Phillip Kuo, MD, PhD

Recent years have ushered in advances in prostate cancer imaging that contribute to better disease localization and more accurate staging, which there-fore affect clinical decision-making. In this 

™ program, Phillip Kuo, MD, PhD, professor of medical imaging, biomedical engineering, medicine, and cancer biology at the University of Arizona, in Tucson, and Andre Abreu, MD, a urological surgeon at the University of Southern California, in Los Angeles, discuss the role of gallium 68 prostate-specific membrane antigen (PSMA)–targeted PET imaging and its role in staging and disease management of prostate cancer.

Current standard of care and limitations in prostate imaging


According to Abreu, the imaging that is currently available for prostate cancer is mostly conventional, including MRI, CT scans, bone scans, and ultra-sound. Kuo noted that MRI has evolved and improved how clinicians visualize localized disease through high-resolution imaging of the prostate gland and enhanced the ability to assess local invasion of adjacent tissues and seminal vesicles. Abreu added that although MRI is useful for identifying diagnostic lesions and tumor staging of locally advanced disease, it has limited utility for nodal staging and metastases. Kuo added that MRI and CT scans are still primarily structural modalities that require a lymph node to reach a certain size to be detected. A lymph node not reaching the size criteria for detection does not necessarily indicate that cancer is not present.


Alternatives include diffusion-weighted imaging, iodinated contrast on CT, and gadolinium-based contrast agents with MRI. Primarily through bone scans, nuclear medicine has played a significant role in prostate cancer assessment, but limitations also exist with this modality. One of the tracers used in bone scans, technetium 99m-methyl diphosphonate (99m Tc MDP), depends on the reaction of the bone to the tumor. Therefore, the tumor specifically is not being imaged. In addition, Abreu noted that ultra-sound imaging has limited capabilities when used to stage prostate cancer or identify suspicious lesions in the prostate. “There is definitely a need for [a] better imaging modality that would allow us to have a better assessment in evaluation and risk stratification of patients with prostate cancer,” he said.


Regarding PET scans, Kuo noted that initially, the only tracer used was fluorodeoxyglucose (FDG) but added that the FDA approval of Axumin (fluciclovine F18) was a notable break-through in prostate cancer imaging. Axumin is a synthetic amino acid that is taken up to a greater extent in prostate cancer cells compared with surround-ing normal tissue.


Kuo anticipates the imminent avail-ability of PSMA PET tracers; however, he noted that FDG PET scans will still play a significant role in certain cases of aggressive forms of prostate cancer (eg, metastatic castrate resistant or neuroendocrine differentiation). With PSMA PET, clinicians will be better able to stratify patients and separate them based on risk and localization of the disease.

“What we expect in the future is that patient populations [will receive] better treatment because we [will] have a better understanding of the disease from the baseline and have better staging. For example, some patients [who we determined to have] just high-risk dis-ease by conventional imaging actually have nodal disease. Now [that] we know that they have nodal disease, they will be classified as [having] oligometastatic disease and will be appropriately treat-ed. [When we use PSMA PET imaging] for [a] patient [who] we thought only [had] oligometastatic disease, we actually realized [that they may] have more disease, and then [we] change the management of [the] patient,” Abreu said.

PSMA PET is bringing something to the space that hadn’t existed before. Abreu added that it is contributing to a change in management of up to 50% of patients with high-risk disease. Kuo noted that this depends on the patient population and agreed that PSMA PET and advanced imaging modalities will have the greatest impact on patients with high-risk, newly diagnosed prostate cancer.


Studies have been conducted that investigate the sensitivity of PSMA PET scans compared with conventional imaging. Investigators subjected patients who had demonstrated bio-chemical recurrence, but no identifiable recurrence by conventional imaging, to PSMA PET.

“Essentially, you’re starting at base-line where the conventional imaging has failed to localize the recurrence. Again, depending on the patient population, sometimes they’re finding sites of recurrence, sometimes [by] a sensitivity of approximately 50%. And there’s a wide range, depending on your PSAs,” Kuo explained.


Kuo stated that by using the new PSMA PET agents, biochemical recurrence can be detected at prostate-specific antigen (PSA) levels, as low as 0.2 to 0.3 ng/mL, which are difficult to identify when using Axumin PET.


“I’ve been fortunate to read hundreds of these scans, and [using PSMA PET], you start seeing [an indication of cancer in] the tiny Virchow node up in the supraclavicular region, which never would have been seen by CT or MRI or any other modality. You would never have suspected that [it] had prostate cancer. For us, that may be the most significant example of where [the cancer] can just skip all the way up into the supraclavicular region. It’s actually a little bit depressing, honestly, as a nuclear medicine radiologist, when you see the bone scans that look completely negative and then you have a PSMA PET scan [that shows that the] patient is just riddled with bone metastases,” he said. Abreu agreed that by using PSMA PET, they can better identify patients who have only pelvic lymph node metastases versus those in whom the disease has spread to the retroperitoneal lymph nodes.


Because bone scans rely on the reaction of the bone to the tumor, the tumor must grow sufficiently within the bone marrow space to reach a considerable enough size to destroy bone, in order to see the reaction on a bone scan. With PSMA PET, the actual tumor is imaged because the tracer targets and binds to the extracellular portion of the PSMA protein, which is expressed 100-fold higher in aggressive prostate cancers.


Abreu expressed that PSMA PET should definitely play a role in every step of the treatment journey for prostate cancer.“[PSMA PET should be used] from diagnosis to staging, to restaging, [and then to] recurrence,” he said. “It should also be used] for evaluation of the treatment afterward, in terms of if there is disease regression or not. When we do the PSMA PET, we can localize the disease.” Abreu added that it is important to know whether the disease is localized to the prostate bed or whether there is nodal disease or metastasis, as this affects dis-ease management.

PSMA PET has played and is currently playing a role in the treatment of prostate cancer, but additional research is needed. Abreu commented that study results will be beneficial for the whole spectrum of prostate cancer.

Gallium 68 PSMA-11 PET for prostate cancer


Kuo indicated that although he does not use gallium 68 tracers often, gallium (Ga) 68-dotatate PET scans are used for imaging of neuroendocrine tumors, and Ga 68 PSMA-11 PET imaging was recently approved by the FDA for prostate cancer.

 In comparing Ga 68 with flu-orine-18 (F18), F18 is exclusively produced by a cyclotron and has a half-life of about 2 hours whereas Ga 68 has a 68-minute half-life and can be produced by a cyclotron or a generator. Whether using Ga 68 or F18, it is beneficial to have it produced in as close proximity as possible, so that it can be transported and used within the designated half-life. Kuo stressed that one should check with their imaging site to determine schedule availability and supply chain details.


Abreu indicated that although he has had access to Ga 68 PSMA-11 PET imaging in California, few centers can provide this for patients.


Kuo added that the approval of Ga 68 PSMA-11 PET for imaging in prostate cancer has led investigators to use this type of imaging in additional studies. VISION is a phase 3 clinical trial evaluating patients with metastatic castrate-resistant prostate cancer who are PSMA positive, as determined through Ga 68 PSMA-11 PET imaging, and who are receiving targeted therapy with PSMA-11 bound to lutetium-177.


“If their tumors express PSMA, they will then take up the radiotracer and show up on our scan; we can actually measure the levels of intensity. If they met certain criteria, then they would receive PSMA-targeted therapy with this lutetium-177,” Kuo said.


Kuo noted recent reports of positive out-comes from the trial, but details have yet to be announced. Although this does not guarantee FDA approval, Kuo added that if outcomes are impressive, approval will be sought. Abreu stated that this would have a positive impact for patients and clinicians would be able to treat with less aggressiveness and invasiveness.


Advancements in prostate cancer imaging will help to personalize therapy and provide more accurate staging. Both Kuo and Abreu are looking forward to encouraging data outcomes from studies on aggressive prostate cancer.

Axumin. Prescribing information. Blue Earth Diagnostics; 2020. Accessed May 7, 2021. https://www.axumin.com/prescribing-information.pdf

FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. Press release. US Food and Drug Administration. December 1, 2020. Accessed May 7, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer

Study of 177Lu-PSMA-617 in metastatic castrate-resistant prostate cancer (VISION). ClinicalTrials.gov. Updated March 25, 2021. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03511664

Articles

This article features insights from Phillip Kuo, MD, PhD, and Andre Abreu, MD, on gallium 68 PSMA-targeted PET imaging in prostate cancer.

UroView: Gallium 68 PSMA–Targeted PET Imaging in Prostate Cancer: Staging and Outcomes

For our final question, we are going to delve a bit into the future. I am going to start with a discussion of the recent positive outcome reported by Novartis [Pharmaceuticals] of the VISION Study. For those of you who don’t know, VISION is a phase 3 clinical trial in which they used gallium-68 PSMA-11 to select patients who were PSMA [prostate-specific membrane antigen]-positive to then get targeted therapy with PSMA-11 bound to lutetium 177. I am sorry to throw out a lot of radioisotopes there. The gallium-68 PSMA-11 is a PET [positron emission tomography] agent that we use to image. If our patients’ tumors express PSMA, they will then take up the radiotracer and show up on our scan. We can measure the levels of intensity. If the patient met a certain criterion—and I was privileged to help in the design for selecting patients for the study—then they would go on, after you have proven that there are tumors that express this PSMA, to receive PSMA-targeted therapy with this lutetium 177, which is a beta particle emitter. 

This radioactive isotope will then, instead of release photons, release these beta particles or electrons of high energy, which will then go on to destroy the tumor. This is what people may have heard of, this theranostics paradigm, where you conduct the diagnostic to prove that the target is there on the tumors, and then you treat it. Novartis very recently reported that there was a positive outcome of the study. The details are still to come, and this does not mean FDA approval, to be perfectly clear, but they are going to be revealing more details on the positive outcomes of that study, with which they will undoubtedly go to the FDA to seek approval.

Prostate cancer imaging, with this revolution that’s coming soon, it is already here in many regards with PSMA PET, can really personalize the therapy. As you have pointed out, starting with the initial staging, particularly the high-risk group, the UCLA [University of California, Los Angeles] and UCSF [University of California, San Francisco] studies showed there was clinically significant detection of nodes in the high-risk patient population. They also showed, in the biochemical recurrence, very high sensitivity and accuracy.

You can personalize your therapy, like I said, along each way. Not only were these patients upstaged by PSMA PET, which we are very used to with FDG [fluorodeoxyglucose], but some of them were even downstaged. This has produced more accurate staging, whether it is upstaging or downstaging. Then there is this final bit with the VISION study, which focuses on the end of the spectrum with aggressive prostate cancers. This was the population with metastatic castrate-resistant prostate cancer that had already had at least exposure to a taxane. These patients have aggressive prostate cancer. We will see these results. Again, thank you for pointing out, whenever you hear about positive outcomes, it is very encouraging, but we also need to hear about the [adverse] effects, of course. There is always a balance between that. In closing, I would like to thank Dr Abreu, my colleague, for participating in this discussion. I enjoyed it and learned a lot, as always. Any final thoughts?

 No, I just want to thank you for what I have learned from you, and sharing with you was a great experience. Thank you for all your thoughts. Thank you for this opportunity. I learned a lot from you.

I appreciate it. Thank you, the viewing audience. We hope you found this 

 video series and discussion to be very rich and informative.

Videos

Andre Abreu, MD, and Phillip Kuo, MD, PhD, on future use of PSMA targeted therapy, including insight on the phase 3 VISION trial, which used 68Ga-PSMA-11 PET/CT to identify patients for targeted treatment with 177Lu-PSMA-617.

Impact of the Phase III VISION Trial

 To move on to the next question, which is important to discuss, particularly due to the approval in December of 2020—gallium-68 PSMA-11 was approved by the FDA, and will therefore officially be the first PSMA [prostate-specific membrane antigen] PET [positron emission tomography] imaging agent to be approved. It was a joint effort, for those of you who do not know, by UCLA (the University of California, Los Angeles) and UCSF (the University of California, San Francisco). Real kudos to those teams who came together from 2 institutions. That is really what the field needed, this cooperative effort. Obviously, there were big teams in each group, but Thomas Hope, [MD,] from UCSF and Johannes Czernin, MD from UCLA are their leaders. Again, kudos to their teams on both sides. I am going to talk a little about what this means from the nuclear medicine perspective. Of course, for those of you listening, talk to your respective imaging centers because it depends upon your regional availability of things. We do not use gallium-68 tracers too much. There actually is another one approved; urologists may not know about it, but they may have heard about it in their surgery conferences. That is gallium-68 dotatate or Netspot, and that is basically a PET octreotide scan, for those of you who may know that. That is a detection of neuroendocrine tumors, so we have had a gallium-68 approved PET tracer.

This is nothing new, but obviously there are a lot more cases of prostate cancer than neuroendocrine tumors. One of the differences in gallium-68 compared to F18 [fluorine-18] is that F18 is exclusively cyclotron-produced. You may not have known that, but in all those FDG [fluordeoxyglucose] PET scans that you ordered, the F18 comes from a cyclotron nearby. F18 has a half-life of approximately 2 hours. Gallium-68—this is easy to remember for your next dinner conversation—has a 68-minute half-life. It is very fortunate; you do not have to have a great memory to remember that. It has both options. It can be made by a cyclotron; the same cyclotron that makes your F18 can make it, but it requires a different target. Just because it may have a cyclotron that can do it does not mean it is making it right now. The other way it is made is through a generator. Some people may have heard of generators, like how we get technetium-99; your hospital may have that technetium-99m generator.

It is a different generator, but there is the same idea; it’s portable. It can literally sit on the counter, this gallium generator, which is very nice because if the half-life is only 68 minutes, you cannot transport it very far. The range that your cyclotron facility can deliver F18 may not be expansive if you are right at that 2-hour limit. That is too far, in many circumstances, for the gallium-68. There are some places that can be supplied with a gallium-68 PSMA-11 and other radiopharmaceuticals that you cannot necessarily deliver from a cyclotron facility. I must emphasize that when it comes to our radiopharmaceuticals, they tend to be very expensive. A lot of the success relies on commercial availability, right? Is it commercially viable? Just because you have a cyclotron there or a generator here capable of doing it, you still have to make it commercially viable. Check with your imaging sites to know their availability, the timeframe they can deliver within, and the supply chain. Initially, when they are first ramping up, they may not be able to deliver it, for example, every single day, so you may have to adapt that schedule. Dr Abreu, as a clinician, can you give us any thoughts on the impact of cost on the accessibility for your patients?

 Yes. Fortunately, from our side, we have this approved, but it is still a great effort, as you said, from great leaders and institutions, and kudos to all of them. Thanks to them, and thanks to the fact that we have some here in California and in Los Angeles that have been helping us for quite some time. Even when they were running the trials to get approval from the FDA, we used to get our patients scanned over there because it acted as a better assessment for us. This is really needed. Sometimes we face some situations and we say, “I wish I had this imaging available.” Now we do, and this is a major change.

Unfortunately, the other side is that there are still only a few centers that can provide this. As far as I know, these are all cash-paid. Insurance does not cover this; it is not available for the population overall. This limits usage to our patients who can afford it, but at least it is a beginning. PET PSMA has been out there for quite some time, and patients ask, “Why don’t we have this in the United States?” Now we do. Again, with time, this will spread. Many institutions will have this; the costs will go down, and we will be able to scan as many patients as needed, as a clinical indication.

 Thank you. The regulatory hurdles and everything are confusing even to people in the field. The FDA approval does not mean automatic reimbursement to those who are not so familiar with this process. It is very confusing to everyone; we have seen it before with radiopharmaceuticals, approval does not equal automatic reimbursement. But it was a huge hurdle. It opens the doors and lowers the barrier for a lot of people to get into research with PSMA-11. It will prove that these PSMA agents as a class are successful, and that is encouraging for the further approval of other PSMA agents, and also commercial reimbursement from Medicare and CMS [Centers for Medicare & Medicaid Services]. Usually from there, it will follow that the private payers will follow Medicare.

The FDA’s approval of Ga-68 PSMA-11 and its impact on ensuring accessibility of generator versus cyclotron for new radiotracers is discussed from a nuclear medicine perspective.

Current Availability and Accessibility of Ga-68 PSMA-11

I will take a moment to comment on the sensitivity of these PSMA [prostate-specific membrane antigen] PET [positron emission tomography] scans compared to conventional imaging. As you said, there have been multiple studies where they basically take patients for whom, by conventional imaging—particularly with regard to biochemical recurrence—they cannot find where the recurrence is at all. Then they do the PSMA PET. Essentially, you are starting at the baseline where the conventional imaging has failed to localize the recurrence. Depending on the patient population, sometimes they are finding sites of recurrence [at a rate of] around 50%, and there’s a wide range of course depending on your PSAs [prostate-specific antigen levels]. Again, this is a familiar concept, even going back to the bone scans, where the sensitivity of bone scans for localizing disease correlated with elevated PSA levels. You see the same, and we saw that with Axumin [fluciclovine] PET, where when you just had really low PSAs, first evidence of recurrence like 0.2, 0.3 [ng/mL] PSAs, it was pretty hard for Axumin to find those. When you get to PSAs of 2 [ng/mL] and above, the majority of the time, Axumin was doing a great job.

With these new PSMA PET agents, the sensitivity has come down so low that even with those serum PSAs of 0.2 to 0.3 [ng/mL], up to 20% to 30% of the time they are still finding the area of biochemical recurrence. And when we are getting up to the PSAs of 2, 3, 4 [ng/mL], in the vast majority of cases they are finding where the biochemical recurrence is occurring. I am so glad you talked about those skip areas. I have been fortunate to read hundreds and hundreds, probably close to thousands now, of these scans. That Virchow node, in particular, is of note; you start seeing that again and again, this tiny Virchow mode up there in the supraclavicular region, something that would never have been seen by CT or MRI or any other modality. You would never have suspected that that had prostate cancer in it. That is, for us, the most significant example of how this can just skip all the way up into the supraclavicular region.

It is a little depressing, honestly, as a nuclear medicine practitioner and radiologist, when you see the bone scans that look completely negative, and then you have a PSMA PET scan, and the patient isriddled with bone metastases. Really, it makes sense because the bone scan, again, relies on the reaction of the bone to the tumor. You have to have the tumor on the marrow start to grow enough to reach a significant size to destroy bone to see that reaction on the bone scan. Instead, with the PSMA, you are imaging the tumor because the PSMA molecule is overexpressed—over 100 times, in many cases of aggressive prostate cancers—and the target of the small molecule agents is on the extracellular surface of this transmembrane protein. It can bind there, and there is lot of this PSMA on these aggressive prostate cancers being expressed. We have, fortunately, a very good and specific target in PSMA for aggressive prostate cancers. I’m going to move to the next question….

 Can I make a point before you move to the other topic? With this, we’re now finding these different site of metastases—lung metastases, decimation, supraclavicular node metastases. Do you think we are discovering a new pattern, or there is hope for this, or a new way that the prostate cancer spreads that we did not know about before, just because we did not know what we did not know?

I think so. Research is still building on this. We caught a glimpse of it with Axumin. When I started the Axumin imaging, I was wondering whether I was right or not. It was similar to the FDG [fluorodeoxyglucose] PET scan days, where, when you first started looking at these FDG PET scans, you knew exactly where to look on that CT or on that MRI, and you just could not find a correlate, and so you hesitated. You would say, “Let’s just follow this up, because I’m not sure.” You needed that test over and over, and then you would get that follow-up from the tumor boards after months and months and years. Then you’d realize you’re right. Of course, you wouldn’t be right with 100% specificity, but you would be right a lot of times. We’re seeing this now. I’ve been fortunate enough to see follow-up serial PSMA PET scans as well to see how patients do without treatment and with treatment. It is useful to know you are right, that you are absolutely right. Now, I think it is going to change the paradigm of what we do, and you alluded to it I think, very poignantly, with the referral to oligometastatic disease. Our definition of oligometastatic disease has been faulty. We know it now—5 sites. That is by conventional imaging.

We know now, with a PSMA PET scan, that we can take that category of patients that we’d define as oligometastatic by conventional imaging, and we are going to find many more sites of disease. I think that is one of the most obvious examples of how this is going to revolutionize things. Honestly, we do not know yet, because what is going to be the new definition? That will be something that is going to require a lot of research because we need to tie that definition to prognosis and response to good treatments in the future, hopefully. Please, do you have any thoughts on that?

 I agree. Fortunately, what we see from the other side is that, we see new drugs coming more recently that again, from one side, we can better biopsy and diagnose these patients more accurately. Secondly, we are now able to better stage our patients and risk-stratify with several levels of stratification—genomics, imaging, markers, you name it. There is not only this, as now the treatment also has been changed over the years. It looks like the entire field is progressing, thankfully.

Another essential principle, when it comes to these intravenously administered nuclear medicine radiotheranostics, is that the lutetium 177 PSMA, when injected intravenously, will then go wherever blood goes and treat this metastatic disease everywhere in the body. If the metastasis has gone down to your leg and your femur, it will treat that. If it is up in your calvarium, it will go up to the top of your head. If it is in your liver, your lung, your lymph nodes—it is capable of treating every system, which is a very important contradistinction to, for example, external beam [radiation], where when you have a painful metastasis in your lumbar spine, they can spot-treat that with radiation, not only for pain relief but also for fracture prevention. But this treatment has the potential to treat every single tumor that’s PSMA-positive, and therefore be able to get ahead of the cancer, and not have to chase after it one at a time once it becomes symptomatic.

Phillip Kuo, MD, PhD, reviews the sensitivity of PSMA (prostate-specific membrane antigen) PET (positron emission tomography) scans compared to conventional imaging. 

Phillip Kuo, MD, PhD

Articles

UroView: Gallium 68 PSMA–Targeted PET Imaging in Prostate Cancer: Staging and Outcomes

Impact of the Phase III VISION Trial

Current Availability and Accessibility of Ga-68 PSMA-11

Evaluating the Sensitivity of PSMA PET Scans