Félix Guerrero-Ramos: Hi, hello, Ashish. Hello, everybody. Thanks for the invitation to be here. As you said, we recently published this systematic review assessing the definition of cure in early bladder cancer. We think this is a very important concept, not only for daily assistance, but also for clinical practice. So why did we have this idea and why did we start doing this? We know that cure is a concept we use every day, especially many times when patients ask us, "Am I going to get cured of this?" Or how do we define the cure of a patient when treating the patient and doing the medical record? But in spite of being widely used, it's very poorly defined. There is no clear consensus on the endpoint or the time point to define cure. And the definition of cure can eventually impact clinical trials, patient communication, and also in terms of reimbursement for new drugs. So we performed a systematic review of the real-world evidence of cure. We did exclude clinical trials because we wanted to have those manuscripts, those papers with a longer follow-up. We defined early bladder cancer as that bladder cancer we can cure that's non-muscle-invasive bladder cancer and localized muscle-invasive bladder cancer. We excluded locally advanced or metastatic muscle-invasive bladder cancer, which is clearly a different entity. And we focused on the studies, we assessed long-term outcomes.
After all the literature review and the search, as you can see on the left-hand side below the slide, we found 110 records that were useful for systematic review. They are all referenced in the manuscript we published in European Urology Oncology. So if we look at the follow-up periods we found in these patients, we see that in this case, you can see the figure for non-muscle-invasive bladder cancer. There is certain heterogeneity in the length of the follow-up in the certain manuscripts we found. But as you see, if you have more radical therapies like radical cystectomy, these follow-up periods are shorter in general than if you have other therapies where you have bladder-preserving options. That makes sense, because if you make a radical cystectomy to a patient with a non-muscle invasive bladder cancer, after a certain follow-up, maybe two, three years and there's no relapse, you can consider that patient will be disease-free and cured. And the same, if we look at localized muscle-invasive bladder cancer, those therapies like trimodal therapy that preserve the bladder have longer follow-ups than those patients with more radical therapies, where we can assess cure earlier than if we preserve the patient's bladder. So looking at some of the data we found, we can see on the left-hand side of the slide that for non-muscle-invasive bladder cancer as compared with localized muscle-invasive bladder cancer, the median time to recurrence is longer.
This is of use, as we said before. Patients who usually preserve their bladders will have a longer time to recurrence than those who even have a muscle-invasive bladder cancer have a radical cystectomy. It's easy to cure these patients if we're doing such a radical therapy. So we saw that most of the recurrences happen during the first two, three years. The median time to recurrence is highly variable, especially in non-muscle-invasive bladder cancer. But after certain time, there is a clear plateau of the risk of recurrence, and thus we can define cure after certain time. We'll see that earlier. So what we concluded is that we need to establish and we need to define what cure is for patients for both clinical trial design and also for informing our patients in the clinic when we are seeing the patients in the office. We think five-year recurrence-free survival as a definition of cure in early bladder cancer. Remember, non-muscle-invasive and localized muscle-invasive is a topic frequently reported as feasible in real-world evidence we have found in this systematic review. This is patient relevant and clinically meaningful, and it's aligned with also some health authorities reports that we have found in this systematic review. We think this should be important to standardize endpoints in clinical trials, also improve patient communication and supporting reimbursement and policy decisions. Not only this, but also in the everyday practice for the follow-up of our patients, we must be aware that after certain time, if there's no recurrence, we can deintensify the follow-up, especially in those elderly or more frail patients who may not need cystoscopies so frequently after certain years without having any kind of recurrence. Thank you very much. And we can discuss anything you'd like. Ashish?
Ashish Kamat: Great, Félix, thank you so much. Like we mentioned at the outset, this is an important thing when we're talking about patients looking at what happens in the real world in the clinic. Because again, in clinical trials, we have relatively artificial definitions sometimes and definitions that we have proposed, of course, not that they're wrong definitions. We recently, in fact, looked at clinical trials to see if CR, for example, in high-risk bladder cancer or event-free survival actually predicts for cure, overall survival. And CR was a relatively impure surrogate, but event-free survival was more of a surrogate. But these are all surrogates. And what you're proposing really, I think, gets to the heart of the matter. How do we talk to patients? How do we define this? So Félix, let me ask you, when you are talking to a patient ... And let's go through the different buckets of bladder cancer, right? You have a patient that's sitting in front of you with a first-time low-grade tumor, a low-risk tumor. What do you tell the patient based on your analysis and real-world evidence? Is there likelihood of having a recurrence or being cured at two to five years?
Félix Guerrero-Ramos: Well, the first thing when we face one of these patients, especially as you said with low-grade tumors, is when they ask you or after the TURBT, you give them the pathology report and you say, "Okay, you had three lesions with a low-grade Ta. You are probably not going to die from this disease. But if you want me to tell you when you're going to get cured, this is difficult. This is a chronic disease. You have a high chance of recurrence. We will do everything. We will do intravesical therapy, clinical trial, whatever, and follow-up. But we can consider you will be cured after certain time without having a recurrence, but you will always be at some low marginal, but at some significant risk of recurrence, even if we get you a certain five-year interval without recurrence."
Ashish Kamat: So Félix, you actually beat me to the next question because I was going to ask you about the low-risk patients and then the high-risk patients and make this contrast, right? Because when a patient says, "Dr. Guerrero-Ramos, am I going to be cured of my cancer?" When they have low-grade disease and you tell them you're going to have recurrences, so you're not going to be cured by the classic definition. But then you have a high-risk patient that has the risk, say T1 high-grade cancer, and there a recurrence is a lot more dangerous. When you propose this five-year recurrence-free survival, it includes all these patients, right? But clearly the implication for the patient is different. How are you recommending we counsel patients on the difference between the definition of cure if you just use recurrence as the definition?
Félix Guerrero-Ramos: Well, we know bladder cancer is a very heterogeneous disease, especially if we speak about non-muscle-invasive bladder cancer. When we counsel our patients, we must take into account that recurrence also includes progression, especially in the study we did. If there's a progression, that's taken into account as a recurrence. We have to adapt our speech to the kind of tumor that the patient has. It's not the same, as you said, counseling a patient with a low-risk, tiny tumor than with a high-risk T1 high-grade that were treated with BCG and may recur. So when we sit in front of the patient every day in our clinic, we must tell them which are the relevant endpoints, let's say, according to their understanding. And we must make our high-risk patients understand that the most significant risk for them is progression or having a muscle-invasive bladder cancer which could threaten their lives. And we have to let them know that, in general, in all these patients this is a chronic disease. They will probably have some recurrences. More than half of the patients in the low-risk group will have recurrences. So we have to make them understand this and also discuss with them, and I ask them when they tell me, "Doctor, will I be cured? When will I be cured?" And I ask them, "What do you mean by being cured? What's your concept?" Some of them say, "I don't want to die from this." So it's easy to adapt the definition to them. "I don't want to have to undergo a TURBT ever again." Okay, so maybe that's not going to be cured for you, let's say in the next five years and all that.
Ashish Kamat: So that's a great point because again, just looking at the systematic review and coming with recurrence, and obviously progression is part of the recurrence, the cure definition is great. But what you mentioned, what matters to the patient? Does this patient want ... Obviously no patient wants to die of their cancer. But some just don't want to have any recurrences, whereas some are okay with recurrences and then you do active surveillance. So I think data such as what you presented, your systematic review, definitely informs the field. And it provides us to have more information and ammunition to talk to the patient because it is really asking the patient that important question, what matters to you? Right? What is your main fear, main concern? Félix, as always, it's a pleasure talking to you. Thank you so much for taking the time. And stay safe.
Félix Guerrero-Ramos: Thank you, Ashish. And thank you everybody for watching. Hope to see you soon again.