Urology Times' 50th anniversary is this year, and we are celebrating by highlighting 50 pivotal innovations from the past 50 years. This week, we are spotlighting advances in testosterone therapy, with expert insight from Dr. Mohit Khera.

50th Anniversary Innovation Celebration: Testosterone Therapy

BPH, benign prostatic hyperplasia, is an extremely common condition that affects 50% of men above the age of 50, and nearly 100% of men as they approach the age of 80. This condition is plagued by lower urinary tract symptoms, which include things like frequency and nocturia, getting up at night due to urgency. Patients can be significantly bothered. Now, when it comes to this condition as a whole, there is a tremendous prevalence to it. There are a lot of patients who suffer with this condition, and it comes in sort of a spectrum. There are patients who have some mild symptoms and do well with things like watchful waiting, time voiding, and dietary changes. There are other patients who will require either medical therapy, minimally invasive surgical therapy, or even surgical therapies for their condition.

Medications for BPH come in a few classes. We have alpha blockers and 5-alpha reductase inhibitors, such as finasteride and dutasteride. We have the PDE5 [phosphodiesterase-5] inhibitors, like tadalafil, and bladder-specific drugs that come in 2 varieties of antimuscarinics and beta-3 agonists. Data from specific classes of drugs show that alpha blockers have been associated with potential conditions such as dementia or even congestive heart failure. When it comes to 5-alpha reductase inhibitors, there are data on their effect on depression, long-term pelvic pain, as well as sexual function issues that can last after the drug has been stopped. Ultimately, when it comes to these medications, a lot of patients may be on them; approximately 14 million men are on these medications. At the same time, there is a fair number of men who start these medications and will stop due to adverse events, fear of long-term effects, as well as intolerance to them.

Over the last year or two, there’s been a tremendous change in the urologist’s armamentarium in treatment options for benign prostatic hyperplasia. There is a need for treatments that are more natural, based on herbal medicine or alternative treatments, in addition to the thorough treatments that we’ve seen in the minimally invasive realm. When it comes to supplements, I can tell you from personal experience, that patients are always very interested. They inquire whether there are things that can help modulate or reduce the burden of their disease or reduce progression. Are there things that they can do with their diet to improve their condition as well? There’s definitely a clear need for alternative therapies when it comes to BPH.

When it comes to options for alternative and complementary medicine for BPH, a simple search on Amazon will yield approximately 30,000 products. The point is, this is a large market where patients have tremendous interest, but there is little oversight. There’s a slew of options when it comes to nutraceuticals, all the way from saw palmetto to pygeum and stinging nettle. There are supplements that have been looked at for prostate and prostate-specific health conditions. When we talk about data, we’ll see that a lot of these supplements don’t necessarily have the strongest data, but some of them do have some compelling mechanism of action and promising worldwide data.

Videos

Expert perspective on the treatment landscape of benign prostatic hyperplasia and lower urinary tract symptoms.

An Overview of Treatment Approaches to BPH and LUTS

 is professor of surgery in the division of urology at Albany Medical College in New York.

Prostate-specific antigen (PSA)-based screening and detection of prostate cancer has remained an active area of research and debate since its widespread utilization began more than 3 decades ago. The imbalance between benefits and harms (overdetection and overtreatment) associated with PSA-based cancer detection, as gleaned from the early results of 2 large trials, resulted in the US Preventive Services Task Force (USPSTF) giving a grade D recommendation in its guideline—ie, recommending against PSA-based screening—in 2012. This quickly and significantly reduced PSA testing and biopsies. Although there was a decrease in overdetection of low-risk prostate cancer, there also were increasing rates of advanced and metastatic prostate cancer over the next few years.

A reassessment of the benefits of PSA-based screening in 2017, supported by long-term data from clinical trials, resulted in an upgrade of the USPSTF recommendations to grade C. The guidance was applicable only to men aged 55 to 69 years, with an individualized decision to undergo periodic PSA-based screening after a discussion of the potential benefits and harms. The USPSTF guidance did not address screening in men younger than 55 years and recommended against PSA-based screening for men 70 years and older. The effect of these changes in recommendations regarding PSA testing or cancer diagnosis is unclear.

A study by Leapman et al sought to evaluate the association between the current USPSTF grade C recommendation and national rates of PSA testing.

 The authors queried the administrative claims database Blue Cross Blue Shield Axis, which provides care to approximately one-third of the privately insured US population. Their goal was to identify patterns of testing in the age group (55-69 years) specifically addressed by the USPSTF guideline as well as among those men who are outside the recommended age range (40-54 years and 70-89 years).

From January 1, 2013, to December 31, 2019, PSA testing trends were studied in male beneficiaries aged 40 to 89 years. The overall median number of eligible beneficiaries for each bimonthly period was 8,087,565, more than 50% of whom were aged 40 to 54 years. The median number of eligible beneficiaries in the group aged 55 to 69 years was 3,372,772, and the median number of men in the group 70 to 89 years was 148,195.

For the entire cohort of patients aged 40 to 89 years, the mean rate of PSA testing increased from 32.5 per 100 person-years in 2016 to 36.5 per 100 person-years in 2019 (

 < .001), an absolute and relative increase of 4.0% and 12.5%, respectively. For the groups specified in the USPSTF statement, men aged 55 to 69 years, the mean rate of PSA testing increased from 49.8 per 100 person-years in 2016 to 55.8 per 100 person-years in 2019 (

 < .001), corresponding an absolute and relative increase of 6.0% and 12.1%, respectively. Among the group of men aged 40 to 54 years, the mean rates of testing increased from 20.6 per 100 person-years in 2016 to 22.7 per 100 person-years in 2019 (

 = .001), an absolute and relative increase of 2.1% and 10.1%, respectively.

For the group of men aged 70 to 89 years, rates of PSA testing increased from 38.0 per 100 person-years in 2016 to 44.2 per 100 person-years in 2019 (

 < .001), representing an absolute and relative increase of 6.2% and 16.2%, respectively. The largest absolute increase in PSA testing was noted in the group aged 70 to 74 years (8.2%, 

 < .001), and relative increases in PSA testing were observed in all subsets of patients 70 years or older.

The data presented by the authors clearly demonstrate that changes in the USPSTF’s prostate cancer screening guideline from a grade D to grade C recommendation (for men aged 55 to 69 years) was associated with an increase in PSA testing in all age groups. Despite maintaining a grade D recommendation (do not screen) in men aged 70 years or higher, this age group demonstrated the largest (up to 16.2% relative) increase in PSA testing. Although no specific recommendations were made for younger men aged between 40 and 54 years, a significant increase in PSA testing was also noted in this group. Whether this increase in PSA testing will reverse the previously reported increased rates of locally advanced and metastatic disease related to insufficient PSA testing remains to be determined.

This raises several clinically relevant questions, including the usefulness of the USPSTF recommendation and how it may affect clinical decision-making regarding PSA testing. It appears that changes to the USPSTF recommendations resulted in unanticipated, wide swings in PSA testing, ranging from insufficient testing after 2012 recommendations to excessive testing following 2017 guidance. Clearly, indiscriminate, population-level screening with the PSA test is inappropriate and harmful due to downstream consequences of overdetection and overtreatment. 

A nuanced approach to PSA-based screening requires assessment of life expectancy and a discussion of risks and benefits of screening 

 to PSA testing. It is a lot easier to include statements in guidelines regarding proper counseling, and shared decision-making, than it is practical in real life. Who should be responsible for the added requirement of thorough counseling? Should it be the urologists, who tend to favor PSA screening, or the primary care providers, who order the vast majority of screening PSA tests? Regardless, it is safe to state that PSA tests are obtained by both primary providers and urologists without specific or sufficient counseling to satisfy the intent of the guidelines.

It is worth remembering that injudicious use of PSA test, and the downstream consequences of overtreatment and complications, can obscure the benefits associated with PSA-based early detection of prostate cancer. The increased rate of PSA testing and resultant overtreatment increases the number needed to screen and the number needed to treat, potentially diluting the positive impact of PSA testing.

Several advances have been made since the 2012 USPSTF grade D recommendation. Risk calculators, additional biomarkers, genomic tests, multiparametric MRI with targeted biopsy, and increasing adoption of active surveillance have transformed the landscape prostate cancer detection and treatment. What was once thought of as a linear inevitability of PSA test resulting in biopsy, overdetection, overtreatment, and complications has been curbed to a some extent over the past decade. We have the ability to apply the brakes at any of these steps along the PSA screening paradigm to mitigate the harms associated with increased PSA testing.

1. Leapman MS, Wang R, Park H, et al. Changes in prostate-specific antigen testing relative to the revised US Preventative Services Task Force recommendation on prostate cancer screening. 

 Published online November 11, 2021.. doi:10.1001/jamaoncol.2021.5143

Articles

"It is worth remembering that injudicious use of PSA test, and the downstream consequences of overtreatment and complications, can obscure the benefits associated with PSA-based early detection of prostate cancer," writes Badar M. Mian, MD.

Unexpected increase in PSA testing after USPSTF recommendations 

The Global Society of Rare Genitourinary Tumors (GSRGT) launched during the pandemic, hoping to give a voice to those who have or treat rare cancers in this space. In a recent interview, 

Philippe E. Spiess, MD, MS, FRCSC, FACS, 

share how they aim to develop an environment that emphasizes education, patient advocacy, and clinical research for this subspecialty—one that has historically failed to receive the spotlight as much as other, more common cancers. Spiess and Necchi serve as President and Vice President of this organization. Spiess is a genitourinary oncologist and assistant chief of surgical services at the Moffitt Cancer Center in Tampa, Florida. Necchi is an associate professor at Vita-Salute Raffaele University and the head of genitourinary medical oncology at IRCCS San Raffaele Hospital and Scientific Institute in Milan, Italy.

 The [GSRGT] was really created as a non-financially driven or incentivized initiative to gather thought leaders who are dedicated to care [for] often underfunded and often heterogeneous tumors, in the sense that because they're less frequent, in many parts of the world, unfortunately, there [are] not consistencies in how they're cared for. Andrea and I have collaborated on research for many years now, and this came about through some of our projects. We realized very quickly that there are some parts of the world where many of these cases are either not reported in the literature, or there are, unfortunately, some inconsistencies in how they're cared for. And sometimes patients are not getting the best-quality care. So, back and forth, the 2 of us really came to the realization that there was a critical need for a society to be funded [that] focused specifically in this area. This was a total grassroots effort. We decided to do this and to embark on this journey together, and it's been incredibly rewarding because we've seen this grow from a concept into something which has really gotten a lot of, I would say, more than just regional or attention among people that are in this area, but within the health care community and oncology community as a whole. There are a lot of wonderful initiatives taking place right now in research, in education, and patient advocacy, which this global society is really focused in. I really do see, in many areas now, there's a lot of reference to what we're working on and what we'd like to develop. I really foresee this becoming a very critical society in this area for many, many years to come.

 I can only echo Phil's words. I think that the most impressive things that we realized since the very beginning is the fact that our primary focus was to give some important reward to patients affected by rare tumors. But, as a matter of fact, we resulted in giving voice to physicians and clinicians dealing with these types of tumors, or for clinicians from underrepresented countries, or clinicians working in the hard territories and dealing with the huge problems of discrepancy, geographical limitations, and so on. So, the huge added value of our work is dedicated to time together with the patient and working on the patient's side.

What makes this society unique from other organizations?

 There are some organizations, whether you talk about [the American Society of Clinical Oncology], the [European Association of Urology], or the [American Urological Association], that have obviously touched on rare cancers, but there isn't a significant focus in it. There are some societies we collaborate with to try to develop a network of centers of excellence for the care of rare cancers. Our focus is complementary to that a little bit. We're trying to do a 3-prong approach. One is education of health care providers globally. That's not only doctors. That could be a general oncologist, or it could be a nurse practitioner, or it could be a nurse. Two is, very importantly, patient advocacy. There needs to be a voice for patients who are impacted with rare cancers, and that's central to what we do and what we've been really focused in. A lot of advocacy groups have come to us and [seen] how we can collaborate. That's very unique. Three is research. We have a lot of initiatives in rare cancers related to research as well. We do have now thought leaders from many parts of the world that are engaged with us, and I think we have an opportunity to do not only clinical trials, [or] retrospective or prospective studies. Andrea has brought up a lot of wonderful thoughts of studies we could really do with pharma[ceutical] support in this area in the future. I think that this is critical. We've had a couple global summits dedicated to specifically focus on rare cancers that have been highly successful, and that's also very different because there are rarely conferences dedicated to this where you're getting all the thought leaders in a given room. When we have a big meeting, typically penile and testes cancer is given a 1-hour session to go over the whole [topic] and all the research. It's not enough, and you can't deep dive into the content—what are the critical needs, demands, and I would say, opportunities from a research standpoint—and really focus on elevating the understanding and education of the global community.

 It’s exciting to realize that we are taking the global trend of the entire management of solid tumors, because even frequent cancers, like prostate cancer or bladder cancer, are becoming much, much [more rare due to] the identification of specific pathways or specific features related to the biology of the disease that actually dissect the disease in multiple diseases. And so, when we are dealing with 

-mutated prostate cancer, we are dealing with rare tumors despite [it being a] globally frequent cancer. The aim of our society and the principles of our work apply to this type of approach that can be applied to any type of tumor that is considered under this perspective. So, we are actually in the same line of clinical research, and we may benefit from our experience in addressing the special needs from the from the patient and physician side, mainly from underrepresented countries towards this global trend of clinical research. And this [causes], of course, huge problems. For example, access to genomic testing, access to new drugs as Phil has already anticipated, [and] access to clinical trials. There are several societies [and] there is an increasing interest towards these types of limitations that we are experiencing in clinical research, in performing clinical research. Patient access in general to any new drug is a problem, and we have set the basic principles to deal with these types of problems.

Please describe the various focus groups that comprise the GSRGT.

 The society is really broken down into multiple different subgroups, and it was critical we do that just because you can't accomplish everything, and you need to have focus. When you look at the hierarchy of the society, our mission is really focused in 3 given areas: Education, patient advocacy, and research. Those are the highly focused areas, and we do have subcommittees. [I'd] really like to mention [that] we have a pathology subcommittee, which has been unbelievably successful. Lara Harik [, MD] from Emory University has done an exceptional job. She's taken this on, and really what she's done is developed webinars and gathered some of the top GU pathologists in the world and turned this into a major conference. I think the first meeting had over 700 people. It was impressive to see the feedback we got. And so, that group works autonomously, but is under the umbrella of the global society. And on the education side, we clearly wanted to make sure, again, we meet the needs of all health care providers. That means we have focused research for physicians and residents, and young trainees. Nursing is a critical area and patient advocacy is a huge area.

On [the] patient advocacy side, we have patients that are leading that effort. I may think I know the needs of my patients, [but] they know far more about what they're dealing with and what they're facing. So, we made that a critical area of focus. That also has been very rewarding because we've been able to work with some international societies in developing that.

On the research side, this is an area we're actively working in right now. There's a lot of opportunity there. We have committees dedicated to clinical trials, to databases, specifically either prospective or retrospective. We've done some survey-type studies as well to understand where the greatest needs are within given areas. In addition to that, we have focus groups divided on these specific disease sites, so penile, testicular, urethral, adrenal—all these areas have specific subcommittees as well. This society also has a leadership team. Andrea and I lead this from a President [and] Vice President standpoint, but we also have a group of leaders from around the world, representing all ethnicities, genders, and others, because we wanted to make sure we were we're inclusive and make sure that we meet the needs and expectations of everybody. Last but not least, we have a funding and a membership group that helps us lead the other subgroups.

 It's exciting to see how many young, talented people are growing within our society, young talented urologists, oncologists. We have set a very, very fruitful collaboration with the European Association of Urology [and the] Young Academic Urologists group. One of our aims is also trying to provide education, research, and career opportunities for young people that are growing in their career. They may have, in our society, the possibility to publish and the possibility to be leaders for the present and for the near future, and to promote international studies. This is not possible at the country level or a single institution level. It is something that we should also consider anytime [we] deal with the people that aim to build a career in oncology. It is not surprising that, as Phil mentioned, the pathologist [is] so far, a primary role in leading activities. The first step that we do every time we [have a] patient with a rare tumor is to ask for a review of the pathological diagnosis. So, this is actually in line [with] the singular physician perspective and the single institution side. And so, the pathologists are a primary role by nature when dealing with rare tumors and based on the developments in molecular pathology and the understanding and edification of new features within more frequent tours, I suspect that they will have a growing interest and role in our society.

What are some prevalent issues that the society aims to tackle?

 [In terms of] the developments of the treatment possibilities for the patients, the geographical discrepancies, the social discrepancies, and the impact of these discrepancies in the possibility for the patient to access any type of cure or surgical intervention is critical. So, we will do everything that's possible to provide that [and] to set up collaborations, to establish connection with major societies and with their providers and regulators in order to see, identify, and network that may help in minimizing these limitations.

On the other side, as Phil has mentioned, we have the clinical research. Doing clinical research internationally has become tremendously difficult, so [what] we can do and what we are aiming to do so far is to provide a network for centers to provide to collaborators in order to set up prospective studies and retrospective studies. The possibility to provide a reliable network of centers that may contribute [to a] specific and reliable amount of patients in specific situations is something that is regarded to as optimal, as an added value. The companies, institutions, and organizations see, from the clinical research standpoint, another added value. And so, in the near future, what they would see is the possibility of promoting and sponsoring trials. This will enable us also to directly impact the clinical researcher with new therapeutic strategies. This is something that is not our primary aim of today because the former initiatives had a prevalent impact on our growth and on our growth and on our interests so far. This is at least from the clinical research standpoint, and then we have the plethora of educational activities and career opportunities that we may provide. They [represent] the major goal together with clinical research.

 There is a lot that we need to tackle in rare cancers. Awareness [and] education are critical. I see that our footprint is there. I think, in a way, starting the society in the middle of a pandemic was not necessarily a bad thing because virtual really allowed us to touch many people from many parts of the world. I think that's one of the benefits we've seen—[that] we don't always have to necessarily travel to meetings. And sometimes we could do this very, very fluidly, particularly in parts of the world where it's challenging to access and for people to reach out or attend meetings. So, I think we have a lot of opportunities. I think there's a huge area we need to tackle because, in many parts of the world, access to care is very limited. We want to continue to touch not only centers where there clearly is expertise, but parts of the world, [like] Africa, South America, parts [where] we have strong affiliations and partners that wanted to work with the global society. We want to continue to grow that relationship, and to continue to play an increasingly important role in that area. And I really do see some exceptional opportunities there, just through some major work we're doing right now on our website, and other things we're doing to elevate that and to provide those resources. One thing that's going to be launching fairly soon is a tumor board case, which will be put on Twitter and other social media sites, where we'll present a case to clinicians. It'll have clinical pearls there in terms of the critical things you need to think about when you're caring for a given type of rare cancers, and those are things that people will be able to apply directly in their practices. Those are really exciting for us.

How can clinicians get involved in the society?

 There are many different ways. We have a high presence within social media. I think that was really critical. We realized very quickly that the good old days of medical journals or just word of mouth is good, but it's not really the way you're able to touch people. Most of us now look at our Facebook, Twitter, Instagram, and whatever else, and it's a really easy way to access. So, definitely people should be on the lookout about the society. Definitely check out our website, GSRGT.com, and our Twitter, @GTumors. Those are a preview of what's out there. There are a lot of resources that are going to be on that website, which we're creating in terms of educational material.

And to formally become a member, there's no catch here. You don't need to pay to be a member. We will not be sending you any news or superfluous type of information, which all of us hate getting on a monthly or weekly basis. This is really pure content, and it's there to meet the needs of people. And so, I want to reassure people that this is really meant to be something which is going to be beneficial for people interested in the care of these tumors.

 These possibilities will, of course, be implemented in the near future and we are going to rebuild and reshape our website. This will be instrumental [in providing] clinicians [with ways] to access and join our society.

Is there anything else you feel our audience should know about GSRGT?

 The important thing to know is that we aim to focus on the regions that are not under the light of researcher education, in particular in the GU space. What is important for us to make people aware [of] is the fact that within our society, they may provide and they may get access to a perspective from clinicians and health care providers that are not currently providing them with [what] they were provided within major societies or the majority of other societies. So, we can provide a different way of looking at things and looking at developments. Despite our growth [in] the United States and Europe, the focus and the primary activities is out there, [for example,] in India, in Africa, [and] in Asia. We may provide this type of special point of view as perspective that is very original in the context of the existing organizations in this tumor area.

 There are a lot of people out there in the health care field who want to get involved in organizations and want to roll up their sleeves, and do impactful work. This is, again, [a] grassroots, non-hierarchical-type society in a sense that we're always seeking people who want to work in various groups or subgroups of our society, or engage, particularly in parts of the world where there may be an underrepresentation. Please reach out to us. We're looking for people, the bright and most engaged. So, definitely something which continues to grow, continues to have a need, and we want to continue to really be a global society. We don't want to be focused in Europe and in North America, solely. We want to be in parts of the world where there may not be any clinicians. We could be a resource for health care providers, and patients as well to make them understand some of the important considerations. We are working with major organizations like the WHO [World Health Organization] and others to hopefully strengthen relationships in the future. I do think that we definitely have opportunities to do that in the coming months and years.

In a recent interview, Philippe E. Spiess, MD, and Andrea Necchi, MD, shared how they aim to develop an environment that emphasizes education, patient advocacy, and clinical research for rare genitourinary cancers.

New society for rare genitourinary cancers aims to build education and awareness

Dr. Gomella, a member of the Urology Times Editorial Council, is professor and chairman of urology at Thomas Jefferson University, Philadelphia.

Our general trend over the years has been this concept of multidisciplinary care, whether it’s for patients with prostate cancer and now increasingly for patients with bladder cancer. I think that when you look at multidisciplinary teams, I think it’s really critical to have certain elements in place. Obviously, the urologist understands a lot of the surgical implications. There are issues with intravesical therapy, which again is often administered by either our advanced practice provider, nurses, medical assistants, depending on the particular environment of the clinic. The interaction I think which has been stressed between the nursing staff actually doing some of the administration and the supervision of the urologist in the clinic is very important.

Things like urostomy management, you really need somebody with ostomy training if you’re going to be a comprehensive, multidisciplinary team. Certainly, on that multidisciplinary team it’s very important to have other support individuals. At our multidisciplinary clinics we have social workers that are involved. While genetic counseling is not yet really firmly embedded in bladder cancer, I’m sure it’s going to be getting there very quickly. Having the availability to have genetic counselors, dietitians to help these patients in times of need and also other social support—psychological support—should be available. You don’t need to have them actually in the clinic but you need to have the ability to refer to other specialists.

We can’t ignore radiation oncology. There’s a lot of work that goes on with bladder preservation today that we’re partnering with our radiation oncologists. The core members of the multidisciplinary team are the urologist, the medical oncologist, and radiation oncologist. Then, we need support staff to help us both in the nursing context and then other healthcare providers to that specialty in certain areas. We’ve been doing multidisciplinary care. In fact, 2021 was the 25th anniversary of our GU [genitourinary] multidisciplinary clinic at the Kimmel Cancer Center, so we’re very engaged with multidisciplinary care. It’s not only good for the patient and the family, it’s also good for our trainees and all the other disciplines who get to work in that environment. I really think that the multidisciplinary team for all of GU oncology, and in particular for prostate and bladder cancer, is the way to go.

Elements that are critical to ensuring that patients with bladder cancer are managed appropriately by various healthcare professionals who will likely interact with patients and their family throughout the cancer journey.

Multidisciplinary Care in Bladder Cancer

I think Karim you make a good point. Traditionally, the urologists are not comfortable with these infusions. Certainly, we’re very comfortable with intravesical therapies but one of the things I think we have to keep in mind is that with immuno-oncology there’s a whole new panel of potential side effect profiles—pneumonitis and GI [gastrointestinal] issues and pituitary issues and things like that. I do think that we’re going to have to be very mindful for this as we go forward. To follow up on that theme a lot of these immunotherapies that we now have in advanced bladder cancer are systemically administered. I’d like Petros to talk about in his clinic, in his medical oncology work, who really does the infusions? Are they always supervised by the medical oncologist and given by the advanced practice provider? How is your daily infusion of immunotherapy in your practice?

 Thanks so much Len and great discussion so far. I appreciate the comments by you, Sam, and Karim. When it comes to systemic therapy infusions, I think the medical oncologist has a major role and our colleagues in urological oncology refer to patients to medical oncologists for any systemic therapy including chemotherapy, immunotherapy, targeted therapy, so on and so forth. One of the main reasons is we have this academic context here and we have additional clinics but in terms of operationalizing and managing the administration of systemic therapies and with the side effects, I think the team here recognized that the medical oncologist has the resources and treatment to, and starts to deal with management of side effects that may happen from systemic therapies.

In terms of your great question about the logistics and the operations of administration, there are many medical oncologists, people who may see the patient, meet, evaluate, assess, discuss all the options, risks, benefits, alternative options, rationale, the data. A decision is made with the patient in an informed and fair decision manner and the patient embarks on systemic therapy, then infusions can take place. In those subsequent infusions an advanced practice provider and nurse practitioner or a physician assistant can see the patient before each administration and evaluate the patient in terms of symptoms, history, physical exam, and laboratory findings and if they feel the patient needs systemic therapy they can go ahead.

When it comes for a scan review, a restating CT of the chest, abdomen, and pelvis, I think with IV [intravenous] contrast, if that’s possible, then the attending medical oncologist sees the patient to do the scan review. In between, there is a continuous communication, I would say, between the practice provider and the medical oncologist and the nursing. It’s a team approach, we have team huddles, and we discuss every patient every week. We can anticipate, predict what might be needed, and also react to any types of side effects. Sometimes patients may come in on [INAUDIBLE] in order to be evaluated for a possible side effect. The last point I will make is we have a close communication with our infusion room and clinic. Like every other cancer center, we try to create space and time so we’re extending the hours in the weekdays including weekends to provide more capacity in the infusion room. And, of course, discussion with the infusion room nurses have a very important role in the administration of systemic therapy.

 Sam, certainly in the community setting there’s a lot more infusion being done. I think in most academic medical centers, I think most of us sort of have an agreement with medical oncology that they do most of the infusions and we handle some other aspects. What do you think the trend is going to be with urologists and infusions, particularly in the large urology groups out in the community?

I think that’s an excellent question, Lenny. I think the large group practices are clinicians; they’re not just urologic surgeons. They provide care for patients. In terms of who is going to be giving the medications, I think in those large group practices, as long as individuals understand, gain the knowledge, gain the importance of careful evaluation, follow up recognition of possible symptoms, therapies for possible side effects associated with immunotherapy, I think there’s going to be a continued trend to include immunotherapy in its IV formulation. Perhaps in the future there will be subcutaneous formulations to provide the medications and treatment alternatives for these patients.

I think the large group practices also understand the importance of a relationship ongoing with medical oncologists, and to be honest, some of those large group practices, as you know, have incorporated oncologists themselves within the group practice to help care for these patients. I think there’ll be a trend towards more large urology practices to do systemic therapy, but I think it will be very limited in scope in terms of who will be actually doing it. Those advanced practice providers would be an essential part of that team as well.

Administration of systemic therapy and management of side effects in patients with bladder cancer.

Treating Bladder Cancer in Community Settings

Metastatic castration-resistant prostate cancer as a sort of a disease state has evolved pretty dramatically over the last couple of years, and we’re really poised to make additional changes. Among the most important issues is actually what happens in the castrate-sensitive metastatic setting. When people talk about a sequence of therapies, the first thing you have to figure out is, what happened when they were castrate-sensitive metastatic? We know that there is level 1 evidence, really practice-changing evidence, that ADT, androgen deprivation therapy, intensification with drugs like abiraterone [Zytiga], or apalutamide [Erleada], or enzalutamide [Xtandi], or docetaxel is the standard of care. We also know that its adoption rate still has a ways to go. When somebody says to me, “What’s a standard sequence for a patient with mCRPC [metastatic castration-resistant prostate cancer]?” There is no standard answer. You have to understand where we were in terms of what the patient’s received, what’s the clinical setting that the patient is currently in, is the patient symptomatic, or is this a PSA [prostate-specific antigen] only mCRPC progression? Are you a user of sipuleucel-T [Provenge] or not? Do you have investigation studies available? Did the patient receive an androgen receptor inhibitor? Abi [abiraterone], or enza [enzalutamide], or apa [apalutamide], in the castrate-sensitive setting? Because that will dictate changes and other changes are coming. We anticipate perhaps early in 2022, FDA [Food and Drug Administration] approval of an agent lutetium-177- PSMA [prostate-specific membrane antigen]-617 adding yet another drug to the mCRPC setting. There’s also evidence that likely will be presented over the next couple of months, which might suggest that patients benefit in the mCRPC setting by adding an ARI [androgen receptor inhibitor], drugs like abiraterone, or perhaps enzalutamide to a PARP inhibitor. There are a lot of changes, and you really have to sort of pay attention, but I think the key is the context of where the patient is by the time they arrive at mCRPC.

When people ask the question, what are frontline therapies for patients with mCRPC? Again, one of the things that I take into consideration before I answer the question is, where is the patient in terms of prior therapies? Were they a de novo presentation with metastatic disease and were they intensified with drugs like docetaxel or an ARI? Were they evolved from prior local therapy to metastatic disease and received androgen deprivation therapy only? What’s the context of where they are in terms of mCRPC? For example, is it a patient who got intensified with abiraterone, and now has a slowly rising PSA in a castrate setting, completely asymptomatic? Versus a patient who again maybe had ADT primarily, and now has not only biochemical progression but has new bone metastases and is symptomatic. How we approach these 2 different patients would be very different. There is limited sequence level 1 evidence to tell us that you must do X, Y, and Z, and part of it is because of not only the heterogeneity of the disease itself but increasingly the kinds of therapies that these patients may have seen prior. And that also may include genomic data. What is the BRCA [BReast CAncer gene] or ATM [ataxia telangiectasia mutated] status of a patient? Are there DDR [DNA-damage response] mutations?There’s no simple answer, but there is a way of thinking about the clinical spectrum that you have to start with to identify what might be the optimal therapy for an individual patient.

Robert Dreicer, MD, provides an overview of the first-line therapy options available in metastatic castration-resistant prostate cancer and the recent advances in detection, diagnosis, and treatment.

First-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer

Benign prostatic hyperplasia (BPH), or prostate gland enlargement, is a condition that is often stigmatized by patients and non-urologists in terms of who is diagnosed, what the diagnosis means, and managing the diagnosis.

 suggested that more physicians should take the time to educate their themselves and their patients on this condition. Specifically, he references new minimally invasive technologies and non-invasive management options for this population. McVary is a professor of urology at the Stritch School of Medicine and director of the Center for Male Health at the Loyola University Medical Center in Maywood, Illinois.

What are some stigmas associated with enlarged prostates from the physician perspective? From the patient perspective?

This is an excellent question because there are misconceptions in both groups, both patients and physicians. Let's start with the patient misconceptions. In terms of enlarged prostates, the idea is that enlarged prostates—so-called BPH—promotes lower urinary tract symptoms, urination difficulties, things like frequency, urgency, getting up in the middle of night, that type of thing. An important misconception on the patients’ side is that this is an issue of old, frail men. When this starts to happen to them, they wonder if this is an “end-of-life” sign. That is inaccurate. Men can start to develop urination troubles due to enlarged prostate beginning in their mid 40s. If it occurs earlier than that, it involves a lot of extra work to be sure that there isn't something else going on. But in the mid to late 40s is when men begin to experience some of these changes. Many of these changes may remain very modest over time. In other men, because of genetics, family background, perhaps lifestyle, this can worsen rather rapidly. So, it is common. This happens to old, frail men, but you don't have to be that in order for these things to start develop[ing]. Even though there [are] many therapies that one can do, it's not a sign of anything ominous for most men. And when I say “most,” I mean the vast majority. I don't want to say it is inevitable, [but] it is certainly common. And in many cases, there's prompt and good treatments. In other men, it's understanding that this is occurring, and if they can cope with the symptoms and signs of this and it's not otherwise affecting their health, they don't necessarily have to receive a treatment. They can be observed and followed and monitored. 

In terms of physicians' misconceptions, and I would say primarily non-urologists’ misconception, is that lower urinary tract symptoms from BPH is unavoidable and it is something that is treated with hazard. What do I mean? Well, they do occur with age, that's true. Although, again, many men who have the symptoms don't require a treatment. You need to assess them to be sure that it is not otherwise affecting their health in the sense that they can live with their symptoms, and their symptoms aren't a sign of a more serious underlying medical problem. If they can live with it, so can the physician. They can be, again, observed [such as through] active surveillance [or] watchful waiting.

The other issue with physician misconception is that the treatments are hazardous, that our interventions are significant and pose significant risk to patients. This is decidedly not true. What am I referring to? Many non-urologists might think that the only option available for men are things like the [transurethral resection of the prostate], which is an effective treatment for prostate symptoms, but the field has evolved, where we have several minimally invasive therapies that do not require hospitalizations, that do not require inpatient surgery, and that can be treated very efficiently and safely in the office setting. Really, patients can come in, have an appropriate office-based procedure for their BPH, and drive themselves home. And after a period of recovery, [they can] have an excellent response in terms of symptoms with a minimum risk on sexual function. So, that's probably another misconception of non-urologists, maybe even some urologists—that BPH treatments impacts sexual function. [It] is true that some do, but the newer minimally invasive therapies are much less likely, and in some cases unlikely, to have any impact on sexual function at all. By that, I mean no impact on erection and no impact on ejaculation, another aspect of sexual function that has probably been underplayed.

How do these stigmas surrounding enlarged prostates affect management of patients with prostate cancer or other prostate-related diseases?

One thing, which is very common, is [that] men equate the urination symptoms of BPH with cancer. So, there can be many sleepless nights where they are worried that they're getting up at night now, and that this is a sign of prostate cancer or bladder cancer. This is decidedly not the case. It's actually unusual that a man with prostate cancer would present with these urinary symptoms. I mean, it is possible, but it's highly unlikely. And so, there's a bit of reassurance that has to occur to patients to reassure them that this is unlikely to be a malignancy. [It's] very common. I think that fear, in some men, leads to panic and perhaps overreaction. [In] other men, it may keep them at home, sleepless at night, and destroy the quality of their life because they're thinking, "Oh, boy, this is going to be the big one." So, I think that has a decided effect on presentation. The other [aspect] really dovetails in with what I spoke about before: "These invasive treatments are going to ruin the quality of my life. They're going to ruin my sex life and make me dependent on pads or catheters." Again, that is unlikely to be the case. These are newer [minimally invasive] therapies. If used appropriately, and that is a doable thing for a skilled urologist, this can maintain or, in some cases, improve not just their urination and quality of life, but also their sexual function. So, that requires an accurate diagnosis, a global assessment of their urination health, their prostate health, and we can discern these issues out with very good accuracy. It's a very rewarding place to be [as] a treating physician right now in terms of addressing some of these BPH issues.

What is the urologist’s role in destigmatizing enlarged prostates?

Having the prostate enlarged, again, does not mean that it's bad for you. I mean, you can have this and be totally [okay]. I'll give you an example. You're an older guy, you're starting to get up at night. You go with some urinary frequency, but your life is such that if you get up a couple of times at night, you sleep in a little bit in the morning and you wake up refreshed. You don't need treatment. If you're otherwise doing okay, if your bladder is getting reasonably empty, and there's no impact on a renal function—and the urologist could discern all this—the urologist can live with you living with that. That requires an assessment and an accurate diagnosis, so you would do a symptom assessment, [or] a quantitative measure of symptoms. You would do some prostate health maneuvers, perhaps a [prostate-specific antigen test], certainly examine the urine, looking for things that might mimic BPH lower urinary tract symptoms. [For example,] a man whose diabetes is out of whack will [have] a lot of urination symptoms. The prostate has an nothing to do with that; his diabetes has to get in better control. So, urologists [are] very skilled at kind of discerning out these issues and getting down to why men are having the complaint. At that point, once you know all this, then it's pretty straightforward in terms of offering men a series of options. You could do it serially, like, try pills, try interventions, perhaps try more significant surgeries. Or men can say, "I'm not a pill taker. I'd like to explore a minimally invasive option right away." That's also completely and totally appropriate. So, you line this up and help patients educate their way through it once you have an accurate diagnosis.

Is there anything else you feel our audience should know about this topic?

I think there's [3] other things. One is that sometimes other physicians will say, "Well, it's only BPH. Live with it, grandpa." I see this, and non-urologists need to understand [the situation] from the patient's perspective, which is really the place where we [as] physicians sometimes falter. From the patient's chair, he looks at some sequelae of BPH urination symptoms equivalent to having a stroke or a heart attack. Now, it's not often life threatening, like one of those diagnoses, but from the patient's chair, in terms of the severity in his life, he equates those. A heart attack is the same as a stroke, which is the same as going into urinary retention. So, it's not a little thing to patients. Sometimes physicians underestimate the impact of these problems on their patients.

And the other [thing], I think, is something we're starting to come to grips with: What can patients do to either improve or prevent? It's pretty straightforward. It's a very consistent picture that there are lifestyle risks, which worsen or contribute to the development of BPH. By that I mean, diet and lifestyle, weight control, and exercise. Just like with heart disease, prostate [and] bladder health [have] a very strong influence from a patient's diet and lifestyle. What's the message? Well, very conveniently, a bladder and prostate-healthy diet is the same as a heart-healthy diet, and a heart-healthy lifestyle. That means lower caloric load [and] that means fight obesity. Try to prevent obesity. And I would say, more vegetables, less meat, and if it is meat, less red meat, more fish [and] chicken type of thing. So, the same thing we've been hearing for probably 2 decades about heart disease. [By] lifestyle I mean exercise. I don't mean Olympic-type exercises. It's moderate exercise. It's 10 or 20 minutes a day, or at least several times a week. It's losing weight; 10 pounds can make a big difference, not just in your heart health, but also in your urination qualities. Patients will report that all the time.

The other thing is [that] there are many non-invasive or minimally invasive treatments, which can be useful to patients, and they need to understand that. The word's getting out, but patients need to hear that more and they need to talk to [a] urologist who is up on this minimally invasive game to hear about that. And the other thing is that it turns out that family history is a strong predictor. So, if Dad and Grandpa both had urination problems, it might be very well that you are at risk for urination problems, and so maybe the dietary issues and the lifestyle issues need to be emphasized

In a recent interview, Kevin T. McVary, MD, FACS, suggested that more physicians should take the time to educate their themselves and their patients on enlargement of the prostate.

Common misconceptions about enlarged prostates by patients and physicians

Welcome to another installment of Uranimals, a video series featuring urologists and their pets, brought to you by Urology Times. From a rambunctious kitten to a whole family of animals, we have some great guests for you today. Let’s see who some of the top medical professionals are spending time with when they’re not in the clinic!

From a rambunctious kitten to a whole family of animals, we have some great guests on the latest episode of Uranimals, a video series featuring urologists and their pets.

Uranimals: Episode 5

: I’m often asked what is a reasonable second-line therapy for patients with mCRPC [metastatic castration-resistant prostate cancer], and when I think about that question, of course, the first issue is what’s the clinical status of the patient and are they symptomatic or not? What prior therapies did they receive, not only in the mCRPC setting, but did they receive ADT [androgen deprivation therapy] intensification in the castrate-sensitive setting? Lines of therapy actually don’t help me very much, because again a patient getting a second-line in mCRPC may actually be getting a third or even a fourth-line of therapy based on prior treatment. Maybe a non-metastatic castrate-sensitive disease. Maybe in castrate-sensitive metastatic prostate cancer. I tend to think about it more as what and where. Where is the patient? What prior therapies have been administered? If somebody says to me, “Hey, this patient has seen a taxane maybe in the castrate-sensitive metastatic setting and received an ARI [androgen receptor inhibitor], and now has overt disease progression and is symptomatic.” My answer may be very different, perhaps cabazitaxel [Jevtana]. I may also ask the question, “What’s the patient genomic status?” If somebody says to me this patient has a BRCA1 [BReast CAncer gene 1] mutation based on germline, I may then say, “A patient who’s seen an ARI or an ARI and a taxane would be a very good candidate for olaparib [Lynparza], and if a taxane has also been given, or rucaparib [Rubraca] because that’s level 1 evidence supported.” Again, the sequence and the number of prior therapies as opposed to an arbitrary line of treatment is important. There are still a lot of unmet needs in this setting. There are new drugs that may be approved here. There is a myriad of new compounds being studied in this setting. We have a dearth of therapies available, as we’ve moved some of these treatments earlier into the castrate-sensitive metastatic setting.

Not infrequently am I asked about how to approach patients whose biology seems to be very different. For example, a patient who may have received abiraterone [Zytiga] as ADT intensification for castrate-sensitive disease and now has slow PSA [prostate-specific antigen] progression is completely asymptomatic and maybe there’s a nodal disease. That’s a patient where I might think about sipuleucel-T [Provenge] or a clinical trial, or even potentially the alternative ARI if the abiraterone response had been very prolonged. The alternative to that is a patient who perhaps has extensive disease both bone and nodal disease, high volume or high-risk presentation with a de novo presentation, has a very short response to ADT intensification perhaps with a drug like abiraterone. I’m very likely to use a taxane in that clinical setting because I need to get some antitumor activity rapidly. I’m not likely to use a therapy like sipuleucel-T or the alternative ARI because I really need to see antitumor activity. Again, there are differences in biology and one has to think about how you might use therapies in sequence based on the clinical status of the patient.

Infrequently, I’m asked about the patient who has said, “Look Doc, I don’t want chemotherapy and might there be other options in the mCRPC setting?” In all honesty, I must tell you that there are very few symptomatic patients, and again, with the use of taxane-based chemotherapy in the mCRPC setting, I think there’s some nuance there. Again, although these drugs were developed, both docetaxel and cabazitaxel in this setting, we know that there is level 1 evidence and we see a modest improvement in survival. But I think that many clinicians who treat a lot of prostate cancer tend to use taxanes in the mCRPC setting when patients are symptomatic because of its rapid ability to improve disease-related symptoms like pain and decreased appetite, weight loss, fatigue, etc. I think part of it is to also recognize the taxanes; both docetaxel and cabazitaxel are actually relatively well-tolerated therapies. So I think it’s important not to lose the utility of a therapy just because of some historical concern or somebody just sort of blankly saying, “I don’t want to have chemotherapy.” That said, there are obviously alternative nonchemotherapeutic options. There are clinical trials and radium-223 for the appropriate patient with a bone-only disease that doesn’t have significant disease-related symptoms. Sometimes the patient who’s had the alternative ARI, who’s had a very long response may benefit from a clinical trial of the alternative drug, and there are a host of agents in the pipeline for investigation. There are still options, although limited options, and again I want to emphasize that taxanes typically are pretty well tolerated. We don’t want to take away from the patient who may benefit from these therapies just simply because they initially say, “Hey, I don’t want chemotherapy.”

Robert Dreicer, MD, discusses the available second-line therapy options and unmet needs in metastatic castration-resistant prostate cancer.

Second-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer

When it comes to prostate health, urinary tract symptoms, one of the best-studied supplements is probably saw palmetto. Now, saw palmetto has been used since the early 1800s. This supplement has been studied extensively in rat liver models, mouse models, and human prostate cells. Ultimately, saw palmetto has a very compelling mechanism of action in a couple of different ways. The first is that it can help modulate the androgen receptor signaling, helping to reduce the conversion of testosterone to dihydrotestosterone, which is a much more potent form of testosterone. The second mechanism that we’re seeing from saw palmetto is that it may help with the inflammatory signal pathway. As we know, as prostates enlarge, there’s definitely an inflammatory component to it. This inflammatory component can come from a multitude of reasons, whether it’s subclinical infections, natural parts of aging, or the fact that you have this imbalance of apoptosis and proliferation. This leads to free radicals that can attract different lymphocytes. When you have these lymphocytes present, this may lead to more inflammation. Saw palmetto may actually help with reducing this inflammatory pathway as well.

Saw palmetto has multiple components to it. I think one of the very interesting parts is that it almost has a signature of the fatty acids that go with it. When you have the appropriate fatty acid signature with saw palmetto, that can be found within the cell membranes of prostatic tissue. That’s what may lead to it working on its mechanism of action, both in the androgen receptor signaling pathway as well as in the inflammatory pathway. When it comes to this specific supplement, it does require the appropriate fatty acid signature to go with it as well.

When it comes specifically to the saw palmetto berry, there’s a multitude of ways to extract saw palmetto and the active components. The European guidelines suggests using a compound known as Permixon. Permixon is derived through the use of hexane. Unfortunately, hexane has been linked, especially in high doses, with a possible carcinogenic effect. Therefore, hexane-derived saw palmetto is not really available in the United States, although the amount of hexane in any of these supplements is minuscule. The other ways that it can be extracted are through a supercritical carbon dioxide extraction method, or an ethanol extraction. With each extraction method, you get a different fatty acid signature. Ultimately, when you look at the ethanol-derived or the hexane-derived, you can have the appropriate fatty acid signature that can end up leading to a more active compound for the saw palmetto.

When it comes to saw palmetto products that are available, especially in the United States, one thing we have to keep in mind is that these supplements are not regulated in this market. As a result, it’s sometimes very hard to tell from the bottle exactly how the saw palmetto was extracted, through what mechanism, how ripe the berries were, and if there is a batch-to-batch variation. Sometimes it leads to a wide variation of the type of saw palmetto and its efficacy that you can get from this compound.

Bilal Chughtai, MD, shares insight on the use of saw palmetto extracts in benign prostatic hyperplasia and lower urinary tract symptoms.

Uranimals: Episode 5

Second-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer

Saw Palmetto Extract in BPH and LUTS: Mechanism of Action and Efficacy