Janelle Hart

In this first installment of Asked by a Resident, Efe Chantal Ghanney Simons, MD, spoke with her mentor, Mark S. Litwin, MD, MPH, about the important lessons that he has learned throughout his career. Spanning personal successes, memorable patients, and influential role models, Litwin describes his lengthy and rewarding career in urology and advises others on how they can succeed in the field. Ghanney Simons is a PGY-6 urology resident and Litwin is professor and chair of urology at University of California, Los Angeles.

 It's such an honor and a privilege for me to have this conversation here with [Mark S.] Litwin[, MD, MPH]. My name is Efe Chantal Ghanney Simons. I'm a PGY-5 resident at UCLA in urology. Dr. Litwin, who's the chair of my department, has served as a mentor and as a sponsor, even preceding my time as a trainee. So, today, we have the opportunity to ask him some questions that we typically wouldn't have the chance to ask an attending in a busy clinical or OR setting. Dr. Litwin, thank you again for your time.

We're just [going to] jump right into it, because we have quite a few questions today. The first question I'd like to ask is, what do you wish you had known when you began your career?

 I wish I'd known how incredibly rewarding it would be. I think I viewed going into surgery and a surgical subspecialty as something that would be highly disciplined and highly demanding. Of course it is that, but I don't think I had a good sense of just how incredibly rewarding it would be. And not just the end game of being an attending and working my way up the academic ladder, but even in the course of residency, in the course of my training, it gives me pause to think back on that now as to how pleasant it's been so far.

 I'm really glad to hear that that's been your experience thus far. Speaking of the highs, I'd like to get a sense of the lows as well. Have there been any barriers that you've experienced in urology? Have there been instances where your identity may have played a role in those barriers?

 Let me answer it in 2 ways. First of all, overall, my sense is that the biggest barriers are those that we erect on ourselves. Not to say that society doesn't also erect barriers that we have to navigate, but I think the biggest ones are those that we put on ourselves in life and in general. On a personal level, as a gay man in urology, I think that the fact that I identify and live my life pretty openly with a husband and 2 kids is something that I perceive might have caused issues or problems for me. I was a surgical resident and urology resident among the Harvard programs in the late 80s, early 90s. It was a very different time, socially, and I was closeted at the time. It didn't really feel like it would be okay to be an out gay person in urology. It's the nature of the field, dealing with men's health, etc. Turns out that patients want the best doctor and the best medical care, and they don't really give a hoot about anything else, most of them. I think that's true for any individual in urology who may perceive that they have an identity difference in some way. I've counseled a lot of women urology residents about this in the past, as to how they would navigate men's health issues as a woman in urology; it's the same for men in gynecology. It cuts across a lot of different specialties. So, I think that that identity played a role in terms of [being] a barrier that maybe I erected, to some extent. And then, I found that just by simply being honest, living my life openly and candidly, no one's really interested in anything in my life other than if I can take out the prostate in a good way, or if I can treat the testicular cancer in an effective way, or if I can manage their urinary tract infection. That's really what it's all about.

 Now, can you speak to us a little bit about some of the greatest shifts you have seen in the field of urology over the course of your career?

 There have been a lot of shifts over the course of the past 30 years. I finished residency in 1991, so 30 years ago, and finished fellowship 2 years later. I would say that the biggest tectonic shift that I have viewed is the change in the administrative aspects of medicine and the demands that we have in order to practice, [as well as] the financial complexities of medicine and those challenges that are created. Administratively, the electronic medical record has been phenomenally great in many, many ways. And it is also soul-crushingly challenging and difficult in many, many ways. I'm not sure people really realize that when we made this mass shift to the electronic medical record, that's been challenging. The way that health care is organized or disorganized in this country is also extraordinarily challenging. I think that's gotten worse over the past 30 years. Patients who need prior authorizations and have formulary restrictions and you name it—it can really put a lot of barriers to practicing medicine. PET CT scans, [prostate-specific membrane antigen] for example, over the past few years required immense amounts of time of the physician to do administrative, financial clearance, and that kind of work. So, I've seen that increase a lot over the last 30 years. I think that is a good reason to really focus on what we like in medicine and what’s effective and what's gratifying, because the negative stuff definitely gets to me sometimes.

 Speaking of focusing on the things that are gratifying, what would you say has been your biggest accomplishment? If you thought about your career as a movie, what would earn you your Oscar?

 That's a great question. It may disappoint you to hear that what I would consider my greatest accomplishment is actually not in my professional life, but my marriage to my husband, Adam, of 32 years so far, and my 21-and-a-half-year-old twins graduating college this year, Rose and Max. I think at the professional level, the accomplishment that I would say is most important to me, and what makes me feel inspired or like my best self, if you will, is seeing my mentees—both current and former—pay it forward, and seeing them take lessons that they've learned during the course of their training, some of which I may have helped them understand and some of which I may have just been a bystander, and begin to mentor their own mentees, be that a medical student [or] some high school student who's going into a STEM field. As mentees get more senior—I’ve been around long enough that some of my former mentees are pretty senior now—seeing them mentor people who are junior faculty, mid-level faculty, and even senior faculty, to me, is the greatest contribution that I feel like I have tried to make. The value of mentorship and trying to model that in a way that's valuable for anybody who needs it—for people who have particular challenges, as well as for people who come in without a lot of obvious challenges—everybody needs mentorship.

 Absolutely, and that's just music to my ears. That certainly resonates—all the points you made about mentorship. Congratulations to your kids with their graduation as well in college. If you weren't in medicine, what would you be doing with your life?

 I think I would be a rabbi. That may be not the response you're expecting. My affection and respect for people of the cloth is immense, and I think that the position that they play, the role they play in helping people through crises and challenging times, as well as being there to witness happy and celebratory times, is extraordinarily powerful and valuable. I have a sideline that I've been doing for the last 25 years or so, occasionally as a mohel, which is the ritual Jewish circumciser. Basically, [it is] just a neonatal circumcision done under local anesthesia in the home with a few prayers added for good measure. I do maybe one every month or two. So, it's not a busy practice, but I so enjoy doing that. I so enjoy being able to serve as the instrument of making the occasion important and meaningful for people who are going through that. If I were in medicine, but not a urologist, I don't know. I can't imagine doing anything else. You don't really choose urology, it chooses you. Once you're chosen, you know, you have to step up.

 So, we're [going to] switch gears a little bit to basically get a sense of some of the lessons you've learned along the way. What would you say is your most memorable patient encounter?

 Over the course of a career, there [are] so, so many memorable patient encounters. The one that came to mind was a young man on whom I was set to perform a post-chemotherapy retroperitoneal lymphadenectomy, RPLND. He was about 30, as is often the case in these patients, and after platinum-based chemotherapy for widely metastatic testicular cancer, he had a large residual mass on his retroperitoneum, just completely wrapped around everything—around his aorta his vena cava, his urinary structures, and it was just a case that I was really bracing for. It was one of these things we look at as an all-day surgery, and you know you're not going to get lunch that day. And it was during the time when we would sometimes admit patients the night before surgery. It's a very foreign concept today because it so rarely happens anymore. I remember going by his room in the evening on the way home from work the night before the surgery—he was doing his bowel preparation—and sitting down on the side of his of his bed. He didn't really understand the gravity of everything he was going to be going through, at least not in the way I did. But he understood that he was undertaking something big and that our lives were crossing at a very important moment for him in the course of his journey to health. As I sat on the side of the bed with him, I took his hand and promised him to do the best I could, to take excellent care of him. I wanted to inspire confidence in him. He asked me if I'd ever done a case like this before, and I thought about whether to answer completely candidly and decided to do that. I told him I had done many cases like this, [and] this was the biggest one I had ever done, but that the entirety of my career thus far was meant to bring me to that moment with that patient and doing that surgery. I think it's true for many of the surgeries that we do, but I really felt a connection with him, a human connection, so that the next day in surgery, it wasn't just removing a mass from around the ureter and the aorta. It was operating on Mr. So-and-so and making sure to hold true to my promise to him. At the end of the day, it was one of these really long days that you just come out totally exhausted. And fortunately, [with] a combination of technical skill and good fortune, we were able to get everything cleaned out. He is now many years post-op. He keeps in touch with me periodically. He went on to a good career, he has great appreciation for what he went through and for the role that I was able to play in helping to get [them] back to health. Now, certainly [for] the patient you see once for a bladder infection or a kidney stone, it's hard to have a long-term meaningful relationship with them. But certainly, in oncology, where we do get to know our patients over long periods of time, and it's very much helping manage them through a crisis, it is really, really meaningful.

 Thank you for sharing that. And again, that's an illustration of the blessing that we have as providers to be able to care for patients in that capacity. What would you say the greatest lesson has been from a patient?

 Patients take it as a given that we know what we're doing, intellectually and technically. But the lesson that's really powerful has been that what they need, in general, is more than that. What they need is some kind of human connection, to know that they're not only having a tumor removed, or a stone cured, or incontinence treated, or erectile dysfunction managed, but that they are themselves being viewed as the complete real human being that they are, and that the human connection with their doctor is part of healing. So, it's more than just technical, intellectual activity that we train for so many years to do, not to disparage the importance of that, but that it really is largely also about healing. Healing happens both at the physical level and at the mental, emotional, and even spiritual levels. And to the extent that we can be instruments of success in advancing all of that and getting them back to health, I think that's the most important lesson. And it is with every single patient, whether they acknowledge it, or you acknowledge it, or not, and it's more in some and less than others, for sure. But that human connection is what's so important.

 As we discuss this human connection or connections that you've made over the course of a career, who would you say are the 3 individuals who've impacted your career the most in the most capacity?

 Number 1, my mother, Sheila, who taught me from an early age the importance of interpersonal interaction and communication and attending to the right brain as well as the left brain, the importance of feelings, [and] the importance of connecting with people, as I was saying earlier. She continues to be an inspiration for me. As a single mother raising 3 children, she turned me on to a book called Love, Medicine, and Miracles by Bernie Siegel, which I highly recommend to anybody at least into oncology, about extraordinary patients and what makes them extraordinary.

The other 2 are perhaps a little more conventional. They would be William DeWolf [,MD,] who was for many years the chief of urology at the Beth Israel Hospital in Boston, and one of my senior professors when I was a resident at the Brigham. He passed away, unfortunately, from metastatic pancreatic cancer not long ago, and was a guiding light for me. He taught me about the importance of thinking big, dreaming big, and using that as a guidepost for my accomplishments. Nothing's impossible is what he taught me.

The other, I would say, to round out the list of 3 also recently passed away actually in the last month or so, is Hardy Hendren[, MD]. Dr. Hendren was the chief of surgery at the Boston Children's Hospital for many years. He was trained as a pediatric surgeon under Dr. Robert E. Gross, and he was at the Mass General for many years and then at Boston Children's for many years. Although he's trained as a general surgeon, his work was all in pediatric urology, and he was widely known as the individual who changed the face of management for kids born with cloacal exstrophy. I did many, many cases with Dr. Hendren that lasted 12, 18, 26 hours sometimes. We would even scrub it out to get a meal. But he taught me the incredible value of pursuing technical perfection in everything that we do. He was a reconstructive surgeon working with teeny, little patients, and so it was especially more important. So, I guess I would say he inspired my technical left brain and Dr. DeWolf inspired my passionate right brain.

 Wonderful. This is a trickier question—may not be for you—but what's the most important thing you've learned in your life? What was your life like before learning it? What was your life like after learning it?

 Easy question for me. The most important thing I feel I've learned in my life so far is the value of human interaction and human connection. I'm not sure I can remember back early enough to before I really knew that, but certainly, since I've come to that realization a number of years ago, it's guided every interaction that I have. I think it's the pathway to happiness for people, not just physicians, but for people in general. And it's really what makes life meaningful. There's a song that was popularized in the 1980s by an acapella group called The Flirtations led by a singer named Michael Callen, [who] died of AIDS. One of the lyrics in the song goes something like this: The only measure of your words and your deeds is the love we leave behind when we're gone. That comes from human connection, and I believe that with all my heart.

 I've definitely felt and experienced that time and time and again every time I've interacted with you. There've been moments where I've texted you to meet. You made space and time, and I felt heard, seen, and appreciated. And so, again, having this conversation with you today is such an honor and a privilege. Now, my last question for you is, if you could turn back the hands of time and talk to your 18-year-old self, what would you tell them?

 Relax and enjoy the journey. Our 18-year-old selves are concerned with getting into the right college to get the grades to get into medical school, to get the grades to get into residency, to get the fellowship or the post-training job. The focus on the destination is significant. And what I can tell you, from my perspective at this point in my life, is that it really [isn’t] about the destination. We all have the same ultimate destination, and I'm not sure we want to get there quite as fast as we may think we want to, but it really is all about relaxing and enjoying it. I think the journey really is actually better than the destination. If I had to complete this sentence: The most important thing residents need to know today is...the challenges of residency are finite, and it does get better. The role that you play as a resident is critical. It is not a job; it is a profession, and that patients and peers, and yes, even faculty, even senior faculty, really do care about your input on a particular case. Some people are more able to show that than others, but I think the reason that any academic went into academic urology, they will tell you, is because of the collaboration. Some of that's with peers, with other faculty, but really most of it is about collaboration with trainees, with residents, with the next generation. I trained in the Harvard system where one didn't really challenge one's superiors, but I think it's healthy. So, relax, enjoy the journey, life really does get better, and make human connections.

 Thank you, Dr. Litwin. Again, this has been an honor and a privilege. I know I keep parroting this because over the past 5 years, I've had the opportunity to learn at your feet, if you will. And just being able to share that with the rest of the world has been incredibly important and just really a joy.

 Thank you very much, Chantal. I would change the metaphor a little bit and say that any teaching I've done hasn't been with you or anybody out to my feet, but it has been walking side by side into the future. Thank you for that.

Articles

"The most important thing I feel I've learned in my life so far is the value of human interaction and human connection," says Mark S. Litwin, MD, MPH.

Asked by a Resident: Dr. Efe Chantal Ghanney Simons interviews Dr. Mark S. Litwin

In today’s world, it is easy to find information on the internet, whether it be through search engines or social media. Much of that information, however, is not reliable.

 confirms this idea by investigating the quality of information regarding recurrent urinary tract infections (UTIs) that is posted on YouTube. In this interview, coauthors 

, discuss the findings of this study and why it is important for urologists to understand where the sources of misinformation are coming from. This study was presented at the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction 2022 Winter Meeting. Huang is a urology resident and Kim is a clinical assistant professor of urology at Stony Brook Medicine in New York.

Please discuss the background for this study.

 As we all know, social media is becoming more and more important in everyone's life. There's TikTok, YouTube, Instagram, [and] really a wide array of medical information available out there on the social media. In the urology literature, we actually have quite a few studies looking at some of the urologic topics, such as prostate cancer, overactive bladder, [and] erectile dysfunction, to [investigate] the quality of those medical information on social media and found that some sources could present as a major source of misinformation for a lot of our patients. So, we turned our attention to urinary tract infections. It's fairly common in my patients, especially female patients. About 50% to 80% of female patients had a history of UTI, and up to 40% of them had recurrent UTIs. So, we were curious to look at the quality of the medical information on UTIs on YouTube. Hopefully, we can have a better understanding of what patients are learning from online materials before they come to the doctor's office. That's where the idea of this study was coming from.

What were the notable findings of this study? Were any of them surprising to you or your coauthors?

 We looked at the top 200 most-viewed videos on YouTube. I think it was interesting that a lot of the videos had relatively poor quality, based on the standardized instruments that we used to evaluate the quality of the material. Only 11% of the videos featured a urologist, which is a very small portion. Less than half of the videos actually featured a medical provider, so a majority of videos are being produced by non-medical providers, commercial media, or individual YouTubers with no medical experience. Then, we found that, very importantly, videos produced by medical providers have better content quality compared to those that did not feature any medical professionals. I thought those were interesting findings. This is consistent with other similar studies looking at online materials on medical information. We found that those that come from a medical institution or medical source or [were] produced by a physicianhad a better quality, with more accurate information.

 And didn't our results also show that most of the videos were actually about home remedies for UTIs and not necessarily other medical advice?

 Absolutely. Another very interesting finding was that a majority of the videos were featuring some kind of homeopathic supplements, such as herbal supplements or certain dietary remedies, to prevent and treat urinary infection. Some of the regimens, such as vitamin C, probiotics, or cranberries, do have scientific evidence—especially cranberries—featured in the [American Urological Association (AUA)] guidelines, but a lot of the other supplements, such as the herbal supplements or certain random dietary remedies, did not really have much of the scientific 

n the literature. Those can pose as potential misinformation for a lot of our patients who are seeking for treatments for UTIs.

With an increase in digital media use around the world, how can physicians combat misinformation?

 Ideally, if we can increase the presence of physicians on social media platforms, I think that can help deliver more accurate and more accessible information for the general public. I know that some physicians, some urologists in our field are making an effort to contribute to higher quality of online patient education material, but for those of us who are really busy with clinics, with the work in the hospital, I think another way to combat misinformation is to have a better idea of what is available on the internet so that we can provide better patient counseling when we see them in office.

 I'll add [that] every day when patients come to the office, everyone has done their "research" on urinary tract infections or other things, and we really need to understand where this information is coming from. I think this study shows us that a lot of the information out there isn't necessarily sound medical advice or given by non-medical professionals. So, I think it's essential to understand where information is coming from so that we can counsel the patients appropriately.

What is the take-home message for the practicing urologist?

 From my perspective, the main take-home message would be [that] social media is obviously very important, and it plays a very big role in impacting [the] patient’s decision to seek proper care and make their medical decision. So, as a urologist, as a practicing physician, we should be aware of the online content so we can properly guide our patients and provide proper care and counseling.

 I'll also add that I know all physicians are extremely busy, but I think it's very important to have a bigger social media presence with sound medical advice. I think it's tremendously helpful for patients, and also for counseling. So, I think in the future, physicians should try to take the time to invest some more energy in this realm. I think it's an area that we've done poorly in, and hopefully, if we increase our presence on social media, it'll help the patients and it'll help the physicians.

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

 I think some of these videos may actually lead to patient frustration, because they're giving some of these home remedies for UTIs. In some cases, they may work, but in a lot of cases they don't. Patients come in extremely frustrated, saying things like, "I don't know what's wrong with me. I've done my research on the internet, I've watched YouTube, and I've done everything they said, and nothing's working. What's wrong with me?" So, I think patients need to understand [that] they don't always work.

1. Huang Z, Jeong R, Lee E, et al. Urinary Tract Infection on Social media: Examining YouTube content as a source of patient educational information. Paper presented at: Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction 2022 Winter Meeting; San Diego, California. February 22-26, 2022. Poster #OM8

In this interview, coauthors Connie Huang, MD, and Jason M. Kim, MD, discuss the findings of their recent study, "Urinary Tract Infection on social media: Examining YouTube content as a source of patient educational information."

YouTube spreads low-quality medical information on recurrent UTIs, study finds

The InterStim X system, a sacral nerve stimulation therapy, has been recently approved by the FDA to help patients who suffer bladder and bowel control issues. In the following interview, 

, discusses why InterStim has been so “lifestyle-changing” for patients with overactive bladder (OAB) and gives some tips as to how clinicians can best implement the system in their practice. Law was recently awarded a Center of Excellence Designation by Medtronic, the manufacturer of InterStim. He is the chief of surgery at Oakwood Southshore Medical Center in Trenton, Michigan, and clinical professor in the department of urology at the Michigan State University Medical School in East Lansing.

What does being awarded Medtronic's Center of Excellence designation mean to you?

Well, it's been a company that I've been affiliated with since 1997, and they've made tremendous progress in terms of developing a much more improved way of not only capturing the patients that need help, but [also] assisting them. I was quite surprised and honored, obviously, because I'm a firm believer that this is an alternative and a solution to a lot of the patients that have life problems, in terms of their incontinence [and] their ability to socialize. [It] brings them out of the house and gets them sociable again, and it's a life changer. So, I was really honored that they even considered me. But, then again, I'm happy to be a part of this organization.

What is your caseload like in terms of patients treated with InterStim?

We probably address 10 to 12 patients every month with the unit. It's a trial period for 1 week and if they get the results that they want, we go forward. The way we've been doing stage 1 has been so successful that at least 95% of the people go forward with stage 2. I'm no longer doing the [peripheral nerve evaluation] PNE in the office because sometimes that doesn't capture the area that I'm looking for, so I'll do stage 1 in the OR with fluoroscopy, making sure that I have a good placement of the neural probe, and then connect that to an external lead wire. For 1 week, they just trial it, and because of that, I've been much more successful in moving forward with stage 2.

How has the use of InterStim improved your care of patients with OAB?

It's been a lifestyle-changer. I mean, there are people [who] were wearing pads, [who] were socially embarrassed, [who] were actually afraid to socialize or be out in public because of the urgency, frequency, and leakage. And then there's the other segment of patients that were in retention and had to cath themselves or wear a catheter. That group of people have also been successfully treated, not to the same degree that the urgency frequency patients in my practice are, but still there's a significant improvement in being able to urinate without cathing themselves or without using a catheter. But, like I said, the biggest improvement in my patients has been the urgency frequency and urgency incontinence, and even some of the patients with irritable bowel. Some of those patients have actually been able to improve their voiding and their bowel movements, so it's not so socially embarrassing. To me, it's a big game-changer, and they don't have the medications [where] they have to worry about the side effects of dry mouth, constipation, memory loss, and some of the other issues that come along with the anticholinergics. I'm excited. I don't go to it as a first choice; I usually trial the medicines at first. Those patients that don't successfully complete what they consider to be acceptable will go forward then with the trial of the InterStim.

Do you have any pointers or tips/tricks you've picked up along the way regarding the InterStim that you can pass on to other clinicians?

I think the main thing is placement of the neural probe on the first go around. To me, I tried [the PNE] in the office, I tried placing a wire, and many times it wasn't exactly where I wanted to be. One of the reps years ago said to me, "Why don't we just do this in the 1-day surgery center?" And I thought, "Well, that defeated the purpose," but when I started doing the stage 1 in the 1-day surgery center under fluoroscopy, and [placed] the neural probe in the proper position, my conversion rate to stage 2 jumped from about 75% up to about 95%. So, I think that's the tip—if you want to really get involved with InterStim, I'm not a big fan of the PNE, but I'm a big fan of placement of the neural probe initially in the right place so that [the] 1-week trial encourages patients to go forward with stage 2.

Is there anything else you would like to say about receiving this designation?

Just thank you. It's very much appreciated. The company has been very solid, and alternative companies have come around and I think they've only made them better. They went up to the challenge and they improved. We've now got an MRI-compatible unit, which is a huge improvement where patients—especially the MS patients that need their MRIs—can keep the unit in. So, I'm just very excited that the company would even recognize, reach out, and give me that designation and that honor. It's just very exciting to be a part of a company that's made such an improvement in patients' lives. That's what I've always tried to do as a physician—just making people happier, making people more comfortable. This company has allowed me to do that, and I thank them for the recognition and the honor.

"The biggest improvement in my patients has been the urgency frequency and urgency incontinence, and even some of the patients with irritable bowel," says David W. Law, DO.

Dr. David Law discusses the benefits of InterStim for patients with OAB

The increased prevalence of radiopharmaceuticals has provided the opportunity for patients with prostate cancer to preserve their quality of life. Although not many of these therapies are FDA approved, there is a lot of promise that they will be paradigm-changing in the future, according to 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies (NY GU 2022), Tagawa presented a talk on the evolution of therapeutic radiopharmaceuticals in prostate cancer.

, he discusses the main points of this presentation as well as other innovations in this space. Tagawa is a professor of medicine and urology and medical director of the Genitourinary Oncology Research Program at Weill Cornell Medicine in New York City. He is also an attending physician on the Cornell campus at New York-Presbyterian Hospital.

Please discuss the main points of your presentation.

At NY GU 2022, I was able to provide a review on therapeutic radiopharmaceuticals, titled, "The Past, the Present, and the Future," [which] really focused on 2 main ones: Radium-223 and PSMA-targeted radionuclides. The background for both is that radiation is one of the cornerstones in the treatment for prostate cancer—most traditionally, either shooting it in with external beam or putting it in with brachytherapy. We use it [to] both cure [patients] as well as [for] palliation, and then more recently, we've had a couple of drugs that have been able to be administered systemically to radiate certain compartments. Radium-223 is a calcium mimetic, meaning that we put into the blood, it circulates around, and lands in bone like calcium and specifically binds to hydroxyapatite. It's an alpha emitter, so a very potent piece of radiation with a very short penetration—just a few cells. [In] the ALSYMPCA trial [NCT00699751], which was in patients with at least 2 bone metastases [who] had symptomatic disease, radium-223 with best supportive care vs best supportive care led to a survival improvement.

Since that time, we've looked at a number of different [possibilities], such as, should we give more, meaning higher dose or more than 6 cycles? That's a no, answered by my colleague Cora Sternberg[, MD]. Should we combine? There are a couple of ongoing phase 2 and 3 trials. One combination that we know to not give is for patients with non-symptomatic or minimally symptomatic metastatic [castration-resistant prostate cancer (CRPC)]. Starting radium-223 with abiraterone, the ERA 223 trial [NCT02043678] showed us that it did not work, [and this combination] lead to increased toxicity in terms of fractures.

 Bone health agents, which we should be using anyway for patients with metastatic CRPC to bone, decrease that chance of a fracture and other skeletal related events. There are [also] 2 ongoing phase 3 trials assessing radium-223 combinations. So, a similar combination in PEACE III [NCT02194842],

 but rather than in combination with abiraterone [Zytiga], it is with enzalutamide [Xtandi] in men with chemo-naïve mCRPC. The investigators in Europe had the advantage of knowing ERA 223 and were able to institute early bone health agents. We've seen data at ASCO a couple of times, including last year, that shows that with the bone health agents, this looks safe, although we do not yet know efficacy. The DORA study [NCT03574571] is the combination of docetaxel and radium versus docetaxel alone in men with metastatic CRPC including bone metastases based on a positive randomized, phase 2 by Michael Morris[,MD] and colleagues. That is enrolling now for men with metastatic CRPC, and we hope to see a benefit from that combination.

We also learned to target PSMA with radioactive particles. PSMA is a cell-surface antigen expressed on the majority of, but not all, prostate cancers. We know that we can label small molecules or antibodies with either alpha emitters or beta emitters and maybe the future would be auger emitters. But for now, what is furthest along are the small molecules (although 1 antibody is in phase 3) radio-labeled with a beta emitter lutetium-177. In the last year or so, 2 randomized trials have read out. A randomized, phase 2 [trial involving] highly selected patients tested lutetium PSMA 617 vs cabazitaxel [Jevtana] in patients with metastatic CRPC after docetaxel. [A] majority happened to receive an AR pathway inhibitor as well, and there were PSA outcome measures that were improved. And then the VISION trial [NCT03511664] examined lutetium PSMA 617 in combination with best standard of care versus best standard of care alone, which led to an improvement in both overall as well as radiographic progression free survival.

Overall, this type of therapy is reasonably well tolerated. There are some specific adverse events that we do associate with these drugs, such as myelosuppression (including thrombocytopenia). There is also dry mouth and nausea, likely having to do with the PSMA-positive sites that these small molecules can reach in the salivary gland and small intestine, as well as the possibility of renal toxicity, although we haven't seen that to a significant degree. Despite the increase in some adverse events, there is a prolongation of time to deterioration of quality of life in the VISION trial, likely because of better disease control. So, these are the radionuclides that are either in practice right now, or likely soon to come, and we look forward to the optimization of these drugs.

Which radiopharmaceuticals are currently the most effective in this space?

Radiopharmaceuticals are clearly effective. We have 2 drugs that have proven overall survival advantages, [but] we have no head-to-head trials. So, we cannot say that one is better than another. These drugs are complementary. We have an alpha that targets bone. The advantage of an alpha is that it's very potent, with very short penetration and bone is a great target for prostate cancer because many men with advanced prostate cancer have bone metastasis. That is an advantage, as there's not a lot of other toxicity. The disadvantage is it goes to only bone and patients without bone metastasis we don't think will benefit, as well as patients with bone metastasis and other sites of extra-osseous metastasis are less likely to benefit in these sites of metastases. PSMA-targeted radionuclide therapy goes to all sites of PSMA positivity. Most of the drugs—in fact, all of the drugs in phase 3—are labeled with lutetium-177, which is a beta emitter. The advantage of a beta emitter is it has a longer path length, so it can go many, many cells. But the disadvantage is a longer path length and a weaker energy level, so there can be the potential for additional toxicity.

[Overall,] there's no known advantage or disadvantage in a head-to-head trial of either one of these, but I do think they're complementary. A relatively common question that I'll hear is, “Can we use both?” We do not know about the combination together, meaning concurrently. We do have some prospective data about sequential use. Most of the data have to do with radium-223 first, followed by one of the lutetium agents. That is 20% or so of many of the prospective trials. There are also data for patients that got radium-223 after these lutetium PSMA agents in some of the prospective, randomized trials, including VISION.

What are some other innovations that are on the horizon in this space?

With the existing drugs, we are looking to make them better. One way, which we've done with many different drugs, whether you're talking about docetaxel, abiraterone, enzalutamide, etc, [is] we made them better by treating a more optimal patient population, and that is early. We think that, particularly for the PSMA-targeted radionuclides, that is going to lead to more major improvements. So, hopefully [that means] translating a median of months to a median of years with a larger hazard ratio. We hope that we can better identify in whatever subset of patient population better patient selection. Imaging appears to be one way that we're able to do that. Hopefully, we'll be able to look at additional factors as well as potential from things like genomics. We're now looking at combinations. An obvious combination to me is in combination with [androgen receptor (AR)] or hormonal therapy, where we might be able to modulate both PSMA expression as well as radio sensitivity. There are a number of other combinations that are ongoing, not limited to but including PARP inhibitors as well as immune checkpoint inhibitors.

What I'm quite hopeful for are PSMA-targeted alpha emitters. We know that alpha emitters work in terms of radium-223, but that's bone-targeted rather than tumor-targeted. So, with these very potent radionuclides, we've seen anecdotes of some very impressive responses with now at least 3 prospective trials that are ongoing. One that is read out with an antibody called J591 radio-labeled actinium-225. There is another antibody radio-labeled with thorium-227 that is also ongoing that I expect to read out later this year. And then, even though the first one published anecdotally was PSMA 617, radio-labeled with actinium-225 because that was retrospective with the first prospective trial being initially last year. So, I think that there is a lot of hope that if we're able to safely administer these targeted alphas, that there is hopefully going to be an even bigger bang for our buck.

With the approved agent radium-223, as well as and probably even more importantly, with what we expect to be the soon-to-be-approved agent lutetium PSMA 617, besides the adverse events that may happen to the patient, we should be aware that there is some exposure to the public. The patient's immediate family and caregivers are likely to be the most effected. Lutetium has a low gamma emission rate, but when we give it at a therapeutic dose, there is a reasonably significant gamma emission where people can be exposed. For the most part, short exposures, especially being feet away from the patient, is not that big of a deal. But, particularly in the first couple of days after a therapeutic dose, we need to be mindful of other living beings. I suppose that could include pets, we generally think about family, so partners, kids, grandkids, etc. [It is] okay to interact, but in the first couple of days, not many, many hours of very close contact.

1. Tagawa ST. Therapeutic radiopharmaceuticals: Past, present, and future. Presented at: 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; New York City, New York. March 11-12

2. Hoskin P, Sartor O, O’Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. 

2014;15(12):1397-1406. doi:10.1016/S1470-2045(14)70474-7

3. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2019 March;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X. Epub 2019 Feb 6

4. Phase III radium 223 mCRPC-PEACE III (PEACE III). ClinicalTrials.gov. Updated July 31, 2020. Accessed March 22, 2022. https://clinicaltrials.gov/ct2/show/NCT02194842

5. Sartor O, de Bono J, B CH, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. 

2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

"With the existing drugs, we are looking to make them better," said Scott T. Tagawa, MD. 

Janelle Hart

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