Raoul S. Concepcion, MD, FACS

Historically, the urology community has been the “gatekeeper” for the diagnosis and management of prostate disorders, malignant or benign. Prior to the advent of medical therapy and minimally invasive procedures to treat benign prostatic hyperplasia (BPH), if one were finishing their training and in search of a job opportunity, the litmus test to determine how busy a urologist was in practice was to ask how many transurethral resections of the prostate (TURPs) were being performed annually? If the number was more than 125 cases per year, that was considered a robust clinical practice. My recollection from my case log as a resident in the late 1980s was maybe 100 cases over a 4-year residency span, and I cannot fathom what that might look like today in the modern era! The transition from open prostatectomy, TURP, medical therapy, and now minimally invasive procedures has required, to some degree, subspecialization to optimize outcomes rather than being the staple procedure for all urologists in practice.

The evolution in the diagnosis and management of prostate cancer has been equally complex. Akin to BPH, the various facets of the disease require the urologist in practice to stay abreast of the many advances and breakthroughs that are constantly being developed in order to stay current and provide state-of-the-art care. To that end—especially in larger independent practices, and certainly in academic centers—we have specialization in certain clinical areas within prostate cancer itself.

The early detection of prostate cancer remains critical and should always be in the hands of urology to educate the broader medical community. Mistakenly, we have applied the term 

 to the various tests deployed. In its purest form, a screening test is used to aid in the detection of a certain disease in an asymptomatic population. A positive test suggests the high likelihood of that condition being present, and a negative test would indicate the absence of disease.

 Prostate-specific antigen (PSA) is not a good test for screening, but if it is used judiciously, it is still the linchpin in early detection of prostate cancer. Despite the controversial and subsequent reversal of the US Preventive Services Task Force (USPSTF) recommendations,

 most PSA testing is still carried out by primary care physicians in the United States.

 It is our role, as the subject matter experts, to educate our primary care colleagues on the limitations of PSA testing, as well as the following:

The goal of early detection is to identify those patients at risk for significant prostate cancer.

Current adjuvant testing to PSA, whether that be imaging or liquid-based testing.

For decades, we have understood that if a man lives into his eighth or ninth decade of life, there is a strong likelihood that he will develop histologic prostate cancer, but not necessarily die of this disease. Most of these individuals will have a lower Gleason Score and Grade Group disease, vis à vis, pattern 3 microscopically. Semantically, as we discuss prostate cancer with newly diagnosed patients or colleagues, it is important for us to be more specific and base these conversations relative to risk stratification.

 Due to the aforementioned USPSTF recommendation and the lay press, many of our patients—and referring primary care physicians—believe that prostate cancer does not need to be treated. We need to emphasize:

Active surveillance for low-risk disease is appropriate for initial therapy but does not mean that treatment will never be indicated.

The role of active treatment, either surgical or radiation, is still indicated in select risk groups.

Systemic therapies may also play a role in those with high-risk disease, especially in light of advanced molecular imaging.

The major shift for many urologists over the past 10 years has undoubtedly been the understanding of how to treat advanced prostate cancer. Here, and in the countless number of publications currently available, the message has been the role of urologists to embrace the management of these patients. The complex nature of the disease, and the multiple agents and regimens now FDA approved for these patients, has led to specific providers within a practice being charged to oversee programs distinct from those managing localized prostate cancer. If we designate an arbitrary definition of “advanced” as any patient that requires androgen deprivation therapy (ADT) for suspected progression of disease, it is critical to acknowledge:

Not all patients with biochemical relapse who have been definitively treated for prostate cancer require ADT.

If ADT is required, urologists need to take inventory of preexisting cardiovascular risks, given the increasing data suggesting major adverse cardiovascular events associated with certain agents.

The standard of care for any patient with newly diagnosed metastatic prostate cancer is the initiation of ADT plus extended therapy, whether that be androgen receptor targeting agents or taxane-based chemotherapy.

The plethora of agents currently available for the patient with metastatic castration-resistant prostate cancer continues to expand, including many trials investigating unique combinations of drugs that are approved as monotherapy.

 The current and forthcoming approvals of various prostate-specific membrane antigen (PSMA) scans will markedly change the therapeutic landscape of the disease, especially as the approval may allow use in staging for high-risk/high-grade prostate cancer.

 Close on the heels of PSMA approval is radioligand therapy, which is already approved overseas, and is soon to be approved in the US. Yet another agent in our armamentarium.

 Probably the hottest and least understood area, the incorporation of germline and somatic testing to manage and define risk will be standard of care. However, incorporating this into our practice models remains a challenge, but not an excuse to ignore at the present.

The number of unique agents and regimens (bispecific T-cell engager, bipolar androgen therapy, androgen receptor transport disruptors/degraders, etc) continue to be investigated, with promising results early on. As our understanding of molecular drivers and resistance continues to increase through genomic testing, the promise of precision medicine may soon become reality.

1. Maxim LD, Niebo R, Utell MJ. Screening tests: a review with examples. 

2014;26(13):811-828. Published correction appears in 

. 2019;31(7):298. doi:10.3109/08958378.2014.955932

2. United States Preventive Services Task Force. Final recommendation statement – prostate cancer: screening. May 8, 2018. Accessed August 23, 2021. https://bit.ly/3mHAXnB

3. Rim SH, Hall IJ, Richards TB, et al. US primary care physicians’ prostate cancer screening practices: a vignette-based analysis of screening men at high risk. 

2014;1:2333392814562909. doi:10.1177/2333392814562909

4. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed August 23, 2021. https://bit.ly/3kndzsn

Articles

"The major shift for many urologists over the past 10 years has undoubtedly been the understanding of how to treat advanced prostate cancer," writes Raoul S. Concepcion, MD, FACS.

The challenges of prostate cancer management

For the most part, for progression to take place, change is inevitable. And change is often very difficult. As someone once told me, if you make a change in your golf swing and it is easy, more than likely you have not changed anything. The urology community has been very progressive over the decades, embracing changes in our clinical world that have led to optimizing patient care while maintaining control, if you will, of the disease states we are accustomed to treating. Although at times this has resulted in fewer operative procedures, which for many physicians is the reason we entered the field, the end result has been better patient outcomes.

Advances in technology generally are the driving force behind these changes, and fortunately, many forward-thinking urologists have been keen in applying them to our field. In the early 1920s, William T. Bovie, working alongside the acknowledged father of neurosurgery, Harvey Cushing, MD, was one of the first pioneers to demonstrate the advantages of electrocautery to stem bleeding in the surgical field.

 A decade later, a urologist in South Carolina, Theodore M. Davis, MD, was able to adapt this technology and incorporate both a cutting and cautery feature into the modern endoscope.

 Thus the birth of transurethral resection of the prostate, which continues to be the gold standard in which all newer therapies, including medical and minimally invasive, must show noninferiority.

For those of us who trained before 1990, prostate biopsy could be considered a form of medieval torture. Blind and either transrectal or transperineal, its complication rates of bleeding and sepsis were extraordinarily high, not to mention the suboptimal sampling due to the lack of imaging and inability to obtain quality samples. Fortunately, a number of our predecessors were prescient enough to adopt prostate ultrasound and template sextant biopsy, which have now led to MRI fusion techniques, again driven by our colleagues. Somewhat forgotten in this discussion is the perseverance of many during that time frame to have practicing urologists trained in prostate ultrasound, wrestling that away from our radiology colleagues. Had those efforts not been successful, it is unclear to me how our current practices might look today.

As alluded to earlier, many of us chose the field of urology for the surgical aspect of the specialty. From an oncologic perspective, mastering the art of nerve-sparing radical retropubic prostatectomy was key to developing a surgical practice. Identification of the neurovascular bundle obviously is a mandate, but controlling bleeding from the Santorini plexus early in the course of the procedure is truly what makes the procedure possible for adequate visualization in a relatively bloodless field. The principles remain the same, but open surgery has now given way to robotically assisted extirpation, which is what most patients opt for when they choose surgical intervention. But as our understanding of the biology of prostate cancer continues to evolve, we must also understand and accept that all prostate cancers do not necessarily need immediate treatment and that active surveillance is truly an option. It is somewhat against our surgical mentality, but it is the correct option for the appropriately identified patient.

In line with this theme, the late 2000s saw the emergence of new therapies for patients with advanced prostate cancer. Many urologists and practices were (and still are) slow to incorporate them into their model for a number of reasons. Probably the most commonly cited is the lack of expertise in prescribing such agents, which was not part of surgical training and belonged more to a “typical” medical oncologist. This paradigm continues to change with the realization that the urologist is perfectly suited to and capable of prescribing and managing these drugs. More importantly, however, our patients have a certain comfort level within the practice.

Part of the shift for many will be incorporating and understanding genetic and genomic testing. Currently, this is heavily weighted to prostate cancer management, but data and literature continue to come forth for both urothelial and renal cancers. That being said, there is no doubt that we will all need to have a working knowledge of molecular testing for risk assessment, family counseling, and therapeutic options. To that end, as a publication, we have opted to include an article in each issue that covers a certain aspect of genomic testing. Our goal is to demystify this area and make it more comprehensible to our readers to achieve better uptake at the provider and practice levels, which currently is very minimal. This, once again, seems to be multifactorial, and we are hoping that educational pieces can assist physicians in their use of such testing and hence their efforts to deliver personalized care.

 Chief Science Officer for U.S. Urology Partners, is editor-in-chief of 

 O’Connor JL, Bloom DA. William T. Bovie and electrosurgery. 

1996;119(4):390-396. doi:10.1016/s0039-6060(96)80137-1

 Goddard JC. That silly operation! The introduction of TURP into Great Britain. The British Association of Urological Surgeons. Accessed May 19, 2021. 

https://www.baus.org.uk/_userfiles/pages/files/museum/Final%20-%20That%20Silly%20Operation.pdf

"As someone once told me, if you make a change in your golf swing and it is easy, more than likely you have not changed anything," writes Raoul S. Concepcion, MD, FACS.

From Dr. Concepcion: Urology's history of embracing change

Let’s say you have this patient, and you have a bone CTthat’s negative, and because of the low PSA [prostate-specific antigen], you have a next-generation imaging scan, whether it’s fluciclovine or PSMA [prostate-specific membrane antigen], that’s also negative. How would you follow this patient moving forward? Are you going to stick with the bone CT because it’s less expensive, it’s more available, and both scans were negative? What are you going to do on this guy?

 It’s one of those where it depends on the overall health and comorbidities of the patient. I don’t think that it’s unreasonable just to continue to follow the patient, especially if there are many comorbidities, and say “Hey, your PSA doubling time is very low. We’ll still follow your PSAs if you remain asymptomatic, if your PSAs remain at a very low doubling time, etc. We’ll continue to observe you.” Certainly, it’s very different in the younger, healthier patient where you want to be more aggressive. At this point, because he’s already had the radiation, it’s somewhat limiting.

On the other hand, to continue to follow the patient is certainly an option there. I do think that periodic scans are part of that observation with next-generation imaging. I certainly think, as Munir mentioned, as your PSA values get higher, the chance of you having positive scans increases. I don’t think it’s wrong to repeat those scans periodically. Alternatively, if that patient wants to be aggressive and keep things low, again, sometimes we’re treating more of a number at this point because we can’t identify where the disease is. Ultimately, you could offer hormone signaling inhibitor therapies. I’m more hesitant to do that, because sometimes changing that, until some PSA level, that becomes more uncomfortable more than anything else, but that’s still an ill-defined type space. I don’t know if that answers the question, but it’s a lot more observation.

I think Judd said it perfectly. We’re trying to figure out what this means. It’s sort of like the old M0 [no metastasis detected], we know M0’s going to go away, depending upon how these scans get approved and in what clinical scenario. I’m going to conclude here, but I’m going to ask each one of you a particular question. Dr Ghesani, we’ve talked about gallium PSMA, we’ve talked about fluciclovine, and we’ve talked about C-11 choline. You also mentioned obviously F-18 FDG [fluorodeoxyglucose]. From the PSMA side specifically, what else is in the pipeline that could we expect to see over the next year or two?

 There are more centers now getting access to gallium PSMA; no doubt that’ll continue to grow. Regarding several other agents, there are at least about 5 combinations, 2 gallium-based and 3 fluorine-based agents. Among all of them, the DCFPyL [fluorine F 18 DCFPyL] is farthest in the review process. It’s hard to tell with the FDA, but of all the available agents, the next one that very likely will be considered for approval, or at least in the FDA pipeline, is DCFPyL. However, there are many other agents…we participated in some of the trials and contributed close to about 50 patients. All those agents will in the very near future be considered by the FDA for approval. In the next 4 to 5 years, I wouldn’t be surprised to see 6 or 7 different molecular imaging agents available.

Judd and Brian, you each get 1 minute apiece with 2 questions. I’m going to go to Brian first because Dr Moul always needs to be the wrap-up, he’s the cleanup hitter. Comment on the greatest unmet need and the key take-home message when it comes to biochemical recurrence and detection.

 The greatest unmet need is the ability to localize the disease reliably at very low levels. I think the earlier we can identify patients who are having recurrence and [provide] potential intervention and/or modification of our plans to make it more precise for the patient is that need. I think that the scans out there right now have made a huge stride in answering that need. Ultimately, as Munir just said, if we have 6, is it going to be all 6 that are great? Do we have a combination of markers we mix together? There are many things coming in the pipeline. I’m excited about it, but I think they’re all in the pipeline because of that unmet need. We’ll see where it comes.

 I think we’re in an exciting time regarding this new imaging and potentially learning more about where the disease is. But I would make a comment that, as you and I have been in practice a long time, and I think I’ve been in practice longer than you, going on 30-some years. I think sometimes we must be careful not to be overly aggressive. I see second opinions where sometimes the urologist or the oncologist has scared the patient to death about a low-level PSA recurrence, and so we must step back. I think this imaging is great if used properly. I worry sometimes that if it’s used too early and we’re too aggressive with a patient, sometimes we’re potentially going to do more harm than good, especially in elderly patients. The take-home message is don’t forget to keep your doctor’s hat on and look at the patient, look at what’s in front of you, and put it in context. We don’t want to do any harm to these patients, and even though ADT [androgen deprivation therapy] and these new agents are great, sometimes we can overtreat these patients.

Judd, I think that’s a great concluding point. Again, it gets back to the old days, “Medicine continues. It’s a lot of science, but there’s a lot of art.” We still must practice the art of medicine. Thank you to Dr Helfand, Dr Ghesani and Dr Moul for joining tonight. I think it’s been a great discussion on a very timely topic. I also want to thank the folks over at 

®. Thanks to the viewing audience that took time out of your schedule, depending upon what part of the country you’re living in, it’s either going to be late afternoon or early to mid-evening. I hope everyone found this to be interactive and found it to be beneficial and impactful to how you will care for these patients moving forward. Thanks so much and have a great evening.

Videos

Dr Raoul Concepcion leads a multidisciplinary expert panel in a discussion about the challenges of long-term follow-up of prostate cancer in patients with negative bone/CT but positive molecular indicators of recurrence. 

Follow-Up After Negative Bone/CT in Prostate Cancer With Molecular Recurrence 

Dr Ghesani, let’s make a hypothetical situation here. Assuming you had access to both fluciclovine and PSMA [prostate-specific membrane antigen], are there any data out there to suggest that at lower PSA [prostate-specific antigen] levels, one modality may be superior? Is it in general, or is one better than the other for soft tissue versus bone?

 First, there is significant published literature on the linearity of PSA levels correlating with the fluciclovine PET [positron emission tomography]/CT. As the PSA levels increase, the sensitivity of fluciclovine goes up. What is also interesting is that in some of those studies they looked at, even when the PSA level was less than 1 [ng/mL], there was still a significant number of cases where the Axumin [fluciclovine] picked up the disease. And in that subgroup of patients, CT and bone scans were completely negative.

To answer the question, no level of PSA is too low for these imaging modalities to show superiority with fluorine- or gallium-based PET scans [compared with] CT and bone scans. If at any point there is a concern, and it’s a clinical question, as Judd mentioned, that this patient does not meet the absolute definition, but the doubling time and then the nadir was not low enough, so there is a high degree of suspicion. In that case, if the insurance companies don’t give you pushback, then clearly the fluciclovine scan will be appropriate. Now, there are some emerging data that have shown, and it’s still early stage, that PSMA scans behave the same way, that as the PSA levels increase, their sensitivity starts to go up. There is at least 1 study that has looked at comparing the 2 and showing some superiority of gallium PSMA scans over the fluciclovine in the setting of very low PSA levels. Again, you must balance that with availability of the agents. Let’s say only fluciclovine PET is available, it still would be very appropriate to do that scan because studies have shown that it performs better than CT and bone scans in that setting.

Are there any data to suggest that the PSMA or the fluciclovine performs better in soft tissue? Does one perform better than the other, or vice versa in soft tissue versus bone? Or is it equal in terms of detection?

 There are still very early data, but they both do very well. What I have seen in my experience—these are not published data, and this has been referenced in some other ways—is that when you do the fluciclovine PET, you usually scan the patients about 3 to 5 minutes after injection. This means that the prostate bed is generally devoid of any urinary excretion, and that’s an advantage because in molecular imaging, you’re always looking at higher target and a lower background. If you lower your background in any specific way, then you are going to pick up things that are even subtle relative to a high background. In that case, the fluciclovine technically can have superiority when you’re looking at recurrence in the prostate bed. Many of the PSMA scans are done at a later stage, and there is invariably some degree of urinary excretion, so the bladder activity can obscure any small area of recurrence technically, that can be only in the prostate bed.

Dr Munir Ghesani reviews and comments on data regarding the sensitivity of imaging modalities in detecting biochemical recurrence in prostate cancer. 

Raoul S. Concepcion, MD, FACS

Articles

The challenges of prostate cancer management

From Dr. Concepcion: Urology's history of embracing change

Follow-Up After Negative Bone/CT in Prostate Cancer With Molecular Recurrence

Sensitivity of Imaging Modalities to Biochemical Recurrence in Prostate Cancer

Follow-Up After Negative Bone/CT in Prostate Cancer With Molecular Recurrence 

Sensitivity of Imaging Modalities to Biochemical Recurrence in Prostate Cancer 