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Philip Koo: Hi, my name is Phillip Koo and welcome to the third lecture in our series, focusing on prostate cancer imaging and therapies. Today, we're very fortunate to have with us Dr. Ajit Goenka, who's an Associate Professor of Radiology at the Mayo Clinic in Rochester, Minnesota, who will be speaking about C-11 choline in patients with biochemical recurrent prostate cancer. And as we're all aware, Mayo Clinic was the world pioneer with regards to the use of choline in prostate cancer. So we're very, very fortunate to have with us one of the leading experts on this topic. So, thank you very much, Dr. Goenka, for joining us on UroToday.com.

Ajit Goenka: Thank you. All right, my name is Ajit Goenka, and as Dr. Koo mentioned, I work at the Mayo Clinic in Rochester in the divisions of abdominal and nuclear radiology, and I have the pleasure and the privilege of discussing with you some of the  experience that we and others have had with C-11 choline imaging of patients with biochemical recurrence of prostate cancer. Let's begin with an overview of biochemically reoccurrent prostate cancer. As we know that prostate cancer is a huge public health problem. However, more than that, 30 to 50% of these patients, once they received definitive therapy go on to develop biochemical recurrence within about 10 years of that definitive therapy, and of these patients with biochemical recurrence prostate cancer, close to 30% of them go on to develop distant metastases within 8 years of development of biochemical recurrence. The definition of biochemical recurrence really is based upon the type of definitive therapy which can be either radical prostatectomy or external beam radiotherapy. 

Eventually, biochemical reoccurrence leads to clinical recurrence, which is basically when you start seeing the signs, symptoms of the imaging manifestations of biochemical recurrence and it eventually leads to morbidity and mortality. It is important to remember that although prostate cancer is a huge problem, most mortality from prostate cancer is not due to primary prostate cancer, but due to recurrent prostate cancer, which means that biochemical recurrence of prostate cancer is the primary entity that is responsible for most mortality from prostate cancer. Now the conventional approach for the treatment of prostate cancer was usually empirical. In a patient who was deemed to be high risk and was suspected to be having recurrence in the pelvis, the standard therapy was salvage radiotherapy. On the other hand, a patient who was deemed to have systemic recurrence was usually treated with an anti-androgen deprivation therapy or a combination of that with chemotherapy. However, due to advanced biomedical imaging, the treatment of biochemical recurrent prostate cancer has become more personalized and imaging plays a central role in the decision of what treatment can be given to a patient. Therefore, it is the responsibility of the radiologist to be able to answer these questions on any imaging modality and not just on choline by CT. 

The first and foremost thing that our referring providers wants to know from us is that is there an imaging manifestation of recurrence and if at all, what is the location, size and the morphology of that recurrence. And the reason for that is because whether it's pelvic or distant metastases is what it's going to determine the type of therapy that the patient will be administered. And finally, what is the extent of the disease? And the reason for that is this entity that is called oligometastatic prostate cancer, which is defined as usually less than or equal to three extracranial metastases. And the reason why it is important to be able to recognize a disease at this particular stage is because in these patients with oligometastatic disease, metastasis directed therapy has been recently shown to have a favorable impact on the long-term outcomes. 

So, let's see where C-11 choline PET imaging fits into this paradigm of biochemical recurrent prostate cancer, and its personalized treatment.  C-11 choline PET Imaging is based on the concept of elevated phosphorylcholine and phosphatidylcholine turnover in prostate cancer cells. The half-life of this radiotracer is 20 minutes which means that an onsite cyclotron is required for its production and administration. C-11 Choline PET Imaging has been relegated as a robust imaging modality for the detection of metastasis in this patient in multiple studies. When it comes to local recurrence, however, C-11 choline PET imaging is considered complementary to prostate MRI. In general, the sensitivity and specificity of C-11 choline PET imaging is extremely high for detection of metastasis. As is true for majority of the other radio racers the rate of positive detection on C-11 choline PET is usually linearly dependent on the PSA levels, and it is usually accepted that a PSA of more than one is a reasonable indication for performing choline PET/CT in a patient with biochemically recurrent prostate cancer. When compared with conventional imaging modalities such as CT and MRI, C-11 choline PET imaging detects early and small metastatic lesions that may, in fact, be often occult on these conventional imaging modalities. Moreover, majority of the detection on C-11 choline PET happens at a PSA level where CT and MRI may really not have much of a role. 

It is important to know the physiologic distribution of C-11 choline PET before we appreciate the extent of disease on an imaging study. In general, salivary glands, liver, spleen, bone marrow, kidney, and the bowel are the organs where we see the physiologic or normal bio-distribution of C-11 choline. As we know that bone marrow or the bones are a common site of disease in metastatic prostate cancer, it is critical to have the windows of the study so that we can pick up certain lesions in these areas of high bone marrow distribution. Now we all know this conventional understanding of the metastatic pattern in prostate cancer. In general, patients either have local recurrence that can happen in the prostate bed or in the pelvic lymph nodes. On the other hand, they manifest with distant metastasis either in distant lymph nodes. However, due to the high volume of imaging that is now performed in this group of patients, we have started seeing what's common and uncommon distributions of prostate cancer.

Let's begin with the common manifestations of metastasis from prostate cancer so these would include sub-centimeter sized pelvic lymph nodes. As you can see in these two different patients with intense choline uptake in the small lymph nodes and remember that on conventional imaging, it would be often difficult to be able to call different nodes that are normal because they have extremely small size. We also see and are able to detect this tracer avid sclerotic osseous metastasis. However, what we also see is that often times we will have lesions that are confined to the bone marrow that may be only apparent on the PET component of the study and may not have an active correlate under the line attenuation correction CT.  As we have discussed previously, C-11 choline PET is not optimal for detection of local recurrence due to the excretion of the radiotracer from urine. However, if we see a patch such as this, which is nodular focal radiotracer uptake and especially when we correlate with prostate MR, we can be pretty certain that we are looking at local recurrence. However, due to the high volume of information that we've mentioned, we have increasingly seen uncommon sites of metastases that are challenging our conventional wisdom about the metastatic pattern in prostate cancer.

Let's take a look at a few of those on C-11 choline PET imaging.  So, this was a 70 year old gentlemen who had presented with biochemical recurrence and the PSA at the time of initial C-11 choline PET was 1.7. Here we have the whole body image. We have that innovation correction CT component and the fused PET as a CT of the same patient. What we see is that the patient had this extremely heterogeneous, peri-nephric and nephric soft tissue that was intentionally tracer avid. In addition to that, patient also had this tracer avid retroperitoneal lymph nodes and noticed that the PSA was only 1.7. Based on the conventional wisdom, we would expect a patient with this PSA to have confined disease usually to the pelvis. Based on this imaging manifestation, our treatment and decision was made to give the patient chemoradiotherapy. And subsequent to the chemoradiotherapy, what we saw is that, there was near complete resolution of the peri-nephric soft tissue, but there was increase in the size and the extent of intensity of the tracer uptake in those retroperitoneal lymph nodes. 

What this example demonstrates to us is that C-11 could, in fact, detect not only the typical sites which in this patient will be retroperitoneal lymph nodes but also the atypical site of metastasis which would be the peri-nephric soft tissue early in the course of the disease at extremely low PSA levels. 

This was another patient who had presented with a PSA of 2.5 at the time of his biochemical recurrence. And what we saw was that the patient on a CT scan that had been performed at an outside institution had left hydroureteronephrosis as you can see here on the axial CT images. In addition to that, there was a delayed nephrogram due to the presence of this hydroureteronephrosis. On that CT scan, the patient was also seem to have the soft tissue around the lower ureter, which on the C-11 choline PET was again tracer avid, our CT guided biopsy, this peri-ureteric mass lesion, confirm that this was actually metastasis from prostate cancer. Again, an extremely atypical site which we were able to pick up on C-11 choline PET. However, the CT scan was not able to show us was that the patient also had a pulmonary nodule, which was tracer avid on the C-11 choline PET and was again proved to be metastatic adenocarcinoma from prostate cancer. 

This patient then went on to have upper lobe resection and chemotherapy. And subsequent to that, he had complete resolution of tracer uptake in that peri-ureteric soft tissue associated with a decrease in the anatomy component. Essentially the patient had complete metabolic response and consequently, the PSA had dropped to an undetectable level. These examples demonstrate to us that C-11 choline imaging is extremely good at defining oligometastasis and it also useful for evaluating the therapy response in these patients. In addition to that, we have also seen other sites of atypical metastases, which will include, focal liver lesions in the background of the physiologic radiotracer uptake in the liver. We've seen focal radiotracer uptake in the testes which was proven to be metastasis from prostate cancer. We have seen isolated breast metastasis in patients and notice the gynecomastia that often these patients tend to have because of the ongoing ADT. We've seen pulmonary as well as peritoneal metastases from prostate cancer. 

The next important modality where we have been using C-11 choline it's with upcoming modality of PET MR. Let's say you have a few case examples to see the utility of PET MR in this particular clinical context. So, we had a 64 year old gentleman who had received surgery and radiotherapy, for his prostate cancer in 2002. He then presented a few years later with the right leg and knee pain to orthopedic surgeon. And it was deemed that his pain was due to degenerative disc disease and for which he underwent a decompressive surgery centered at L-5 and S-1 but without any relief. He subsequently had a PSA drawn, given his history of prostate cancer and that PSA came back at 2.8 which suggested that he had a biochemical recurrence.

Based on that clinical context where a patient was referred to us for PET MR to localize any site of disease. These are the images from the survey component of the PET MR. What we saw was this subtle radiotracer update that seemed to be going to the sciatic foramen. Much better appreciated on this fused PET MR and even better appreciated on the coronal image from the PET MR where we can see that this nodular tracer uptake was extending along the plexus. When we look at the images from the fused focused part of the PET MR we noticed that the radiotracer uptake was much more pronounced. In addition to that, we had findings on the MR component of the PET MR which included asymmetric thickening of the pelvis on this side associated with nodular enhancement that was extending along the plexus. 

Based on these findings, there was a concern for metastasis involving the neural plexus and the patient then had a CT guided biopsy of that region which confirmed that, these findings were due to malignancy. So, this patient had what we consider to be an increasingly described phenomenon, of perineural metastasis from biochemically recurrent prostate cancer. 

Here’s another patient that demonstrates the utility of PET MR. This was a 59 year old gentleman, with an aggressive form of primary prostate cancer for which he had received radiotherapy. Subsequently, he presented with biochemical recurrence and a PSA of 6. One of the criticisms of PET MR and not just in the context of C-11 choline is that Pet MR is inferior for the detection of pulmonary metastasis. 

However, in this patient, when we look at the fused MR majors, we notice that he had several foci of radiotracer uptake scattered in both the lungs. Based on these findings, the patient was advised to have a follow-up imaging on an image guided biopsy. On the subsequently performed CT scan, we notice that these foci of radiotracer uptake, correlate with extremely small pulmonary nodules ranging in size from three to five millimeters. So, what this case example demonstrates to us is that on PET MR it's not necessarily the size of the pulmonary lesions, but the intensity of radiotracer uptake that determines whether or not we'd be able to pick up those lesions. 

This patient then underwent a biopsy of one of those pulmonary nodules which came back as metastatic prostate adenocarcinoma, which confirmed our earlier suspicion. And based on these findings, the patient underwent ADT with concurrent docetaxel for six cycles. This demonstrates utility of PET MR in these complex patients. 

So, what we have seen so far is that imaging has become central to the personalized management of patients with biochemical recurrent prostate cancer. We've seen that while prostate cancer is a huge problem it is usually the biochemical recurrence which is a main contributor to morbidity and mortality for prostate cancer. We have seen that C-11 choline PET imaging is a validated technique for detection of metastases in these patients and it is challenging the conventional wisdom and knowledge that we had about biochemical recurrent prostate cancer. In particular, it is quite good at any time oligometastatic disease, as well as individual sites of metastasis that may or may not be a ban on conventional imaging.

Finally, we also saw that PET MR using C-11 choline PET has the potential to be a one stop shop for the evaluation of patients with biochemically recurrent prostate cancer.  However, it obviously needs more research and validation before one can recommend its use usually on all of these patients. And finally, PET MR detection of disease in these patients provides us an opportunity for personalized treatment approach, which has the potential to improve the outcomes of this extremely moderate neoplasm. With that, I come to the end of my presentation and I thank you for your attention.

Philip Koo: So, you know, as of the date of this recording, April 2019 in the US at least there are two FDA approved PET radiopharmaceuticals diagnostic radiopharmaceuticals. C-11 choline and F-18 fluciclovine. What are your thoughts on, you know, how urologists or radiation oncologist should choose what tests to pursue? 

Ajit Goenka: Yeah, that's an extremely good question. And you are right that right now we have only two of them that are C-11 and fluciclovine and we hopefully will have PSMA in the near term available in the US as well. So yes, it raises a lot of questions in terms of first and foremost whether these are equivalent to each other or do these radiotracers have different utility at different stage of disease. But the short answer to your question is that usually the decision whether or not to purchase one of these radiotracers is the local availability. C-11 choline requires an on-site cyclotron and it's something which may not be widely available to a lot of practices and even for that singular reason fluciclovine is the one that is usually likely to be performed and available to a lot of those practices. And we do have fluciclovine that can be performed at one of our sister sites which is in Florida and it has its own set of challenges, but I know that for those lesions, we need something which is not necessarily considered the best. So, if let's say we had both of these radiotracers available given what we know about C-11 choline especially in biochemical recurrence, I would prefer that. But the decision, as I said is ultimately determined by what is available to the referring provider at the time of seeing that patient.