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Ashish M. Kamat: Welcome everybody to Urotoday's Bladder Cancer Center of Excellence. Today we're going to do a slight detour and talk about penile cancer.  And for this, I have the distinct pleasure of inviting one of my close friends and colleagues, Phil Spiess, who is Professor of Urology and GU Oncology and Assistant Chief of Surgical Services at Moffitt Cancer Center. We also have the pleasure of welcoming Jad Chahoud who studied here at MD Anderson Cancer Center and now is a system member of the Department of GU Oncology at Moffitt Cancer Center and specializes in the management of penile cancer patients. Phil and Jad, welcome and take it away.

Phil Spiess: Thank you very much, Ashish. Thanks again, first of all, Ashish, for the invitation and for UroToday for the opportunity to discuss penile cancer, which, as we all know, is a fairly rare cancer and is one, unfortunately, where there have been some challenges in improving patient outcomes and I think this will be a great topic just to discuss and sort of highlight some novel opportunities to improve patient care. In terms of disclosures, I don't have any specific disclosures other than serving on the NCCN Committee on bladder and penile cancer and as the vice-chair, as well, as a new society that we've just launched a few weeks ago, which I'll be happy to just give you a brief introduction to, referring to the Global Society of Rare Genitourinary Tumors.

Just to give you an outline, I'd like to just highlight some important topics related to penile cancer, and then we'll delve into the topic. For the purposes of the presentation today, I'd like really to focus on advanced disease. Advanced being bulky disease of inguinal nodes and recurrent disease and I would say that's probably one of the most challenging areas in the management of penile cancer in terms of caring for these patients. In terms of penile cancer, as we all know, it is a fairly infrequent cancer. If you look at cancer society reports for the past year, about 400 deaths reported secondary penile cancer. For the most part, it represents less than 1% of all malignant neoplasms that is seen in US and in Europe. We clearly see a higher prevalence of this cancer, unfortunately, in some areas, some parts of South America and Africa and India as well.

One of the first topics to highlight is there has been some changes in the staging of penile cancer in the past year. The AJCC launched the eighth edition in which really the main focus here is the T2 to T3 distinction. It used to be that we didn't really make much of a distinction between spongiosum and cavernosum involvement. In fact, we do see, based on some data actually from MD Anderson and in a collaboration with our institution, that corpus spongiosum involvement actually does better than cavernosal involvement, so there was the distinction between T2 and T3, and I always sort of highlight the fact that whether or not the urethra is involved really is not a distinguishing feature anymore between T2 and T3.

Really, another important factor is for the nodal status, whether you have nodes up to two millimeters, two unilateral inguinal lymph nodes that are involved without external extension, that represents N1, and if you have greater than two nodes, whether that be on unilateral or bilateral side, without external extension, you go onto N2. This is, I would say, a somber, but really highly relevant slide. Really, it was one that sort of highlighted the fact, if you look at registry data from both SEER and from Europe, you see, ultimately, when you look at the five-year survival rate from penile cancer, ultimately it has not improved. One of the most, I would say, depressing thing we see is that we often see that the systemic regimens that we have for the management of this condition have been for the most part disappointing, and I know that Jad will discuss a little bit some of these exciting new opportunities and trials that are taking place.

Again, if you look at it, in some countries we see that there was an increased incidence of penile cancer over time, and similarly, we see that as males get an older age, typically over the age of 65 or so, we see really a peak in the incidence of penile cancer. We also see, when you see and look here, that again, if you look at the mortality rates over time, ultimately, they really, for the most part, have not changed in the past probably 15 to 20 years. Again, highlighting the fact that we still have a lot of work to do in optimizing the management of advanced disease.

Again, this is one that sort of shows, for the most part, the incidence has gone up in some parts of the world, like in Norway, but again, the survival rate is flat and mortality rate, for the most part, has not improved. I will say this is just a review article that I was fortunate to write with a colleague and friend of mine for Germany. We do understand that penile cancer, for the most part, goes and progresses along two pathways; the HPV related pathways in about 40, 60%, and HPV negative pathways, which, for the most part, are very challenging to treat for many parts. For the most part, they do not respond to systemic therapies and our radioresistant. We do understand as well that HPV, as a pathway, we understand some of the modulators through the retinoblastoma gene, for example, P53. I think there's a lot of excitements and immunotherapies, for those part, may have a role, particularly in these. I think vaccines as well as a novel area that's being pursued.

This is just a review that we published and actually just was released about a week ago in Nature Reviews Urology and it highlights the fact that yeah, we understand now some of the pathways and definitely there are some targetable areas that we feel that there are some systemic therapies. Unfortunately, one of the challenges with penile cancer is due to the rarity of cases, it's very hard to do phase two, phase three clinical trials really focused on penile cancer, and often it's sort of encompassed with other squamous cell carcinomas when it's being looked at in phase two and phase three studies. Jad will take us on some of these exciting areas in terms of some of these systemic therapies that are being looked at.

Jad Chahoud: As Phil was mentioning, looking at the immune side of these, on your left hand, you can see that one of the first things that have been used as a biomarker for immune therapy response in other solid malignancies has been the PD-L1 expression, which is significantly high in penile cancer, ranging between 40 to up to 60% in different studies, but another important thing that we probably would need to explore in a cancer that is in part of [inaudible] driven is also looking at the tumor microenvironment as a whole and the multiple complex integrative things that go in different compartment of the immune environment. That work is being undertaken right now between Anderson and Moffitt Cancer Centers.

We tried to look at immune microenvironment by doing multiplex immunofluorescence and this is our first work. We wanted to look at cytotoxic T-cells and macrophages and try and look at interaction in different immune compartments. These are slides highlighting the multiplex immunofluorescence work. As you can see on the left side, the first images show a high infiltrative macrophage tumor microenvironment versus on the right hand of the first figure a low environment, low macrophage environment. On the second graph, we can see highly cytotoxic exhausted T-cells infiltrate. The first one in orange and then on the right side you can see a low cytotoxic exhaustive T-cells, and we're highlighting these images in our initial work. We have shown that when the tumor microenvironment is highly infiltrated with macrophages, which are seen as CD68+ cells, that can predict disease-free survival, overall survival and cancer-specific survival in a cohort of around 70 patients with this disease.

We also were able to show, as you can see on the next slide, that the exhausted cytotoxic T-cells when they were hired in stroma environment, that was also predictive of disease-free survival and overall survival and cancer-specific survival in penile cancer. We are taking this work now one step further and trying to validate it with a cohort with looking at different types of macrophages between M1 and M2 to see if that is a specific role for the M2 macrophages in creating an immune hot versus immune-cold microenvironment.

In conclusion, our work was able to highlight that elevated macrophage density in the tumor microenvironment was significant, a lower risk of recurrence and improved overall cancer-specific survival, a low level of exhausted stromal cytotoxic T-cells will improve penile cancer survival, and further work on specifically evaluating the role of T-cell infiltrator macrophages in penile cancer is underway.

Phil Spiess: I'd like to take it back now in terms of, really, I would say, what is the standard approach to fairly advanced disease. When we say advanced, we're talking about bulky. People define that typically anything over three to four centimeters and an important factor, and I see this among some of the patients that are referred to me, is we were all taught that when someone presented with penile cancer with palpable nodes in the inguinal area that we should treat these patients with a course of antibiotics for several weeks. That paradigm has shifted to one in which a biopsy of those nodes to confirm whether or not they, in fact, harbor metastatic disease is probably the more prudent approach.

There's many reasons for that. One is obviously you do not want to delay care. You want to identify patients who have advanced disease early on and get them on to systemic therapies. Ultimately, the course of antibiotics is ultimately just delaying care. There are some instances when clearly, of course, antibiotics may be beneficial, particularly if you have overlying cellulitis and you feel that you need to treat that. Obviously, you may impair getting these patients onto systemic therapy or potential patients who have shotty nodes in the setting of an infection and you feel that may be an indication of a more inflammatory infectious source. You see, ultimately, that the performance of a biopsy, like many other cancers, is excellent with really sensitivity and positive predictive value in excess of 90 to 95%. The risk of needle track, which traditionally is always a concern in the oncology world, is really essentially 0%.

This is some, I would say, pivotal work that was done actually by one of my mentors at MD Anderson, Dr. Curtis Pettaway, and Lance Pagliaro. They really did a very important phase two trial looking at multimodal approach to penile cancer. They had done some previous retrospective work looking at this, but in the setting of bulky disease, in the absence of distant disease, they were able to show that giving systemic chemotherapy in the form of TIP based chemotherapy for four cycles followed by surgery in a cohort of 30 prospectively gathered patients at least showed that response rates of about 50% were generated and about 73% of patients went on to surgery.

When you look at the complete response rate, it was only about 10%. When you look at last followup, again, 30% of patients were without evidence of disease at 34 months. It really highlighted the fact that really bulky disease should be looked at as a multimodal systemic approach in how do you treat patients for several reasons. These patients clearly are at risk of progression of their cancer, and you want to perform surgery, ultimately, when you feel they would benefit this procedure. Some of these survival curves really highlight the fact that whether or not they respond to chemotherapies, you see here on the bottom curve, really makes a very significant difference in progression-free and overall survival and you clearly see as well that unfortunately, for the most part, these patients are at very high risk of progression of their disease and ultimately deaths secondary to disease.

This is some work we did as part of a collaborative. This was just published a couple of months ago in the British Journal and it really tried to see if we can optimize and identify optimal responders to neoadjuvant chemotherapy. It's just an extension of some of the work in the phase two trial of Dr. Pagliaro. It highlighted the fact, again, if you see, [inaudible] activity, ultimately, is a predictor of clear progression, and clearly patients who have a poor performance status do worse as you see here. Lastly, but not least, is clearly the bulk of disease clearly is a strong predictive of how patients do.

As you see, as well, is that whether or not patients are candidates for neoadjuvant chemotherapy, if they are, and they get it, they clearly do better. If they're not, and they get potentially suboptimal therapy, clearly there's really not that dramatic a difference. Although this was still significant, the curves do, for the most part, somewhat are less divergent. This is actually a very useful, I would say, predictive model you can use in your practice in terms of predicting recurrence in patients after they undergo surgery. Really, what we did is we looked at patients who underwent surgery and tried to see what were the drivers of which ones ultimately would benefit from adjuvant therapy. You see here, the number of lymph nodes resected, the number of positive lymph nodes for metastatic disease and the pathological nodal status and surgical margin status all sort of come in to help you predict ultimately risk of progression, ultimately, potentially who could benefit from systemic therapy, and the link there allows you to directly access this useful risk calculator.

This is a meta-analysis we also published and Jad was part of this collaboration with a fellow. We really wanted to sort of put all the systemic data, systemic review data, together from both the retrospective and prospective and try to really gather what essentially is what we anticipate to be response rates. We have a phase two. We do as well have some retrospective data. When you're sort of asking yourself, what's, ultimately, the likelihood of response, the objective response rate in the score's plot is about 53%. Again, about half the patients will respond and that's somewhat consistent with what Dr. Pagliaro had reported in phase two. Also, in terms of complete response rates, it was 16% that was noted here when you sort of took all the data together. That's typically what we tell patients; about a 10 to 15% CR rate is what you anticipate.

One of the important factors, again, that is important to highlight is clearly, as we were just discussing, is you have a subset of patients clearly, which will benefit from systemic chemotherapy, but at this point, when you sort of gather the data from large data registry data in terms of what predicts survival, and this was done at National Cancer Database, over 1100 patients were looked at, and you see that there is been a sequential increase in utilization of systemic chemotherapy in patients, and a large part came from that phase two study, and also from guidelines, which sort of advocate for that. The factors which predict how a patient ultimately is going to do in terms of overall survival is still surgery. Inguinal lymph node dissection was associated with better overall survival, so whether they underwent chemo, radiotherapy did not predict overall survival. It was only surgery that did.

I think this is highlighted quite well here. When you look at the survival curves, you see, again, if you had surgery, whereas if you did not, clearly these curves are somewhat splayed. Again, among the cohort of patients that did not undergo surgery, whether they got chemotherapy or whether they had radiotherapy essentially made no significant difference in the curves. Obviously, when you look at data from a registry data set like this, there are some inherent selection biases. Maybe the patients that had a better performance status were the ones that underwent surgery. There's clearly some caveats to looking at this data. Also, an important factor is when you look at the patients who underwent inguinal lymph node dissection, as you see here on the right curve, ones that everyone inguinal lymph node dissection, whether or not they had chemo or whether they had radiotherapy really made no difference. These curves were consistent, but the curves really splay ultimately based on whether or not they underwent inguinal lymph node dissection.

We also published, really, an editorial letter looking at this data, really, in two large data sets; one taken from our center and one from our colleagues and collaborators from Milan, Dr. Necchi's group. Really, again we saw that utilization in neoadjuvant chemotherapy had improved and had significantly, and about 67% of patients had received neoadjuvant chemotherapy. Again, the factors that predicted survival, both cancer-specific and overall survival, was surgery with no perioperative treatment associated with improved outcomes. Again, you see here that nodal status really was a strong driver of progression-free cancer-specific and overall survival.

Management of local recurrence and this is actually some data that's unpublished, which one of my fellows just gathered. I thought this would be highly relevant to sort of look at, and this is really looking at a large data set of over 1400 patients who underwent inguinal lymph node dissection and looking at the patterns of recurrence, and this is an important factor is that recurrences typically will happen the first two to three years as you see here. Most distant recurrences, really, the peak is about 12 to 18 months and people always ask, well, how do patients with recurrences do? Well, you clearly, for the most part, patients who have local recurrences typically are salvageable with another form of local therapy or regional therapy, but the patients who unfortunately who have distant recurrences either in the pelvis or distant sites really do quite poorly and are very hard to salvage with various forms of systemic therapy or clinical trials.

We looked at, I would say, a question which was written, for the most part, has been poorly studied is: what do you do with patients who undergo surgery for inguinal lymph node metastasis and have an occurrence in the local regional areas? Is there a potential role of doing essentially salvage surgery in that area? We looked at a cohort, a highly selected cohort, I would say, of 20 patients and we saw the median time to recurrence was about seven months. Most of these recurrences in the regional area typically will happen within, again, the first six to 12 months and of that cohort of 20 patients that underwent salvage inguinal lymph node dissection and regional recurrences, you see about nine of 20 patients where NED at last follow-up. I would say there is a subset of patients close to maybe 40 or 50% of patients that are potentially salvageable with surgery, usually as in the form of a multimodal regimen. Typically, I would say that PET CT is a very useful modality in helping you tease out which patients potentially would benefit from this.

These are some of the curves, again, highlighting the fact that in a subset of patients, there's no question there may be a role. I do want to highlight a fact that some centers and colleagues have asked me, what's the role of using radiation as a salvage modality in the same setting? This is some data that was reported from the group from the Netherlands and unfortunately, the data with salvage radiation is really not as good. Most of these patients typically will progress. You see overall success of salvage radiation was only successful in about less than 10% of patients.

How about doing a more aggressive surgical resection for isolated retroperitoneal nodal recurrences? I would say that's a highly, highly, highly selected cohort of patients. These are patients typically who have a recurrence in an isolated retroperitoneal site who have stability disease typically for at least six to 12 months. Again, PET CT is a very useful modality to help you look at and identify those patients. Really, in some instances, you see that some patients are salvageable and cleared. There may be a role, but again, this really should be discussed in a tumor board and really including the input of medical oncologists, surgical colleagues in radiation, oncology colleagues as well.

I definitely would highlight the fact there are some very interesting and novel clinical trials that are taking place right now. I think that this is definitely going to be more to come in terms of the role of immunotherapies in these patients. I think that it's definitely an exciting time to hopefully treat these cancers because clearly there is much to do. Last but not least, I just wanted to highlight an important clinical trial that's taking place as part of a large collaborative across United Kingdom, United States, Canada, and in fact, some select sites in other remote areas including South America and India actually is being looked at. That's the InPACT trial, which is being led by Dr. Nicholson and Pettaway. I've been privileged to be involved with this trial as well, overseeing the Surgical Oversight Committee from North America.

They highlight, really, two simple points is that this study is really looking at patients with more advanced disease, bulky disease again, and seeing if there's a role of, again, neoadjuvant chemotherapy or chemoradiotherapy in these patients. And patients who have high-risk features, high-risk features being the presence of bulky pathological nodal disease or external extension are then candidates for randomization two, which is to undergo a pelvic lymph node dissection or adjuvant chemoradiotherapy. Just to give you an idea where this study is at: thus far, 39 patients have been accrued to the study. I would say that although accrual was slow, most of this is clearly identifying sites that see a decent or adequate amount of patients, and also making sure they have a multimodal committed team of colleagues that are involved in this care, but we're definitely excited to see that the accrual is significant improving, and hopefully we will be reporting out in the years to come.

Last but not least, as I mentioned earlier, there is an initiative taking place really to study and to highlight some educational opportunities in the care of rare genitourinary tumors. This is the Global Society of Rare GU Tumors that's just launched a few weeks ago and this is some information for those interested. This is a society we really need to highlight colleagues and patients and families. We're interested in getting additional information and potential resources in terms of trials that may be available for patients. Thank you very much.

Ashish M. Kamat: That was great, Phil and Jad. You guys really covered a whole lot of advances in a very short time. Maybe we could go in and move backwards a little bit in some ways. Phil, do you want to expand a little bit on the Global Society and how it ties into the penile cancer algorithm and what you expect to both gain and offer from this endeavor?

Phil Spiess: Thanks, Ashish. I'm so glad you asked that. Really, I think the EAU, the AUA, SEO do a wonderful job advancing knowledge and research in many areas, including penile testicular cancers, but what we really highlighted is there may be additional opportunities to really have a focus on caring for these cancers through, really, a gathering of expert thought leaders, but also colleagues that want to know more about these cancers and really that came to be that we really thought that it would be a wonderful opportunity, particularly right now where clearly virtual meetings and the societies allow us to collaborate and interact through multiple international sites to do so. This collaborative really is trying to gather people who are interested in really advancing the field.

What we're trying to also do is involve parts of the world, potentially, where there may not necessarily be resources in terms of experts or educational material for colleagues. As an example, one of the initiatives that Global Society of Rare GU Tumors is planning on doing is gathering a pathological subcommittee, which will develop the educational resources and virtual lectures and webinars for pathologists in some parts of the world that may not necessarily have the experts to have a resource of information they can gather. I'm excited to see there's a lot of enthusiasm taking place with regard to this society at this point.

Ashish M. Kamat: No, it's really great. Thank you again for inviting me to be part of it more. More than honored to join the society. Let's go to the penile cancer aspect of things now. You covered a lot of information, which is really great and our viewers can go in and track the video and follow the data. If I could put you both not so much on the spot because you guys do this all the time, but maybe highlight some common clinical scenarios that urologists and uro-oncologist, a medical oncologist might face when they see these patients in their clinic and share with us how you would recommend we, counsel patients. Start out with the small penile tumor, then the locally advanced tumor. Counsel them on maybe minimally invasive surgery versus the traditional groin dissection. In general, walk us through how you counsel different patients.

Phil Spiess: I think that's a very important topic is that there's a lot of, I would say, misinformation related to penile cancer, and oftentimes, as we all see, sometimes these patients present somewhat late with their disease. I think there's an important educational resource for healthcare providers to be aware that these cancers, although rare, they clearly do happen, but the patients that we do see in our practices with localized and small volume disease, for example, that is confined to the primary site, oftentimes those patients are excellent candidates for local, I would say, organ sparing treatments, and you're able to excise and resect the tumors with really, truly excellent outcomes and maintain really excellent quality of life. I definitely see that is something that's being advocated for more and more, but there's no question. I think anyone who has these types of tumors do benefit from coming to high volume centers, where clearly there is the expertise and the ability to offer some of these more innovative and reconstructive techniques.

For the patients for advanced disease, I'll definitely let Jad comment on this, but there's a question. I think there's an important opportunity to care for these patients in a multimodal fashion and I would say most of these patients with advanced disease, if they're candidates for these trials like InPACT, we clearly consider it. For those that aren't, we discuss them as a multidisciplinary group and ensuring we use systemic therapy or radiation therapy when appropriate to try to optimize their outcomes.

Jad Chahoud: I completely agree with Phil. From our experience working in a big academic center, we cannot emphasize the importance of having a multidisciplinary group that focuses or has a niche or has an interest in penile cancer and the importance of having these patients being treated at big academic center, where clinical trials are available now a bit more on the clinical side, beside the discussion that goes at the beginning of viewing the images with Phil and Dr. Johnstone, our radiation oncologist, who is our partner that focuses on penile cancer care. The next step from a medical oncology standpoint, as we've highlighted in the talk, we expect that 50% of the patient only will respond and then from this 50%, unfortunately, another 40 to 50% will have relapse of the disease. From the first day I meet the patients, I try and gather HPV information.

The reason is not only potentially prognostic and we're having more and more data highlighting that patients with HPV positive tend to have better prognostic outcomes than HPV negative, but also since it can open clinical trials that are focused on HPV TCRs or HPV [inaudible] therapy or HPV vaccine therapy if they end up having relapse disease and their HPV positive. Looking at a MSI, looking at the molecular pattern, seeing if we have any specific mutation that can be an opportunity for the patients to be enrolled in a clinical trial, or if the patient has to go back home to receive salvage therapy. Now we have recent FDA approvals two, three weeks ago for Pembrolizumab for patients with a tumor mutation burden higher than 10. We've had a couple of patients we've treated with Pembro in the advanced setting, and we'll probably going to be reporting this case and with high tumor mutation burden and have had a good, excellent response to Pembrolizumab with long universal survival.

I think trying to get this information early on, even when you're still planning therapy is very important because the disease phase is quick. When the patient relapses, we need to have your plan that day because they're going to have probably local complications from wound and whatnot.

Ashish M. Kamat: Really, Phil and Jad, that's been a great discussion. We could go on on this topic for quite some time, but in the interest of time, let me ask you, Phil, if you could tell us what's coming down the pike? What do you think are going to be some of the advances that we should look out for, I guess, in EAU and ASCO 2021 when it comes to penile cancer?

Phil Spiess: Yeah. Great question, Ashish. I think, at first, I congratulate our colleagues from Europe, the eUROGEN initiative of gathering Centers of Excellence that care for penile cancer really is providing some wonderful data from high volume centers and really setting a benchmark of quality in the care and then the research. I do definitely applaud that. I will say that I see some really exciting opportunities in the management of penile cancer. There's no question for a localized disease. I think the utilization and adoption of peanut sparing regimens is just improving more and more today, so I definitely see that there is going to be improved emphasis on offering that to patients and particularly in patients with lower-volume disease. There's no question that robotics, minimally invasive techniques like dynamics, [inaudible] biopsy, something that our colleagues in Europe, particularly in the Netherlands and the United Kingdom have really refined at a very high level is going to really continue to redefine the management of patients with high-risk tumors with the absence of nodal metastasis.

In the advanced setting, I think there is no question. I think the InPACT study will provide some very benchmark quality data in terms of current regimens with systemic therapy. And I think, as Jad was nicely highlighting, there is no question. I think we're seeing more and more that the role of immunotherapies is continuing to being refined for the management of these conditions. Some research that we're working on right now, which I think Jad is leading and I'm definitely involved in some interesting trials and efforts is HPV vaccines is something which is also evolving fairly quickly and really finding novel ways of potentiating immune response to these tumors using either vaccines or various forms of CAR T, for example, is something which is being looked at in tumor-infiltrating lymphocytes. I think there is definitely some evolution that's taking place and I definitely think now it's a matter of optimizing potential use of immunotherapies potentially with these other ways of potentiating an immune response.

Ashish M. Kamat: That's a very nice summary. Once again, guys, thank you so much for taking time off from your busy schedules. This has been a wonderful discussion for our audience. You brought up vaccines, of course, we're in the throws of waiting for a vaccine for COVID-19, but until then, educational activities such as these are really beneficial. I really do thank you. Both of you stay safe and stay well.

Phil Spiess: Thank you very much.

Jad Chahoud: Thank you very much.