Patient Selection for Radioligand Therapy: Case Study Discussion - Amir Iravani & Evan Yu

April 11, 2024

Phillip Koo hosts a discussion on patient selection for radioligand therapy (RLT) in prostate cancer, featuring Amir Iravani and Evan Yu. The conversation delves into complex clinical decisions involving advanced prostate cancer management. Dr. Iravani presents a patient case to illustrate challenges faced in treatment progression, highlighting the patient’s journey through various therapies including androgen deprivation, chemotherapy, and the consideration for lutetium PSMA-617 treatment amid supply shortages. The discussion emphasizes the nuanced nature of RLT patient selection, supported by detailed PSMA PET imaging analysis and the evolving therapeutic landscape. The session underscores the critical role of multidisciplinary teams in navigating these intricate clinical scenarios.


Amir Iravani, MD, Associate Professor of Radiology, University of Washington, Theranostics Director, Fred Hutchinson Cancer Center, Seattle, WA

Evan Yu, MD, Professor of Medicine Division of Oncology, University of Washington School of Medicine, Section Head of Cancer Medicine, Clinical Research Division, Fred Hutchinson Cancer Center, The University of Washington School of Medicine, Seattle, WA

Phillip J. Koo, MD, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, AZ

Read the Full Video Transcript

Phillip Koo: Welcome to UroToday. With the rapid adoption of radioligand therapies into our clinics, I think patient selection with regards to which patients should undergo RLT versus those who should not becomes a very important topic and a very nuanced topic that has a lot of different flavors and questions that have arisen now that we're using it much more often in the clinic. To help us tackle and answer some of these questions, we have a wonderful multidisciplinary team from the University of Washington and Fred Hutch. We have with us Dr. Amir Iravani, who's an associate professor at the University of Washington and director of the Theranostics Program at Fred Hutch, and Dr. Evan Yu, who's the section head of Medical Oncology at Fred Hutch and also a professor of medicine at the University of Washington. So thank you, guys, for joining us today.

Evan Yu: Thanks for having us.

Amir Iravani: Thanks for having us, and it's a pleasure to be part of this educational forum.

Phillip Koo: Great. I know, Amir, you've prepared a couple of cases, so we'll go right into it, which I think will really showcase some of the questions that a lot of us are facing when we are managing these patients with advanced prostate cancer. So take it away, Amir.

Amir Iravani: Thank you. I'm presenting case one. He's a 73-year-old man who was diagnosed with prostate cancer in 2014. The PSA at the time of diagnosis was 260 with a Gleason score of 7. The bone scan and CT scan showed metastatic disease in osteocytes and also retroperitoneal lymph nodes. In August 2014, he was started on androgen deprivation therapy with bicalutamide and Lupron injections; however, he had a period of response but progressed in June 2017 when abiraterone and prednisone were started. Six months later, the disease progressed and treatment changed to enzalutamide, which also lasted for six months. Chemotherapy with cabazitaxel was initiated and continued over a long period, almost four years.

In late 2022, early 2023, PSA progression was noted, and the patient, in December 2022, was considered for lutetium PSMA-617 treatment. However, due to a supply shortage, the drug was not available, and the patient did not get treated. There was a discussion at the time about what would be the next line of treatment. At the same time, the patient's performance status declined, with significant fatigue, poor appetite, intermittent nausea and vomiting, which was also in the background of the patient's heart failure. The decision was made for the patient to go ahead with radium treatment. The patient received three cycles, but ongoing clinical imaging and biochemical progression was noted. At that time, in May 2023, the patient was re-referred for consideration of treatment with lutetium-177-PSMA.

Now we are going to the maximum intensity projections of the PSMA PET images that the patient had at initial consideration of lutetium-PSMA treatment on the left side and the follow-up in May 2023 on the right side. What you can see on the left side is there are multiple sites of PSMA-expressing disease predominantly in the bone, with a small volume of nodal disease also in the chest and mediastinum. At the time, PSA was 116, and the image on the left was acquired by F 18 fluorinated agent of the PSMA DCFPyL, which is another FDA-approved agent currently used. On the right side, you see there is marked progression of the disease with now diffuse osseous metastatic disease involving the entire skeleton and also a small volume of nodal disease, again, in the mediastinum. This image on the right side is acquired by Gallium 68 PSMA-11, which is another FDA-approved agent used in prostate cancer. At the time, PSA was 114.

Phillip Koo: Great, thank you, Amir. If you don't mind going back to the prior slide, and Evan, maybe we would love to hear your thoughts with regards to how you approach patient selection. Obviously, this case is a little complicated because this patient was diagnosed in 2014, RLT has been around for a couple of years now. What are your thoughts here when you see this case?

Evan Yu: Yeah, great question. The first thing I think about, in relation to RLT, is whether this patient is an appropriate candidate or not. And I do think this patient is definitely an appropriate candidate. They've received a potent androgen receptor pathway inhibitor; they've actually received a couple with abiraterone and enzalutamide; they've received taxane chemotherapy with cabazitaxel. Curiously, they never received docetaxel, which we usually give before cabazitaxel, but sometimes we find that cabazitaxel, 20 milligrams per meter squared, has situations where it may be less toxic, not knowing the entire details of the case. If the patient had peripheral neuropathy, sometimes we'll go with cabazitaxel because it causes less peripheral neuropathy than docetaxel.

But first off, this patient's definitely eligible. I will just comment that now in the modern era with intensification, this patient probably would've gotten more than Lupron and bicalutamide upfront. They had their abiraterone added probably when the patient developed metastatic castration-resistant prostate cancer. This patient probably would've gotten androgen deprivation therapy and abiraterone right upfront. Some could argue with de novo high-volume disease, which I'm suspecting this patient has, that that could indicate their indication for triple therapy, where one could give androgen deprivation therapy, abiraterone, and docetaxel or androgen deprivation therapy, darolutamide, and docetaxel.

So that's how the modern-day case might be a little bit different, but certainly no one can fault this. This patient was diagnosed a decade ago, so we didn't have all this data that we have now. But I definitely think this patient is a candidate based on their clinical disease state and past treatments.

The next question then comes to the PET imaging and certainly what I look for with PET imaging is that they definitely have PSMA uptake. Certainly, I like it above blood pool; I would like it even above liver, which blood pool, I think, Amir can tell us better, you both can probably tell us better, but is around SUV of 2 and I think liver probably lives around SUV of 7.

There have been some studies done that look at who's the ideal candidate and who's going to get the best outcome. It looks like if you do total body mean SUV and quantify that, which is, again, a little researchy, I wouldn't say that that's standardly done, but in the realm of moving towards AI in the future, I think it'll be easier to do such quantifications. Those with a mean SUV greater than 10, and again, total body SUV mean greater than 10, tend to be the ones that do the best. That doesn't mean that if you don't have it greater than 10, you won't do well. You still can get benefits from lutetium 617 PSMA, but the ones that get the most benefit are the ones greater than 10. I don't have that number here, but just visibly looking at this, this patient looks like a very reasonable candidate and I certainly would proceed.

Phillip Koo: Great. Amir, from your perspective, you get these PSMA PET-CTs prior to potentially initiating RLT. What are the key points that you're looking at and what are the key points that you'll communicate to the medical oncologist when there is a referral for a potential patient?

Amir Iravani: Yes, I reiterate what Dr. Yu mentioned about this patient selection. When we look at the whole body images, obviously we look to see if there is any site of disease that has expression of the PSMA above the organs of reference, particularly the liver, which has been defined by VISION as a threshold to go. Also, when we look at the images, we also look at the homogeneity of expression of the PSMA across the sites of disease quantitatively. It currently helps us in clinical practice to see whether all sites of disease expressing a sufficient amount of PSMA get enough targeted by the lutetium PSMA treatment.

As you see in the patient on the left side of the imaging, there are disease sites which are expressing PSMA intensely above the liver, maybe twice or three times even above the liver, and some of the lesions, if you compare it to the salivary glands, the parotid, and submandibular glands, you see actually they're as intense as the salivary glands. Also, there are the quantitative metrics, as Dr. Yu mentioned, like full body quantitative metrics, that are showing promising predictive and prognostic value. But also qualitatively, when we look at the organs of reference, particularly salivary glands, there is some evidence when they get close to salivary glands or above salivary glands, showing that this may be a good treatment option and the patient may respond.

One thing that's interesting in this case, I want to mention, when you look at the right side there is diffuse disease, but visually when we look at the right side image, we see the intensity of uptake might be lower than what it was 6 months prior. But this is an important event that happens as well when the disease extent is high and there is a phenomenon called sink effect when the entire radiopharmaceuticals goes to the disease site. So, the organs of reference, for instance, the liver and particularly salivary glands in this case, you see as having lower intensity of uptake. It doesn't mean that the patient has lower intensity and may not respond to treatment. It just means that there's so much disease that the entire injected activity goes through the disease sites and it's kind of averaged with the lower kind of SUV values if you're going to go by the SUV values in the same case on the right side.

Phillip Koo: Great. So, this is an interesting case where the patient was referred early due to supply issues, wasn't able to get it, received three doses of radium, and then was able to get the lutetium-177 PSMA. Amir, can you show us what happened afterwards?

Amir Iravani: Right. Yeah, the patient was considered suitable and these are basically how it's progressed over time. These are the baseline laboratory results. The patient's hemoglobin was 9.9, white cell count was 3.7, slightly lower than the normal range, both values; platelets were within the normal range and kidney function was normal. So, over time, we can see the PSA of the patients after the first cycle of treatments dropped significantly; the second cycle, further drop; the third, fourth, and fifth cycle, we see the PSA dropped to 8 from 144.

What you see on the left side here is the PSMA image at the baseline, and what you see on the right side here is actually a SPECT-CT 24 hours after the fifth treatment, which we normally, and as standard care, currently do at Fred Hutch Cancer Center, and some institutions do SPECT-CT or post-treatment imaging and use it to change the clinical management or decide about whether subsequent cycles of treatment are suitable. We see that laboratory tests after the fifth cycle of treatment on the right side, show the laboratory, particularly blood counts, remain stable despite very extensive bone disease.

Phillip Koo: Great. Last question to you, Evan, when you get a patient who has this type of response, what's going through your mind and how are you planning for the next steps?

Evan Yu: Yeah, I'm thinking this is an outstanding response, and the things I'm paying close attention to are, as Amir nicely outlined, what are their blood counts? I want to make sure their kidney function is still good, I want to make sure their marrow is strong, and I want to make sure that they're not suffering a lot of other side effects, so in particular, xerostomia, dry tear ducts, etc. Those are things that might make me use clinical judgment and say, for somebody who's having an outstanding response and might be getting side effects, how hard do I push to finish things out?

Now, this patient has already had five cycles, but I might be asking that question after three or even four cycles and saying, "Should I be proceeding with cycle five and cycle six on schedule every six weeks, or should I be thinking about saving those doses?" The issue about dose deintensification, using dosimetry, all these issues are not yet solved. So we don't really have anything to guide us yet other than clinical judgment, but toxicity is something that will always guide us, and if the patient is starting to get a lot of side effects and they're doing great, we have to recognize that this is not a curative therapy, this is a life-extending therapy and quality of life is as important. We might do better to keep it in our back pocket, let the patient's toxicities improve, and then come in and use them later. But this has been a great response and I'd be very pleased with this, and I'm sure the patient would be very pleased.

Phillip Koo: Great. Well, thank you. Amir, that was wonderful for case one. Let's move on to case two.

Amir Iravani: Case two, he's a 70-year-old male, was diagnosed with prostate cancer in May 2016. PSA was 245 at the time of diagnosis with a Gleason score of 9. Similar to the other case, bone scans showed multiple bone metastases and also lymphadenopathy in the pelvis and outside of the pelvis. The patient started bicalutamide and Lupron. At the time, the patient was also discussed to receive docetaxel per CHAARTED trial, however, he decided not to opt for chemotherapy. About 1.5 years later in 2018, the disease progressed and the patient started with enzalutamide. At that time, the patient continued on enzalutamide for almost 3 years.

3 years later the disease progressed and the patient was enrolled in a clinical trial for about a year, which was discontinued due to progression. Following the clinical trial, after progression, the patient received four cycles of docetaxel and then moved on to cabazitaxel for six cycles after the progression on docetaxel. In November 2023, that was the time that the patient was referred for lutetium PSMA and received a PSMA PET scan. While the patient was waiting to be scheduled for treatment and just after the PET scan, the patient's clinical status deteriorated; he developed anuria, acute kidney injury, and creatinine increased to over 11 with a GFR of less than 5, which required hospitalization. The patient had hydronephrosis bilaterally and received bilateral percutaneous nephrostomy tubes.

Going through the images, this is a PSMA PET at the time when the patient was considered in November 2023. On the bottom, we see there is a very large mass in the pelvis, as you can see here, highly expressing PSMA; in fact, this mass is pushing the bladder anteriorly and what we see anteriorly is just what is left of the bladder with a small amount of urine activity. On the top, this is the hydronephrosis which is happening here on the left side. We can see the dilated pelvicalyceal system and also decreased uptake in the cortex of the kidney compared to the right side, which indicates there is dysfunction of the kidneys occurring.

Phillip Koo: Great. If we can go back to the prior slide, I think, Evan, this is an interesting case and just one area I’d like to focus on is the decision between docetaxel and then going on to cabazitaxel. How do you approach patients at that decision point, whether to start, perhaps, a second taxane or try something like lutetium-177 PSMA?

Evan Yu: In the old days, old days being just less than a handful of years ago, that's all we had. So that's what we would do. At this point in time, which we're talking in mid-2023, certainly there were other options. So I’d probably, in this more modern era, prefer not to go straight from docetaxel to cabazitaxel. But again, in the old days, being less than a handful of years ago, that's what we did and there's clinical trial data to support the survival benefit of cabazitaxel after docetaxel. So it’s definitely not wrong.

I would look to insert some other treatment option. Maybe I would’ve used lutetium-177 PSMA earlier, Radium 223 wouldn’t be wrong here. But this patient, it sounds like, was referred from the outside and cabazitaxel, as a medical oncologist, is in your toolbox, and sounds like that's what the medical oncologist reached for and it's certainly acceptable.

Phillip Koo: Great. This patient comes in for acute kidney injury, high creatinine; you put in bilateral percutaneous nephrostomy tubes because of the hydro and the renal function improves. Obviously, a lot of practices that aren't familiar with this might see that renal function and maybe not think lutetium was an option. Maybe, either one of you, can you sort of talk us through your approach and your thought process with regards to renal function in a case like this?

Evan Yu: I can do the clinical part first and then I'll let Amir talk about the concerns with certain radioligand therapies in renal function. The clinical part, for me, is this person obviously had bilateral hydro because they had a huge bladder mass, and so it wasn’t because of lymphadenopathy, which can happen as well, but that huge bladder mass has just taken out the bilateral ureteral orifices, leading to nephrosis.

I will just say that, personally, as a GU medical oncologist, I'm a little less intimidated by that because I know, mostly from our experience with bladder cancer, that the best way to get someone's creatinine clearance better is to put in bilateral percutaneous nephrostomy tubes. That's how we frequently take a patient who we don't think is a cisplatin candidate in the neoadjuvant fashion for bladder cancer and make them a cisplatin candidate by getting those perks in quickly, and the creatinine clearance can actually recover very, very quickly. Internal stents, probably not feasible in this case. With that huge mass, they'll never see the UO and be able to get it up there. But even if they were able to, that's not what I would've recommended here if I want renal function better to receive the next line of therapy. For speed, expediency, and effectiveness, I would've recommended bilateral percutaneous nephrostomy tubes, as the patient received. Amir, if you want to comment on where you feel comfortable with treating a patient with radioligand therapy and renal dysfunction.

Amir Iravani: Sure, that's an important question as well. This has also been addressed in some consensus statements through the Society of Nuclear Medicine and Molecular Imaging. This case, I think, brought up the important issue that many patients that we treat in clinical practice are not the patients who were previously treated in clinical trials. So these patients could have low bone marrow reserve or their kidney functions might be impaired to begin with. The importance of kidney function is that, because these drugs mainly clear through the kidneys, the kidney impairment actually prolongs the time that the drug stays in the bloodstream, and so there is increased marrow toxicity in these patients if the kidney function is impaired.

In clinical practice, we have lowered the threshold for kidney function impairment; for instance, in VISION and other clinical trials, an eGFR of 50 was used. In clinical practice, we had discussions with the medical oncology and multidisciplinary team meetings, and we have brought that threshold to lower kidney impairments, even to an eGFR of 30. For borderline kidney impairments, we consider this treatment considering other treatment options available.

One important point we consider, also, is particularly for patients who have hydronephrosis or obstructive uropathy, we would like to see that's been relieved before treatment, not only just improving the kidney function, but also the amount of activity that may retain within the pelvicalyceal system actually increases the radiation to the kidney and further impairs the kidney function.

Phillip Koo: Great. Amir, just real quick in terms of radiation safety, is there anything special that you would do for this patient knowing that they might get RLT?

Amir Iravani: Correct, that's an important question for radiation safety because these patients have nephrostomy tubes and now have bags bilaterally, which need to be taken care of in terms of radiation disposal. These patients, obviously, we will have an extensive educational meeting with the patient about how to handle radioactive urine, particularly within the first few days after treatment when the urine is highly radioactive. Although this patient is still going to be disposing of the radioactive urine through the normal toilet and other ways, but handling it using gloves, not being in contact with the urine are all things that we tell the patients and educate the patient to be able to handle this, particularly after the treatment.

Phillip Koo: Great. Can you give us now the follow-up on this case? I believe this patient did go on to get RLT.

Amir Iravani: Right. After improvement in kidney function, the patient received RLT. We see, again, similar, this is the baseline mass. The patient received cycle one, this is the post-treatment SPECT after cycle one. We see intense uptake in the bladder and the pelvic mass and also two other bone metastases. The patient received cycle two and cycle three with a dramatic decrease in the PSA from 262 to 10. And this actually, after cycle three, continued to drop to 1.6.

What you see on the bottom here, this table, you see how the blood counts progressed over time. So this corresponds to the baseline, cycle one, and cycle two. When we look here, we see a gradual decline in the blood counts, particularly for the platelets and white cell count here, and also the hemoglobin is slightly. We see, particularly after cycle three, about 4 weeks after cycle three, the platelets dropped significantly to 22. The creatinine remained normal. So at this time point, there was a discussion with the team, and given the response, we see that further treatment was withheld. Interestingly, the nephrostomy tubes were removed and the patient was able to urinate normally without anything after cycle three.

Phillip Koo: Great. Evan, this kind of goes back to what you were talking about earlier, great response, but now we're seeing some adverse events. Can you talk about what you're seeing in the clinic? Is this something that you're seeing where their counts decrease rapidly like that and the timing of that type of cytopenia?

Evan Yu: Yeah, absolutely. This is something that we do see, and I would do the exact same thing as was done in this case. I would hold the treatment here. Now, I might talk to the patient about it not being... I might not use the term hold; I might use the term delay. And what I might do is instead of evaluating every 6 weeks, this might be somebody I evaluate at 9 weeks, 12 weeks, even at 18 weeks.

We recognize that we only have FDA regulatory approval for six doses. So I always remind patients that, "It's okay, but my goal is to get you all six doses and to prolong your survival. I don't know that I need to get all six doses in within 36 weeks." So first off, I reassure the patient, I remind them that, "you've had an outstanding PSA response and that this is an agent that goes to tumors that are expressing PSMA. And so if your PSMA expression has gone down, all your other markers, your disease is shrinking, as you can see on the CT scan, your PSA has gone down, you might get less bang for your buck if we were to just kind of plow ahead."

And so, psychologically, that helps the patients out a lot. They recognize that the toxicities can be significant with platelet counts like this. The right thing to do is to hold and see how it goes. But I would watch this patient's counts, offer them reassurance, and let them know that it's time to relax a little bit, enjoy life without treatment, but if and when the time's right, we can potentially get it going again.

Phillip Koo: Great. I think those are wonderful words of advice and thank you very much. These two cases were very enlightening. I think it really showcases some of the real-life problems that we encounter every day, so thank you very much for helping us answer many of these lingering questions.