Advanced imaging for recurrent PCa: Is the future now?

Peter L. Choyke, MDNewer imaging techniques are rapidly changing how recurrent prostate cancer is managed. Peter L. Choyke, MD, chief of molecular imaging at the National Cancer Institute in Bethesda, MD, is at the forefront of many of these developments. Dr. Choyke discusses current methods of detecting biochemical recurrence with imaging, promising new techniques to localize recurrence, and cost considerations. Dr. Choyke was interviewed by Urology Times Editorial Consultant J. Brantley Thrasher, MD, professor and chair of urology at the University of Kansas Medical Center, Kansas City. 

Prostate cancer is certainly a disease where we see biochemical recurrence. Right now, clinical parameters such as when the recurrence occurs, margin positivity, and possibly Gleason sum are what generally lead us to adjuvant therapy. How do you see imaging coming into play, both at present and in the future?  

This is a very important part of the natural history of prostate cancer, and our tools are pretty limited. The discovery of biochemical recurrence is based on PSA, but there’s very little information about the location of the recurrence. Currently, if we use imaging, it’s CT, a very crude technique, and bone scan, which is not going to be applicable to the vast majority of patients.

MRI is a method that is getting more attention in biochemical recurrence, especially high-resolution, endorectal coil, 3.0 Tesla MRI, where we can really cone down on the prostate bed and look for areas that are abnormal in signal or enhance abnormally. Inherently, these findings are nonspecific. It could be granulation tissue, inflammatory tissue, or it could be the site of the cancer. What I’m particularly excited about is the new breed of positron emission tomography (PET) agents, which target prostate-specific membrane antigen (PSMA), that potentially target and localize where the recurrence is. That’s the missing piece compared to what we have today.    

NEXT: What do you see as the newest technology in contemporary imaging that might hold promise?

In the past, most of our PET scans have been fluorodeoxyglucose (FDG) PET scans, but prostate cancer isn’t glucose avid. So we look at C-11 choline, C-11 acetate, and other agents. What do you see as the newest technology in contemporary imaging that might hold promise?

As you mention, the C-11 compounds such as C-11 acetate and C-11 choline have short, 20-minute half-lives that can only be used at sites that have cyclotrons and radiochemistry; it really limits where it can be made. So they’re out on practical reasons, but there are some F18 agents like F18-labeled choline and F18 FACBC. We’ve looked at them, and they’re pretty good.

However, the agents that have been described as a “tsunami” taking over this field are the PSMA-based agents. In Europe, they are labeled with gallium 68, which is conveniently a 68-minute half-life agent. I’m using, in collaboration with Johns Hopkins, an F18-labeled version of the same thing. These agents target the external domain of PSMA, and they have incredibly high sensitivity for cancer, especially the more aggressive cancers-the kind that recur. We’re beginning to see small recurrences at PSAs less than 0.5 ng/mL in a range where you can really make a difference.

Are you biopsying those to make sure you have tissue confirmation?

Absolutely. They’re very challenging to biopsy. The other way of validating is to have the patient irradiated and see if the PSA goes down, but that’s less satisfying.

NEXT: "We’ve been thinking about using transurethral photosensitizers to bring light to the tumor recurrence in the prostatic bed as a focal therapy."

Let’s say that we do identify a spot, and we don’t rule out micrometastatic disease elsewhere. Do you think it makes a difference? If you can identify a low PSA then target adjuvant radiation to that spot, would that be all we could offer right now?

I think that’s all we can offer right now, but I think this opens up some huge possibilities. First, does it make a difference? Clearly, cancer that’s recurring after a good radical prostatectomy is an aggressive form of the disease, so we’re already dealing with tigers, not kittens. That makes it a harder task.

Read: Imaging tool shows accuracy for lymph node staging

However, I would argue two things. One is that the cancer will never be smaller than it is at that moment, and it will never be more homogeneous. In that sense, we are missing a window of opportunity because, as the cancer gets more and more evolved and castration resistant, it becomes more difficult to treat.

If we could offer very effective therapies at that time, they are going to have to be molecularly guided. We’ve been thinking about using transurethral photosensitizers to bring light to the tumor recurrence in the prostatic bed as a focal therapy. I believe this would bring the field back into urology.

NEXT: Who best to take care of this?

That raises another question, which is, “Who best to take care of this?” If it’s identified in the radiology suite, why not treat it then?

I think this is inherently something that’s better approached minimally invasively through the urinary tract, if possible. I’m not a urologist, but I’ve become very aware of the delicacy of the sphincter after surgery. You want someone who really understands that mechanism to be doing the treatment. Minimal invasiveness-getting the cancer but not destroying the rest of the tissue-is extremely important to outcomes that are good both from an oncologic but also a quality of life point of view.

If we have better imaging on the horizon and we can identify where the cancer is, then why not use targeted therapy? Do you see that as a future possibility?

I see that as the way of the future for sure. You want to kill the cancer, but you don’t want to cause collateral damage, especially near the sphincter but also the seminal vesicle or lymph nodes.

Also see: Fusion biopsy increases detection of high-grade PCa

I think these focal treatments are going to be very important. The question is how. It’s not simply a laser light burning things; we need something smarter than that. There are evolving treatments, for example, those that are molecularly directed. I’m particularly interested in photosensitizers. The idea is to only damage cells where the targeted photosensitizer has attached and not where it hasn’t. Very highly selective kill zones are the goal. We’re only dealing with a few millimeters of tumor, so it doesn’t have to be a battlefield.

NEXT: "If we can image the tumor and identify its location earlier, the key becomes making sure we have better treatments for it."

The radiation oncologists have always told us that we’re telling them too late. Telling them the tumor has recurred and PSAs are reaching a threshold, they feel, is like calling the fire department after the house has burned down. If we can image the tumor and identify its location earlier, the key becomes making sure we have better treatments for it.

I’ve had good, hard discussions with radiation oncologists who are involved with this topic about why the radiation field cannot be narrowed to the exact site of recurrence, but there’s a big reluctance to do that. Perhaps brachytherapy is something that we could think about in the future as a guided therapy, or radioisotopically labeling some of these agents so that they just go to the spot and kill the tumor cells. We need to get to that point, and I think it’s a huge opportunity.

Have you read: Prostate cancer test could reduce overtreatment

Dr. Ganesh Palapattu at the University Michigan wrote a very interesting piece about this in which he pointed out that most of the men who end up dying of prostate cancer go through biochemical recurrence. If you can stop patients’ cancers from moving down the track, at that point you could have a significant impact on the death rate.

Let’s talk about the patients who’ve failed previous radiation therapy and whose prostate is still in place. Where do you see some of the new imaging technology being used in those cases?

That’s a challenging group because they’ve failed biologically. One consideration is whether there is danger in putting more radiation on top of the radiation they have already received. In theory, there is not. We tend to think that if you flunk radiation, you’ve got to move on to something else. If you could deliver brachytherapy to that area, for instance, there’s no reason why more radiation is not possible.

There are other alternatives, including cryotherapy, HIFU, and laser, but there are problems with those. It’s a big problem but I think it’s addressable.

Read: Long-term PCa surveillance data point to favorable outcomes

Also, the PSMA agents work fine as imaging agents in that setting, as we’ve seen in a number of our cases and cases in the literature involving recurrences in previously irradiated patients. One big advantage there is that you can use all of the new fusion technologies to direct the therapy because the prostate is still there. The concept of using MRI to guide biopsy and then perform focal treatment is very valid, but very difficult once you lose the anatomic landmarks of the prostate. With the prostate in place, it’s a very valid way to go.

NEXT: Do you think we’re going to get good enough to be able to avoid having to do a targeted biopsy?

Do you think we’re going to get good enough to be able to avoid having to do a targeted biopsy? Let’s use the case of a lymph node in the periaortic area. Are we to the point yet where we could target that with radiation?

We’re very close. We need some formal studies. It’s a bit like the Wild West right now, with some institutions doing incredible numbers of cases, but the literature is a little bit clinical and not rigorous. There’s not a lot of biopsy validation.

Often, the intuition is ahead of reality and the intuition is that it will work. But we’re not there with data to convince the regulatory agencies, payment agencies, and others. I think it is a matter of time, given the urgency of the situation and the emotional aspect of this disease at that stage. Biochemical recurrence is an awful situation. There’s a lot of pressure to move forward, and I think that will happen.

Let’s talk about cost. Will the average urologist have access to fusion MRI and PET scan technology that’s widely available and not cost prohibitive? Right now, third-party payers aren’t paying for a lot of this.

Absolutely. It’s a process. Even the fusion biopsy is not reimbursed, and that’s manifestly useful. It’s a long trek to get to that point. I don’t have a crystal ball to say when that’s going to happen, but I’m very sure we’ll be practicing differently in 10 years than we are now.

Think about the history of FDG, which was a research agent until 1999 and then suddenly was approved by the FDA for a limited number of cancers. People said it was too expensive, and we didn’t have the machines, but 3 or 4 years later, we have PET CT in virtually every hospital. We had a whole network of companies crop up in a matter of a few years to manufacture FDG, and we’re in a much better place right now. I pay around $150 for FDG now, and it was thousands of dollars 10 years ago.

Do you have any other comments?

I think it’s a very exciting time. I’ve spent my whole career working with urologists, and I see this as a big area of opportunity.

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