Raoul S. Concepcion, MD, FACS

If that patient presented today, and came to you as a second opinion, is bone scan and CT your choice still? Describe to me what other imaging modalities you might consider.

 Thank you again for inviting me. It’s an honor and privilege to be on this panel. With regard to the current day and age, the answer to this also will depend on which geographic region you are in, because there are certain agents that are approved that are widely available, and there are others that have more limited availability, because of either half-life limitation of the agent, or the way the FDA approval has been structured. Let me expand on that. Going back first to your question, the bone scan and the CT scan would not be the standard of care now, because there are other options. These options include the PET [positron emission tomography scan]/CT agents or PET MRI, if there are certain geographic regions that have it available. The most widely available agent right now is the fluciclovine, which is a fluorine-18–based agent. It has a half-life of close to 2 hours. Therefore, for most commercial radiopharmacies around the country, there is a network sufficient that if there is any PET scanner in any geographic region in the country, they will have access to fluciclovine.

There are a few other agents, such as C-11 choline, which is available and approved. However, because of its half-life, the availability is going to be limited very close to a cyclotron, or most of the times, the sites that have a cyclotron can access that agent. As of November, or December of 2020, the very first PSMA [prostate-specific membrane antigen] agent was approved by the FDA, and that is the gallium PSMA agent. That has the approval primarily through UCLA [the University of California, Los Angeles] and UCSF [the University of California, San Francisco]. However, UCLA and UCSF have been kind enough not to hold onto the IND [investigational new drug] proprietarily, so there is access if there is a cross reference to the IND for the sites that are doing the studies and have approached the FDA to cross reference it. Finally, there are many other PSMA agents that are available through the clinical trials. So, if any one of the sites is participating in these trials, there is access to those PSMA agents that are still not approved by the FDA. However, we’ll discuss them later during our subsequent discussions on the imaging side, but that is also an available access through the clinical trials.

Perfect. We’re going to go to a second polling question. I think the audience has already seen this. If this patient presented today, and assuming you would re-stage the patient, what imaging modality would you choose? Dr Ghesani gave a nice and brief summary on this. Would the audience continue to do their first restaging technetium bone scan and CT of the abdomen and pelvis, with and without IV [intravenous] contrast, whole body MRI, fluciclovine, gallium PSMA PET, C-11 choline, or other? This will give us [an idea about], as Dr Ghesani said, what’s available out there in your various marketplaces, because it’s not equal around the country. I think your point is very well taken. I don’t think a lot of people realize that when the gallium PSMA scan was approved, that it was specifically for UCLA and UCSF.

Looking at the polling question, we’ve got about 23%, a quarter, would still do bone scan, CT. Nobody would do a whole-body MRI. Close to 50% is going to use fluciclovine. Finally, 30% are going to do gallium PSA [prostate-specific antigen]. Judd, what do you have over there at Duke [Cancer Center]?

 I really appreciated Munir’s comments. I think from an academic standpoint, he’s right on target. The problem is, at least in the trenches where I’m at in North Carolina, a lot of times insurance carriers will not cover the Axumin [fluciclovine] scan until you’ve done the bone scan and CT. Often, I don’t know if Brian’s running into that in Chicago, but you order it, and then I’ll get a call to do a peer-to-peer [discussion], which is never really a peer-to-peer, it’s someone on the other end who doesn’t really know what they’re talking about, but that’s another story. They will say, “Have you done a bone scan and a CT? We need to see a negative bone scan and a CT before we’ll pay for the Axumin.” I don’t know, that needs to change, because it’s a waste of money. Nevertheless, that’s what we’re facing in early 2021.

 I think that most clinicians, and certainly insurance companies, don’t necessarily recognize that the sensitivity of a bone and CT scan is very limited. Historically, as you said, and back even in the early to mid-2000s, and even today, we order these tests. However, half of it’s out of necessity to meet insurance standards, but the sensitivity, at levels less than 10, and less than 20 [ng/mL] certainly, are poor. Moreover, it’s been studied and suggested that up to 90% of scans at that level will be negative, but nonetheless, that’s our gold standard for what we compare against. When those studies came out, it was because choline was being FDA approved at the time, and you needed a PSA level recurrence of about 2 [ng/mL], at minimum.

Therefore, a lot of these insurance companies adopted a level that said, “Hey, not only would you have to get a CT and a bone scan first, but I want to see your patients’ PSA level at about 2 [ng/mL] before we’re going to approve that.” There is some variability there, and certainly Medicare is better, but it’s frustrating. The point here is that if we can locate that disease and we can treat this at volumes when the tumor is still small, certainly, patients are going to have better outcomes.

Post-surgery, there have been many trials that say if you treat patients at an early time, when their PSA values are between 0.2 and 0.5 [ng/mL], they’re going to do better than if we wait until those values are higher. We typically want to get these types of what we call next-generation imaging scans, or these PET/CT scans, whether it’s fluciclovine or a PSMA scans, at earlier levels, which we believe help patients better. I agree with Judd that often, I must go through those hoops, although it’s a futile exercise and extra radiation exposure to the patient. From there, the patients become frustrated because I don’t hide my angst for these hoops. But I think it’s the way that we get the right scans these days.

Videos

An expert panel reacts to polling data on choice of imaging modalities for patients with prostate patients after definitive therapy and share their insights about best practices.  

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer 

Here’s our first case; pay attention to the dates here. In 2010, we have a 58-year-old white male who presents to urology with a PSA [prostate-specific antigen] of 15 ng/mL, normal DRE [digital rectal examination]. He undergoes a TRUS [transrectal ultrasound] guided biopsy, and shows 5/12 cores positive, all Gleason group 2, which as many of you know, now has been broken out as 3+4 [Gleason grade group 2 (3+4)]. Additionally, the staging work-up, bone scan CT was negative. The patient underwent robotically assisted radical prostatectomy, and surgical pathology shows a pathologic T3a, so he had capsular involvement. Again, all Gleason grade 2; surgical margins and seminal vesicles were negative. Six months post-operation, his PSA was 0.8 [ng/mL]. Then, the patient relocates for his job and has no follow-up. Let’s go to the next slide.

He returns to the area in 3 years, and he has a PSA of 8.3 [ng/mL] now. Remember, his nadir, his 6-month PSA after surgery was 0.8 [ng/mL]. He’s completely asymptomatic. He undergoes a work-up, restaging, and he has a bone scan and CT scan, which are negative for metastatic disease. To the audience, would you start this patient on ADT [androgen deprivation therapy]? Again, he had a radical prostatectomy, pathologic T3, Gleason [group] 3+4, asymptomatic, PSA was 0.8 at 6 months, and now the PSA is 8.3 [ng/mL], completely asymptomatic. Let’s see here, two-thirds of the audience say they would start ADT; 17% said no; 16% to 17% said there’s not enough information.

Raoul Concepcion, MD, presents the case of a 58-year-old man who had a radical prostatectomy 6 months prior and discusses how aspects of the case influence treatment selection. 

Case 1: 58-Year-Old Man 6 Months Post-Radical Prostatectomy 

When you do have a biochemical recurrence, you’ve defined what that looks like for you regarding surgery and radiation. I think Judd has brought up some very good points relative to looking at the initial Gleason [score] at the time of therapy, especially in the patients with radical prostatectomy [RP]. I think the…data spelled that out at [Johns Hopkins Medicine]. What are the factors that are going to say, like you said, just because you have a biochemical recurrence and a rise in the PSA [prostate-specific antigen] doesn’t necessarily mean it’s cancer cells; it could be benign cells. What are the parameters? What are some of the things that are going to push you to say, “I better initiate ADT [androgen deprivation therapy] in this patient?”

 …Or some form of therapy. I think that is a lot of the art form. I think it’s not a simple straightforward [idea] that everyone who has a biochemical recurrence needs treatment. If you look at the data, not everyone who has a biochemical recurrence will ultimately go on to succumb from prostate cancer or develop obvious metastasis. I think that the timing of the recurrence is imperative. Notably, someone who has a PSA recurrence 10 or 15 years later is different than the guy who has a recurrence almost immediately, or within a few months following treatment.

Additionally, regarding the patient’s comorbidities, if a patient is much older, even though it’s a number and very few of us can give up following that number for some reason, we still are reluctant to initiate treatment if there are a lot of comorbidities or underlying factors that they’re more likely to die from. I think timing and how fast that PSA is doubling, or the kinetics underlying that PSA, if those PSA values are increasing rapidly, we’re a lot more concerned that that is prostate cancer. Because, if it is benign glands, the rate of rise or changes over time is going to be a lot slower, and typically, you’re not going to get to a lot higher values like you would if it were cancer.

I think the Hopkins data in the surgical patient were that if you had a Gleason [score] greater than 8 at the time of surgery, if the biochemical recurrence was inside 3 years, and the PSA doubling time was less than 9 to 12 months, that patient was definitely, to your point, going to be at risk from succumbing to his disease if therapy wasn’t initiated.

Experts in prostate cancer discuss considerations for initiating ADT therapy after definitive treatment in patients with prostate cancer in the context of biochemical recurrence. 

Considerations for Initiating ADT After Biochemical Recurrence in Prostate Cancer 

Brian, how do you define PSA [prostate-specific antigen] nadirs, because I think this is an important point, in the surgical patient and in the radiotherapy patient?

 Ultimately after surgery, when we take out the entire prostate, we’re really expecting that PSA to go to a value of undetectable, 0 [ng/mL]. There are certain definitions, because we use ultrasensitive assays, etc. For the most part, we want to see that at what an equivalent value is of 0 [ng/mL]. At our institution, that is less than 0.02, or less than 0.001 [ng/mL], which I have seen depending on the assay. If after surgery that level rises to a value of 0.2 [ng/mL], I think everyone would agree this is a common definition that would be considered a recurrence. There has been some evolution, especially for men with higher-risk disease, that if you’re using an ultrasensitive assay and you are seeing consecutive rises of that PSA before they’re actually getting to a value of 0.2 [ng/mL], most people would agree that that’s a recurrence as well. There is some devil in the details there, but certainly, I think if you’re going to walk away with this, the value of 0.2 [ng/mL] after a surgery would be considered a recurrence.

For radiation, it becomes a little trickier because we still have the prostate gland that’s in situ, and there is some benign tissue there, so there is for many patients, a level of PSA that exists. Your PSA will get down to some lowest value, or that nadir value. There have been various definitions that have been used throughout the years. I typically use what’s referred to as the Phoenix definition, which is a value of 2 ng/mL greater than their lowest value. Again, if you see consecutive rises at least a month apart, consistently rising more than would be expected, I also have some suspicion there that earlier intervention or recurrence may be warranted.

Judd, we know that in the surgical patient, that nadir happens quickly, usually within 6 months, if it’s going to get to the level that Brian was discussing. What about with the radiation? When do you start to say, “OK, I’m at 6 months, I’m at 12 months, or I’m at 18 months?” When do you feel comfortable? I think as Brian pointed out, it’s not going to go to less than .001 or less than .02 [ng/mL]. What does that time frame look like in the radiation patient?

 That’s a great question. In the classic teaching, in the era before androgen deprivation therapy [ADT] was used with radiation, the radiation therapy itself would sometimes take up to 18 months to clear the prostate cancer. Therefore, we’ve been always taught that you need to sometimes wait up to 18 months if it’s a patient who’s just receiving radiation, and you wouldn’t necessarily want to do a biopsy. You also have a PSA bounce phenomenon that sometimes can occur. Now, all the high-risk patients and many of the intermediate-risk patients are also receiving ADT with the radiotherapy. With the ADT, their PSA should go down generally more quickly, especially if you’re using an antagonist like Degarelix, or now the new oral option, relugolix. In general, the PSA typically nadirs, I see it nadir usually within 3 to 6 months in men who are getting hormone therapy with radiation.

The only additional point that I would make is that sometimes in guys who had low-risk or intermediate-risk disease and had a modern-era radical prostatectomy [RP] with aggressive nerve sparing, bladder neck sparing, and urethra sparing, we see low levels of PSA that are not cancer-related. Therefore, I agree with Brian that in the high-risk patients, you can jump on a PSA recurrence quickly, but I would caution the oncologists in our audience tonight that you must look at the RP pathology. Moreover, if it was not so bad pathology, and if the guy has a PSA of 0.13, or even 0.2 [ng/mL] a couple of years out, I tend to follow those patients because there is this phenomenon of benign glands at the margin. We know from the Mayo Clinic’s series and our work at Duke [Cancer Center], that honestly, sometimes up to 30% of patients can have this in long-term follow-up, a little bit of PSA in the system that’s not cancer-related.

Brian Helfand, MD, PhD, describes the ways in which the PSA nadir can be defined after definitive therapy and the implications of the definition used for patients with prostate cancer. 

Raoul S. Concepcion, MD, FACS

Articles

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer

Case 1: 58-Year-Old Man 6 Months Post-Radical Prostatectomy

Considerations for Initiating ADT After Biochemical Recurrence in Prostate Cancer

Defining PSA Nadir After Definitive Therapy in Prostate Cancer

Raoul S. Concepcion, MD, FACS

Articles

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer

Case 1: 58-Year-Old Man 6 Months Post-Radical Prostatectomy

Considerations for Initiating ADT After Biochemical Recurrence in Prostate Cancer

Defining PSA Nadir After Definitive Therapy in Prostate Cancer

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer 

Case 1: 58-Year-Old Man 6 Months Post-Radical Prostatectomy 

Considerations for Initiating ADT After Biochemical Recurrence in Prostate Cancer 

Defining PSA Nadir After Definitive Therapy in Prostate Cancer 