Imaging Prostate Cancer with F18 Fluciclovine PET - Neha Maithel & Isis Gayed
January 28, 2022
Neha Maithel, MD, Assistant Professor at the University of Texas Health Science Center at Houston, Division of Hematology/Oncology
Isis Gayed, MD, Professor of Nuclear Medicine in the Department of Diagnostic and Interventional Imaging UT Health at Houston
18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.
The Role of 18F-Fluciclovine-PET/CT in Improving Cancer Control Compared With Conventional Imaging Alone for Salvage Postprostatectomy Radiotherapy, the EMPIRE-1 Trial Journal Club – Christopher Wallis & Zachary Klaassen
Neha Maithel: Welcome everyone to this presentation. We're going to be talking about imaging in prostate cancer with F-18 Axumin PET. So my name is Neha Maithel, I'm an Assistant Professor at the University of Texas Health Science Center at Houston. I'm part of the Division of Hematology and Oncology.
Next slide. So prostate cancer as per the American Cancer Society, it affects about 191,000 new cases of prostate cancer in 2020. One in 41 men will die from prostate cancer and the lifetime risk of being diagnosed with prostate cancer is about 14.3%. However, the risk of dying from prostate cancer is only 3.6%. And a lot of this is attributed because of the new medications that we have, as well as the new imaging modalities. Now we know the presentation of prostate cancer, early stages are usually asymptomatic and most cases are detected by serum PSA or an abnormal DRE.
What we also know is that approximately 50% of patients who've had radical prostatectomy or definitive radiation, will have recurrence within their lifetime. Now prostate cancer, especially in patients who are at high risk, is a progressive disease. With ongoing advancements in image technology, the ability to identify previously undetectable metastasis, may result in a shift in the definition of disease states and improved outcomes.
Next slide. Conventional imaging. We can see that conventional imaging, the FDA approved bone scans as early as 1970s. With bone scans, we are able to detect bone diseases more specifically than CT imaging. But oftentimes, it is hard to distinguish these lesions from degenerative disease or traumatic lesion versus a metastatic disease. The FDA did approve the CT scan for prostate cancer in 1971 and a full body MRI in 1977. However, some of these imaging may not detect tumors that are less than a centimeter in size or when the PSA is less than 20. These modalities have limited sensitivity for detecting small volume sites and may underestimate the burden of disease. This really highlights the need for more advanced imaging to detect metastatic or recurrent disease.
The RADAR 1. The RADAR is the Radiographic Assessment for Detection of Advanced Recurrence, is a group that initially convened to provide recommendations for the early identification of prostate cancer metastasis. RADAR 1 recommended preferred traditional imaging modalities and specifically when and how imaging should be performed. So looking at their recommendations, newly diagnosed patients should be scanned only in high risk patients and intermediate patients who have at least two of the following: either if the PSA is greater than 10, the Gleason score is greater than seven, or if you have a palpable disease, which is greater than T2b. In biochemical recurrent patients, that's when your first scan the PSA is between 5 or 10. And the image frequency is typically when the PSA is greater than 20 and every time the PSA doubles and this should be at least three months apart. In M0, castrate resistant patients, again, now the first scan should be when the PSA is greater than two, and the frequency is when the PSA doubles, or if the PSA is greater than five. Again, not more frequently than every three months.
Next generation image modality includes PET CTs. A PET is a functional imaging technique that is able to detect metabolic activity, blood flow, and apoptosis. PET CT imaging allowed for the early detection of metastatic disease and biochemical recurrence after primary therapy. The use of PET CT in patients with prostate cancer has been advanced by the development of new radiotracers, including our F18 Axumin, the 11C-choline, the 18F sodium fluoride and the F18-FDG. These new radio tracers allow for detection of recurrent and metastatic disease with superior, sensitivity, and specificity to conventional imaging. The data of course is more robust in biochemical occurrence.
Now looking at the FDA approval, we've seen that there's been remarkable change since the 1970s. In 1970s, like again, bone scans and CT scans were approved. In 1977, we got the full body MRI. In 1997 was when F-18 FDG PET was first approved. In 2011, the C-11 PET 2016 was very landmark because that was when the F-18 Axumin study was approved. And most recently we've had the F-18 PSMA. Now the C-11 choline, which was initially approved by the Mayo clinic is not readily available. The half life of the C-11 is within a few minutes versus F-18 Axumin where you know that the half life is at least two hours, which allows this radio tracer to be more readily available.
Now, what is F-18 Axumin? So F-18 Axumin is actually an amino acid analog. Cancer cells we know have up regulated amino acid transporters as they need amino acid for self replication.. Targeting amino acid allows for good localization of cancer cells. So what we know is that this F-18 Axumin is taken up by the amino acid transporters throughout the body, but it's upregulated in cancer cells. The two major amino acid transporters are the ASCT2, and the LAT1. And these are especially upregulated in prostate cancer. Now F18 Axumin is not metabolized or incorporated into newly synthesized proteins, which again allows us to focus on lesions that are metastatic or are abnormal. Another great thing about the F-18 Axumin is that it's limited in its urinary activity, which allows for the localization of tumors adjacent to the bladder.
When we're looking at the different radio tracers in the next generation imaging. So we have the F-18 Axumin, which again, is immuno acid transporter versus the C-11 choline is present in cell membrane synthesis and so this is an C-11 acetate is in lipid synthesis. The sensitivity, as you can see is much higher for the F-18 Axumin as compared to the C-11 choline and acetate. The indication of F18 Axumin is in local and distant recurrence C acetate. The pro which we talked about where we have the slow urinary excretion, as well as it's more sensitive at a lower PSA when compared to acetate and choline. The Choline, as you can see, it's a little bit... It has a moderate specificity and a moderate performance at low PSA cutoff. However, this, again, needs to be validated in larger studies. So looking at the Locate trials, what this study did, was it enrolled 213 patients who received PET Axumin study who had originally had a negative or equivocal finding on a standard of care imaging.
So one of those conventional imaging that we talked about including the bone scan or CT scan. And what this study found was that 30% of those patients who had a negative or equivocal finding on the standard of care imaging, 30% of those were picked up by PET Axumin study, and they were able to detect lesions in the prostate, or the prostate bed. 38% of the lesions were picked up outside of the prostate with the majority of them being in the lymph form. What this study also found was that the detection rate for the PET Axumin radiotracer was increased as the PSA level rose, as you can see with the curve in figure B here. And then lastly, what they also found was that extraprostatic regions consistent of lymph nodes, the off soft tissues and parenchyma lymph nodes were more widely detected versus extra pelvic lesion and extra pelvic node.
Now the EMPIRE 1 study was also was a very pivotal study because it was the first study that looked at Axumin PET CT versus conventional imaging head to head. This study was published in the Lance oncology, and it was also presented in 2020 Astro. It's a phase three trial that enrolled 165 men who had undergone radical postprostatectomy, but subsequently had rising PSA levels, signaling the presence of a more aggressive cancer. All patients who were enrolled in this trial initially underwent conventional imaging with bone scan, CT, or MRI for their initial treatment planning and those that were negative for detecting cancer in the bones or outside the pelvis.
The men were then randomly assigned to two groups. The first received radiation based off conventional imaging. The second group received underwent PET Axumin study, and the treatment was planned according to those findings. So if you look at the images here, the image on the right shows that there was a 12% difference in treatment planning if PET Axumin study was used as compared to conventional imaging. The figure on the left shows us that the PET Axumin study was far superior than conventional imaging when detecting lesions throughout the body, the prostate bed, as well as in the pelvic lymph node, which was again noted in the LOCATE trial as well. Next slide please.
So the RADAR committee met again for the Radar three imaging recommendations, and these recommendations really changed with the next generation imaging. So what we can see is that in newly diagnosed patients, we know what the Radar 1 recommendations were of when to do the imaging, but they recommended doing the next generation imaging for those who had equivocal or negative finding with conventional imaging. And they had still a high suspicious of metastatic disease. That's when you would do a next generation imaging. In biochemical recurrent patients, they said to consider next generation imaging for patients who had a PSA greater than 0.5, or if their PSA was less than 0.5, it can be considered based off the different technique of the next generation imaging.
In M0 castrate resistant patients, they recommend doing next generation imaging in the setting of a PSA doubling time of less than six months, especially when an M1 therapy would be appropriate. And then when we're looking at M1 patients, again, they recommend doing next generation imaging when patients need at least one of the following criteria; either with the doubling of the PSA since the last set of imaging, every six to nine months, despite even the absence of a PSA rise, change in symptom symptoms or change in performance status. So they really expanded the indication of doing next generation imaging in M1 disease patients. And now Dr. Gayed will continue the presentation with the imaging aspect of the presentation.
Isis Gayed: Thank you, Dr. Maithel for a very informative introduction for clinical aspect of Axumin PET imaging. I'm going to continue with the PET imaging aspect of it. I'm Dr. Isis Gayed, professor of nuclear medicine in the department of diagnostic and interventional imaging with UT Health at Houston. And I have to start by saying that we were very happy when F-18 Axumin got approved by FDA in 2016, because it was really the first F-18 PET imaging radiopharmaceutical, specifically for prostate cancer. And all our clinicians were waiting for radiopharmaceuticals, like F-18 Axumin. It was easier to work with than the C-11 choline or C-11 acetate. It was widely available and readily available.
So I really consider it as a milestone for molecular imaging of prostate cancer patients. And therefore it was very quickly incorporated into our imaging protocols and the clinicians started referring patients to us very quickly after we were able to get the radiopharmaceutical. Our protocol usually asks the patient to avoid any significant exercise the day prior to imaging, because big part of the dose we inject does go to muscles. So we do request the patient to refrain from any jogging or exercise for 24 hour before imaging.
We also ask them to fast for four hours prior to the scan to decrease any gut or stomach activity. We do ask them to void 30 to 60 minutes prior to the scan. We initially were asking them to void immediately before the scan, so that we would have an empty bladder, but we found that this was actually causing some difficulties in interpreting recurrence in the prostate bed. So we did modify the protocol so that the patient would have a little bit of urine in the bladder when they are injected. Scanning; usually we inject 10 mu, intravenously, and immediately scan after the injection within three to five minutes. And we start from the pelvis and go up towards the head and we do include the whole skull in the image.
So it's really from the upper thighs and goes all the way up to the top of the head. And it usually takes 20 to 30 minutes to complete an Axumin study. So it's not very long, it's quite tolerable by most patient, and they can do it very comfortably. And you get a beautiful Axumin scan at the end. So the imaging protocol will give this normal Axumin PET scan, and we do review both the PET only on the right side, you see in black and white and on the left side, the PET CT fused images. We have picked this color scale, it's called GE on our camera. It's a nice color scale to find metastasis when using this color scale. However, you are free to pick whichever color scale you are comfortable with, but from our experience, this was a very good color scale for us to detect even very small metastasis.
So the normal distribution of Axumin 40 to 45% will go to liver and pancreas. Very little will go to the lung and bone marrow. And some of the activity you will see in bowel and a little bit in the heart. The excretion in the urine is only about 5%, which helps in detecting recurrence in prostate bed or in the prostate. However, 50% of the dose will go to muscles, as you can see here. And that's why we ask the patient to avoid or refrain from any vigorous physical activity the day before the scan. The highest tumor to normal tissue contrast is going to be between four to 10 minutes after we inject the Axumin. And 60% of that uptake will start to fade away from tumor over 90 minutes after injection. So the earlier we image the better for detecting recurrent disease or metastatic disease.
So when Axumin was approved, it was mainly, at that time, for one indication which is a suspected prostate cancer recurrence based on elevated PSA level following prior treatment like prostatectomy or radiation therapy. And the reason it was approved for only one indication was based on the EMPTRE study, which actually looked at that particular patient population, which is patients with rising PSA after treatment of prostate cancer and showed the overall accuracy of detection of disease of 77% in 103 scans, 71% accuracy for detecting disease prostate bed and 90% accuracy in extra prostatic recurrence.
So based on the Empire study, FDA approved Axumin for that particular indication. However, in our experience, Axumin has been helpful in many other scenarios and many other indications, which I'm going to share some of them with you through case studies that we have done at our institution and we found Axumin very helpful to us. Case one: demonstrates the value of Axumin PET in follow up response to therapy. This is a 78 year old male who presented with bilateral hip pain and left lower extremity swelling as his first presentation for prostate cancer, which was metastatic in July 2019. The patient had non-contrast CT, which showed pelvic lymphadenopathy, and multiple sclerotic lesions in bones. And the sclerotic lesion was confirmed metastatic by bone scan. Patient was treated for two years based on these findings and conventional imaging.
So this is his bone scan, initial bone scan as a baseline showing all those multiple small bone lesions involving spine, ribs, even skull, sternum, pelvis and femurs. And this is his bone scan after two years, we can see that he did respond quite well to the treatment with resolution of many of his lesions in spine and ribs. However, the lesions in the pelvis remained plus the riwhichght ischial bone showed increase in uptake. So at this point we were thinking, this is probably a flare phenomena, however, we were not a 100% sure. So the clinician proceeded to an Axumin PET scan to try to resolve whether the patient has completely responded to treatment, or there is still residual active disease. At that time, his PSA level was 2.2. So the clinician ordered the Axumin PET scan, which showed very small, subtle areas of activity, as you can see in the right sacral ala, and in the L4 vertebra and in the right ischial tuberosity.
So that indicated to the clinician that despite very good response to therapy and resolution of many of previously seen lesion, there is still few sites of active disease at the PSA of 2.2. So the clinician continued therapy further. So Axumin did help the clinician to evaluate response to therapy and decide on further therapy in that case.
Case two: will show us the role of Axumin PET in detection of site of reactivation of disease and resolving controversial findings by other imaging modalities. So, this is a 77 year old man diagnosed with prostate cancer in 2016, had lymph nodes and bony metastasis seen on CT. Patient received systemic therapy with long term androgen deprivation with good response and his PSA decreased all the way to 0.6. So this is his baseline CT scan, which diagnosed his disease with a nodular prostate with calcifications and retroperitoneal lymph nodes, as well as small sclerotic lesions in bone. These such bone metastasis were confirmed with the bone scan, showing all those small metastatic bone lesions.
So two years after in 2018, his PSA started to rise again. He repeated bone scan, but at this point there was no evidence of any metastatic disease, not in the pelvis, nothing in the femurs, nothing anywhere else in the skeleton. So the clinician of course, with a rising PSA proceeded to an Axumin PET scan, and clearly it showed recurrence in the right iliac lymph nodes extending up even to the retroperitoneal lymph nodes. And the bone lesions that were initially seen at diagnosis did not show any uptake of Axumin at this point. So it was clear that the recurrence really is in lymph nodes and not in the bone anymore. So Axumin did help identify where is the site of reactivation of disease in patients who previously had bony metastasis and lymph node metastasis.
Case three will show how Axumin can help resolve controversial or contradictory clinical and imaging presentations. This is a 71 year old male with past medical history of prostate cancer who underwent radical prostatectomy in 2015. Patient had persistent elevated PSA level and neck pain for some time. A bone scan was performed in July 2017, which showed lower cervical spine uptake that we were not able to decide whether it is metastatic or degenerative in nature. Cervical spine is quite a common site for degenerative arthritis. So it's hard to differentiate metastasis from degenerative changes. So this is the bone scan, and this is the uptake in the cervical spine, which could be metastatic, but also could be due to degenerative arthritis. So the patient proceeded to an MRI, which has showed a partial collapse and sclerosis of C4 vertebra. However, that was felt to be due to deformity in that vertebra C4, half of the vertebra was deformed and caused quite a bit of derangement, I would say, of the posterior element. So it was felt that this lesion is really not metastatic, but rather related to the deformity in C4 vertebra by the MRI. However, the PSA was still high. Clinician is still trying to find a reason for a high PSA in this patient with a bone scan that is not decisive and an MRI telling that this is not a metastasis. So the clinician proceeded with an Axumin PET scan and it showed intense uptake at the C4 vertebra, as well as another lesion in the left tempo frontal area of the skull, which confirmed bony metastasis so the clinician started treatment as a metastatic prostate cancer based on the Axumin PET scan.
Case four, which is my last case, will show how Axumin helps in lytic lesions figuring out the etiology of lytic lesions and in compression fractures. We always conceive the bony metastasis and prostate cancer as being sclerotic. However, Axumin with detection of a very early bone lesion in prostate cancer, we started to realize that many of the prostate cancer metastasis in bone can start as lytic lesions and they sclero with time and treatment. So now we are seeing a lot of prostate cancer, bony metastasis presenting as lytic lesion on the Axumin scan. Also compression fracture was always a kind of deficiency in bone scan that we were not able to determine, is the compression fracture due to a metastasis as a pathologic fracture or is it just an insufficiency fracture? So Axumin helps in many of the compression fracture to make a decision. This is a 74 year old man who was prostate cancer treated with local radiation who developed back pain, lower back pain following treatment. So a CT scan of the spine was done and showed an L5 chronic compression fracture with infiltrating lytic lesion.
This is how it looked on the CT. As you can see a big lytic lesion involving the L5 vertebra and the L5 vertebra was completely collapsed. So again, an Axumin PET scan was done to try to evaluate, or confirm the etiology of this large lytic lesion and figure out the etiology of the compression fracture. And this is how it looks, very intense uptake in the lytic lesion in the L5 vertebra exactly at the site of the lytic lesion, which confirmed prostate cancer metastasis to L5 vertebra as an etiology of the compression fracture and this lytic lesion. So with this, I would say that Axumin PET scan has so many roles and plays a very helpful role in many patients with prostate cancer and in different scenarios, more than the approved FDA indications.
However things are not always easy and obvious and we do face some difficulties with Axumin PET scan. Those difficulties can come from urine in bladder or urethra, which can be misleading and can be interpreted as recurrent disease in prostate bed or prostate cancer prostate bed or the prostate gland. Also, sometimes there can be some small, subtle, hidden lesion on fused images because of the nature of fusion that you can see on PET only images. And I'm going to show you an example of this.
Also, benign bone lesion can give false positive scans with Axumin and the most difficult and disappointing scenario is when you have a patient with rising PSA and you do an Axumin PET scan, and you don't find anything because most of the time, the clinician are really, really reaching out to the Axumin scan to find disease. So I'm going to show an example of urine in the urethra that gave us a little bit of hard time to try to figure out, is it a recurrence in the prostate versus just, a little dilated urethra in this patient. The only way you can maybe figure out that this is urine in the urethra is reviewing the images in different slides, orientation.
And I always find the sagittal as the best to see urine in the urethra. And this is a very nice, clear example that this urethra had some of the urine all along the urethra and the uptake here was very central in location. So we felt that it is probably urine in urethra. However, to be sure the patient did go for an MRI, which showed no evidence of disease recurrence in the prostate. So we were comfortable and more confident at that point that this was just urine in the urethra.
Another difficulty, as I mentioned, small subtle lymph node metastasis might not appear very well on fused image, and you really need to go to the PET only image to find them. This is an example of very early recurrence in a very small lymph node in this patient that was seen only on the PET alone image and after we increased the intensity quite high, we could see the lymph node. Patient got treatment and with repeat Axumin scan after treatment, the lymph node has disappeared. So I really recommend that the PET only images would be reviewed first before going to the fused imaging.
And as I mentioned, a negative scan is always a big disappointment for everybody in a patient with rising PSA. And that's an example of one of those patients where his PSA went way low and the clinician was happy with the result. However, it started to rise again late in year 2020, an Axumin PET scan was done in January 2021, and it was completely negative. We couldn't find anything. However, the PSA continued to rise very quickly, and the patient had a repeat of the Axumin PET scan in November 2021, which I think was quite a long wait to repeat Axumin PET scan.
We usually recommend for the clinician with a negative scan is to repeat within three to four months. And most of the time, if you wait a little bit and repeat the scan, you will find the source of the rising PSA. So this patient, they just waited too long, but the repeat scan showed recurrence in right pelvic lymph nodes, which were actually very small lymph nodes. They were sub centimeter lymph node, and could not be detected by conventional imaging, MRI, or CT scan. So, only the Axumin was able to find the new metastasis in the lymph node. So negative scan initially probably going to turn into positive if you wait few months and repeat the scan.
And with this, I would like to conclude that F-18 Axumin PET has significantly improved prostate cancer patient management through early detection and localization of site of active lesions. And I do believe that F-18 Axumin PET has a big role and helps in the follow up of response to therapy in many prostate cancer patient. Although there is no big study to support this conclusion. However, we do see it on a day to day basis in our clinical practice. And I do thank you very much for your attention, and I hope this presentation was informative to you. I also would like to thank the SNMMI Prostate Cancer Outreach Working Group for stimulating this presentation, supporting us and helping us through the preparation of this presentation. Thank you very much.