I'd like to thank the PCRI once again for inviting me to speak. As always, I feel that it's such an honor to have this opportunity and forum to assist men and their families as they navigate through the frustrating and scary uncertainties of dealing with prostate cancer. I do completely understand how agonizing it is to try to get all of your questions about prostate cancer answered, especially during one of the most challenging moments in your life. As I've mentioned before, it is my sincerest hopes that my presentations in some small way will help deliver you to a most optimal outcome as you move forward on your journey to defeat your cancer.

For disclosure, I need to mention that Mayo Clinic and I have received licensing payments for PD1 and PDL1 related technologies. So today I hope to cover the topic how to recognize and treat prostate cancer recurrence after undergoing initial definitive therapy for localized forms of prostate cancer. By the way, my presentation is broken into three parts. Kind of like a three course meal with a little appetizer, a huge entree, and a heavy dessert that you might want to skip because you feel so bloated after listening to me for so long.

In 2025, roughly 300,000 new cases of prostate cancer were diagnosed in the US alone. In the US alone, between 90,000 to 100,000 of these men underwent some form of surgical treatment for their prostate cancer. Another 65,000 men received some form of radiation treatment as first-line therapy for their prostate cancer. However, over time, up to 50% of these men will experience some form of prostate cancer relapse due to failure of their initial surgery or radiation treatment.

So, who's this lecture for? This lecture is for any man with localized prostate cancer who has previously undergone treatment using some form of minimally invasive treatment, some form of radiation therapy or some form of surgical prostatectomy. In terms of objectives with today's presentation, I hope to help you better understand details pertaining to the therapy or procedure you previously underwent to treat your localized prostate cancer. Help you determine if you're truly free of cancer. Help you recognize if your cancer might be returning or relapsing. and finally help you understand what treatment options you might have if your prostate cancer is relapsing at its original location or somewhere nearby inside of your pelvis. In this presentation, however, I will not discuss which forms of initial prostate cancer treatment for localized disease are most effective versus which forms of treatment are least effective. Sorry.

So before we get started, let's clarify some terms that I'll use in this presentation. For instance, definitive therapy typically refers to forms of treatment that are intended to wipe out prostate cancer that is mostly confined to the inside of the prostate or spread just slightly outside of the prostate. Relapsing prostate cancer refers to a recurrence of prostate cancer that takes place after an initial attempt to wipe out prostate cancer has failed. Localized prostate cancer typically refers to a form of prostate cancer that is entirely confined to the inside of the prostate or within an anatomical boundary where the prostate used to reside. And finally, regional or juxto-regional prostate cancer typically refers to forms of prostate cancer that have spread to nearby areas such as pelvic lymph nodes or other areas within the pelvis.

Anyway, throughout the world, there are many breathtaking venues to enjoy exciting concerts, shows, presentations. In contrast, for today's presentation, the venue is the pelvis. So let's talk a bit about the pelvis. The pelvis is essentially defined by a ring or perimeter of bones called the pelvic bones. Within the ring of bones resides the true pelvis, which is essentially like a cylinder, not much bigger than a large coffee mug. Within this cylinder resides the various structures and organs of the pelvis. This includes the left and right iliac blood vessels that split off from the aorta and vena cava. These vessels deliver blood to the legs and to the pelvic organs. In addition, lymph nodes inside the pelvis typically follow alongside these iliac vessels. Just in front of the iliac vessels are the colon and rectum. In addition, the left and right ureters can be found in front of the iliac vessels. These ureters deliver urine from the kidneys down into the bladder. Immediately in front of the rectum and ureters are the bladder, the prostate, the seminal vesicles and the urethra. In fact, the back surface of the prostate, seminal vesicles and bladder rest directly upon the ureters and the front surface of the rectum. Finally, it is within the prostate that prostate cancer first appears. It is important to note that cancer growth inside the prostate can be tiny or it can be extensive and associated with one or more sites of growth within this otherwise very ugly and annoying little gland.

So now let's talk about definitive treatments that are available for management of localized prostate cancer. There are three general categories of localized prostate cancer treatment. The first category of therapy is referred to as minimally invasive or non-surgical treatment of prostate cancer. Minimally invasive treatments include HIFU or high-intensity focused ultrasound which uses sound waves to heat up and destroy cancer cells inside the prostate. Cryotherapy or cryoablation which freezes cancerous tissues inside the prostate. Focal laser ablation which uses laser energy to destroy cancer inside the prostate. And finally, TULSA-PRO which uses directional ultrasound from within the urethra to destroy tumors in the prostate.

So exactly what should you expect after undergoing a minimally invasive procedure for management of localized prostate cancer? In general, this is a very difficult question to answer, um, because it's hard to predict and define what a favorable treatment response is. Specifically, indicators of favorable response are highly individualized for patients that undergo minimally invasive therapy. At a minimum, over time, you should expect that your PSA value will remain lower than the PSA value that you started with prior to undergoing your minimally invasive procedure. In addition, you should see no evidence of cancer recurrence on follow-up imaging, especially prostate MRI over time.

Moving on, a second broad category of treatment which is often used to treat localized prostate cancer is radiation therapy. Radiation therapy includes low and high-dose brachytherapy. Low-dose brachytherapy often uses radioactive seeds that are permanently implanted into the prostate to deliver radiation over time. In contrast, high-dose brachytherapy employs temporary catheters which are used to deliver high-intensity radiation into the prostate for roughly 5 to 10 minutes. Another form of radiation treatment that is used for localized prostate cancer is proton beam therapy. Proton beam therapy delivers radiation to the tumor while minimizing effects on adjacent tissues and organs such as the rectum and the bladder. IMRT or intensity modulated radiation therapy is perhaps the most commonly used and well-known form of radiation for treating prostate cancer. IMRT shapes radiation to the prostate while generally sparing healthy tissues around the prostate. IMRT is usually delivered daily over 6 to 8 weeks, but not on weekends since radiation apparently doesn't work on weekends due to the strange behavior of physics in the medical world. In contrast, SBRT or stereotactic body radiation therapy can be used to deliver high-intensity levels of radiation to the inside of the prostate in approximately five sessions rather than 30 to 40 sessions for conventional IMRT. SBRT is pinpoint accurate and is increasingly popular as a treatment for localized prostate cancer.

As an aside, it should be noted that radiation therapy can be used to treat either a very small or a very large field within the pelvis. For instance, brachytherapy is typically used to treat only the prostate and not the seminal vesicles. Brachytherapy is usually administered to men with relatively low-risk small cancers within the prostate. In contrast, IMRT, SBRT, and proton beam therapy can be used to treat men with low, medium, or high-risk prostate cancer. And the extent of the field being treated can vary depending on the patient's anatomy and aggressiveness of disease. For instance, men with low-risk cancer, i.e., small volumes of disease and low Gleason score might not receive extensive irradiation of their seminal vesicles. Whereas men with higher-risk disease with larger volumes of cancer and higher Gleason scores might receive more comprehensive irradiation of their seminal vesicles and regions around the prostate. Likewise, men with very high-risk cancers and/or early spread of cancer might receive a more extensive field of radiation. This form of radiation therapy is called whole pelvic radiation, which treats the entire prostate, seminal vesicles, and pelvic lymph nodes.

In summary, there are multiple forms of radiation therapy that can be used to treat localized prostate cancer. Additionally, it is important to note that radiation therapy is highly individualized and that treatments can vary substantially from patient to patient and doctor to doctor. For this reason, you should always know details about your radiation treatment. Always keep a copy of the radiation plan or the radiation map for your personal records.

So, how can you determine if you're responding after radiation therapy? In order to assess whether you are responding favorably to radiation therapy, most radiation oncologists use the PSA nadir plus two rule. We'll discuss this in detail shortly. In addition, you should generally expect low and stable PSA values over time. Likewise, you should expect no evidence of cancer recurrence on follow-up imaging, which should include prostate MRI as well as PET imaging when indicated.

With regards to the PSA nadir plus two rule, most men who receive radiation therapy for localized prostate cancer will also receive hormone therapy for 12 to 24 months. While on hormone therapy, a PSA value of less than 0.10 nanograms per ml or undetectable is expected. The lowest PSA value that is achieved during or after radiation is called the nadir. Therefore, for most men who receive radiation while on hormone therapy, the PSA nadir will be less than 0.10 nanograms per ml. After halting hormone therapy, however, PSA values will typically start to rise again. This rise in PSA often occurs when normal prostate tissues regain activity. Therefore, assuming that a man achieves a PSA nadir of less than 0.10 nanograms per ml, following completion of radiation and after halting hormone therapy, a PSA value of two or less would be considered an acceptable value. Conversely, however, a rise in PSA above two would suggest relapsing cancer. For men who did not receive hormone therapy, however, PSA might not achieve an undetectable value and thus a nadir value of X might represent the lowest PSA value achieved after radiation therapy. Therefore, a PSA value below X + 2 might reflect a favorable response to therapy, whereas a PSA value above X + 2 might reflect relapsing cancer.

Okay, so that was painful. To be honest, I'm not sure that I trust any metric of response that requires measurements of the position of the sun as Stonehenge or the use of mathematical formulas to calculate. Even worse, many radiation oncologists now feel that the Phoenix criterion should be amended to a PSA less than nadir plus one as opposed to nadir plus two to signify potential cancer relapse. At any rate, let's move on.

The third and final broad category of treatment for localized prostate cancer is prostatectomy. Prostatectomy and lymph node dissection refers to the surgical removal of the prostate and lymph nodes from the pelvis. As with other forms of localized treatment, there are multiple different forms of surgical prostatectomy including open radical prostatectomy, laparoscopic prostatectomy and robotic prostatectomy. As the name implies, surgical prostatectomy involves the removal of the prostate. This surgery when conducted properly results in the removal of the entire prostate, seminal vesicles and a segment of urethra. In addition, pelvic lymph node dissection involves the removal of some lymph nodes around the prostate. This cartoon shows what a surgical specimen should look like after surgical prostatectomy. Note that the seminal vesicles which look like bunny ears should be removed completely while still attached to the prostate. Also note that part of the urethra called the prostatic urethra is removed with the prostate because this part of the urethra actually runs through the center of the prostate like a straw through an apple as is depicted in this cross-sectional cartoon. Anyway, after surgical removal, the site where the prostate and seminal vesicles used to reside are now called the prostate fossa or bed and seminal vesicle fossa or bed. Also, please note that removal of the prostatic urethra actually leaves a gap that needs to be closed in order to complete the surgery. To close the gap in the urethra after prostatectomy, the bladder neck is stretched downward and then sewn to the early part of the penile urethra. This surgical connection is called the vesicourethral anastomosis or the VU anastomosis.

As with other forms of treatment for localized prostate cancer, surgical prostatectomy is highly individualized. Surgical prostatectomy can vary substantially from patient to patient and doctor to doctor. For instance, some surgeons remove no lymph nodes or only a few lymph nodes at the time of surgery. In contrast, some surgeons will remove up to 40 or more lymph nodes during surgery. Likewise, some surgeons will only remove lymph nodes from the pelvis corresponding to the side of the prostate where the cancer was found. Whereas other surgeons will remove lymph nodes from both sides of the pelvis irrespective of location of cancer within the prostate. It is important to note, however, that no surgeon can ever remove all of the lymph nodes from the pelvis, which will be relevant when we talk about relapse. Anyway, it's for this reason that you should always obtain a copy of your surgical and pathology records to keep with your own personal personal medical records.

So, how do you know if you're staying cancer-free after prostatectomy? In stark contrast to a minimally invasive procedure or a radiation-based treatment, the expectation following surgical prostatectomy is quite simple. Specifically, it is expected that you will have an undetectable PSA after your surgery forever. And as always, follow-up imaging should not show any signs of prostate cancer relapse over time.

In the next section of this presentation, I'm going to discuss how to recognize and manage prostate cancer relapse after failing initial treatment for localized cancer. In general, after a patient has undergone a treatment for localized prostate cancer, a rise in PSA over time would likely indicate a recurrence of cancer. Alternatively, follow-up imaging might reveal one or more sites of prostate cancer relapse after localized treatment has failed.

In terms of symptoms, it is important to note that most men will not have any symptoms to indicate that their prostate cancer is growing back after treatment. Therefore, the development of symptoms is not a reliable indicator of prostate cancer relapse after localized therapy. On the other hand, a few men will develop symptoms that herald a recurrence of prostate cancer. For instance, some men might develop problems with urination. This could include painful urination or a weak urinary stream or the sensation of incomplete elimination of urine. This typically occurs due to blockage of the bladder or urethra due to recurrence of prostate cancer. Conversely, some men will experience a new onset of incontinence. This typically occurs due to invasion of the urinary valve or sphincter or bladder neck by relapsing prostate cancer. Another symptom of cancer relapse is gross hematuria which refers to visualizing blood in the urine. This typically occurs due to invasion of the bladder or urethra by recurrent prostate cancer. One ominous symptom of cancer relapse is the onset of problems with bowel movements. When a man starts to feel like he has to push harder in order to pass his stools. This could indicate invasion of the patient's rectum and anus by recurrent prostate cancer. Likewise, the appearance of blood in the stool could also indicate relapsing cancer involving the anus or rectum. Another sneaky but serious symptom of prostate cancer relapse is the sensation of pain in the pelvis. This could include pain radiating to the penis or perineum or rectum. On occasion, this could also present as pain that radiates to the groin, testicles, or legs. Typically, these types of pain are due to invasion or compression of pelvic nerves by lymph nodes that are enlarging due to cancer invasion. In some men, cancer can actually be seen invading directly into the nerves of the pelvis.

The bottom line is that you should demand regular and long-term follow-up after undergoing treatment for localized prostate cancer. An absence of symptoms is no guarantee that your prostate cancer is not relapsing. Follow-up should be provided at regular intervals and should include both regular PSA testing as well as some form of imaging. Related to this discussion, it's important to note that there is never a time where you can declare yourself completely free from the threat of prostate cancer relapse. The concept that being free of prostate cancer for 5 years means that you are cured of your prostate cancer is simply mythical. In our clinic, we routinely see patients who have failed definitive treatment of localized prostate cancer even 10 years or more after treatment was given.

So if your prostate cancer recurs, what pattern of relapsing prostate cancer might you see? Of course, one possibility might be local recurrence in which your prostate cancer grows back at or near its original location. Kind of like a dandelion growing back by its roots after it's been picked. Another possibility is that your prostate cancer could come back at one or a few discrete sites either nearby or far away from the original site. I typically refer to this type of recurrence as focal or oligometastatic prostate cancer recurrence. Little spots forming outside of the pelvis for instance. Another possibility is that your cancer might recur at multiple sites within a zone or compartment or region of your body. These zones could include the pelvis, the retroperitoneum or the chest. I typically refer to this form of recurrence as zonal recurrence. And finally, your prostate cancer could relapse in a widespread fashion throughout the body. I refer to this as diffuse recurrence of prostate cancer, which is also referred to as systemic metastatic disease recurrence. Incidentally, in case you are curious and want to investigate more, I've included some internet links that will direct you to some of our previous lectures that touch upon the management of local, focal, zonal, and diffuse forms of prostate cancer relapse. For today's presentation, I will only be discussing management of local relapse as well as a specific subset of zonal relapse that is called regional or juxto-regional relapse of prostate cancer within the pelvis. However, before I jump into a full-blown discussion about management of local and regional prostate cancer relapse, I'd like to make a couple of general comments.

Okay. For some men who experience prostate cancer relapse after primary local treatment has failed, simple observation might represent a reasonable option for management. Specifically, it might be reasonable to simply monitor a tiny site of recurrence, especially if the tiny focus of recurrent cancer remains relatively stable over time, meaning that it doesn't grow or generate increasing levels of PSA. This might also be true for a minor recurrence situated in a location that doesn't threaten any of the major structures in the pelvis such as the urethra or a ureter or the rectum. Also, if a patient is frail or has other serious health issues, simple observation of recurrent disease might make the best sense for that patient. However, observation of relapse is only reasonable if a patient is willing to undergo very close follow-up with repeat PSA testing and repeat imaging, preferably every 3 to 4 months. If you're interested in more information regarding recommendations for follow-up and proper imaging of prostate cancer, please use these links to view additional lectures pertaining to these topics.

Another general consideration pertains to the use of hormone therapy for treatment of relapsing prostate cancer. This table shows various forms of hormone therapy that are available. Conventional and androgen receptor pathway inhibitors or ARPIs or RPs. Hormone therapy can be used for management of relapsing localized prostate cancer irrespective of whatever form of therapy the patient initially received. However, it's important to note that when hormone therapy is used alone, all by itself, it is purely suppressive or palliative in nature. Also, it's vital to note that prolonged use of hormone therapy alone will inevitably lead to the development of resistant forms of prostate cancer that can be even more difficult to treat down the road. Kind of like treating rust on an old Camaro with spray paint. Looks good for a bit, but then yikes. For these reasons, I think hormone therapy should only be used as a single modality of treatment in patients who have no other options for treating their relapsing prostate cancer. I also think that hormone therapy is reasonable for individuals who are not healthy enough to undergo other forms of more aggressive intervention. However, I strongly advise against the use of hormone therapy alone to treat young healthy individuals who have other more definitive treatment options available to them.

One circumstance where I do think that hormone therapy should always be used is when radiation therapy, specifically IMRT, is being given to treat local or regional relapsing prostate cancer. It has been clearly demonstrated that hormone therapy increases the effectiveness of radiation therapy. In general, 12 to 24 months of hormone therapy should be administered during and after the administration of radiation therapy. Finally, hormone therapy can be used either continuously or intermittently. With regards to ARPI agents that I have listed here, I believe that ARPI agents should only be used in patients who are resistant to regular hormone therapy. These days, I personally feel that ARPI agents are being overused to treat patients with relapsing localized prostate cancer. Also, if a site of relapse has been identified, it's generally a good idea to pathologically confirm that cancer is present at the relapse site by pursuing a biopsy. It's also a good idea to rule out other sites of relapsing disease such as metastatic sites using MRI and PET imaging. Finally, for patients who have not had their prostates removed, it is always important to thoroughly assess the prostate itself prior to providing treatment of relapsing disease, especially if the relapsing disease is at a location outside of the prostate.

Okay, one final general comment. I'd like to point out that managing relapsing prostate cancer can be both extremely complex and extremely risky. As such, I think that you should always make a major effort to find a physician who is highly specialized and experienced with managing relapsing disease. Virtually anyone can hold a hammer and a chisel, but very few people can carve Michelangelo's statue of David. In other words, not everyone can do a great job of handling relapsing cancer. As such, I think it is imperative that you find an expert if you're going to tackle relapsing prostate cancer. By the way, for you guys out there who are saying, "Hey, Quan, that isn't a chisel. That's a center punch." I already know that. I just didn't have a chisel in my toolbox to prep this photo. Okay, back to our main topic, localized prostate cancer relapse.

So, how do you know if you're experiencing relapse after minimal invasive treatment? Well, relapse after minimal invasive treatment is typically identified when PSA values are rising over time and/or when evidence of disease recurrence is seen on follow-up imaging. Overall, the most common form of prostate cancer relapse that occurs following a minimally invasive procedure tends to be intraprostatic relapse. This means that the prostate cancer is actually growing back inside the prostate itself.

So what options do you have to manage intraprostatic relapse? For many patients, some form of radiation therapy may be the best option for treatment of intraprostatic relapse. IMRT, SBRT, or even brachytherapy all represent forms of radiation therapy that can be used to treat intraprostatic relapse. Prior to treatment, a prostate biopsy is almost always required to confirm relapsing disease. Also, you should always undergo a PET scan to make sure that the cancer has not spread outside the prostate prior to undergoing radiation therapy. Unfortunately, however, sometimes SBRT or brachytherapy may not be feasible due to pre-existent damage to the prostate, which makes focal forms of radiation more hazardous. In support of this, here's an example of a patient with intraprostatic recurrence after HIFU treatment. This patient's prostate was heavily damaged by HIFU, which actually caused a hole to appear in the right side of his prostate, as is seen inside the red circles here. That white spot is a hole in the prostate. Fortunately, this patient's relapsing disease was on the left side of his prostate. Ultimately, this patient was successfully treated with stereotactic radiation by one of our skilled radiation oncologists at Mayo.

For some young and extremely healthy individuals, intraprostatic relapse might be best treated using salvage prostatectomy. Salvage prostatectomy represents a comprehensive way of treating intraprostatic relapse. Prior to prostatectomy, a biopsy is always required to confirm presence of cancer. Also, a PET scan should be obtained to rule out metastatic disease beyond the prostate. At the time of salvage prostatectomy, a pelvic lymph node dissection should be performed to rule out or remove any regional metastatic disease that might be lurking in the pelvic lymph nodes. Finally, some patients might be a candidate for a second form of minimally invasive therapy to treat their intraprostatic recurrence. However, be warned, this type of treatment should be undertaken with extreme caution, since the risk for recurrence and complications is extremely high.

Moving on. So, how do you know if you're experiencing relapse after undergoing radiation therapy for localized prostate cancer? Well, as I mentioned before, relapse after radiation therapy is typically identified when PSA achieves a value of 2.0 or higher above the PSA nadir or when disease relapse is evident on follow-up imaging. As with minimally invasive procedures, the most common form of cancer relapse that is encountered is intraprostatic relapse. In general, this form of relapse can be very tricky to diagnose and frequently requires outstanding imaging with MRI and sometimes PET evaluation to aid in diagnosis. A targeted prostate biopsy with expert pathologic interpretation is frequently required to confirm recurrence.

As I previously mentioned, there are multiple forms of radiation therapy that are used to treat localized prostate cancer. Here's an example of a patient who was treated with brachytherapy. In this X-ray, you can see multiple iodine-125 seeds that have been placed uniformly into the patient's prostate using a needle. Here's an example of a patient who has prostate cancer growing back in between the brachytherapy seeds. Using MRI, you can easily visualize the location of the brachytherapy seeds since they appear as black holes in the prostate itself. Okay. Relapse of prostate cancer after brachytherapy can be tricky to diagnose and treat, especially due to scarring that occurs after brachytherapy seeds have been placed. By the way, doesn't this prostate with all the black holes remind you of Bonnie and Clyde's car after they were ambushed in the movie or Sonny's car in The Godfather? Anyway, here's an example of a patient who suffered prostate cancer relapse after proton beam therapy was used to treat his localized cancer recurrence. Here's an example of a patient with intraprostatic relapse after conventional IMRT therapy was used to treat his localized prostate cancer. The whole prostate's filling up with cancer again. And finally, here is an example of a patient with a very ominous form of prostate cancer relapse after failing conventional IMRT therapy. In this case, the patient and his physicians assumed that the patient was doing just fine since the patient's PSA was undetectable after his radiation therapy. Unfortunately, this patient experienced a relapse of prostate cancer that didn't produce any PSA at all. And this whole thing is relapsing disease. Okay, all of it. In this case, recurrence was found only using C11 choline PET imaging. Biopsy of the recurrent cancer revealed a very poorly differentiated form of adenocarcinoma of the prostate. Non-PSA producing neuroendocrine and small cell cancers can also be encountered after any form of failed therapy for localized prostate cancer. To learn more about non-PSA producing cancers, prostate cancer heterogeneity and various forms of PET imaging that can be used for prostate cancer evaluation, you can watch these prior PCRI videos or presentations by our group.

So what options do you have for treatment of intraprostatic cancer recurrence after failed radiation therapy? Well, everyone has heard the statement that once you are treated with radiation therapy, you cannot receive any more radiation therapy. Surprisingly, however, this statement is not absolutely accurate. For select patients who fail definitive radiation therapy for localized prostate cancer, some forms of radiation therapy may still represent reasonable options for treatment for recurrent disease. For instance, for patients with a small and discrete lesion or individuals who were radiated many, many years ago or patients who originally received a less than aggressive initial dose of radiation, SBRT or brachytherapy might represent reasonable options for treatment of intraprostatic relapse. Here's an example of a patient who failed radiation therapy from many years ago. He was treated using high-dose brachytherapy.

For some young and extremely healthy individuals, intraprostatic relapse might be best treated using salvage prostatectomy. As I mentioned before, salvage prostatectomy represents a very comprehensive way of treating intraprostatic recurrence of disease. At the time of salvage prostatectomy, a pelvic lymph node dissection should also be performed to rule out or remove any regional metastatic disease that might be hiding in the pelvic lymph nodes. Here's a young individual who experienced a rise in his PSA from undetectable to 5.7 after undergoing definitive radiation therapy for localized prostate cancer. Following a biopsy which confirmed the recurrence of prostate cancer, the patient underwent salvage prostatectomy. Following surgery, PSA dropped to undetectable levels and the patient did extremely well. Okay.

Finally, some patients might benefit from a minimally invasive procedure. A minimally invasive procedure to treat their intraprostatic cancer recurrence following failed radiation therapy. In general, this type of treatment should be undertaken with extreme caution since risk of complications and recurrence of disease is high. In general, prior radiation can compromise healing. Therefore, overly aggressive, minimally invasive procedures can lead to the development of chronic wounds that can worsen over time, leading to complications like fistulas, which we'll discuss later on. Here's an example of how cryotherapy was used to eliminate relapsing prostate cancer within the prostate of a man who failed radiation therapy for treatment of his localized disease. This is his disease before with a PSA of 10. After cryotherapy, PSA dropped to 0.31. No disease is there. Patient did well. Okay, deep breath here.

Finally, let's talk about relapse after surgical prostatectomy. How do you know if you're experiencing relapse after undergoing surgical prostatectomy for localized cancer? Well, as I mentioned before, prostate cancer relapse after prostatectomy is typically identified when PSA values go from an undetectable level to a detectable level greater than 0.10 nanograms per ml. Alternatively, recurrent disease can also be discovered on follow-up imaging. Following prostatectomy, intraprostatic recurrence is obviously not an issue since the prostate is gone. Instead, cancer can relapse within tissues where the prostate was once in contact with the various structures in the pelvis. These sites include the VU anastomosis as well as the surgical beds of the prostate and seminal vesicles. Here's a patient who experienced a VU anastomosis recurrence of prostate cancer following prostatectomy. That tiny little dot there. Here's a patient who experienced a relapse of his cancer in the prostate bed. And finally, here are two different men who experienced localized seminal vesicle bed recurrence following prostatectomy. One on the right side and one on the left side.

So what options do you have for treatment of cancer recurrence in the prostate fossa, seminal vesicle bed, or VU anastomosis after undergoing prostatectomy? Once again, without question, radiation therapy represents one of the most effective methods to treat cancer recurrence at the VU anastomosis or within the surgical beds of the prostate or seminal vesicles. IMRT or SBRT represent the most common forms of radiation that are used to treat localized cancer recurrence following prostatectomy. In addition, hormone therapy is often administered with radiation treatment, especially when IMRT is used for treatment of locally relapsing disease. As I mentioned before, roughly 12 to 24 months of hormone therapy is typically administered with IMRT radiation.

One of the most common questions that's asked in my clinic is, "Well, why can't surgery just be used to cut out locally relapsing disease following failed prostatectomy?" In general, surgery is not an option because the cancer that is relapsing in this situation is typically residing within the connective tissues and the scar tissues that comprise the prostate and seminal vesicle beds and the VU anastomosis. Surgically removing cancer from these areas would be akin to removing the cement that holds together a brick building. The only exception to this situation might be when a portion of the seminal vesicle or a big chunk of the prostate remains in place after prostatectomy has been performed. Finally, a minimally invasive procedure can sometimes be used to treat recurrences after failed prostatectomy. In general, if the site of relapse is small and very discreet, a minimally invasive procedure might prove effective for eliminating recurrent disease.

What about treatment of other forms of localized regional cancer relapse? For instance, in men who have previously undergone either a minimally invasive procedure or a radiation-based procedure, the seminal vesicles themselves can represent a site for localized prostate cancer relapse. Here's an example of prostate cancer recurrence within a seminal vesicle after treatment with radiation therapy for localized prostate cancer. See that seminal vesicle filling up with cancer. For many patients, radiation therapy may represent a good treatment option for relapsing cancer involving seminal vesicles. This is certainly true for patients who have previously failed a minimally invasive procedure. For patients who have failed prior radiation therapy, however, further radiation treatment will depend on several factors, including whether or not the seminal vesicles were aggressively radiated before. For such patients, seminal vesicle recurrence might be best addressed surgically. Seminal vesiculectomy can be used to remove recurrent disease especially when the site of recurrence is small and singular. Finally, in some patients, an isolated seminal vesicle recurrence can be destroyed using a minimally invasive procedure. Freezing procedures such as cryoablation can be used to eliminate small recurrences in the seminal vesicle.

Relapse of cancer within the pelvic lymph nodes also represents a fairly common occurrence after any form of localized treatment for prostate cancer. Recurrence of cancer in the lymph nodes is usually referred to as regional or juxto-regional cancer relapse. Here's a patient who experienced bulky recurrence of cancer within several of his pelvic nodes after failing cryoablation procedure. You could see these almost golf ball-sized lymph nodes in the patient's pelvis. Here's a patient who experienced relapse prostate cancer in multiple pelvic lymph nodes after undergoing prior prostatectomy. And this patient did have a pelvic lymph node dissection, but he still had pelvic lymph node recurrence of disease.

So what options do you have for therapy for patients with pelvic lymph node recurrence of cancer? Once again, for most patients, radiation therapy may be the best option for treatment. This is certainly true for patients who have previously failed either surgical prostatectomy or a minimally invasive procedure. For patients who failed prior radiation therapy, however, salvage radiation of the pelvic lymph nodes will depend on several factors, including whether or not the patient received radiation treatment of his lymph nodes before. For select patients, pelvic lymph node recurrence might also be addressed surgically. Pelvic lymph node dissection can be used to remove recurrent disease, especially when only a few lymph nodes are involved. This is an example of a patient who experienced prostate cancer relapse within several pelvic lymph nodes. These lymph nodes were removed by one of our highly experienced salvage surgeons here at Mayo Clinic. This is kind of an important slide. So PET has become very popular and a lot of people are finding little lymph nodes filled with cancer all over the place. So, a lot of these patients are going to their surgeons and they're saying, "Well, can you take out these lymph nodes?" Well, you have to remember on a PET scan is that because of the bloom of the imaging agent, the lymph nodes look bigger than they really are. And unfortunately, there are a lot of patients that we see in our clinic who have been taken to the operating room in an effort to remove the involved lymph nodes and lo and behold, the lymph nodes are still there because the surgeon couldn't find the lymph nodes. So if you're going to use salvage pelvic lymph node dissection to treat this form of disease, you really need to be very careful and you need to go to someone who's highly experienced. Otherwise, you might have an operation and find out that the lymph nodes are still there after the surgery. Okay, it's a little sidetracked.

Finally, in some instances, an isolated site of pelvic lymph node recurrence might be treated using a minimally invasive procedure. Here's an example of a patient who underwent cryoablation of a left perirectal lymph node after failed prostatectomy and radiation therapy for localized recurrence. So, there's the little lymph node there next to the arrow. It was frozen and this patient did extremely well as PSA dropped right down to undetectable levels.

So what about other forms of pelvic prostate cancer relapse? Prostate cancer relapse involving the rectum occurs much more commonly than one might expect. This likely occurs since the back of the prostate essentially rests against the front surface of the rectum. At any rate, cancer relapse involving the rectum can be very serious and can actually lead to obstruction of the rectum. Treatment of rectal recurrences often requires a combination of systemic therapy such as hormone therapy along with radiation therapy. Unfortunately, for some patients, complete treatment is not feasible and occasionally some patients will require surgical removal of the rectum or anus with some form of colostomy drainage. So, this is the cancer invading into the rectum of this patient here.

Recurrence of prostate cancer inside of the bladder also occurs much more often than one might think. Since the bladder is contiguous with the prostate, it's not hard to envision how prostate cancer sometimes crawls up and invades into the bladder. Identifying bladder involvement by relapsing prostate cancer can be extremely challenging. PSMA PET imaging is very poor for detecting recurrence of disease involving the bladder. In most cases, MRI, cystoscopy, C11 choline, PET scan imaging might be required to identify relapsing disease within the bladder itself. On occasion, prostate cancer can also relapse within the penis. Here are two patients who experienced penile relapse prostate cancer. Recurrence of prostate cancer within the penis is regarded as a systemic form of disease recurrence. Most often this form of recurrence requires treatment with hormone therapy in combination with radiation therapy or cryoablation if possible. Here's a small recurrence at the tip of the penis. This is a large recurrence involving the entire penis.

Prostate cancer can relapse within the urethra itself. As with penile recurrence of prostate cancer, urethral relapse prostate cancer can be treated with hormone therapy, sometimes given in combination with radiation therapy. This is a cystoscopy which shows these barnacles or these things growing into the urethra. That's prostate cancer growing right into the urethra. You can see it on the PET image here. Occasionally we do see patients who have relapsing prostate cancer within their testicles. For isolated relapse of cancer within the testicle, surgical removal of the testicle can prove to be curative. Here are two examples of men who present with isolated prostate cancer relapse within a testicle. Here's one and here's one right here. Both of these were successfully treated with surgical removal of the testicle.

Everyone has heard rumors that prostate biopsies might be capable of spreading prostate cancer. Based on what we've observed in our clinic, we do believe that prostate cancer can occasionally be spread by mechanical manipulation. Here's a patient who experienced prostate cancer relapse in a prostate biopsy site in his peritoneum. All right. The abdomen and pelvis are actually separated by a thin membrane kind of like cling wrap. This membrane is referred to as the peritoneal membrane. Here's an example of a prostate cancer relapse growing along the pelvic side of the peritoneal membrane. This line here, that's the peritoneal membrane being invaded by prostate cancer. On the pelvic side, the inner walls that define the pelvis can also serve as a site for relapsing prostate cancer. Here's a gentleman who has a significant relapse of his cancer in front of his tailbone in the back wall of his pelvis. That whole thing there. Finally, here's an example of a patient who experienced a tiny rise in PSA 12 years after undergoing initial treatment for his prostate cancer. PET imaging revealed a very tiny recurrence of cancer along a nerve emanating from the sacrum just in front of the tailbone. Invasion of pelvic nerves by prostate cancer can sometimes cause very vague pain in the pelvis, penis, perineum and legs of individuals experiencing prostate cancer relapse.

So now let's talk a little bit about some critical situations that we see in association with relapsing prostate cancer. In general, the bed for the prostate and seminal vesicles encompasses an area that's approximately the size and shape of a silver dollar. Even though this bed is relatively small and thin, it encompasses a number of very vital structures within the pelvis. These structures include the front surface of the rectum, the back surface of the bladder neck, the two ends of the ureters that drain the kidneys, and the two valves or sphincters that control urination and elimination of stool. It's for this reason that prostate cancer relapse must be taken seriously. Relapsing prostate cancer within this small 1.5x 1.5 inch area can inflict a serious world of hurt if it is not recognized and treated early on. Related to this, virtually any form of localized recurrence of prostate cancer can result in obstruction of one or both kidneys. Obstruction of a kidney is called hydronephrosis. Hydronephrosis can occur without any symptoms at all and can result in total loss of kidney function. Here is a patient who had significant obstruction of his left ureter and kidney due to relapsing prostate cancer in his left seminal vesicle bed. So there's the recurrence. The kidney is blocked. It's blowing up because it can't drain and it's dying. Okay. Regardless of the cause for kidney obstruction, drainage of the kidney is typically necessary and sometimes an urgent matter. For some patients, drainage can be provided by placing an internal stent that bypasses the cancer blockage to permit urine to drain into the bladder. Unfortunately, for most patients with relapsing localized prostate cancer, drainage of a blocked kidney can only be provided by placing a nephrostomy tube that drains the kidney straight out of the patient's back into a collecting bag. Finally, in extreme cases, relapsing cancer can obstruct everything in the pelvis, including the kidneys, the bladder, and the rectum, as was the case for this patient. His bladder is blocked, both kidneys are blocked, and his rectum's completely blocked. Fortunately, using surgery and immunotherapy, we were able to actually clear this patient's cancer. However, the patient does have a colostomy and an ileostomy to drain his stool and urine.

Many of the patients who we see in our clinic have already undergone one or more procedures to treat localized prostate cancer. And many of these men experience infield failure, which specifically refers to a recurrence of prostate cancer inside of a region that has already been treated with prior radiation therapy. In my opinion, infield failure represents one of the most challenging forms of prostate cancer to treat. Even worse, patients who experience infield failure are at enormous risk for developing a fistula. When you examine the pelvis in cross-section, it looks like this with the pubic bones in front, the neck of the bladder behind the pubic bones, and the rectum directly behind the bladder. A fistula refers to an abnormal connection or tunnel between organs. Men with fistulas typically complain about pain in the pelvis or pain while walking. Often times a patient might have recently undergone placement of a urinary catheter or cystoscopy in the months just prior to developing a fistula. Fistulas can form as an abnormal connection between the bladder or urethra and the pubic bone. Alternatively, a fistula can form between the rectum and the bladder. Symptoms related to this type of fistula include gas and stool being eliminated during urination or urine being eliminated through the rectum during a bowel movement. In general, a patient with a rectovesical fistula will complain of painful urination or vague pain in the pelvis. Sometimes a patient will develop a fistula that connects his rectum to his bladder and his bladder to his pubic bone. Many of these patients develop sepsis, repeated urinary tract infections and osteomyelitis of the pubic bone. In many of these situations, the osteomyelitis of the pubic bone cannot be cured and can only be suppressed with chronic antibiotic treatment. Some patients will die from chronic infections caused by fistulas. This patient, this is a patient who developed a fistula between his bladder and his pubic bones after an attempt by his local urologist to open up a scar that the patient developed following prostatectomy and radiation therapy. Unfortunately, this patient developed sepsis and a fungal infection of his pubic bone. The arrows that you see actually depict the infection spreading out from the pubic bones on PET imaging. So you can see these bluish streaks coming out which is infection coming from the bone. Here's another patient who developed a large abscess and a fistula during his um uh involving his entire pelvis after undergoing after undergoing traumatic placement of a catheter in the emergency room. Forceful placement of a catheter resulted in perforation which connected the prostate bed with the rectum. At any rate, once again, I implore you to always make a major effort to find a physician who is specialized and experienced with managing relapsing disease. You don't want to suffer a disaster as you try to treat your relapsing cancer. Remember, virtually anyone can pick up a paintbrush, but very few people can paint the Mona Lisa. You definitely want an expert to be dealing with your prostate cancer relapse. Trust Leonardo.

Okay, so here is the final stretch of my presentation. The big final yawn. In recent times, one question pertaining to the management of localized prostate cancer has generated a great deal of debate and discussion. Specifically, the question pertains to what is the best treatment for imaging-negative or image-negative patients with prostate cancer relapse. Imaging-negative or image-negative patients refers to men who have undergone prostatectomy for localized prostate cancer who then subsequently experience a rise in PSA after treatment without any documented evidence of cancer relapse on imaging. Historically, men who develop a rising PSA after prostatectomy have been advised by their physicians to undergo some form of radiation therapy for presumed local or regional recurrence of cancer. In fact, current AUA, ASTRO and SUO guidelines recommend that patients undergo radiation therapy of their prostate fossa or their pelvis when PSA becomes detectable after prostatectomy even when no cancer is found on imaging. Parenthetically, I'm not sure I feel comfortable listening.

To guidelines from Astro because I thought that Astro was George Jetson's dog. At any rate, in support of the current guidelines, there have been published studies that indicate that early radiation of the prostate bed or the whole pelvis improves survival for patients who experience a rise in PSA after prostctomy.

Conversely, there have been some studies that suggest that waiting for radiation targets to appear as PSA rises reduces rates of cure that can be provided by early radiation therapy. Another argument in support of providing early prostate fossa or pelvic radiation therapy for rising PSA after prostctomy includes published observations that early radiation therapy is beneficial for the management of other forms of cancer even in the absence of identifiable disease on imaging.

At any rate, the current recommendation is to provide radiation treatment after prostatctomy in patients who have arising PSA even if a sight of cancer can't be identified. Additionally, additionally, it's recommended that radiation therapy be provided before PSA achieves a value of 0.50 nanog per ml per ml. And finally, it has been suggested that the lower the PSA value at the time of radiation, the better the outcome.

However, many patients express concerns about having their prostate, fossa, or entire pelvis radiated when a sight of relapse has not been identified. For many of these patients, this approach simply doesn't make sense, like hunting with a blindfold on. Clearly with the dramatic evolution of PET and high quality MR imaging, the rationale for irdiating the prostate phosphor pelvis in the absence of identifiable disease is making less and less sense these days.

Also with increased use of MR and PET imaging, I think that postp prostatctomy patients who have a rising PSA and no findings on imaging represent a shrinking and relatively niche population of patients. For these reasons, I believe that today's population of post-prostc patients with a rising PSA and no findings on imaging is much different than the cohorts of patients who were studied in older radiation trials before PET imaging was ava available. Thus, results from prior trials that showed survival benefits due to early radiation treatment must be interpreted cautiously in the context of today's population of post-proc men.

Anyway, one of the biggest concerns that I have with the terminology for image negative relapse seems to be uh the fact that the definition is nebulous and somewhat open to exploitation. For many patients that we see in our clinic, negative imaging means no imaging was conducted at all. Additionally, for some patients, image negative disease refers to patients who were declared negative after one single attempt at imaging was made when serum PSA values were ridiculously low. For other patients, image negative relapse pertains to patients evaluated by CT or bone scans, which are essentially useless for identifying early cancer relapse. Alternatively, some patients have only been evaluated PET imaging, which by itself is inadequate to assess relapsing disease deep within the pelvis.

Specifically, our group recently reported that use of PET imaging alone will miss one half of all recurrences in the prostate or seminal vesicle bed or at the view anosis. For this reason, we reported that PET imaging should always be used in combination with MR to identify forms of local relapse that might respond best to radiation therapy. At any rate, it's my feeling that failure to map sites of recurrence before providing any form of therapy can compromise overall treatment.

So why are physicians seemingly so obsessed with irdiating the prostate fausa andor the pelvis as soon as possible? Well before 1986 dete detection of recurrent disease was essentially based on digital rectal examination. Hence, by definition, it was thought that all recur rec recurrences of prostate cancer were local recurrences found in or around the prostate fossa, unless of course you had very long fingers. By the way, the reference to digital rectal exam is not the same use of the word digital that drives artificial intelligence. Even though many of us physicians have been accused of being very artificially intelligent.

Anyway, also in 1980s, everyone embraced the holstedian model of cancer recurrence which suggested that all relapses occurred in a stepwise fashion with local recurrence first right here followed by regional spread of disease and then metastatic dissemination of cancer. But much has changed since 1980s. For instance, surgical prostctomy has undergone several major advancements that likely diminish rates of local relapse. In addition, we now know for certain that a rise in PSA is not synonymous with local cancer recurrence.

In support of this, my colleagues and I previously published this mapping study which reported contemporary patterns of prostate cancer relapse in patients who experienced a rise in PSA after prostatctomy. Specifically, our study revealed that prostate cancer relapse occurred locally in the prostate and seminal vescal bed or at the vonmosis in only 33% of patients after prostctomy. In contrast, 25% of patients experience a combination of both local as well as mastic recurrence. And finally, 45% of patients experience some form of metastatic relapse of disease in the absence of any local recurrence. From this we surmise that at least a third of patients or more will not benefit at all from earlier radiation due to relapse of disease outside of the prostate fossa or pelvis.

So why does it matter that some patients might not benefit at all from earlier radiation therapy for image negative disease? Well, radiation can cause side effects in up to 11 to 26% of patients. Also, a near miss in which a prior radiation uh field ends up grazing an actual sight of disease can complicate subsequent treatment. For instance, here is a patient who is advised to receive whole pelvic radiation by his local physician instead of waiting for a clear sign of relapse to appear. During second opinion consultation, we encouraged the patient to wait until a sight of relapse was established by imaging. Ultimately, when the patient's PSA achieved a value of 0.17 nanog per ml, a sight of relapse on the front surface of the bladder was identified. SPRT without any hormone therapy was used to eliminate this side of recurrence within three sessions. The patient had an excellent response therapy. If treatment was given without imaging as initially suggested, this side of cancer would have been either missed altogether by the radiation or grazed by radiation, thus warranting additional future treatment.

Also, the aggressive push for radiation at PSA levels of 0.5 or even lower worries me since a percentage of these patients may not necessarily harbor clinically significant forms of cancer recurrence. Performing radiation therapy at extremely low PSA values eliminates opportunities to delineate between clinically aggressive cancer versus more innocuous forms of relapse. For instance, here is an image negative patient whose PSA has only risen a very tiny bit from.3 to 047 over the last 12 years. Likewise, here's a patient whose PSA rose to 1.4 over a 9-year period. Ultimately, however, this patient's rise in PSA was due to median lobe regrowth, a benign prostic hyperplasia or BPH or old man's disease, which was reected due to obstructive voiding complaints. No cancer was found in this specimen here.

Okay. At any rate, most discussions regarding treatment of small of a small rise in PSA after prostctomy assume that the rise in PSA always occurs due to significant clinically significant relapse of cancer. But this may not be the case since some studies have suggested that up to 30% of low-level PSA relapses after prostctomy may be due to either residual benign prostatic tissue regrowth or more indolent non-aggressive forms of cancer recurrence.

Anyway, the key question is whether a patient puts himself at risk by waiting to identify sites of prostate cancer relapse. Personally, I do not think so at all. Perhaps the best evidence supporting this supposition is our recent experience with management of oligastic prostate cancer. We now know for certain that oligomeastic disease can develop slowly over many years after prostctomy. We also know that these oligo mastic lesions often respond well and completely to metastasis directed therapies. If you shoot the spots, they disappear. PSA goes down to nothing. In addition, olastic disease is often seen in the absence of local recurrence and metastasis directed therapies frequently do not require any comradiation of the prostate, fossa or whole pelvis. From this, one might conclude that an interval of observation does not likely put a patient in harm's way and that disease recurrence can certainly occur independent of locally relapsing disease.

At any rate, I believe that the overall trend is moving towards identification of sites of relapse prior to administering radiation therapy for subjects with a rising PSA after prostctomy. new studies supporting a role a vital role for MR and PET imaging in order to guide radiation therapy for rad uh for patients with a rising PSA after prostctomy are being published almost every day now. Moreover, the advantages of imageguided therapy versus early radiation treatment of image negative patients is now being formally studied in a clinical phase 2 trial being run by doctors Chararma and Phillips here at Mayo in Rochester. So hopefully we will soon know the answer to the question how best to manage imaging negative patients who are experiencing a rise in PSA after prostatectomy.

So that concludes today's presentation. Before I finish, I'd like to thank all of my colleagues who helped me put this lecture together. I had a ton of questions that I didn't even understand and hopefully I've presented this well to all of you. I must say that I'm so fortunate to be surrounded by the absolute masters of treatment in especially in the arena of relapsing prostate cancer. This includes my outstanding colleagues in radiation oncology and urology. These are the salvage surgeons and our minimally invasive interventional therapy group. If you experience a relapse of prostate cancer, I encourage you to please feel free to reach out to any of these outstanding physicians using the scheduling phone numbers I have provided. And of course, I'd like to thank my very dear friends on the Quan team. I wouldn't be able to survive without you. By the way, aren't you impressed how AI can make me look so much better? And then before we end, I'm just going to click through our previous presentations with the um QR codes and links in case you want to follow up on some of our lectures to get a better idea of how to manage advanced prostate cancer. I I think I've been giving presentations now um since 2011, which is now 15 years. All right, that's it. Thank you.

That was excellent. And you know, I'm not just saying that because I want to be your friend because you're really famous. Well, partially I'm saying that, but uh you moved at a good pace. had a lot of topics. How did you feel about that talk?

I think it's a tedious talk, but I think it's a necessary talk. You know, uh when I put it all together, um as I shared with you before the presentation, I I literally it got up to 360 slides and then I had to cut a bunch of stuff out. But, you know, I try to put these talks together for patients that are experiencing different circumstances. Not every patient has the same circumstance. And I'm hoping that patients will find what they need in this kind of encyclopedic presentation that deals with relapsing disease.

Well, I think it's great. I It's a challenge though. There's a lot of stuff to cover. The most important question I thought I would ask you, I would just come right off the bat and ask you. All right. Do you know who played in the 19 in the 2026 National Basketball Championship game a few weeks ago and who won that game? So, can you tell me who played the two teams and who won that game and who's the national champion? And I'm going to bet right now that there is no way I'm going to bet you a free lunch at Outback Steakhouse at Mayo Clinic that you're not going to get this right. So what are your answers to the first and second question?

Well, the answer is that I wish University of Illinois had won and beaten Yukon and then kicked the butt of Michigan. Okay.

Okay. Oh my goodness. So who played in the championship game? But once you get to the championship game, you gota root for the Big 10. So I rooted for Michigan.

And who won that game?

Michigan won big time.

Thank you. Thank you. And I now owe you lunch next time I'm at Mayo Clinic. I really thought there was no chance that you would get that correct, you know.

Um I actually didn't watch the game. I I heard about it on the news.

I don't care. I don't care you didn't watch. I just I I bet all the audience. I've asked you sports questions for over 10 years. You never get any of them right, which I think is a testament to the fact that you're just working all the time. So, I was convinced. I told all my colleagues that you're not going to get this question right and you did. So, now I'm just going to tell you what your gift's going to be. I'm going to send I'm going to send you an official Michigan hat. National championship hat. Okay. So, you got to put that in your office. National champions.

All right. All right.

Well, if you just uh spend a little money, maybe you could actually get me a national championship hat.

I will get you a national championship hat.

Okay. All right. It's got to say national champion. Yep.

I mean, I'll ask PCR to pay for it, but I'm I'm gonna send it.

Okay.

All right. You want to talk relapse? Because that to me is the word of your talk. All right.

Relapse. And I want you to comment on a couple of things I thought about when you said relapse. So when I hear relapse or recurrence, right? What people are often confused about and you and I have talked about this for years and I want you to explain it from your standpoint. Some people think of relapse as a sudden return of the cancer. So the cancer was gone, there was no cancer and boop, it came right back. or was that cancer always there and it finally showed its face? Can you explain just kind of that physiology of relapse? What how should I look at my relapse? Is it that it came back or it was always there? How do you look at it?

So I yeah I think that that's a really great question and I think a lot of patients ask that question. It it was always there. So prostate cancer, if you think about the little cancer cells, they have the capacity to basically hibernate or hunker down or protect themselves and go into kind of a quesuscent state. Just like seeds out in nature, seeds can be blown everywhere, but under until conditions are proper, they may not grow. So many patients that undergo localized treatment, you know, you blast away with radiation, you do your surgery and everything and all of a sudden you discovered that the cancer is coming back later on. It's not that it went away. It was that the seeds or some element of the cancer was there. It was either not detected because it was microscopic and too small or it was not detected because the cancer cells were sleeping or is not detected because no one looked in that area. But over time those things can come to life and they can start to grow again. And it's kind of um you know when I first came to Mayo you know we used to write papers. Well, if you had a prostctomy 10 years ago, you're never going to have a recurrence. And then all a sudden we start seeing recurrences 11 years later. So we wrote a paper. Well, if you had a prosttomy 11 years ago, you'll never have a recurrence after 11 years. Then here comes a guy with 15 years. So the bottom uh to me the incredible thing is that these cancer cells can go quiescent and they can pop up down the road at incredibly long intervals 10, 15, 20 years later. You can see a relapse or recurrence of the cancer, but it's not that it went away. It's just been sleeping or hiding in the soil of your body. So you do see I wouldn't say on a regular basis but you do see individuals like I have a friend who's 15 years out from his radical prostatctomy and he just had a relapse. We have we have tons of those kinds of patients. And so that's why you know I tried to make the point that you know we used to always tell everyone well if you're clean five years you're cured. That's simply not the case.

Yeah. Yeah. But the advantage I'm not not we'll talk about this later but the advantage with all this great imaging is you can find it earlier now and maybe get a second shot at cure right I mean

Can you comment also I hate to be redundant from your talk but these are important points and I never really thought about it I'll tell you the good thing about your talk sometimes I'll look at your talk and go well the audience already knows that that's pretty basic and then I realize when I think about it well no they don't I don't think many doctors understand what you're talking about So, I love that you kind of go over the stuff that people already just kind of assume you're supposed to know, but I don't know how they're supposed to know it. Here's something I've never heard anybody say, and I'm kind of paraphrasing what you said your whole talk. Relapse is a specialty. And don't see that's kind of what I took from your talk. You know, we think of, oh, I need the best surgeon. They have to have done 5,000 radicals. I need the best radiation oncologist. He hasn't done 5,000 patients. I need the best blah blah blah. But we never talk about if there's a concern about relapse after primary treatment, you should go find people that handle it like a specialty. And now I'll stop talking. What do you think?

I I think that that's absolutely true. I I think that um you know, the assumption is that everyone knows how to handle relapse and that's simply not the case. And I I think that people would be shocked to find out um how little familiarity a lot of physicians have with actually handling relapse. Um I think that you know many centers, many fancy places you go to, they do the primary surgery or the primary radiation very well or the primary minimal invasive procedure. But then when it comes to relapse, people tend to be reflexive. They don't think about it. They just say, "Oh, hormone therapy or oh, radiation or oh, whatever." You have to be incredibly thoughtful to deal with relapse. And unfortunately, the reason that we're seeing so many patients in my clinic, and all of them are relapse patients, I mean, I only see relapsing patients. We see eight to nine thousand patient visits a year and we're constantly getting bombarded with these patients. And a lot of these patients will go to their physician and the they'll say, "Oh, you got a relapse. Go get radiation and that's it or go go start taking these hormone therapies and that's it. That's as deep as the conversation goes." But it it it's a terribly complex problem to solve and the approach has to be extremely thoughtful. And the downside of not being thoughtful is very often you don't treat the problem. You end up with another problem and then another problem. And as my talk tried to point out, sometimes those problems can become quite catastrophic in terms of side effects or even compromising overall life expectancy.

That's interesting. I didn't really I never really thought about it, but the fact that the majority of your patients are relapse patients, that makes sense.

Yeah. I mean, that that's virtually all we have, you know. I mean, you know, after my prostatctomy, my PSA went up and I got put on this medication and what the heck's going on? Or after my radiation therapy, my PSA went up and they did this, this and that, and what the heck's going on? So, that's all we handle. And as far as I know, um, we, um, kind of have a very large experience with dealing with relapsing patients, a very unique experience. And you also said during your talk that part of the problem in relapse is people are just suddenly giving you radiation, suddenly giving you hormone therapy, suddenly giving you some of the newer medications without giving it thought. Right.

Yeah. They It's It's scary to me because um the classic example is, you know, a patient says, "Well, my PSA is going up." And you know, you and I had a little conversation last night. Basically, if that patient says, "My PSA is going up." and he goes to a radiation guy. Well, the radiation guy may give radiation. Goes to a medical oncologist. That medical oncologist might put the patient on hormone therapy. Goes to your urologist. Urologist will look the patient over to see if there's any surgery that can be done. But beyond those steps, there's really no consideration of how to solve the problem. So, it's kind of binary. either they can solve the problem with whatever they do or they say well you know I don't have a solution for this or go see my colleague I was hired at the Mayo Clinic in 2002 the number one indication for an appointment at the Mayo Clinic was not for prostatctomy it wasn't for radiation therapy it was for rising PSA after failed primary treatment

so what that tells you is that the number one form of prostate cancer that we are dealing with in the world is not necessarily the newly diagnosed stuff. It's the iatrogenic results of therapies that didn't work. So this is an I call this an iatrogenic epidemic.

Yeah. This is kind of a an epidemic that physicians created where patients have this secondary problem and I think it's very important to get it handled correctly. You know,

but you know, we went through several decades where physicians, many physicians were doing their best. They they thought they knew where the cancer was, so they they they treated they thought it was localized and they were basically confined to what they had at the time. The imaging was not that great. And we're only talking about five, six years ago.

Yeah.

I mean, so yeah. So really, that's what's so interesting about your talk. It makes me think about this whole situation of relapse. But can I can I ask you a couple other questions around relapse before we kind of jump around?

Sure. Sure.

Okay.

Another me another message you had about relapse uh is what you call and it plays in this area is imaging negative cancers. Okay, so now we're going to move into the biggest controversy that people are going to deal with when they watch your video on relapse. What you see is not completely what you have, right? What I meant by that is that

what you're telling people to do is look, let the PSA get up there. I I ideally want to see it on some kind of test, imaging test. Maybe it's choline, maybe it's PSMA, maybe it's MRI. I want to wait to see it. But the problem is half the other world is screaming at the patient going, "Look, your PSA is getting really high. We're not seeing anything. So, we have to drill this sucker now." So, this is a many part question because I want you just to comment on this. The criticism is going to be of what you're saying is that if you want me to wait for my PSA to increase high enough, right, how high is too high before I need to get it treated? Because some people have PSAs. You know these people, they'll go to two, three, four. They you can't find any cancer. So, are you telling people just to sit back and be patient and let that thing go up as high as possible or are you just saying most of the people eventually have their cancers show up on an imaging test, so just be patient? What exactly you talk are you are you telling people in terms of how long they should really wait because they're being told by the other half of the medical establishment the longer you wait the higher the PSA gets the less likely I can cure your relapse.

Right. So you have to uh we have to go back um about 15 minutes ago. Yeah. We have to talk about cancer coming back. So when a person relapses, the seeds are planted and you're waiting to see where those seeds of cancer are sprouting, but the seeds have already been distributed. They've already been disseminated in the body. They're there. So you're trying to figure out where are the seeds going to grow. Treating someone earlier does not change the distribution of the seeds. Okay. So the answer to your question is tricky because for some patients I have to read the room. Some patients are not going to want to sit on their cancer because they want to do something. They want to do it now because psychologically they feel better having something done right now or they've been told by their physicians that the cancer is zooming around their body like a Mazda commercial. Zoom zoom zoom and it's just spreading like wildfire all over the place which is not true but that's what they've been told. So if a patient is very very concerned, I will tell them of course we can go ahead and treat you. Actually to be honest with you, the way that we're dealing with that now is that we're just having our patients enter the randomized phase three study which will randomize them either to early treatment versus PET imaging if they wish to participate in that. But when I do say we can treat it, I also provide the caveat that there's a chance that what you're having treated is not going to solve your problem. So that they don't come back later and say why is my PSA going up after I got my whole pelvis radiated and after I've come off my hormone therapy. So it's very very different for different patients. We have published papers that clearly show that if you wait as the PSA goes up, you will see the distribution of disease. And for guys that let their PSA go very very high, you know, 10, 20, 30, 40.

Yeah.

Where you find the cancer is typically in the retroparinium and in the chest. And that's not because you waited. That's where it was hiding and that's what made it so difficult to find in the first place. Okay. Does that make sense?

It does. But you're still happy in that case for letting it go that high.

As long as the patient fully understands and you know is in agreement. And ironically, well, you might not find this all that strange, but a lot of our patients that actually let their PSA rise a great deal.

Yeah.

What do you think their vocation is?

What is their vocation?

Physicians.

Ah, interesting. Interesting. So they already understand that you know this is not something that you can force this is something that is this is nature and the distribution of their disease is determined by nature not by practice okay

so the vast majority of our patients that say hey look I don't care if my PSA goes 65 as long as it's not bugging me I'm okay.

Yeah. A lot of those people are physicians.

That's really interesting because I I just relate everything from my my background, you know, from, you know, preventive medicine standpoint. In the old days when I was trying to tell people it's okay to take a statin, it's okay to take cholesterol drug and they said no, it might be dangerous. I said, you know, the first people who take a cholesterol-lowering drug when they need it, it's the cardiologists.

Yeah. Right.

So, Right. So, it kind of gives you a hint as is when they look at the data how they feel about it. But, you know, we never coers or try to force these things upon people. Everyone's got a different comfort level.

Yeah.

Um, like I said, you know, we have patients that come back and say, "Well, Quan, you and Mark use the word cure for prostate cancer, and you guys are wrong." Um, you know, obviously everyone sees things in different shades of gray and everyone has different comfort levels and different things that they can tolerate. But perfectly in the world of what I really think is going on, I don't think that you can get a higher cure rate just because you're blasting earlier. Okay.

Okay. And some of the references we can talk about in a little bit. Some of the references that you put in your slide deck are some of the newer references that are showing that if you wait, you put in three references that I asked it was still there. I believe I don't know. You just have to remind me. You put three references in that were very recent that shows the benefits of waiting in a couple of clinical studies right now from Europe and the United States. So I encourage people to always also look at Dr. Quan's references. I was impressed that you put those there and we could talk about that in a minute. Um, but it makes me think of this. It makes me think of also false positive relapses for a second. Can we talk about that? You you mentioned, is this very common? For example, finding benign tissue, someone that's had a prostatctomy for example, but there's some benign tissue left and ultimately it starts to make PSA and it grows. Are you seeing relapse, what I call relapse false positives where something lights up and you're thinking, "Oh, there's cancer that's back and then you go looking further and it turns out to be a benign condition that set off the alarm." Is that very common in your practice?

Yeah. So um before I go there

the the the last part of my talk was a byproduct of a kind of a debate that I had with a very esteemed radiation oncologist Dr. Brian Davis here at Mayo. Yeah,

we we recently gave this as debate and the reality of the matter is the radiation oncologists are keenly aware of the fact that um imaging may play a bigger role in managing prostate cancer in the future and they're not averse to it. Um, as part of that debate, um, the conversation did come up about, uh, you know, biologically insignificant PSA recurrences. And I referenced an article in my presentation today. you were probably in the bathroom while I was talking about it, but that the reference says that some people suspect that 30% of low-level PSA recurrences actually are not clinically significant and that means that they don't necessarily progress over time or that might be due to microscopic benign disease that's left at the VU anastmosis.

Yeah. that grows over time. Normal prostate tissues make PSA. So if you shave a sliver of normal prostate off so that you don't damage the sphincter or whatever, that's going to pump out a tiny amount of PSA over time. Or sometimes a guy will have recurrence of disease inside the bladder. That's the median lobe of the prostate that did not get taken out with the surgery. And the article that one of my um residents gave me was uh basically saying that they think that 30% of these low-level recurrences of PSA don't manifest as clinically significant disease down the road. Meaning that some of it's benign or some of it's very indolent very indolent in nature. The conflict though that comes about is then you have some radiation oncologists or physicians that are saying, "Well, if you don't irdiate that thing before you hit a PSA of 0.2, you're not going to be cured." Well, that's a huge conflict because you have to watch the PSA over time to know is this biologically significant or is it biologically insignificant? But then if you have a mandate that says well you have to treat everything that hits point 2, you're going to be treating everyone. So this is why this is a hot debate. This is why it's an interesting debate. The conclusion in all honesty is that people think that we need a randomized trial to answer the question definitively.

Yeah.

And you know that's what I think that um people at our institution are trying to do. Uh at the same time however I have to say that I do think that this may be a self-fixing problem because more and more relapses are being identified with more and more imaging which is getting better and better every day.

So this may be a problem that resolves itself over time. We'll see.

Well, you're implying a few things. But you're implying if that resonance correct and you believe that 30%. You may be implying that not too near not not too far in the in the future or maybe even right now there's going to be a category of relapse patients who go on active surveillance for relapse.

Basically in other words they'll be just monitored. Is that is that what you're implying too? because that's

so in in some regard I did have that in my talk where for some patients I think observation's reasonable.

I personally I didn't explicitly say it in the video or in the presentation but my opinion is if the PSA ain't moving and if the relapse spot is tiny and things are stable over time observation is a reasonable option. Absolutely.

I'm counter Quan now because that's my job. Okay, I hear what you're saying. You make a compelling argument. But what you're also assuming in this argument, which I don't think anyone's ever said to you or the girls and boys at Mayo Clinic, is that if you want to see something on an image and say that's where the cancer is, what you're assuming is that's the limits of the extension of the cancer. In other words, you're saying it's the ultimate that picture is the ultimate telltale sign of how far your cancer has spread. That's also why I'm waiting for it. Do you see what I'm saying? But what if that's not true? Or do we have enough data to counter that? What if the picture you're seeing is just a part of the cancer and the cancer could actually be in a variety of other locations and you're just getting way too excited, Dr. Quan, about your picture test because you came up with choline. Now there's PSMA, now there's MRNI, MRI, and you're just getting way too excited about imaging tests and what they tell you. What do you say about that?

Yeah, and I agree. I mean, there are times where we don't know. So, when we see a profile of disease on um some form of imaging, you never know if you're seeing the entirety of the disease or if you're just seeing the tip of the iceberg. Right.

Exactly. Um, so you just never know. So you have to counsel a patient. And we have certain parameters that make us feel better and certain parameters that make us feel worse. If a guy walks in and he has a PSA of 35, tiny PSA, and he has a history of Gleason 7 prostate cancer, well- behaved stuff, and the recurrence is this big and it really hasn't been changing that dramatically over time recently, then a lot of times we'll say, well, that might be the entirety of your disease. Let's see. Let's kill it and then let's watch. Okay.

However, if you have a guy that walks in the door, and this is going on all over the place now, ever since we talked about olastc disease and treatment and all that, a guy walks in, he's got, you know, two little spots you can barely see on a PET scan. He's got a history of Gleason 10 and he's got a PSA of 15. There is no way that those two little spots represent the entirety of his prostate cancer. And you know that if you treat those two little spots, that guy's going to walk back in the office in three months and he's going to be filled with mastic disease. So you know there's a number of things that we try to consider in aggregate to make the right decision regarding management and that's why this is a specialty. This is a specialty.

Fair enough. Fair enough. What the extension of what I just said and again even though we're friends I got to make sure that everything's on the up and up here. Like I'm I'm coming to see you and this is how I would act. what you kind of imply in your talk is that you like to use these imaging tests. And so, especially when it comes to relapse, you have to admit, I think one of the most interesting things that I've seen and I deal with and I've heard is that people are looking for relapse everywhere with a PSMA, for example, and then they do an MRI and they realize the the that the relapse is in the bladder. So, that the PSMA had a hallow effect and it obscured the ability to see the tumor in the bladder. So, what I'm starting to hear from you and others is that everyone, Dr. Quan, should get a PSMA or a PET CT and an MRI ideally to find relapse. It seems the more and more I'm moderating, the more and more some of the top gurus, you're I'm placing you as a top guru. More and more the top gurus are saying, you know what, ideally, I'd love to have not only a PET CT, but an MRI if I think there's relapse. Is that how you feel?

Absolutely. There's no question. So, you know, the all everyone has to remember that all of these imaging devices have blind spots. A choline PET scan has a blind spot for certain forms of disease. A PSMA PET scan has a blind spot for certain forms of the disease and certain locations such as the bladder. An MRI is the best way to look inside the liver. And neither PSMA PET scan nor the choline PET scan is good for looking inside the liver.

An MRI is excellent for looking inside the bladder. C11 choline can see it. Sometimes PSMA cannot see it. So one of our uniform policies is that we do vary our imaging and we do try to get different angles of view on the disease in order to know comprehensively what's going on with our patients.

When you do those scans in my brain I'm thinking that you always want to correlate data with data. And maybe I'm wrong. What that means is that I find that a lot of people go around the country and world, they get a scan done, but they don't know what their PSA was when they got the scan done. Don't you ideally want to know, for example, the PSA right around the time anyone gets a scan of any kind to correlate the data points?

Yeah, there's no question. Yeah. You know, for a number of reasons, people cherrypick testing

and then you end up with the testing, but it's taken out of context of what's going on. And so, you know, our standard order set is, you know, um PSA, testosterone, alkaline phosphotase, liver function tests, and uh a PET scan and plus or minus MRI on the day of the visit. on the day of the visit.

Interesting.

Another place that you see this mistake being made a lot is that the guy will you'll say, "Well, this guy has one spot on the PSMA PET scan and his PSA on the day you found it was two." And then you send your patient to the radiation guys who for whatever reason they can't get the guy into their office for 3 months. And then they treat them that day without repeating the PSA. So then you check the PSA after they've been treated and it's three and you say, "Oh my god, this is failing." But it's not failing because what happened in the interim is the PSA went up on the day of treatment and you didn't know about it. So there's a lot of this kind of I think uh evaluation sloppiness that happens in the medical field and it always occurs under the opaces of well insurance won't permit it or we're trying to save money or whatever. But what people don't realize is by being sloppy or by skipping things or cutting corners ultimately things become more expensive because you have to sort through it you know.

Yeah. Yeah. That's well said. That's well said. I talked to a guy not that long ago. I have a lot of friends out there. He got a his PSA had always been between one and one and a half. He got diagnosed. Anyway, long story short, he gets SBRT and then the note said, "All right, PSA's already dropped from almost three to back to one and a half." And I thought, "What? He's never had a PSA more than one and a half." Turns out the day before he got his radiation, the radiation oncologist pulled the PSA and he had a jump. He had a jump in his PSA. had he not pulled that PSA at that time,

like I say, of the image or when you're about to be treated, you're missing out on an important piece of data. However, as your friend, I'm going to once again play devil's advocate. Here we go. Okay, so I hear what you're saying. You're convincing me. This sounds great, but who pays for all this stuff? Dr. Quan, if you want me to get an MRI, you want me to get a PSMA PET or a choline, you want me to get all these imaging tests and these tests, are you finding that insurance or this gets covered or are you finding that the patients get whacked with a huge bill?

Our patients get it covered by insurance at the Mayo Clinic.

So then you're saying mayo's great, but Mayo is synonymous with two things. great medicine and something I put on my Reuben sandwich. Right. So, what I'm trying to what I'm trying to say is if you're saying Mayo can get it covered, a really good center or really good practice should be able to get these covered even if they don't go to Mayo. Is that what you're saying?

Yes. And I also think that there's a certain amount of nealism out there with regards to imaging. So, if you say, "Well, the patient wants a PET scan and I don't fully agree with it." Guess what? It ain't going to get covered. If you say, "Well, it's imperative that this patient receive PSA or receive PET imaging because he's got cancer at a site that's not yet disclosed, and that his entire outcome for therapy, which it could include tons of radiation, tons of hormone therapy, whatnot, are going to be contingent upon finding that spot. Well, likelihood is that you're going to get your scan approved." Okay. Um, this is where once again there's a difference in terms of the art versus the reflective practice of dealing with relapse. Personally, I feel that a lot of patients when they go to see their physician with relapse, they're not treated well because they represent some kind of failure or nuisance in the eyes of the doctors. Um, that's why this requires some thoughtful process to really sit down and say, "This is the story. This is what you're dealing with and this is why it's important."

Yeah, I think that's a good point. What we've learned is many of the insuranceances when challenged, even when they reject it, when challenged correctly and and with some thought and data and the backing of the practice, a lot of them get overturned. That's part of one of the videos that your team gave, one of the one of the videos that was um another part of that that PCRI gave and Alex gave. People need to watch how to challenge the how to challenge insurance. They need to watch those videos. I mean, that's that's a whole world in and of itself. Anyway,

but I don't I don't think it's all insurance. I mean, I think it's physicians, too. You know, I think that physicians, you know, I I do think that there are physicians that you don't need no imaging. You don't need no you just take these pills. That's it. And that's not the way to do this.

Yeah. But I I hear you're saying, but you need your teammates to help get you there to win the national championship. Just like Michigan, right? They needed all five players. Sorry.

Well, number one, I don't have personal friends like you, so I have to worry about that. I never went to a school that has a sports team that, you know, the the headline at Grenell College in in my alumni magazine was Grenell wins its first football game in a thousand days.

I know. I I feel bad for you at Mayo Clinic that you don't have a football team or basketball, but if you did, you would lose every game. But I told you this when we were first friends. I think Mayo should have a new mascot. It should be the calculator or it should be the Mac computer or something. That's just my suggestion. Okay, I'm going to ask you a question that has to go back to imaging. And this is this is a little bit left fieldish, but we we never talk about it. So, I want to know what you think. When you have when you deal with a relapse, let me This is a two-part question before I go to the weirder question. What we're dealing with a lot is you see these PSAs that were always sort of flat. It could be after a prostatctomy, undetectable, you know, it could be even even a 0.009. Some of these some of these will hold at 0.01 and then suddenly after 10 years they'll start to move and they're getting closer to

0.1 but they're not quite there. Well, that's a large change and so some people are opting for imaging before waiting for the traditional 0.2 or a higher value. My argument, and tell me if I'm wrong or not right, some of these people that are pushing for imaging earlier as they see their PSA move, even though it's not within guidelines. I think the one benefit is that if there's something there, that you win potentially. If there's something that they don't find, they don't find anything there, you win potentially. Don't you think it's better for all these people trying to get their scans and images done earlier, despite the false positives and all this, don't you think it's better to sometimes just get it earlier in the PSA rise than wait for these larger values? I'm talking about is your initial PET CT scan.

Yeah. I I don't think we just published one of our papers just came out recently. 12% of patients that have a PSA of zero will have metastatic disease. Okay. 12%. And that's for PSMA PET. 12% of patients that have an undetectable PSA will have a positive C11 choline PET. And I happen to know that those two populations don't overlap. So in the ideal world where you know, everyone gets everything covered all the time, isn't there a movie like that? Won an Academy Award everywhere, every place. All at at any rate.

If it were available to everyone, I would get the PET ASAP to start with as a baseline because if you have a baseline PSA or baseline PET, at least you know what's changing because sometimes it's just not binary, you know. I know. So, and sometimes we do I mean, several of the cases I presented PSA of .17, PSA of 0.14, PSA of .12, you can see things. So, sure.

Yeah. So, what you're implying is someone had a flat 0.02 for years and years after a radical, suddenly over the next year they get almost up to 0.1, they're getting nervous. Give me a scan. Someone that had radiation, you know, they're hanging out at say 7 forever and suddenly now they're at 17. So they're going to ask for a scan. People are going to ask for it. I I see the downside is fighting with insurance and I see the downside as some false positive. But what you're I think what you're saying is that the upside exceeds the downside in those cases.

I think that you're going to pick off disease and I think you're going to see it. And I think that for patients especially that are very nervous that something might be happening, you know, it's reasonable. And again, context means a lot. You know, if a guy has a a Gleason 10 that didn't produce much PSA to start with, well, hell yes. I would get the PET scan immediately.

Um for a guy that, you know, um is not making much PSA, even that little increment could be a huge change for them. Yeah.

Uh, okay. Here's my left field question. Ready? You're not going to believe I'm throwing this at you. I apologize.

University of Michigan.

This leads me to two questions. Have you ever used a liquid biopsy on a patient with relapse? So, you can explain what liquid biopsy is. I know you use them, but have you ever just sought more data and took two tubes of blood looking for some cell-free DNA, looking for a mutation, just looking for something in the blood of somebody that's showing up in the scan, metastatic disease or not, or you can't find it and the PSA is going higher and higher. Do you ever lean on liquid biopsy for relapse or is that just a silly thought?

That I think that that's going to be a conversation down the road. Um, we have a huge experience with liquid biopsies. I personally don't think that they're there yet for finding disease that you cannot visualize. Um, I think that if you get a liquid biopsy, you're going to possibly get some readouts that are not very informative or very useful. And I don't think that the sensitivity of this is kind of like circulating tumor cells or whatever CTCs or whatever. Um, I just don't think that these tests are quite there where they provide the information that you might be looking for to find occult metastases.

So it's more of an exception rather than a rule for you.

Yeah.

Okay. Here's something else you said that's interesting and I jumped all over it. Dr. Quan says, "Keep your radiation plan." The plan that for your personal records, right? And I put, this is rhetorical, I'm sorry. I put, "Does that include a personal CD copy of your PET CT scan and images plus the formal report for a second opinion?"

Yes.

So, so can you can you explain this and I'll give you an example of a a situation that uh I have to deal with recently. So can you explain why you say this and then I'll give you my thought.

So it's really um we see it like I said we have a lot of patients that we see that have relapse either after radiation therapy or prostatectomy followed by radiation and whenever I have to come up with a strategy to treat these patients the question rises up well what did they irradiate before and how much and the problem there is that if you don't have the records and if you don't know what was done before you cannot come up with a plan to treat them moving forward. So our radiation guys, you know, who are outstanding. I mean, it's unbelievable what our radiation guys can treat, but they always have to, you know, send their moles out to find the old plan to figure out how much radiation the person received. And the really rotten part of this is some centers are very poor at keeping records.

So then you have patients that come in and their centers either don't exist or they've gone out of business or that doctor is retired and you don't know what's been irradiated and what hasn't been irradiated and because of that the patient may may not be treatable because you don't know what happened in the past. And the other reason that I say this is something that I woke up to because it was explained to me by you know Dr. Stish, Dr. Phillips, Dr. Davis at our institution. I was actually shocked at how much variation there is from doctor to doctor to doctor on radiation. So even if Dr. Stish or Dr. Phillips tells their best friend at University of Michigan or University of Rochester or UCLA or UCSF, I want you to treat this area this way. It doesn't necessarily get treated that way. And you have to have the the plan. You have to have the records. A lot of times these these these patients see us and they say, "Well, can I get my radiation locally?" I say, "No, get it here because I know what these guys are doing." The minute you step out the door, you don't know exactly what's going to happen unless you have the record in front of you. So, there's a lot of variation. There's a lot of variation in terms of and same with surgery. you know, even within our corridor here.

Different surgeons do the surgeries different ways so um basically I think it's very important I actually, you know, I said that the original talk was 360 slides I had a list of all of the reasons why you have to have the plan and I had a list of all of the reasons you should get the the surgical reports and the pathology reports because these are things you need to look for but the talk went long but it's a very important thing to get those records for your files.

I've talked to a few friends I would like to throw in the word friends these are no names went and got these are situations where they went recently around the United States they got a PET CT done and there was something on it and the people reading it don't have the experience of someone who's read 10,000 or 20,000 scans. Anyway, the point was, and it shocked me, that they said, "Well, we'll get then they wanted a second opinion on it, or they wanted another doctor at an institution to see it." They said, "Well, we'll get it out there in the next several weeks." And they didn't know that when they were there, it's their right under the HIPAA privacy rule, it's their right when they're there to request a CD copy of their of their imaging. So, in these cases, they took the CD copy that they got within 24 hours, FedExed it to another opinion, and got an opinion. Sometimes it was a false positive, sometimes a false negative, but they got this expert second opinion within a week because they got a copy of their own disc right after the image was done. So, the reason I loved what you said is that I c I I'm sorry I'm creating a lot of work out there, but I like the idea of they're going to make a bunch of CDs and they're going to send them out. They should make a copy for you and you should take two or three or whatnot just in case you have to take the ball and then send that out to the next opinion faster. So anyway, the take-home message is always request the record, always request the CD because you may be the person that has to get it out to the second opinion very quickly.

Second opinion pathology, you know, same deal. A lot of times you get a read, you got to get it verified by the experts. The PET imaging. A lot of times, you know, it's it's worthwhile to get a second opinion at Mayo because sometimes the the scans are faulty. Sometimes they're misread, misinterpreted. There's a whole host of reasons that you need to get read. Sometimes I get I would say that you know one of the most common things is a lot of times we'll get outside PET scans or whatnot and you know it's 85% correct but 85%'s not going to cut it when you have to treat a guy for relapse. You have to see all the spots. You have to know what's going on. So, and you know, I don't want to make it sound like, you know, it's Well, first of all, HIPAA is about protecting patients privacy.

Yeah. It's not anything that's done to a patient, anything that's handled medically, it's their right to own it all. It's them. That's right. That's exactly. I mean, there's there you know, so they that's I've been talking to PCRI for for 15 years now and if there's one thing that I've been consistent about every single time is patients have to advocate for themselves, period. You cannot rely upon anyone else. You can't rely on the secretary, you can't rely, you can't rely on the Quan team necessarily, even though I think we're excellent at what we do. You have to own it.

Yeah. You have to own it. You have to ask the right questions. You have to have your data in front of you. You have to have the information. You have to curate it. And you have to And a lot of our patients actually walk in with folders. Radiology, pathology, surgical report, everything in folders. And it occurs over time. So they can tell you exactly what's happened. And that's the right way to do it.

Remember you talked about pelvic anatomy. You know a question I've never asked you about pelvic anatomy slide. Hey, just by the way, do you believe the spread of cancer is like a pebble dropped in a pond? You drop a pe a pedal. Uh, you can see how tired I'm getting. You drop.

Skipping stone. Skipping stone is the answer.

Well, no, but so I'm saying when you drop a pebble in a pond, you see it kind of spread. So it goes from prostate, it goes outside the prostate. So that's that's the holian that's a holstedian model for cancer spread which is it starts locally and then spreads out. That is not the way that prostate cancer spreads.

So tell me how prostate cancer spreads then if it doesn't spread that way. You're saying it can skip it can skip areas.

It's it's it's stochastic. It can go anywhere at any time and it can show up anywhere at any time.

But how's it moving from point A to point B? It has to move through the geography.

So the way I the way I think of this is I think of Mark Moyed and you throw him into the river, a raging river with rapids. And where is he going to wash up? He could wash up just a hundred yards downstream or he could survive and wash up five miles downstream. Cancer cells spread and it's not simply that they spread to point A then to point B then point C. They have to spread, land, survive, multiply, then throw out additional. Sometimes when a cancer cell is released into the bloodstream or into the lymphatics or whatever, it does not have the tools to be happy in the pelvic lymph nodes. But if it floats around and hits a bone spot, it's going to be happy. Likewise, another cell may not like the bone. It might like a lymph node. So the bottom line is that cancer spreads in a stochastic fashion. And it's not systematic. It's not stepwise like the pebble in the water.

Yeah, that's sort of a hybrid. I think that's a good way of putting it. So, it uses the highways and byways, but where it pulls off in the rest area and reveals itself could be anywhere. I want to make a point off a paper. A lot of papers I've always kind of focused on. Very few people have really studied pelvic anatomy and lymph node number. And one of the best papers that uh I saw was actually done in China. It was actually done in cadavers. Anyway, the point was, they did an extensive lymph node dissection in males and they found out that the number varied in the pelvic areas from as little as 20 to 24 to as high as 60. And so I don't know if you had a comment on that. I I when you talked about lymph nodes, nobody ever talks about the fact that they're also very individualized. I mean, you're supposed to have a certain number, but some people have a lot more than others.

So, yeah. So there's there's two sources of variability on a lymph node dissection. One is surgeons preferences. So some surgeons don't like doing pelvic lymph node dissections. On the other hand, you know, back back many many years ago when I used to do prostatectomies.

Yeah. It is striking because you can have a patient that has a lot of tissue tissue packets or areas of lymph nodes and then you can have other patients that it's barren. It's it's empty. And I think that maybe it has to do with um you know, kind of how much fatty tissue is down there and how much other tissues are down there.

Um so I think that I think that the lymph nodes a lot of times are there but they are so microscopic that they're incidental but then when they become pathologic they become more evident or when they become inflamed but there is a huge amount of variation a huge amount. Exactly. And I think that's.

And and this is it's really interesting also because you can have patients that have had very excellent pelvic lymph node dissections, but they still manage to have pelvic lymph node recurrence of disease. So you sit there and you go, I thought I stripped out that whole area and look, something grew back. So there are a lot of things we don't fully understand, but the the bottom line is that there's variation, you know.

Yeah. Exactly. Because you know some surgeons will do pelvic lymph node dissection take you know seven on this side, eight on that side and you go woo that's a lot not knowing that you know you could have 40 or 40 or more individually such individual variation but um I'm glad you made that comment. The next thing we jump to is the Phoenix definition which you you love talking about. I'm just going to I'm just going to tell you my my take on it and this people's definition of when you've been radiated what's a magical PSA number above your nater. Now remember nater is the lowest point that your PSA reaches right after treatment right now and not as in immediately after treatment. I'm saying that after you're treated what's the lowest your PSA becomes. Nater is actually an Arabic word that comes from meaning basically the opposite of the zenith. So, um, I thought you would find that interesting. So, we've kind of taken that word and nater is supposed to be something that is very low and that's the thing you hold on to. So, what Phoenix did in the 1990s, we used to say three consecutive PSA rises and they said, "No, no, no." Then in 2006, they meet, they met in Phoenix. Gee, I wonder where they got the name. They met in Phoenix and then they said that was Roach's paper and he's going to be speaking in the fall. He said a PSA rise by 2 nanogram/mL or more above the nater PSA. But here's my takehome from where we are with that. Not only do I agree with you that the game has changed with imaging, but depending on the technology you're using, you need to talk to the experts in the field for what that Phoenix definition really means. So what I mean by that is lately there's a couple big groups doing SBT and they're finding lower naders than EBRT and they're finding a lot of bounces, a lot more bounces. So they're coming up with papers from other institutions around the world saying that that the the Phoenix definition holds some accountability, but there might be too many false positives. So it might have more probability of being accurate 18 or plus more months after you're treated. So the take-home message for nater like after radical prostatectomy we're saying 0.2 or higher and now there's this Stuttgart definition that is 1.2 two or higher after HIU. Now, it's not universal, but it's trying to be accepted. All I'm trying to tell the audience, and I'll let you have the last word, is this Phoenix definition is okay, but you have to sit down with the expert who's who's done your treatment and say, "Well, what's the equivalent of that for me?" whether I've had a radical, whether I have SPRT, whether I've had HIU, because it's not universal amongst all treatments, including that of one type of radiation. Does that help or did I confuse everybody in the audience?

It's a cluster.

It's a cluster. Do you you can't add the second word. The point is you need to sit down with your treatment people, your treatment team and say how much value should I put in this PSA meaning relapse and you have to have. You have to have the discussion of PSA bounces after radiation. There's a lot of them especially after SPRT.

Sure. I agree with that. I think that um you know the the the fact of the matter is you know the field is being bombarded with all kinds of technologies and the definitions are evolving and I think that um interpretations are changing um and these interpretations are changing based on where practices are located. Are they in Europe? Are they in the United There's a whole bunch of stuff going on. So if you really try to wrap your mind around it, I think it's very difficult. I tried to stick with generalities to keep it simple because I I don't I don't think that a normal patient can can tackle this with without using a a Cray computer, you know.

Yeah. And but but we don't you don't want someone just hugging that Phoenix definition and going this is binary. This is the end all be all of what it means to have a relapse without understanding the nuances and having that discussion with their team. I'm I'm more focused on trying to convey the message that you got to keep your eye on the ball.

Yeah. You can't just sit there and have a physician tell you, "Oh, well, you fall under the threshold for relapse based on the Phoenix criteria. Ergo, you shouldn't worry about your prostate cancer. You have to follow up your prostate cancer and you have to watch the trends."

That's right. That's right. So in this this comprehensive paper done by all these different institutions they were finding a 30% false positive rate just for example using SBT with that definition and so they've tried to hone it and make it a little bit better and add certain parameters which you could talk about with your team. So just because a PSA rise happens after radiation doesn't mean relapse. It could be a bounce that eventually comes down again. So I don't know.

But the but the reason the reason it's so complex once again is because every physician treats every patient differently. So some of them will use a little bit of hormone therapy. Some of them will use a higher dose on stereotactic treatment. Some people will treat part of the seminal vesicle. Some will not treat it. What I tried to explain in the talk is everyone's treated differently and everyone treats differently. And when you are following things in general, you you want your PSA to stay low.

That's right. And not rise. Okay. That simple.

By the way, guess where the Stoutgart definition for HIU came? Uh in terms of 1.2 and higher after higher higher after treatment. Guess where the Stoutgart definition came from?

Jersey.

Alex was talking about this beforehand. I was talking I said, "No one's no one talk anymore. I'm so excited. I actually made these signs a while ago." Okay. So, you have a couple of references that talks about waiting to see on the image where your cancer is before you hit it, suggesting that may be a better approach. So you used a bunch of references on your slides which I pulled. The one reference that I thought was most compelling was the one from Denmark where they said by using the PET CT it not only and waiting till you see it. Not only was it helpful against the cancer, it improved overall survival. Overall survival. Okay. So that led me to make a new sign for you that I have never shown before and you should talk about it. Dr. Quan references PSMA PET CT showed improved survival. Can you comment on the fact that it is a fact today that when you get a PSMA PET, you can comment on choline, you're basically getting a full body scan that in some cases can be accurate. Look, it can pick up at the bladder. It can pick up at the brain. These are papers that I looked at across the board. Breast, colorectal, esophageal. These were case studies. Gastric, kidney, liver, lung, lymphoma, pancreatic, thyroid, and others. So can you mention the fact that the other thing about the PET CT today unlike a few years ago with bone scans and these other things is that you're not just looking in some cases it's picking up other adenocarcinomas or other cancers in other places that have helped people get a cancer or find a cancer early that could be very aggressive. Can you comment on the fact that I now believe that a PET CT scan comes with catches, but it also comes with pros. It may be for some people a very good full body scan, a more accurate full body scan. What say you?

PSMA PET scan can definitely pick up other malignancies. We don't know all of the other malignancies that will show up. Definitely some of those will show up. Yes.

C11 choline PET scan. We had already compiled probably 30 malignancies that show up on C11 choline PET scan. In terms of full body scan, so it depends on what your definition of full body. So, we do have um patients that have metastatic disease on the tip of their head or down lower by their knees or below that the disease is cut off because they only scan you from mid forehead to mid thigh. So, it's not full body scan in the sense of it shows your entire body. But where I've always liked PET, and this is where people have always poo-pooed or minimized it, and I don't know why, it shows soft tissue and bone. It shows organs, and it shows virtually everything. And the reason that's important is because the people that are oftentimes arguing against the PET scan are saying, "No, no, no. You just use a bone scan." And you go, "What the heck? A bone scan just looks at bone. Yeah. Yeah. Yeah. But that's what we use in our clinical study, you know, and you know, it's only showing bone. So, a PET scan will image everything in its field from your forehead down to mid thigh. And if you request, you can actually get the PET scan to be done. I when I put the request in here at Mayo Clinic and people laugh at me, I say from uh from the top of the head to the tippy toes. Tippy toes.

And that way you get everything on the scan. And that's soft tissues, muscles, tendons, bones, organs inside and out, top to bottom.

It's that's the point. It's an all-in-one scan. It doesn't mean it's it's perfect at those other sites. Like you said, it picks up it can pick up cancer in other organs, right? It can pick up something going on in the bone, right? It can pick up something going on the lymph nodes, right? It can pick that's what I mean by full body.

And it can pick up things. So we published already we published so the original JAMA article that talked about metastatic disease rising PSA. Yeah. So rising PSA first evidence of metastatic disease the original papers Scardino and all all those guys JAMA. Eight years from time of rising PSA to metastasis took eight years using conventional imaging. A classic paper. With C11 choline PET scan and we sent it to JAMA they would not publish it with a C11 choline PET scan you can find your first metastasis within on average one and a half years at a PSA of less than you know uh two. So there is a 7-year lead time advantage in terms of finding metastatic disease or finding recurrent disease using a PET scan compared to conventional imaging seven years.

Yeah. I mean the downside is I'm not going to talk about the downside today because we don't have time. The downside are some false false positives. However, you have you. Conventional imaging has false positives. That's true. Much more than PET scan. Much more.

I wasn't supposed to get a reaction out of you. I was moving into another topic.

Yeah. Well, you know.

No, but what I'm telling you is is that if you have a patient, think about it. Now, I want you to think about the nerdy move that I just did. How I have no life. I went back into all the literature so far on the PET CT including choline including PSMA you can even talk about fluciclovine anyway I went through the literature because I have no life and they are picking up cases these are the ones that I went through bladder brain breast colorectal esophageal gastric kidney I'm not saying it's perfect for these but incidentally they were picking up some serious disease and cancers in all these other locations so that culminates in if you give someone a PET CT and everything else looks clean and you're comfortable that you're going after the prostate cancer but everything else all the organs look clean. Do you actually have that discussion with a patient and say hey by the way this is what Moyet calls a full body scan. I know you don't say that's what Moyet says, but this is what Moyet calls a full body scan. And by the way, whether it's, you know, in the skeleton or in the liver or the spleen or the lungs, it's fully clean and you should feel good about that. Do you have that conversation after the scan?

We if we treat a patient and we're talking about, you know, where they're at with regards to their disease and their overall health, we do sometimes compliment patients for, oh, your scan's clean, which means that, you know, it because that's that's talking about cancer. We see many other things. Yeah. You see inflammatory disease in the lungs, you see inflammatory disease in the abdomen, you see a myriad of other things which you know are sometimes worth commenting on. But yeah, I mean if a patient has a clean scan, we'll comment on it, but you have to have you have to be careful.

Yes. So there are forms of malignancy that can especially in the liver. The liver, you can get burned. And the other thing that people don't recognize is that, you know, we're talking in the context of PSMA positive, there's a lot of malignancies that don't express PSMA on them.

So, just because you don't see something on a scan doesn't mean that something bad isn't happening in that patient.

Yeah. No, it's it's not foolproof. I'm just saying it's a it's a snapshot.

So, I have a question for you. So, how on earth did they when they scanned the patients for um PSMA PET, how did they find breast cancer in women?

You can find breast cancer in a man.

Okay, there you go. No, I'm saying I I'm just saying that I had a friend I had a friend who was 83. I was a friend who was 83 and they thought he might have recurrence and he actually used your terminology. He said that he had a Gleason, you know, nine all throughout. Anyway, long story short, he heard the word you said on a PCRI lecture. He said, "Sometimes you have a smoldering cancer. It's hanging out. It's still there." And so, everyone was kind of delaying his PET CT. And he said, "You know what? To hell with this. I'm just going to get it." Anyway, PET CT was fine. And the rest of his organs and bones and everything else it could pick up from head to toe as a snapshot seemed perfectly fine. And the physician met with him and said, "Wow, you're in your 80s and the rest of you looks great. This is not an end-all be-all foolproof." And I I thought to myself, yeah, he's right. You know, the rest of the scan looks pretty amazing for someone in their 80s. It looks really, really healthy. It doesn't mean that you've got a free card and nothing's going to go wrong. It just means that's the ancillary thing that goes on when you get this scan that you should talk to your doctor about because you got the scan anyway. All right. You have developed quite a name lately for actinium. I'm not going to say why. I'm just going to say that Lutetium's great, but Actinium is going through phase three trials right now. There's two companies right now uh moving toward phase three looking at uh castrate resistant prostate cancer and giving Actinium. Can you so and they're giving it to some people who have failed Plara or Lutetium also and there's a lot of buzz around Actinium potentially getting approved in the United States in the next few years. How do you feel about that buzz? Uh do you think it's appropriate or do you think this is just all flare and no fudge we used to say?

Well, I think that actinium definitely is a very powerful agent. And I think that for some patients it's highly beneficial. I mean, we have patients that failed Lutetium and have responded to actinium and they've gotten durable and uh kind of meaningful responses from therapy. But just like any new technology or any form of therapy, you know, there's an upside and a downside and some of it we haven't even yet figured out. Um I have had a lot patients that were treated with actinium as many as 10 years ago now and um a lot of those patients develop sequelae of renal insufficiency um because I think actinium as an alpha emitter um does uh put a lot of radiation through the kidneys and I think that the good news is the patients did very well to um uh survive their prostate cancers after being treated. With a dramatic response therapy. The bad news is that some of them developed renal insufficiency and for some of them that's an agonal event, you know. Um so I it's just like everything else and you know this thing always boggles my mind and I tell this to every patient that I get, you know, you can have a patient that's failed eight different things and they can be down to their last last treatment and you can give it and even if It's sometimes illogical, sometimes it'll work great, but then for a lot of patients it won't work. So with Actinium, I've only worked with it in the context of fairly severe disease. However, we have had some patients that have early disease that we have treated with it and I think it's a very powerful agent. No doubt it's stronger than Lutetium. I mean, I always talk about paint paint strippers. You know, the average paint stripper can get the paint off, but if you're really struggling, get the actinium, you know, get the stronger stuff.

That's interesting. I'll tell you, as these as these trials launch, you know, Novartis and others have this PSMA action and other trials. You know what I found most interesting before your talk? I found that as these trials launch, one of the exclusions of the trial was grade two or higher dry mouth. So, if you're already going into the trial with pretty severe dry mouth that is affecting how your diet is handled, it was an exclusion. And so, do you want to comment on just that dry mouth side effect? You see a lot of that, right?

Yeah. I I have to be honest. I mean, I think that, you know, we my clinic sees such sick patients that we don't necessarily we're we're not necessarily super sensitive of all the side effects of all the therapies because our focus is basically keep keep our patient alive. But I do see a lot of patients that are receiving radiolyan therapies that complain bitterly about the long-term consequences of dry mouth, loss of appetite, you know, they don't enjoy their meals anymore and all of that. And I don't I don't think it's inconsequential. I mean, I think that it's something that we're going to have to tackle or deal with as we move forward. Uh, actinium definitely definitely will be harder on on salivary glands than Lutetium.

Yeah, but it is moving along. It's moving. People are offering it. I don't know if you heard that. That's my dog. He's obviously back home. He wants to be in the video with you. He always wants to be in the video with you. Last two and then it's a softball question at the end. Immunotherapy. You used to be the king of immunotherapy. What happened here? So, let me just tell you right now. Let me just tell the audience one of the big immunotherapies out there is Keytruda. It's now approved for 18 different cancers but not prostate and now it comes in an injectable form which is pretty interesting. So I pulled this from the company and just bear with me a second. Here's where they have indications right now. FDA indications immunotherapy melanoma non-small cell lung cancer malignant pleural mesothelioma head and neck squamous cell. Just hold on with me a second. This is impressive. Classical Hodgkin, uh, urothelial cancer, microsatellite instability, which you can talk about, esophageal, cervical, gastric, liver, biliary tract, Merkel cell, renal cell, endometrial, cutaneous, squamous cell, car, I could keep going. Triple negative breast cancer now, right? We didn't think it would work in breast cancer, but triple negative now. Ovarian cancer, on and on and on. And you were the king of immune therapy, but we still don't have it in prostate. What is going on, Dr. Quan with immune therapy and prostate cancer. We have one out there, Provenge, but that's long ago. Why isn't there more getting approved in the area of prostate cancer?

So, I started my career at NCI NIH and I had the great great great fortune of working with probably one of the greatest scientists of contemporary time, Dr. James Allison. No question about it. The guy was brilliant and he's the one that came up with the idea of checkpoint blockade for the treatment of cancer. Um he's the one that discovered it. He won the Nobel Prize in part for that. And his first drug that he launched was ipilimumab which is your.

Yeah. Um, we started that work. I got to work with him on that back in about 1995. And I, my contribution to the conversation, aside from getting to carry his luggage and stuff like that, was that uh, I thought that we should try it on prostate cancer. And I pursued that doggedly. Um, and I introduced him to the American Urologic Association and to the Prostate Cancer Research Foundation uh, at that time and we had prostate cancer in our targets.

Yeah. And I actually was the PI of one of the trials that got published, one of the first trials of ipilimumab BMS investigator.

Yeah. BMS043 for the treatment of advanced prostate cancer. And we missed the approval point by a fraction of a percentage. And from that point on, every subsequent immunotherapy trial got worse. The outcomes were worse. We could not get any of these things approved for a treatment of cancer. I was involved in the discovery partially involved in the discovery of Keytruda and of um uh Opdivo and Jim Allison continued his work with uh uh ipilimumab and we tried to combine these things nivolumab with ipilimumab and all of these agents and they've been tested in various combinations for prostate cancer and all of the trials are falling short of the um point that you need to get approval. Having said that, I've had great opportunity to reflect on this and I've been watching my clinic very carefully and what I discovered I I shared this with you last night. Um back a couple years ago, we started getting um Guardant360 tests uh liquid biopsies for genetics on patients and one of the readouts on the genetic testing is some something called um tumor mutation burden. Tumor mutation burden. So in lay language, tumor mutation burden is a readout of how many mutations are present in a cancer cell. So I sit there and I'd look at these things and I noticed the more we treat a prostate cancer patient, the higher that number started to go.

Yeah. And I sat there and I was thinking, isn't it weird because every time we treat someone and they fail therapy and they get another therapy and they fail that therapy, the mutation burden goes up. So then one day I was sitting here and it dawned on me, well gee, I wonder if the pro and I thought about all the clinical trials that were run. The intuition with the clinical trials was let's do a clinical trial for really advanced disease. Oh, we failed. BMS 043 failed. And the reason it failed was because the guys were too sick. Let's move this trial to a healthier population. And then we ran a healthier population, BMS095. We failed even worse.

Yeah. That's. So actually the mistake that I believe we made is that we should have been looking at sicker populations. And the reason why is because as the patient gets sicker, their tumor mutation burden increases. In lay language, the immune system cannot recognize a cancer cell if it looks like a normal cell. But the more mutations it acquires, the more freaky it looks to the immune system. And then the immune system can sniff it out and kill the cancer cell. So then I went back to Guardant and I said, "Show me all of the tumor mutation burdens for every single malignancy you have in the world and rank them which when a guy walks in the door or when a person walks in the door for cancer therapy, what is their tumor mutation burden?" And the number one top mutation burden was melanoma spontaneously. So what that told me and then renal cell carcinoma, bladder carcinoma, everything at the very very bottom, garden variety breast cancer and garden variety prostate cancer. They were at the bottom. The tumor mutation burden of those malignancies even under stage 4 conditions, metastatic conditions, is relatively mild. So the immune system cannot recognize those advanced forms of cancer until they've failed several therapies. The only difference or the only exception to that is if prostate cancer has M8 or MSI high status.

Microsatellite instability high status. Those patients do respond to immunotherapy. Patients with high mutation burden, exceptionally high, do respond to immunotherapy.

Yeah. But I think in my heart, and this is unproven, this is just my speculation, and I'm old enough to have looked at this for a long time. My speculation is that the reason prostate cancer hasn't worked thus far is it doesn't acquire mutations at a rate fast enough like the other malignancies where it can signal to the body that it's a foreign predator that needs to be picked off by the immune system.

Yeah. No, I mean that makes a lot of sense now. But just for the audience, there's a very small percentage of people that do have enough tumor mutation burdens when you do a liquid biopsy or MSI high. Both of those are indications under for example the FDA and Keytruda that regardless of the cancer type indirectly if you have prostate cancer and you exhibit those features you can get the drug and then you see so you've seen some people get the drug who have those characteristics do they respond?

So, we always follow our patients just like with PET scan, we also follow them with Guardant on their follow-up visits if they have recurrent disease. And we're always surveilling our patients for an increase in tumor mutation burden or the acquisition of certain targets including MHI high or MSI high status. Yeah, those patients MSI high status. If a guy has MSI high status, he has a very high probability of responding to immune checkpoint inhibitor immunotherapy. Um the tumor mutation burden is more of a graded response. If it's a very high tumor mutation burden, there's a good chance accompanied by you know aggressive phenotypes such as small cell and so forth, they may respond to immunotherapy. But the bottom line is when our patients get a tumor mutation burden of 13 or more uh mutations per megabase DNA, you know, if if needed and if we run out of options for therapy, we can get immunotherapy approved for them.

Yeah. That falls that falls in once you hit double digit mutation per megabase uh 10 or greater uh you fall into the possibility of getting Keytruda. So there is that segment of the population. That's awesome. I appreciate that. Last two softballs. One's a softball and the rest is I just I'm looking for something profound at the end. I apologize for this question. I wasn't going to ask you. I don't know who I'm scared of. I'm not Maybe I'm scared of some people, but AI and prostate cancer. I put sorry, I just had to ask or I would get in trouble. You know, I we just get the question a lot like AI this, AI that. So, I you I just wanted you I don't know if you have any general comment on AI.

Tried to tell the joke. So, um the thing that drives AI platforms is digital technology. Digital technology and urologists are the innovators of digital technology. Digital rectal exam. Okay. So, we invented all this stuff on AI and everyone accuses us of being artificially intelligent. So, we've been there for a long time. All right. Okay.

I you know. You gotta keep your day job.

So, you're not you're not I'm I'm not going to leave this interview without you some grand. Digital technology. Artificially intelligent. Yeah, we're there. We're there. Where they.

I I think that I think that where artificial intelligence will really be helpful will be hopefully probably um looking at PET scans for reading out what's going on with patients um for looking at pathology. I think that that's going to be um um I'm kind of hoping that uh it might be also useful in terms of you know we get a blood test we look at the genetics and then we sort through this kind of uh chaff or um barrage of genetic information that we might be able to sort out adverse signals that um indicate serious disease not so serious etc etc etc. Um, you know, I don't think that it's going to get to the point where someone comes in and says, you know, th here's my PSA and this is me and tell me what's go. I hope it doesn't go in that direction because I think we already do a lot of that where we just clump people into buckets and just say, you know, this is what you need to do.

Okay. Do you want me to give you the last question that I was contemplating not asking you, but I thought you.

Digital rectal exam? Okay, digital technology. It's right here. Okay.

Just think.

about that. Try to feel it.

>> I feel it right now. Well, I felt it last time, that's for sure. Um, >> okay. For the audience, I hate to say this again. >> I think I've published I've written almost 200 papers. Uh, I for over 20 years had to review a paper every month for doctors to listen to to get credit. I I just gave that up because I'm trying to slow down and retire from doing too much work. But I still see thousands of papers a month, I would say, because I'm still writing papers. I'm still teaching students. And I came across this paper on March 5th. And I don't know why I thought I need to know what you think of it, but that's what happened. And it was published in JAMAMA oncology. And here's the basis of that paper. And I want to know how it applies to your thinking. And we have not rehearsed this. I've never brought this up with Dr. Quan.

Here's the new study from Richardson L. And it was done with a variety of institutions from the University of North Carolina, Honolulu, Rochester. It was a very popular, it still is very popular since its publication online March 5th. They looked at patients with tumor types including solid tumors and some of them were GU cancers. And they called them older patients if they were 75, 80 and above, whatever you want to use the word for older. Anyway, the take-home message which surprised a lot of doctors is that the older patients with advanced cancer, they wanted quality of life over survival when the question was actually posed to them in a session. It didn't mean that they didn't want it. It just meant that walking away from this analysis of this paper was this massive attention toward look I really want quality of life and I'm not so sure we're getting it enough in cancer but I want you to understand why this paper was published because it was a way to scream quality of life is really something that patients of all ages especially as we get older they really want and the argument was we're missing out on that we're not asking enough. And so I'm not asking you to comment on the paper. I'm asking you about is that your experience that when you sit down there is a tremendous discussion of quality of life or at least there should be because you were talking about all these different drugs that are being offered, all these different things right up front. Maybe we're using too many too quickly and they come with quality of life issues. They're great medications, but there has to be a quality of life discussion. So somewhere in my rambling, there is a question for you. But do you find that a study like that is reflective of your experience in your clinic?

>> I think that fundamentally quality of life is a personal um parameter that sometimes shifts with patients. I don't think you can just say you know it's a binary thing. Here's you have pri quality of life. Here you don't. >> We spend a lot of time with our patients. Lots of time. Lot more than you would believe. And I feel that I have to read the room every time I go in the room for whether the guy is 40 years old or whether the guy is 90 years old. And I have to tell you that I've had patients that are older that want to cling to life come hell or high water. >> Yeah. >> And I have other patients that say, "Well, you know, this whole thing is getting ridiculous. I don't want to keep going." I think it's an individual decision. And I always tell my patients as much as possible that I'll hit it as hard as you want me to hit it for as long as you want me to hit it, but it's your word, not mine. And I have had patients that, you know, we tell them that we hope we can help them and we hope that they can get better, but after a couple times seeing me, they say, "Well, Dr. Quan, you're a disappointment. Your treatments are disappointments. you haven't got me there. I want to quit. And I'm fully respectful of that. At the same time, we have other patients that we're saying, I'm not sure we can give you something anymore because we're scared of what we're going to do to you. And the patient's demanding it. They're demanding it and they're offended if you don't offer it. If you could show me what quality of life means in three words and put it into a survey and then say that this metric has been met or has not been met, then I think that that paper has value. Mhm. >> But I don't think the paper has value in the lives of normal human beings who are constantly faced with different kind of feelings about what's going on with their cancer and different side effects of their therapies and and so forth and so on. I think it shifts. >> I really do. And I think you just have to remain very fluid when you manage patients. Um, you know, again, what I say to patients is we'll do what whatever you want. We'll try as hard as you want, but we'll give up also when you want. And when we run out of options, fully run out of options, we always have the conversation. I think I think we're at the end of the road, you know. >> Yeah. Well, I think but I think you'd agree with the paper in the sense that the last sentence in the abstract was suggesting there's a possible lack this is a quota this is a quotation. It's a possible lack of responsiveness of the current oncology care delivery system to patient preference.

>> I think that I think that that hits the nail on the head. I don't think it's about quality of life. I think it's about respect. >> Yeah, that's a good point. I think that fundamentally every human being, every patient I run into at their core, they want to be respected. They want to they want you to hear their complaints. They want to hear you to hear about their symptoms. They want to hear you to hear about their struggles and their fears. And I think the difference between a patient that has a good quality of life with their physician is that the physicians either listening or they're not listening to all of these different things. And so we have learned sometimes the hard way that patients have fears and things that you have to tease out of them. And you have to create a comfortable environment where they can speak their mind, share their fears, share their insecurities, talk about what their worries are, and get an honest answer of what the hell's going on. If you don't do that, I don't think that you're providing the kind of care that they want. And I'll tell you, that's my greatest fear over AI. AI ain't going to cover that. I think that the things that once made medicine great, the compassion, the sensitivity, the humanity of it is being washed out by AI. Some of my patients are dying and they're just plain lonely. They haven't faced death and they haven't sat alone in that circumstance and they want someone to listen. That's all they want. And I think that that's what we offer as physicians or that's what we should offer. It's not about, you know, did you do the robotic? Did you tie the knot that way? Did you do this? Did you try this agent? I mean, I have patients that walk into their doctor's office and the doctor says, "Well, your day is done." And it's almost like they're congratulating them that their life is over. That's all of the respect that the patient gets. The patients are shattered. You know, if some if I knew that, you know, I was walking in a room, someone's going to tell me I'm going to die tomorrow, I'd be scared as hell. I would be just horrified. And being horrified in a moment where, you know, you got a young family, you got, you know, it's just mindboggling. And then to have the added insult of, well, I can't see you in my office for 3 months and oh, your insurance didn't pay for this and all that. I mean, I personally admire my patients because they're dignified, they're brave, they're courageous. Somehow they keep it together. I know for a fact that I would not be able to keep it together like my patients do. I would be oozing all over the office. I would be, you know, a puddle on the floor. I would be disgraceful in terms of my manners and my attitudes if I had faced a lot of things that the patients face. So, you know, I think that papers are fun to write and you know, I think I get the point of what they're saying. I agree that you can't just keep and you know, we're guilty of it, too. We say, "Well, let's try radiation." We and then nothing is worse than having a patient say, "Well, Dr. Quan, I did everything that you told me to do and it didn't work. That's that's a horrible day for me >> and it doesn't escape me that it's happened. I feel terrible about it. But, you know, if if I won every time, I'd probably be treated better than I am as a urologist, right? You know. >> Yeah. Yeah. So I think that uh but you know I I do think that the paper is basically saying that we as physicians should be more human and more sensitive to what's going on with our patients.

>> That's a better way of paraphrasing it than I did. You can see how when I read it, I was excited to get your opinion of it because I think there's a lot of agreement there when you kind of dig into it that um we have to work on patient preference better and quality of life is is a big deal when it comes to prostate cancer. We know that. So, you said it better than you summarized it better than I could have. I'm going to leave it at that. Um, and with that, uh, I know you're you're probably still thinking, is he really going to send me a hat, a national championship hat? And the answer is, of course, I'm going to keep my end of the bargain. And you have to put that in your office. Otherwise, I would be devastated as a friend of yours that you didn't put that hat in your office. Is there >> I'll put it right next to my University of Indiana National Championship football hat. Okay. >> Yeah. Big 10. I love them. People forget I get stuff from Ohio State fans. I love it. I get stuff from Indiana. I see I'm not one of those that get just big. It's all Big 10. It's all love. I mean, I want us to win, but if we can't win, I want I want them to win. Anyway, I thought I'd keep with the basketball theme. >> Total slam dunk. Thanks for being you. Gift is in the mail.

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Relapsed Prostate Cancer | 2026 Mid-Year Update | Eugene Kwon, MD + Mark Moyad, MD Q&A #PCRI

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