Urologists, You’ll Never Walk Alone! - Gianluca Giannarini

December 27, 2021

Gianluca Giannarini joins Ashish Kamat to discuss a recent publication from European Urology Oncology, an editorial titled, "Urologists, You’ll Never Walk Alone! How Novel Immunotherapy and Modern Imaging May Change the Management of Non–muscle-invasive Bladder Cancer".  Dr. Giannarini discusses the management of patients with high-risk non–muscle-invasive bladder cancer (NMIBC), especially those with recurrence despite adequate bacillus Calmette-Guérin (BCG) therapy, which is one of the most urgent unmet clinical needs in oncourology. Currently, there is no universally accepted standard of care for such patients and although radical cystectomy (RC) is strongly recommended as the preferred option by several reputable guidelines, many patients are either unwilling or unfit to undergo such major surgery. Moreover, even contemporary radical cystectomy can be associated with high morbidity, non-negligible, albeit low, mortality, and lower quality of life, and may represent overtreatment for a proportion of cases.  This presentation and conversation focus on the future of treatment with a multidisciplinary approach to patient management.  

Biographies:

Gianluca Giannarini, MD, is a Staff Member at the Urology Unit of the Academic Medical Centre "Santa Maria della Misericordia" in Udine, Italy.
He qualified from Udine University in 1998 and trained in Florence, Pisa, and Leuven before a 2-year clinical research fellowship at the Department of Urology of the University of Bern, Switzerland.  He is a Member of the Prostate Cancer Committee of the EAU Section of Oncological Urology (ESOU) and a Member of the Scientific Committee of the Italian Association of Urology (SIU).  He is Consulting Editor for European Urology and a Member of the Editorial Board of BJU International and Minerva Urologica e Nefrologica.
He authored 140 articles published in peer-reviewed journals, mainly in the field of urologic oncology.  He was awarded the Matula Italian Award in 2014.
His clinical and research interests focus on urologic oncology, pelvic reconstructive urology, and prostate MRI.

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas


Read the Full Video Transcript

Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urology and Cancer Research at MD Anderson Cancer Center in Houston, Texas. And it's a great pleasure today to have with us, Professor Gianluca Giannarini, who is an Associate Editor of European Urology Oncology, Chair of the EAU Guidelines Office Dissemination Committee, Board Member of the EAU Section of Oncologic Urology, an Associate Member of the EAU Section of Urological Imaging, and his normal day job is at the Santa Maria della Misericordia University Hospital in Udine, Italy.

Gianluca, thank you so much for taking the time to join us today and discuss with our audience a little bit more in-depth your recent editorial publication which was titled, "Urologists, you'll never walk alone". Clearly, this publication got a lot of attention on social media and other channels with a lot of discussions. Most of it, very positive, some of it from people that didn't understand the message. And I'm looking forward to hearing your little discussion today, and then of course we'll chat at the end of your presentation. So with that, Gianluca, I'm going to hand the stage over to you.

Gianluca Giannarini: Thank you, Ashish, very much. It's a real honor to be invited to discuss all the issues around an editorial, which I have to admit is quite unusual for UroToday. So it is I think a double honor. And yes, so this slide is of course the first part of the title, which, as you said, could be probably interpreted or misinterpreted, but I will give you the correct interpretation here in the next minutes.

So just to give credit, it was really a collaborative effort and I'm also presenting and discussing on behalf of Andrea Necchi, who is the Senior Author for this editorial. And we were really able to put together, I would say the top or most of the key opinion leaders on bladder cancer. And I will just mention them briefly. They are both medical oncologists and neurological surgeons. So thanks again to Neeraj Agarwal, to Andrea Apolo, to Petros Grives and Shilpa Gupta, and Alberto Briganti, you, of course, Ashish, Francesco Montorsi, and Morgan Roupret.

I think the premise of this editorial is that we are living really at the crossroad of different pathways and lines of research. So on the one hand, we were lucky to have harmonization of the definition, endpoints, and clinical trial design in the high-risk non-muscle-invasive bladder cancer. And this is of course due to the great work that you, [inaudible 00:03:09] Ashish, and the IBCG have done. We are also lucky to have in 2018 the document of the FDA guidance, of course, in the conduct of these trials. And that has, of course, fueled the interest in developing new treatment options for these patients.

On the other hand, we are witnessing the efficacy over the last years of the new immunotherapy, the immune checkpoint inhibitors in the advanced urothelial carcinoma setting. And of course, the next logical issue was to test these effective drugs at various stages of disease until we had in January 2020, the approval of the first immune checkpoint inhibitor, pembrolizumab for a particular population of high-risk non-muscle-invasive bladder cancer, so patients with BCG-unresponsive and Cis-containing tumors.

And then the third line is the advances in imaging, in modern imaging. And of course, the multiparametric MRI holds really great promise, and the VI-RADS system, as you probably all know, is a really new current system that has been externally validated in discriminating the non-muscle invasive from the muscle-invasive disease. And it has also been validated in some series, just predicting the probability that patients with the non-muscle invasive can spare with TUR, or alternatively, we can identify those patients that are at high risk of understaging of the initial TUR. So really key advances in the bladder cancer landscape.

But the real clinical unmet need is of course patients with BCG-unresponsive, non-muscle-invasive bladder cancer. So the current guidelines, and I'm quoting two of the most representative ones, the EAU and the AUA, of course, recommend as a stronger option, radical cystectomy in those patients who are eligible of course, to major surgery. And as an alternative, but with a weaker strength of recommendation, either the enrollment in clinical trials or the so-called bladder-preserving strategies.

The same is for the AUA, it's again, radical cystectomy is the preferred treatment option. And of course, and mainly due to the FDA approval, the pembrolizumab or the systemic therapy is recommended only in select patients and in the profile we discussed a few minutes ago. So what we did really research, is the new and the ongoing trials testing immune checkpoint blockade in non-muscle invasive bladder cancer. And as you see here, there is really an explosion going on over the past five years.  So this is quite a busy table, but just to summarize, we have trials testing the new immunotherapy paradigm in the BCG-naive or in the BCG-unresponsive or refractory, depending on the [inaudible 00:06:56] definition. We have trials testing a single agent or a combination in BCG or with other agents or with radiation therapy, which was traditionally considered ineffective for this disease setting. And mainly, the way of administration is intravenous. This is a table of phase II and phase III trials, and you may imagine how many more there are of phase I, and phase I/II.

So, based on this data, we postulated a possible shift in the paradigmatic treatment of high-risk non-muscle-invasive bladder cancer. So clearly we foresee that the indication to radical cystectomy, which is still major surgery with major morbidity, may possibly decrease, and in parallel, new bladder-sparing therapy may possibly increase. This is also mirroring the profile and the preferences of patients that we are seeing and visiting in our practice, in our office, and are probably mirroring also the new wave of clinical trials that we are seeing in the muscle-invasive setting, with many of these patients accepting to be randomized to bladder-sparing therapies, many of them requesting actively a bladder-sparing treatment.

Of course, TUR will remain the standard of care, but probably will be possibly spared in select patients that can be directed immediately to the treatment because they are harboring most likely an aggressive disease. And we are now, we are quoting the BladderPath study that we have recently discussed on UroToday as well. And of course, a great promise is held by the novel liquid and imaging, and we are referring to multiparametric MRI again, biomarkers, which are now really a reality in other settings of the disease.

We, of course, are also very cautious not to come to any easy conclusions. And so we discussed the challenges in adopting this paradigm. So just because we have many treatments, now we have to figure out which is the best sequence or the best combination. So whether the immune response triggered by the BCG, which remains the backbone of this immunotherapy with patients, is needed to improve the response rate to this new immunotherapy remains, of course, unknown. And I think that is quite an important point as to the methodology to adopt.

So we know from the FDA document that the phase two, single-arm trials probably are sufficient to approve the new agents, but we also found out that many of these ongoing trials already have phase three randomized trials. So this begs the question really if the new wave of research should be indeed phase three randomized control trials. The non-invasive liquid and imaging biomarkers are really a way to spare the traditional assessment, which is mainly still surgically based. But we all know that, as of now, we do not have any validated biomarker, and this is a great area and also great promise for the future.

We are also quoting a recent publication in Nature Communications by a collaborative group, and Lars Dyrskjot, who is the senior author. And of course, they are ongoing research finding out the molecular classifier that can really stratify the risk of disease progression beyond the known and the clinical-pathological variables. And of course, this is an ongoing field, but that too holds great promise.

What about the regional lymph nodes? Because traditionally we know that many of these patients have a high risk of harboring extravesical disease, probably in up to 15% of the high risk or very high-risk patients. So is this really an issue? We don't know. And again, another point to discuss is the best way to administer this new therapy. Should it be systemic? Should it be intravesical? And this, of course, has several implications, and the logistic ones probably are one of the closest. Or should they be combined? Because probably a rationale is there.

So the final take, and of course I'm coming back to the title. Because as Ashish said, there was some resonance of the editorial across social media. So I think the main message is that, and I'm slowing down here the talk, so I give more emphasis. So the era of the urologist treating non-muscle invasive bladder cancer, namely high-risk disease, with TUR, BCG, repeat TUR, or repeat BCG, and again, TUR, BCG, and probably ending up with a cystectomy is over. Urologists need to embrace the new era of multidisciplinarity and be an active part of the paradigm changes in the field of bladder cancer.

They are all, seeing as a first probably doctor, these patients, so they should cooperate with other health care specialists. And again, I'm referring to the medical and radiation oncologists, radiologists, pathologists, and geneticists to be at the forefront of research and clinical practice. And we really believe because some of this is already a reality that the future is a personalized treatment based on patient characteristics and preferences beyond the traditional clinicopathological features. And with that, I thank you for your attention.

Ashish Kamat: Thank you so much, Gianluca. Remarkable presentation. You covered a lot of the important points from the thought process and not just a manuscript. So that was great. So let me ask you a couple of key questions. When we talk about the title, which is, "Urologists, you'll never walk alone". The way I look at that is that it is actually an encouraging sign. That means that now our patients with bladder cancer will have true multimodal management, multidisciplinary management, which is what they all need. But could you comment a little bit on the practicality of that situation? And you could speak mainly to Italy and Europe if you can share some of your knowledge and insight since you are on a lot of the committees. How does that work in a practical situation? For a patient with non-muscle invasive bladder cancer, what do you envision as the optimal flow for that patient?

Gianluca Giannarini: Yeah. So again, as you correctly pointed out in a reply to the main post on Twitter, of course, the Urologist, you'll never walk alone is a promise and not a threat. And so that said, I think that we, of course, are at the beginning of this paradigm shift. We have to really be smart and think about the best logistics to really offer our patients all the options they deserve. And so clearly we have to collaborate and to work in strict and close fashion with the, I would say the radiologists and the pathologists, of course, they are important specialists. And of course, with the medical oncologists, because as said, many of these treatments are administered or will be administered systemically. So we, as urologists are not used to probably, or many of us, or most of us are not used to delivering this treatment. And so clearly we have to work within the multidisciplinary clinic or group, and then of course overcome the logistic barriers that may develop.

Ashish Kamat: And from the perspective of the patient, do you foresee that every patient will now be seen in a multidisciplinary clinic, or will we still rely on the judgment of the urologist as to when a patient should and needs to be referred to other clinics?

Gianluca Giannarini: Yeah, so I think personally, or at least in Italy or in Europe, you have the experience of the prostate cancer unit. And I think that we have already identified a big proportion of patients requiring the management within the multidisciplinary group, and probably they should not be 100%. And I think the same could be applied to non-muscle-invasive bladder cancer patients. So probably really the high risk and the very high-risk patients should be really discussed in this scenario, within this environment, because of course, I'm pretty sure that the quality of the treatment that could be offered would be increased.

Ashish Kamat: Right. Could you comment a little bit upon how you envision the radiologists and the MRI and VI-RADS, how they might be incorporated into the care of patients?

Gianluca Giannarini: Yeah, so in the editorial, we discussed or we dedicated a paragraph on the MP MRI, and of course, most of the data we have been referring to the muscle-invasive bladder cancer setting. So we also use huge caution to extrapolate this data in the earlier non-muscle invasive bladder cancer setting. Although probably there is no border, no barrier anymore between the very high risk, non-muscle-invasive in the bladder and the muscle-invasive bladder cancer.

So the big question probably that at present cannot be overcome is again, the monitoring of the carcinoma in situ. Because by definition, it is a flat lesion. So as to now, even with the more sophisticated 3-tesla MRI, this disease entity cannot be identified. But I think that we have, and we should have to explore either within the clinical trials, the potentiality of the MRI in identifying the, let's say the bad high-risk non-muscle invasive disease. So in this case could probably be spared a new TUR because we probably see that these deserve a more aggressive treatment.

Ashish Kamat: And again, your insights have been very useful and very helpful. In your role as the Chair of the EAU Guidelines Dissemination Committee, and of course, the multiple other offices that you hold. Do you have any pearls to share with our audience as to maybe some efforts that you might be thinking of, or that might be underway as far as disseminating this philosophy to the urologists across Europe and of course, North America?

Gianluca Giannarini: Yeah, sure, Ashish. I think this is a great point. I think that the problem is ... So the call to arms that we were doing in this editorial was mainly related to the community urologists. Because we know that probably in the academic center, the mind is more open, and probably a multidisciplinary clinic, it is already going on. So really, I think we have the responsibility to really share these new advances and also give a new way of thinking to the urologists who are still refractory to embrace this new wave. And I think we are really exploring a new way of guidelines dissemination, and really targeting different profiles of the audience. So of course, from the web [inaudible 00:21:59] to the podcast, to targeting the nurses and the patient advocates, I think one thing that is clear is really that probably the patients' preferences and wishes are changing towards a more conservative approach to their bladder cancer.

Ashish Kamat: Thank you again, Gianluca, for taking the time and sharing your thoughts with us. Stay safe, stay well, and hopefully, we will get a chance to see each other in the near future.

Gianluca Giannarini: Yeah. Thank you very much, Ashish. And see you all quite soon.
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