- with suspected metastasis who are suitable for initial definitive therapy;
- with suspected recurrence with elevated serum prostate specific antigen (PSA) level.
INITIO is Western Canada’s only private PET/CT scan facility with over 20 years’ experience, offering Rapid PET/CT and CT scans and nuclear medicine treatments with no wait list. INITIO has diagnostic scanning for cancer, cognitive impairment, and cardiac sarcoidosis, and now offers gallium-68 PSMA-PET imaging and lutetium-177 PSMA therapy for prostate cancer. With these latest additions, INITIO Medical Group reaffirms its commitment to providing the most advanced and effective treatments to patients and looks forward to the positive impact these will have on the lives of those affected by prostate cancer.
About Isologic Innovative Radiopharmaceuticals
About Telix Pharmaceuticals Limited
Visit www.telixpharma.com for further information about Telix, including details of the latest share price, announcements made to the ASX, investor and analyst presentations, news releases, event details and other publications that may be of interest. You can also follow Telix on Twitter (@TelixPharma) and LinkedIn.
 Public Health Agency of Canada, 2021.
 Telix ASX disclosure 20 December 2021.
 Telix ASX disclosure 2 November 2021.
 Telix ASX disclosure 14 October 2022.
Dr. Charles Wang
Dr. Carlos Casiano
March 22, 2023
Thomas Hope joins Phillip Koo to discuss real-world challenges associated with patient selection, laboratory abnormalities, and workflow issues in treating patients with lutetium-177 PSMA in a high-volume care center. He also talks about the need to identify when to stop therapy and how to spread out doses effectively while minimizing toxicity. Additionally, Dr. Hope highlights the importance of post-treatment SPECT imaging to track patients over time. He emphasizes that there is still much to learn about this therapy, particularly for low-expressing patients who do not meet the therapy criteria but meet the criteria for the VISION trial.
Thomas Hope, MD, Assistant Professor, Abdominal Imaging and Nuclear Medicine, University of California, San Francisco, San Francisco, CA
Phillip J. Koo, MD, FACS Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona.
Read the Full Video Transcript
Phillip Koo: Hi, welcome to UroToday. Today we’re very fortunate to have with us Dr. Tom Hope from UCSF, who’s very familiar to all of us. Thank you very much for joining.
Thomas Hope: Thank you for having me again.
Phillip Koo: We’re almost a year since the FDA approval of Pluvicto, Lutetium-177 PSMA, and now that we have a little bit of experience, there have been some challenges, I imagine, in real world types of situations that weren’t necessarily addressed in VISION. Can you enlighten us with regards to some of those challenges and how you deal with them, especially from the perspective of a high volume center?
Thomas Hope: Yeah, so there’s a ton of challenges and it’s a learning curve for sure, especially for nuclear medicine physicians who aren’t really used to treating patients who are so sick. So I’d break them up into three categories.
The first main category I would go with is patient selection. How do you determine who to treat? And the issues with that are a couple fold. So A, low expressing patients, patients who have a PSMA PET where you have an SUV of eight. It’s slightly higher in the liver. They meet the criteria. You’re pretty sure they’re not going to do very well. Maybe they have higher volume disease. How do you prioritize PSMA radioligand therapy over second line chemotherapy or other treatments? And I think we don’t really understand how to handle these. I call it the VISION gap. The people who don’t meet criteria for therapy but do meet criteria for VISION, particularly on the lower end of that in terms of expression. How do you handle those patients.
I think the second struggle is patients who have laboratory abnormalities. I get lots of emails, “Do you use the VISION cutoffs for hemoglobins or platelets? What about patients with renal failure, et cetera?” And I think it’s really important, particularly in the VISION patient population where patients are sick and there’s no other treatments available. You can’t not treat a patient because their hemoglobin is 7.8. You transfuse them just like you would with chemotherapy, and I think we’re not used to that obviously in nuclear medicine, all the supportive care that you need for patients with marrow disease, et cetera.
And it’s also I think one of the lessons I learned early on. You’ll stop chemotherapy, you’ll let the counts recover, but if they have a lot of marrow disease, their counts may never recover, and you got to be really careful pausing, waiting for people to recover and actually be more aggressive than you think you would need to be in these patients who have significant marrow disease.
And same with kidney failure. VISION, if I remember, the cutoff was EGFR of 50, and that’s a pretty high cutoff. A lot of patients have an EGFR less than 50, and we don’t really see any kidney toxicity from lutetium PSMA radioligand therapy. We obviously treat patients with lower GFRs, and even if it’s under 30, we’ll have a tumor board discussion about whether or not we should treat those patients. The main issue if you do have kidney toxicity baseline is actually marrow exposure because you have prolonged blood pool activity. So selecting patients, how you do that is actually quite difficult.
I think the other aspect that I struggle with is on the other end, when do you stop therapy? What is treatment failure? You don’t have much to go to after this. So when patients PSA starts to rise, you keep treating. How much progression is too much progression? Once you see a new lesion and you’ll see a lot of patients whose bone disease shrinks, but their liver disease grows slightly or their nodal disease changes differently, or maybe their quality of life’s improving, but they’re actually progressing in some areas. How do you handle that and when do you determine that it’s end of line for these patients and you should stop therapy? So I think that’s something I really struggle with in, and how to define ending of therapy in patients who aren’t doing as well.
And then also in the same vein, patients who do well, do you spread out doses? Your PSA goes down by 90% after two cycles, what do you do? Maybe you have a little bit of uptake. We do a lot of post-treatment SPECT imaging, and I find that incredibly valuable to track your patients over time. How do you use that information with a PSA response to delay a dose? Do you wait for the PSA to rise? There’s a lot of patients, your PSA after cycle one, it does weird things because you’re treating the disease, but then it’ll start to come down.
Once it comes down, then it will sort of nadir and some patients will just keep going down for months. Other patients will come right back up. But how do you use that treatment, holidays, et cetera, to actually spread out the doses and use it as effectively as possible while minimizing toxicity.
And then I think the third one is just workflow. A couple fold. So A, can’t get doses. It’s very hard to get this. There’s production issues obviously, and so we don’t have availability of doses, so it’s very hard to prioritize your patients. There’s a lot of these patients coming through nursing resources, scheduling resources, nuc med technologists, all of that to help set this up, is actually quite a herculean effort to get programs up and running. I think all of us around the country are sort of learning a lot of lessons this time through about how to actually get these treatments to the right patients effectively and as quickly as we can.
Phillip Koo: Great. So you know, talked about the VISION gap with patient selection. We have lab abnormalities, we have when to start, when to stop, and then we have those operational issues. So it’s actually really comforting to know that someone like yourself in a high volume center with experience is still running through these challenges and finding ways to overcome them. So what type of advice would you have for those in the community or those centers that are just starting, how to manage and deal with a lot of these situations that you necessarily can’t always plan for?
Thomas Hope: So I think the most important aspect of this is having a really close relationship with your medical oncologist. And I think that’s the relationship that’s really key because your medical oncologists that you’re working with to manage that patient will have seen this patient over a long period of time, will know them, will know their goals of care, will know their marrow history, will help you with the transfusions. Obviously if we don’t do much transfusions, we work with our team in medical oncology to manage all that. So I think that relationship is absolutely key. The multidisciplinary discussions, tumor boards, all of that, you have to work together as a team. So I think with iodine therapy historically, you get sent a patient, you give them the pill, patients get treated, everyone does well because it’s such an effective therapy, they go away. This is very different. It’s not just they come in the door, you give them the drug. You have to really work with the team and really help manage the patients, have a little more ownership than maybe we’re used to historically in nuclear medicine.
Phillip Koo: Great. So we’re going to shift gears a little, and we know now that PSMA-4 is positive. We anticipate hopefully the results being released in May and then maybe a label expansion soon following that. What are the nuances or things that we should be thinking about once this hopefully gets approved in that pre-chemo therapy space?
Thomas Hope: Yeah, I think as you move earlier, toxicities mean more. So when I was describing the struggles we have with patients with marrow injury, et cetera, that’s very different when you’re in a VISION setting and there’s likely not other treatments afterwards. So I’m much more willing to take a risk and treat patients who have low counts or kidney failure or something like that earlier on. There’s more available options. They have longer lifespans that toxicities are more cumulative. So if you go in the castration sensitive, I’m more worried about dry mouth than I would be in a VISION setting. So having five years of dry mouth is very different than having eight months of dry mouth, et cetera. So I think, and as a general thing, when you’re moving earlier on, you need to be more and more cognizant and concerned about the patients and the toxicity because they have a longer lifespan after the treatment.
So I think that has a couple rules. So a, do we need six cycles? We need to start to be a little more judicious about how many treatments we give when we give them, how do we spread out the doses and how do we use this most effectively in our patients rather than just pounding patients with our treatments. I actually personally think the pre-chemo post Enza RC environment is actually the sweet spot for PSMA radioligand therapy upfront. When you’re treating patients, ADT and receptor inhibitors, those are going to increase your expression. And when you progress in the CRPC setting, that’s actually probably the place where these drugs are going to have the best effects.
I like this space and I think it’s where the drugs will end up, majority being used in the long run, but we have to start to learn about that. As I’m learning right now about the post-chemotherapy sort of end of this train, the patient populace are able to learn as well about pre-chemo. These will be lower volume patients. A lot of these patients that we enroll in these trials we’re enrolling in the eclipse trial, which is the same thing as PSMA-4 with lutetium PSMA, they’re much lower volume than we’re seeing in our standard of care lutetium PSMA-617 patient populace. So how we think about that’s different.
Phillip Koo: That’s really great insight. I think oftentimes we hear about PSMA-4 and all these different trials that are bringing it earlier and we think, “Oh, it’ll be better tolerated. Not a big deal. We don’t have to worry about side effects.” But you’re right, the side effects when they do happen are going to mean more, and I think it’s something that we all have to be prepared for. One question that comes up oftentimes is the safety of radium and lutetium, whether one’s goes first versus another. What are your thoughts on that now that we have some data?
Thomas Hope: Well, data was a very, very generous term to use. There’s data that obviously patients who went on VISION had, some of them had radium beforehand. No evidence of increased bone marrow toxicity from that. I think the community in general, I don’t think really appreciates how well radium’s tolerated. It’s actually an incredibly well-tolerated drug, doesn’t actually cause very much marrow toxicity. And I’m personally concerned that the use of radium is going to go down. It’s already not high enough and it’s going to go down with the introduction of lutetium PSMA. Now, how should it be used? I think as a different question, right? Alsympca, the trial that led to the approval of radium is an interesting inclusion criteria from an imaging standpoint, right? Because it’s supposed to be we’re treating only bone disease, but it allowed patients who had three centimeter nodal beds in it, which is sort of crazy, right?
Three centimeters is a big, big lymph node. Obviously you couldn’t have a liver or lung metastasis, but pretty large lymphadenopathy. And that might be why you didn’t see patients who had PSA responses in that trial. But at the same time, there was nearly a four month overall survival benefit in a poorly selected patient population. So you got to remember that. So now we have PSMA PET, we know who’s bone dominant, right? Or not bone dominant, but bone only. And probably about 40% of patients have bone only disease. So then the question comes, “Okay, I have a patient on a PSMA PET, bone only disease. How do we determine between radium and lutetium?” I mean, obviously there’s no right answer. We don’t have any data to tell us about that. But generally speaking, right? If you have a bone scan that matches the PSMA PET, good uptake on the bone scan, that’s something that would push you towards radium.
And then if you have on the PSMA PET SUVs of 80, and that’s going to push you to lutetium, right? And then also to me in general, the lower the volume you are, the more likely I think I would use radium. I think radium’s a little better tolerated. And so maybe I would use that as a window of opportunity to use radium, and then you would go on to lutetium. I mean, clearly there’s clinical data out there that there’s no evidence of additive marrow toxicity when you sequence radium before lutetium. So there’s no right answer there, but I think it’s something our community has to figure out how to deal with instead of just forgetting about radium, which I think is a big concern for me.
Phillip Koo: Those are wonderful comments. I agree a hundred percent. The radium is underutilized and it is very safe. And I love how you talk about PSMA PET allowing us to select patients better. And I have no doubt that if we could identify those bone only patients, yes, they probably might have a PSA response and they will respond better. And also looking forward to the piece three data with Enzalutamide, hopefully that shows some good results there as well. Well, thank you very much, very insightful. Learned a lot and appreciate you taking the time to be with us.
Dr. Tom Hope from UCSF talks about the challenges faced in the real world using Lutetium-177 PSMA treatment a year since its approval by the FDA. He breaks them down into three categories. First, there is the issue of patient selection, particularly those with low expressing patients, who don’t meet the criteria for therapy but meet VISION criteria, particularly on the lower end of expression. Second, he talks about patients with laboratory abnormalities, particularly in the VISION patient population where patients are sick and there’s no other treatment available. Third, Dr. Hope talks about the challenge of workflow, particularly with regards to the availability of doses, staffing, scheduling resources and the setup of programs which is quite a herculean effort. The aim is to use the treatment as effectively as possible while minimizing toxicity. Dr. Hope also touches on when to stop therapy and how to determine treatment failure. He suggests the use of post-treatment SPECT imaging to track patients over time.
Landscape of Prostate-Specific Membrane Antigen Heterogeneity and Regulation in AR-positive and AR-negative Metastatic Prostate Cancer
Nature Cancer, April 10, 2023, 11:00am EST https://www.nature.com/articles/s43018-023-00539-6
Dana-Farber Cancer Institute authors
Himisha Beltran, MD; Martin Bakht, PhD
t has long been known that the androgen receptor (AR) – a structure that triggers cell growth in response to the hormone androgen – controls the production of PSMA in prostate cancer cells. In the Nature Cancer study, researchers led by Dana-Farber’s Himisha Beltran, MD, and Martin Bakht, PhD, found that PSMA expression is lower in liver metastases than in other parts of the body, regardless of expression of the androgen receptor. They also found that some tumors that test negative for the AR do express PSMA and that some AR-positive tumors don’t – which led them to look for a control mechanism that doesn’t involve the AR. Their search revealed that the HOXB13 protein as a key regulator of PSMA: when castration-resistant prostate cancers go without the AR, HOXB13 can control PSMA on its own. This and the discovery of an “epigenetic” mechanism for suppressing PSMA demonstrate that the system of PSMA control is more complex than once thought and that prostate cancer has multiple subtypes that may be optimally treated by specific targeted therapies. The study authors also identified amino acids that are upregulated in metastatic prostate tumors low in PSMA. The discovery may lead to new biomarkers that complement PSMA imaging in identify prostate cancer subtypes.
This work supported by the Prostate Cancer Foundation, Department of Defense (W81XWH-17-1-0653, W81XWH-22-1-0010, W81XWH-22-1-0197), NIH/NCI (R37CA241486 and P50-CA211024 to H.B.), and Japan Society for the Promotion of Science. Partial support for the work provided by NIH Center Grant P30 CA08748 (Small Animal Imaging Core Facility and the Radiochemistry and Molecular Imaging Probe core). Support from NIH R35 CA232130, DOD-IDEA Award Grant W81XWH-19-1-0536 and National Cancer Center is acknowledged. Support of Blue Earth Diagnostics Ltd for providing the 18F-Fluciclovine and 18F-rh-PSMA tracers is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Scientists at the Dana-Farber Cancer Institute have found new information about a protein called prostate-specific membrane antigen (PSMA) that is found on most prostate cancers. PSMA can help doctors determine where prostate cancer has spread in a patient’s body and can be treated with a new radioactive therapy. However, in 15-20% of patients with advanced prostate cancer, PSMA production stops. The researchers found that the production of PSMA is controlled by a protein called HOXB13, in addition to the androgen receptor (AR) that triggers cell growth in response to the hormone androgen. The researchers also discovered that PSMA expression is lower in liver metastases than in other parts of the body and that some tumors that test negative for the AR do express PSMA, while some AR-positive tumors do not. The researchers hope that their findings will help doctors select PSMA-targeting therapies for specific patients and lead to new biomarkers that complement PSMA imaging in identifying prostate cancer subtypes. Overall, this study helps doctors better understand the complexity of prostate cancer and may lead to improved treatments for patients.
The patient was treated using Alpha DaRT at the Jewish General Hospital (JGH) in Montreal, Canada.
Fine needle aspiration of well-differentiated pancreatic adenocarcinoma. Credit: Ed Uthman / commons.wikimedia.org.
sraeli medical device firm Alpha Tau Medical has announced that the first pancreatic cancer patient has been treated using Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) in a feasibility and safety study.
The patient with advanced inoperable pancreatic cancer was treated at the Jewish General Hospital (JGH) in Montreal, Canada.
Alpha DaRT is being developed to deliver potent and conformal alpha radiation to destroy solid tumours by intratumoural delivery of radium-224 impregnated sources, without affecting the healthy tissue surrounding the tumour.
Short-lived daughter radioisotopes will be released and diffused from the sources when the radium decays. They emit high-energy alpha particles to destroy the tumour.
Alpha Tau CEO Uzi Sofer said: “Getting this trial underway is another huge milestone for the Company, as we continue to focus on treating tumours in internal organs.
“We would like to thank Dr Corey Miller of the JGH for enrolling and treating the first patient in this very important feasibility and safety trial.
“This trial is a cornerstone of our overall strategy to broaden the use of the Alpha DaRT in other hard-to-treat indications such as cancers of the brain, lung, vulva and breast.”
Alpha Tau plans to enrol 30 patients with Stage II, III, or IV pancreatic cancer and those with an inoperable pancreatic tumour, for the feasibility study of Alpha DaRT.
The study is designed to evaluate the safety, feasibility and efficacy of Alpha DaRT for the treatment of advanced pancreatic cancer.
Metrics such as overall response rate, overall survival and change in blood levels of CA19-9 will be studied to determine the efficacy.
In June 2021, the company secured Breakthrough Device Designation from the US Food and Drug Administration (FDA) for Alpha DaRT for the indication of squamous cell carcinoma (SCC) of the skin and oral cavity without curative
Alpha Tau Medical, an Israeli medical device company, has treated its first pancreatic cancer patient, in Canada, using their new treatment called Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) in a feasibility and safety study. The patient had advanced inoperable pancreatic cancer and was treated at the Jewish General Hospital in Montreal, Canada. Alpha DaRT is a treatment that aims to destroy solid tumors using alpha radiation without harming the surrounding healthy tissue. Alpha Tau plans to enroll 30 patients for the feasibility study of Alpha DaRT. The study is designed to evaluate the safety, feasibility, and effectiveness of Alpha DaRT for the treatment of advanced pancreatic cancer. The company is also looking to broaden the use of Alpha DaRT to other hard-to-treat cancers such as those in the brain, lung, vulva, and breast. In June 2021, Alpha Tau received Breakthrough Device Designation from the US FDA for Alpha DaRT.
April 6, 2023 — MRI-targeted biopsy prompted by elevated prostate-specific antigen (PSA) levels identifies fewer clinically insignificant prostate cancers than systemic biopsy, according to a paper published April 4 in the Annals of Internal Medicine.
And it’s comparable to a systemic biopsy protocol for detecting clinically significant disease, wrote Dr. Richard Hoffman of the University of Iowa in Iowa City.
“[MRI-targeted] biopsy alone versus systemic biopsy after elevated PSA results detected fewer clinically insignificant prostate cancer cases,” he noted. His commentary was submitted under the auspices of the American College of Physicians (ACP) Journal Club in response to a study released in 2022 in the New England Journal of Medicine (NEJM) that explored the efficacy of MRI-targeted biopsy after elevated PSA levels.
The biggest potential harms from PSA screening are overdiagnosis and overtreatment of low-risk disease, Hoffman explained. To further assess the NEJM results, he wrote a response paper that included data from 17,980 men between the ages of 50 and 60 who participated in the GöTEBORG prostate cancer screening 2 (Göteborg-2) trial.
The men had undergone PSA screening, and those with a PSA level equal to or more than 3 ng/mL had an MRI of the prostate followed by either an MRI-targeted biopsy alone for suspicious results or a systemic biopsy regardless of MRI results (and if needed, a targeted MRI biopsy of suspicious lesions). Of the total Göteborg study cohort, 11,986 men had an MRI-targeted biopsy alone and 5,994 had the systemic biopsy with MRI-targeted biopsy if indicated.
The MRI-targeted biopsy alone identified fewer low-risk prostate cancers compared with the systemic biopsy protocol and reduced the number of unnecessary biopsies performed. It also showed a similar rate of detection of clinically significant prostate cancer as the systemic approach, Hoffman noted.
|MRI-targeted biopsy alone compared with systemic biopsy after elevated PSA results|
|Type of identified prostate cancer||Systemic biopsy||MRI-targeted biopsy|
|Clinically insignificant (Gleason score 3+3)||1.2%||0.6%|
|Clinically significant (Gleason score equal to or greater than 3+4)||1.1%||0.9%|
The findings are “provocative but not practice-changing,” Hoffman summarized, stating that since the Göteborg-2 trial was conducted at a single Swedish center, its results may not be generalizable. He wrote that “although reducing overdiagnosis is important, effectively reducing overtreatment depends on the uptake of active surveillance and adherence to monitoring protocols.”
“Regardless of the biopsy strategy, men with low-risk prostate cancer should be encouraged to consider active surveillance as a way to reduce the potential harms of screening,” Hoffman concluded.
A recent study has shown that MRI-targeted biopsy for detecting prostate cancer in men with high levels of prostate-specific antigen (PSA) identifies fewer clinically insignificant cases than systemic biopsy. The study found that using MRI alone to detect prostate cancer revealed fewer low-risk cases compared to the systemic biopsy protocol, but it also reduced the number of unnecessary biopsies. Dr. Richard Hoffman, who commented on the study, explained that overdiagnosis and overtreatment of low-risk prostate cancer are potential harms of PSA screening. Therefore, accurately identifying the severity of prostate cancer is crucial to ensure that patients receive the most appropriate treatment. The MRI-targeted biopsy was found to be comparable to the systemic biopsy in detecting clinically significant prostate cancer. “Clinically insignificant” means that the cancer detected is unlikely to cause any significant harm to the patient or shorten their life expectancy. In some cases, treatment for these low-risk cancers can cause more harm than good, leading to unnecessary procedures and side effects.