This is a 55-year-old who presented with nocturia and a PSA of 4.5. A digital rectal exam revealed a T2 area of hardness. Biopsy was positive for Gleason 3+3, now called combined Gleason scores of 1. Clinical stage was T1c, but he had a lump so maybe it was a d2. Patient went on active surveillance. About a year later, his PSA had risen to 10. Repeat biopsy now showed a Gleason 4+3, and 8 of the 12 cores were positive. So, the patient clearly had more advanced disease. Whether it was there before or not, it is hard to be sure.

He was asymptomatic and started on goserelin. About 6 months or so later, his PSA did not go down. What was unusual is his PSA, in fact, rose to be 34. So, you have a case almost of de novo resistance to hormone therapy. That should only occur in about 5% or less of patients.

CT scan was negative. Because the PSA was rising, they began him on abiraterone and prednisone. Within a short period of time, although his PSA declined to 15, he had a cardiac arrhythmia, which does occur with abiraterone. So, the treating physician decided to switch to enzalutamide. Again, a perfectly appropriate decision. Enzalutamide did not have any negative effects, but also did not lower the PSA much.

So, now another 3 to 4 months goes by and the patient begins to develop back painor not even back pain, just an achiness&mdash;and some mild fatigue. The doctor says, &ldquo;Well, let&rsquo;s reimage.&rdquo; CT scan shows bone metastases. A fluoride PET bone scan confirms lumbar and pelvic bony metastatic disease. PSA is up to 45, and the ALK phosphatase is starting to rise. The patient has symptoms, mostly fatigue, but also a rising PSA, new findings on x-rays, and new findings on the fluoride PET scan.

At that point, it&rsquo;s extremely appropriate to begin radium-223. The patient develops a drop in the PSA, which isn&rsquo;t that common with radium. Normally, the PSA does not drop much, but it fell from 45 to 25. His ALK phosphatase comes down into the normal range, and his symptoms of fatigue begin to improve. He has had 4 doses. The questions are: was this the right sequencing? Should he get additional radium, etc? So, we&rsquo;re going to cover some of those topics.

Treatment for Newly Diagnosed Prostate Cancer

Looking at this case, the patient has an atypical response to hormone therapy. Almost always, the PSA drops when you give an LHR agonist like goserelin, leuprolide, or degarelix. So, the fact that the PSA did not drop suggests that the patient has developed a de novo castrate-resistant state. Perhaps the patient was already castrated, perhaps he had hypogonadism, perhaps his testosterone was below 100. We don&rsquo;t know that because the testosterone level was not drawn at the time of goserelin administration, but that&rsquo;s usually the case. If the patient does not respond to leuprolide, goserelin, or degarelix, they probably are already hypogonadal and they developed a de novo, or nearly de novo, castrate-resistant state. So, this patient has an adverse outcome. There is not going to be a good outcome.

The case is somewhat atypical in that he doesn&rsquo;t get a good response to leuprolide and goserelin. And, moreover, he doesn&rsquo;t get much of a response to abiraterone. And, again, we don&rsquo;t know all the details, but the fact that the patient only gets a drop from 30 to 15 on the PSA and then gets cardiac arrhythmia, probably atrialwhich is the most common, secondary to salt retention, by abiraterone&mdash;it&rsquo;s appropriate to switch to enzalutamide.

Well, at that point, we now already know that enzalutamide is not going to be a long-term benefit. At ASCO this 2017, there were 2 papers showing that once enzalutamide or abiraterone failed, switching or adding another drug didn&rsquo;t give you much benefit. In fact, I think it was it was the PLATO trial that showed that the average duration of benefit of the second-line androgen blocker was only 3 months. This patient is spot on; 3-month benefit, not a lot of benefit.

Now, do you need to image at that point? The answer is, yes, it&rsquo;s reasonable to image. What images do you do? Well, right now, insurance doesn&rsquo;t usually pay for the fluoride PET. I love to get the fluoride PET; it&rsquo;s a more sensitive test. But many times, the insurance just says no, and we can sometimes get it under a Cooperative Group research agreement. But still, we usually can&rsquo;t get the fluoride. So, you do a regular technician bone scan, a CT scan, and tumor markers. And sure enough, based upon all of those factors, PSA is rising, symptom of fatigue is going up, and he&rsquo;s got new bone metastases on the fluoride and probably on the regular bone scan. And he&rsquo;s got a CT scan sign of progression.

Why do we do the CT scan? Well, CT scan is done so you don&rsquo;t miss liver metastases, because fatigue can be a sign of liver metastases. I&rsquo;m glad he doesn&rsquo;t have liver metastases, but I wouldn&rsquo;t be surprised if, down the road, a highly aggressive tumor like this will pop up with liver metastases. Right now, all he has got is fairly limited bone metastatic disease. Therefore, it is highly appropriate to begin radium-223.

CRPC: Responding Poorly to AR-Targeted Agents

When would you start radium-223? Radium-223 is probably best given early before chemotherapy. That&rsquo;s not to say you should not give chemotherapy first, but the tolerance of radium-223 is best in patients before they get chemotherapy. So, I tend to always either give radium right away if I see progression, or if I&rsquo;ve given docetaxel or a taxane in the hormone-sensitive phase, I will then follow-up with radium fairly quickly. When they show progression, they&rsquo;re going to get radium.

In this patient, we have a poor response to initial hormone therapy, a toxicity with abiraterone, and then a short response to enzalutamide with symptomatic deterioration. It&rsquo;s very appropriate to begin radium right there. Now, you could also argue that the patient should get sipuleucel-T. That would also be appropriate. So, I might consider now stopping enzalutamide, giving sipuleucel-T either concurrently with, or immediately following, radium. But we already know this tumor is probably not androgen-driven, or at least not very androgen-driven, so you&rsquo;re going to get to chemotherapy fairly quickly. So, we get through 4 doses of radium-223. The patient is doing well; the PSA drops, the symptoms improve, the ALK phosphatase drops. All indications are that we&rsquo;re on the right track.

So, the issue of combining agents is gaining momentum. In the not long ago days, we would always give sequential therapy: one agent, then another, then another, then another. This is reminiscent of the way we used to treat Hodgkin&rsquo;s disease before MOPP and ABVD. There&rsquo;s no reason to give sequential single agents. We know they can combine well together. Giving radium with abiraterone, giving radium with enzalutamide, and giving radium with sipuleucel-T are all very easy, appropriate, and fine.

Giving it with chemotherapy is a little more difficult. So, I generally do not put them together. I will either give radium first, followed by chemotherapy, or chemotherapy first, followed by radium. And my preference is to layer the radium in with a less myelosuppressive drug, such as abiraterone, enzalutamide, or sipuleucel-T.

So, here we are now. The patient has already had 4 doses of radium and is doing well. We have strong evidence that you should give 6 doses. Every studythe Expanded Access study, ALSYMPCA, the European Expanded Access Worldwide&mdash;showed that it was always better to give 6 doses of radium rather than 4. And if it takes a little bit of effort on the part of the doctor and the part of patient to get 6 cycles, it&rsquo;s worth the effort. So, try to hold off. In many cases, you will find that as you get to the fourth cycle of radium-223, the PSA will start to rise a little bit.

And there&rsquo;s a tendency by doctors and patients to say, &ldquo;Oh, the radium&rsquo;s not working and I should switch to chemotherapy.&rdquo; Resist the urge. Stay with radium, finish the 6 cycles. Everything we know about radium means that you have to go to 6. In fact, there are clinical trials looking at 12 doses of radium compared to 6 or even higher doses of radium. So, we are looking at more radium, not less. Dose response is not yet fully defined and, therefore, a minimum of 6 doses of radium is, in my opinion, mandatory.

Layering Therapies for mCRPC

At this next juncture, there&rsquo;s no question that radium-223 has to be given for 6 doses. Then the question is, what do you do next? The radiation oncologist may wish to radiate those bone metastases to consolidate the response. Or, alternatively, a radiation oncologist may have said, &ldquo;Well, I want to radiate those lesions first.&rdquo; I don&rsquo;t have a problem either way with that. In fact, if you wanted to radiate the bone and give radium-223, that would be perfectly appropriate. In ALSYMPCA, that was allowed. In all the expanded access programs, that was allowed. And there was no excess safety signal in those patients who got radium concurrently with external beam radiation. So, there&rsquo;s no problem. Giving radium with chemotherapy, that&rsquo;s another story. It&rsquo;s a little harder to achieve, and so, therefore, you have to be careful.

Now, how do you coordinate that with your radiation oncologist or your nuclear medicine physician who&rsquo;s giving the radium? Well, the medical oncologist really has to be the one who drives this ship because you&rsquo;re the one, as a medical oncologist, who has to sequence these agents or layer them. And you&rsquo;re going to have to say, &ldquo;I need to get the radium in, I need to give him a little bit of rest, and then I&rsquo;m going to come in with chemotherapy.&rdquo; Because although this patient had a nice drop in their PSA from 45 to something in the 20s, that does usually not often occur. And usually, if anything, the PSA is starting to rise after 4 cycles, but stay the course. That&rsquo;s the take-home message: stay the course, don&rsquo;t stop after 4 cycles.

Whenever I get to a patient and I say to them, &ldquo;Okay, you&rsquo;re going to get 6 doses,&rdquo; I may have the radiation oncologist go, &ldquo;Well, their PSA is rising and they don&rsquo;t feel that good.&rdquo; I go, &ldquo;It&rsquo;s okay, it&rsquo;s okay, you can finish this up.&rdquo; Sometimes it&rsquo;s very difficult to finish, but you insist upon it. You say, &ldquo;This is what gives optimal survival, optimal quality of life, optimal pain control, and gives you the longest duration of benefit with radium-223.&rdquo;

So, what are the indications to start radium-223? A lot of my colleagues say, &ldquo;Well, the patient doesn&rsquo;t have pain. Therefore, they don&rsquo;t need to start radium.&rdquo; That&rsquo;s wrong. You don&rsquo;t need symptoms to start radium, you need some minor symptoms. But in ALSYMPCA, the randomized phase III trial, they didn&rsquo;t need to have pain. All they had to have was symptoms. That could be fatigue, weight loss, appetite loss, any number of minor symptoms. We had patients on ALSYMPCA who only were taking acetaminophen or nonsteroidals. And yet they, in fact, had the greatest degree of benefit.

If you wait to give radium-223 to patients with bone pain, you will be disappointed. Radium is not given for pain; it&rsquo;s given for improvement in survival, improvement in quality of life. It reduces the need for narcotics. It reduces the time to need for chemotherapy. It has a whole host of benefits, but primarily being given for reduction of pain is not its primary endpoint. Only about 20% or so of patients when given radium will have a drop in their pain. So, you need to give radium as a life-extending, life-prolonging therapy when you have a 6-month window to do so. You don&rsquo;t want to wait until the very end when the patient has had everything under the sunincluding external beam radiation, chemotherapy, abiraterone, sipuleucel-T, and enzalutamide&mdash;and then you go, &ldquo;Well, I guess now I should use radium.&rdquo; Well, that&rsquo;s not the right time.

In the old days when we had strontium as the only available radiopharmaceutical, it was given for pain, but it also had severe bone marrow suppression. And so, there was a lot of disappointment with strontium because it would induce severe bone marrow suppression when given too late in the course of the disease. So, again, radium-223 is not the same as a beta admitter, like strontium. Radium-223 is an alpha emitter with minimal bone marrow suppression, albeit you can get bone marrow suppression in the face of a super scan or extensive prior chemotherapy or extensive prior radiotherapy. Again, everything points to give radium earlier in the natural history of the disease.

mCRPC: Medical and Radiation Oncologist Collaboration

In the past, the radiopharmaceutical agents were typically beta emitters, which were quite good at going into the bone and treating disease so that patients did achieve a palliative effect. Unfortunately, they really were not specific, so there was a lot of bone marrow failure. And, justifiably, a lot of oncologists were reluctant to use the beta emitters, because there was no survival advantage and patients often were precluded from having additional therapies due to their bone marrow compromise. Xofigo, radium-223, is quite different in that it&rsquo;s an alpha emitter, and because of that, the deposition is different. It&rsquo;s a calcimimetic. It goes specifically to the parts of the bone that are affected by cancer, but it spares the bone marrow, so there&rsquo;s much better tolerance and less myelosuppression. The most important thing about this drug is that the ALSYMPCA trial showed there was a survival benefit. So, not only does it relieve pain and prevent secondary skeletal events, but patients who are treated also live longer.

It&rsquo;s very important that these patients are evaluated in a multimodality clinic. A urologist, a urologic oncologist, and a radiation oncologist should review the patient&rsquo;s case and determine what the appropriate therapy is. We have so many different treatment options now, and the concept of therapeutic layering is so important. It&rsquo;s vital that these clinicians decide what the proper order is. A patient who has very bulky lymphadenopathy or visceral disease should be treated with chemotherapy. On the other hand, early on in the castrate-resistant phase, if the patient has bony involvement, that would be a patient who I would strongly consider for radium-223.

For this patient, it&rsquo;s quite logical to use radium-223. The patient has clear castrate resistance and their PSA is rising despite the fact that they were treated with androgen suppression. Once we get to that phase and there&rsquo;s bony involvement, we know that we have to intervene in order to improve survival. If the patient has bony involvement but lymph nodes are either not present or less than 3 cm, and there is no visceral involvement, these are the patients who are most appropriate for radium-223.

As a radiation oncologist, it&rsquo;s very important that I interact with the urologist, urologic oncologist, and the radiologist. And it&rsquo;s very important that we utilize the latest studies. For example, sometimes patients will have a completely normal looking bone scan, but the sodium fluoride PET/CT scan will show early involvement. That helps us identify patients early in the course of disease who are most appropriate for therapy such as radium-223.

We know from the ALSYMPCA trial that less than 70% of patients received a full 6 cycles of radium-223. That&rsquo;s a major impact on their outcome. We know the patients who received 1 to 2 cycles did not do as well as the patients who received the full 6 cycles. So, in discussion with a urologic oncologist, I always stress the importance of identifying these patients early and supporting them through the full 6 cycles. Those are the patients who will receive the maximum clinical benefit.

Radium-223 for mCRPC: A Radiation Oncologist's Viewpoint

Let&rsquo;s talk about imaging. Prostate cancer is well tracked by the use of PSA. The need for imaging is somewhat diminished. But whenever there&rsquo;s a clinical situationPSA rise, new symptoms, fatigue, weight loss, minor pain&mdash;it&rsquo;s probably reasonable to reimage because you want to know the disease status. And you need to know whether the disease is bone dominant or nonbone dominant. Now, you can give radium in the face of soft tissue disease, provided the lymph nodes are not overwhelmingly dominant. So, if you have 6-cm lymph nodes and only 1 or 2 bone metastases, you may not want to give radium. You may want to focus on the chemotherapy because, of course, radium will not hit nonosseous metastatic disease.

I always, if I&rsquo;m about to think about radium, image. I go, &ldquo;Well, let&rsquo;s make certain that you don&rsquo;t have liver, lung, or a large-volume soft tissue lymph node disease.&rdquo; Small-volume soft tissue disease is fine, but you&rsquo;ve got to watch it. Because during a time you&rsquo;re suppressing the bone disease with radium, the soft tissue disease may progress. That&rsquo;s why I prefer the therapeutic layering. I prefer to give radium for the bone and, at the same time, cover any soft tissue disease in the lymph nodes, for example, with either abiraterone or enzalutamide.

For this particular patient, I probably would have given radium at the time that I started the abiraterone, because then when I give the radium along with the abiraterone, and if they have an abiraterone side effect, I will add the enzalutamide. And by the time I get to the point that enzalutamide is not working at about 6 to 7 months, then I&rsquo;ll be ready to go to chemotherapy. Because now you&rsquo;re going, &ldquo;Well, the enzalutamide is not really working and what about soft tissue disease?&rdquo; Fortunately, in this case, there&rsquo;s no soft tissue disease so you&rsquo;re allowed to go a little bit beyond the radium point, which I would start looking to end. In other words, after 6 cycles, and if the disease starts to progress, that&rsquo;s when I want to bring in chemotherapy or an alternative antiandrogen.

Given the fact that the second antiandrogen benefit is quite shortand we learned that at ASCO 2017, it&rsquo;s 3 months&mdash;if you get the first antiandrogen, you may get 12 to 15 months on average. That&rsquo;s the perfect time to give radium. What I do is, for example, if they get abiraterone, their PSA falls nicely, usually stays down for 7 or 8 months, and then you begin to see a little creeping up of the PSA. That&rsquo;s when I&rsquo;ll give the radium, because I know that abiraterone is going to fail, probably within 6 to 7 months.

So, I put in the radium right there. If I wait too long, then I&rsquo;ve got to rely upon the second antiandrogen, such as enzalutamide in this case, and that is only going to give me 3 months. You need to play the chess game with the cancer: what is the cancer thinking? What is the cancer doing? What is its behavior going to be like? And you need those 6 months of radium to be the best you can for your patient with bone-dominant metastatic prostate cancer.

To summarize, bone metastatic disease is extremely common90% to 95% of patients with prostate cancer. Bone metastases are the major single cause for morbidity and mortality in prostate cancer. Radium is the only directly cytotoxic agent that targets the bone, can prevent bone pain, prevent reduction in quality of life, and extend the life of the patient with bone-dominant metastatic prostate cancer.

Imaging for mCRPC and Treatment Decisions

Imaging is used for the diagnosis of metastatic prostate cancer in many different ways. We can be looking for solid organ metastatic disease as well as bone metastatic disease. Depending on the situation with the PSA, we may be looking at different areas. So, the different modalities that are available inside of the armamentarium of the radiologist, as well as the oncologist, is CT, PET/CT, MRI, and then also some multiparametric MRI of the prostate.

The decision tree about when to do imaging in patients with metastatic prostate cancer is dependent on local patterns as well as some of the national guidelines. I think the key things we have to be looking at are, what kind of treatment the patient had, what their PSA trajectory is, and what is their level of suspicion that they have metastatic diseasewhether that be clinical symptoms, etc.

So, some people are advocating seeing CT or PET/CT at intervals every 6 to 12 months. I think that it really has to be personalized depending on the patients&rsquo; PSA situations and also looking at some of the national guidelines. One of the things about prostate cancer is, every patient is very unique, and so some of the experiences that we&rsquo;ve had have shown me that some people manifest their disease in very, very different ways. I think choosing the right imaging modality is as critical as how often we do the imaging. And so, trying to identify where the most suspected site of recurrence is going to beis that going to be a wildly metastatic disease or an oligometastatic disease pattern&mdash;is extremely important. I think choosing the imaging modality is really, really critical in assessing it. And with some of the new advents in technology out there with regard to new types of PET technology, I think it&rsquo;s a very exciting time to be able to offer these types of modalities to our patients.

So, the patient who we talk about in this case here is really interesting in the fact that they had what was suspected to be low-grade disease and then they were on active surveillance for a long time. Once a decision was made to actually pursue more active treatment, part of that was informed by a biopsy change that had shown that they actually had more aggressive disease, and I think that that&rsquo;s a potential place where we could implement something like multi-parametric MRI to assist.

The ability of multi-parametric MRI is really to inform decision making by talking about the degree and grade of the tumor, as well as the possibility of extra prostatic extension. So, I think that that&rsquo;s one place where we could have implemented imaging. I think the guidelines are stating to us that in patients with PSAs below a certain level, CTs really aren&rsquo;t that helpful in assessing for metastatic disease and then specifically assessing for local progression of disease. I think before the metastatic disease, multi-parametric MRI could be a very helpful technique for assessing the grade of this person&rsquo;s tumor.

After the development of metastatic disease, I think the critical aspects about determining the intervals for imaging should be the PSA and also a symptomatology from a clinical standpoint. So, if this patient has developed bony metastatic disease, as we&rsquo;ve seen on both the CT as well as on the PET scan, we want to ensure that should the patient&rsquo;s symptoms worsen at all, we image them to make sure that they don&rsquo;t have any complications of these metastatic diseases in their bones. In addition, we want to make sure that we have enough cross-sectional imaging as well to ensure about the presence or absence of lymph node metastatic disease and also solid organ metastatic disease as well.

I think multidisciplinary care is at the very heart of prostate cancer care and really all oncology care right now. I feel very fortunate to be part of a group that talks about cases at length when we have patients come in, and really, the patient comes to one room and all of us rotate around that patient. That discussion can be extremely helpful: the radiologist providing some guidance as to what imaging tests are available, the oncologist providing some guidance as to what they might be looking for, and the radiation oncologist and the urologist being informed and being aware of what the possible options are with regards to treatment. So, I think it&rsquo;s a really helpful thing and it&rsquo;s hopefully where prostate cancer care is going all over the world.

The most critical thing in regards to multidisciplinary collaboration is communication and having regular meetings where we get a chance to talk about these patients, how they&rsquo;re doing, and also how each of our groups can assist the other. I think that is the most important part of coordinating care. I think having tumor boards as well as multidisciplinary case conferences where these more straightforward cases, but also the more difficult cases, are discussed is extremely helpful and will really help our patients.