founder of our UK Bladder Cancer Charity, one of them to fight bladder cancer. And without those two men, then the trial would have been much less successful. And it is wonderful that we can change practice for other patients that come along and that is really their legacy.

Petros Grivas: Alison, this is a fantastic story, and thank you for outlining all these details, very granular information, which I think will be very useful for the audience. And also the tribute that you pay to all these people, who have died as you said, over time, and the major contributions they had. It takes teamwork, it takes a leader to change practice. So congratulations once again. I would like to thank you so much for your time today and looking forward to more interactions in the future and collaborations, Alison.

Alison Birtle: Yeah. I look forward to it. Thanks very so much, Petros.

Petros Grivas: Thank you. And thanks to the audience for your attention.