Conversations With Prostate Cancer Experts

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Imaging In Community Practices

Dr. Rodney J Ellis is a Professor of Radiation Oncology at the University Hospitals of Cleveland and a radiation oncologist at Case Comprehensive Cancer Center.

He spoke with Prostatepedia about how prostate cancer imaging is used in community settings and how it is impacting patient care.

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Prostatepedia: Why did you become a doctor?

Dr. Ellis: I was seven when I told my parents I was going to be a physician when I grew up. They said, “Oh, Rod that’ll be really nice.” No one else in my family had gone to college, so they didn’t really expect that it was likely to happen.

I thought it was cool that my family doctor, who delivered my brother and me, had his wife in his office; they ran the office together. I thought that’d be really nice to work with my wife and run our own business.

Once I got to medical school, I realized that doctors do a lot of work that’s controlled by the insurance companies, and I became less enamored with primary care medicine. When my grandfather and an uncle developed cancer, I became more interested in oncology. It made me focus on how cancer impacts families. I had an opportunity to do a rotation in radiation oncology and met the mentor who taught me so much, which changed what I wanted to do in life.

That’s how I ended up in radiation oncology, initially working with monoclonal antibodies to image cancer and direct where you place radiation, either in the operating room with brachytherapy or intraoperative radiotherapy.

Over the last 20 years, as the field has blossomed, we’ve developed even better techniques for dose painting and giving high doses in regions. Largely, that’s been the focus of my academic career.

Have you had any patients who stood out in your mind as having changed either how you see your role as a doctor or how you practice the art of medicine?

Dr. Ellis: Yes, especially since advanced imaging has come out and over the 20 years that I’ve been doing it. Sometimes, when I see a patient in long-term follow-ups, I think, “Wow, the advanced imaging we used actually predicted death from prostate cancer the day I saw him, but I just didn’t know it those ten years ago.”

When I look at the new imaging today and how it’s changing what we’re doing, I think we’re truly personalizing medicine.

I’ve seen numerous patients where I could determine whether their cancer was curable based on an image. If it is curable, does it change how you may image that patient? More often than not it may. For maybe one in three cases, it does nothing for you. You do the image, and the good news is it didn’t show any spread of disease. The bad news is it didn’t show any localization of the disease either. The test didn’t really help us; it just didn’t resolve the questions we had. For about two-thirds of my patients, it adds to their care. New data from ASTRO this last week shows in the Locate trial that even negative studies may have significant changes though, such as staying in surveillance versus aggressive local therapy if a study is negative.

What kinds of imaging studies do you use currently with your patients?

Dr. Ellis: I use standard imaging, whether that’s bone scan, CT scan, or MRI. We’ve been very image-based in our approach to treat prostatecancer for many years. Currently, we use a lot of MR-based imaging and the functional imaging of MRI to look at these within the prostate gland. The dilemma for patients is whether there is any disease outside of the prostate gland. Much of the literature that I’ve published over the last two decades worked with the previous imaging agent that was FDA-approved for looking for spread of prostate cancer called ProstaScint. We’ve published on that with ten-year data showing that it was able to predict deaths from prostate cancer. It was useful for helping to select where to give higher doses within the prostate gland, when giving radiation to improve cure rates. That’s been largely improved upon with newer imaging agents, both the Axumin PET scan that is currently FDA-approved and the C-11 Choline that’s available at Mayo Clinic.

Worldwide, there’s a lot of interest in PSMA-based PET imaging. That is the same molecule that ProstaScint looked at years ago, only now the marker is looking on the surface of the cell rather than on the cytoplasmic, or internal surface, of the cell. This has greatly improved the PET agent over the previous generation products.

What are some of the limitations that you face?

Dr. Ellis: Prostate cancer is non-uniform. All the cells are not going to be alike. They’re going to metastasize or develop different traits at different times. We can image some cells nowadays with Axumin PET. That looks at the synthetic amino acid that gets picked up more commonly by prostate cancer, but it may be applicable for some other cancers as well.

On the other hand, some cancers express PSMA, and may show up with a PSMA-based PET. Not all cancers show up with one or both, so we don’t know which agent is best for which particular patient.

The biggest limitation right now is that the only one that’s FDAapproved is Axumin PET. As a member of the National Comprehensive Cancer Network (NCCN) Prostate Board, I’ve looked at it and made recommendations to add that for standard imaging. The board has also made recommendations that, as newer agents come out, they should be considered as well.

How are these newer imaging studies impacting treatment?

Dr. Ellis: Well, I can give a great example. We had an add-on patient today who had been treated with hyperthermia in Germany, which progressed locally. We had treated him with proton therapy into the prostate, and for a while, he had responded to therapy, but his PSA had started rising.

Today, he came in for follow-up, and we did an Axumin PET this morning. I’m waiting for the results to be read by the radiologist. But on my review, it looks like he’s got a solitary metastatic focus that lights up in the right chest, adjacent to his airway. The question now is what to do in that setting. If you’ve got one site of metastatic disease that’s a clear distance from the prostate, the standard of care is to go on to hormonal therapy and give additional agents either orally or systemically for metastatic prostate cancer.

One of the opportunities these new agents may open up for us is to treat limited metastatic disease—or oligometastatic disease, which means that mets are present in only one, two, or a few sites—with radiation or other techniques to ablate that tissue and potentially prolong life for those patients.

Are these newer imaging studies, such as Axumin PET, available in every community?

Dr. Ellis: I think that Blue Earth, the company that’s been promoting that agent, is doing a great job of getting it out further into the community. The limitation with most nuclear medicine studies is the half-life of the agent. In other words, from the time you make it to the time you use it, it decays. The second it’s made, its half-life is in minutes, so it can only be used locally in the facility where it’s made. In Axumin’s case, it’s about three hours from the time before it becomes too weak to use in imaging.

They’ve got to start producing it in more areas and be able to get everyone who needs the image within a three-hour radius. The reality is that they may never be able to reach everywhere in the United States with that kind of a radius.

Well until that happens, do a lot of patients travel to you or other locations in the United States to get the scan? Are they coming on their own, or are they being referred by their doctors?

Dr. Ellis: It’s a little bit of both. It’s a fairly new agent, so I don’t think there’s a lot of patients who are aware of it yet. I’m a member of their speakers’ bureau, so I’ve got a bias. I can be honest and say yes, I’ve been working with the company to promote and let people know about it. They are still getting the word out, so a lot of patients don’t know about it yet.

I have started to see patients come specifically to ask if we do the test. I don’t know how many are coming directly to me versus how many are coming to our nuclear medicine department, where the test is done, but we are certainly using it much more frequently today than we were using previous imaging studies.

What about the doctors? Are they routinely referring patients to you? Is there any trouble finding people who can read the results of these scans?

Dr. Ellis: Urologists, the primary caretakers for many of these patients, are becoming acutely aware of all the data that’s coming up worldwide on PSMA-based imaging with PET scan. They’re interested in nuclear medicine scans and cutting edge technologies to image their patients. What people aren’t really sure of is what to do with that information yet, so there’s more work that needs to be done to categorize the patients for the appropriate treatment.

Medical oncologists are starting to become aware now; certainly, the radiation oncologist is aware. Yes, there’s more work to be done teaching the physicians.

So, we’re gathering more information, but we’re still not sure what to do with that information?

Dr. Ellis: Right. And we’re not sure whether it’ll impact every patient, that’s the problem. Is it going to be useful for every patient? Of course not. Will it change it in a large majority of patients so it becomes clinically significant? We think so. Right now, it’s only FDA-approved in patients that have had prior therapy. They have had prior radiation, surgery, or systemic therapy, and we have a reason to think that the therapy failed. Then, you image them.

But it is even more interesting to know, in the patient who is newly diagnosed, will these agents be used to help us see exactly where the cancer is located and to make a decision between surgery or radiation, and whether they will be used to make a decision about where to radiate.

Are there any studies now looking at Axumin PET in newly diagnosed patients?

Dr. Ellis: I believe the company is certainly interested in investigational studies in answer to that question. I would have to defer to them about which studies are currently open and active.

Do you still educate patients about imaging studies?

Dr. Ellis: That is a huge part of what I do. And the best way to do that is publications. Publications get out there, and they don’t go away. People read them, and they learn about these studies from trusted sources. But until publications can get done, going out and doing person-to-person education or webinars are other ways to get the word out.

Do many patients ask about imaging studies, or is it something that you tell them about?

Dr. Ellis: Both. I think there’s an educated group of patients out there now, more so than 20 years ago, when I started my practice. It’s probably information from the internet. Everyone has access to the internet. If you search for prostate cancer and start spending some time, you’ll come across the imaging data. They bring those questions in.

If you look at the changes in diagnostic medicine, imaging, and genomics, we have all this new information, but we’re still grappling with what to do with it and what it means.

Dr. Ellis: Yes. We’re wrestling with all the information that’s coming and how to best assimilate all that information for an individual patient.

Do you have any last thoughts about imaging studies, either for people newly diagnosed or facing recurrence?

Dr. Ellis: I would like to see more people lobby to get advanced imaging approved for newly diagnosed patients. Unfortunately, many of those patients don’t have access to it, and I’d like to see the people who are doing clinical research present their data to help support that, if there is emerging data to do so.

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Dr. Thomas Hope: New Directions in Prostate Cancer Imaging

Thomas Hope, MD, of UCSF and the San Francisco Veterans Affairs Medical Center, is keenly interested in novel imaging agents and therapies for prostate cancer and neuroendocrine tumors.

Prostatepedia spoke to him about novel imaging for prostate cancer.

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What are some of the newer imaging techniques available across the globe? How do they work, and when are they used?

Dr. Hope: I do a lot of radiopharmaceutical imaging. We inject radioactivity into people, and then we image it with a positron emission tomography (PET) scanner to locate where the radioactivity has gone. We label these small molecules (proteins) with the radioactivity and use those proteins to target different places in the body. In this case, we try to figure out where prostate cancer is.

There’s been a whole host of developments over the past 20 years of increasingly improved detection strategies for prostate cancer. The old-school fluorodeoxyglucose (FDG) PET imaging technique has been around for 30 years in the United States, and they have used sodium fluoride worldwide for just as long. For bone imaging, sodium fluoride can tell you where obvious metastatic bone disease is. FDG is actually the stable for the majority of PET/ CT imaging we do in the world, but it’s used primarily for other cancer types that are hypermetabolic or use a lot of glucose. When prostate cancer is in the earlier stages, it typically does not use a lot of glucose.

There’s been this hole in prostate cancer treatment for patients with biochemical recurrence. These are patients who have undergone definitive therapy and have a rising PSA. Neither of those two imaging modalities really help them. But a couple of new agents have been developed.

Choline-based agents, such as fluorocholine and C-11 choline, have been used in the United States and Europe. The Mayo Clinic brought choline C-11 to market in the US. Those radiotracers are certainly better than FDG PET or sodium fluoride PET in localizing particularly soft-tissue metastases, but they fail at lower PSA values.

When your PSA gets below one, you really don’t see much disease, and the studies are also quite difficult to interpret. The next imaging agent, is Axumin (fluciclovine). Fluciclovine is another amino acid tracer, just like C-11 choline, that’s used in biochemical recurrence. It was FDA-approved two years ago and has been used fairly frequently with biochemical recurrence. It’s probably, in my mind, equivalent to choline imaging. Fluciclovine itself is not really used outside of the United States because, if you have the availability of other radiotracers, you wouldn’t use fluciclovine. Yet in the United States, fluciclovine has become the mainstay because it is reimbursed by Medicare and readily available. Prostate specific membrane antigen (PSMA) compounds have been developed by a number of groups and companies over about ten years. The big change came with the gallium PSMA-11 compound, which is a small molecule that was first developed at the University of Heidelberg in Germany. Gallium PSMA 11 is a unique compound in that it wasn’t patented. No company controlled it, and so any site that wanted to use it could just sign up and get the precursor delivered to them. Very quickly, a large number of sites around the world started using PSMA-11 to image patients with prostate cancer. It is not approved in many counties, although technically, it is approved in Switzerland and Israel. Outside those countries, it is used on a compassionate-use basis. In the United States, it is being used under Investigational New Drug (IND) authorization from the FDA. The fact that it was so quickly adopted and widely used led to a huge number of articles in the literature.

In addition to PSMA-11, there is a whole host of other PSMA compounds. Gallium PSMA-R2 is being developed by AAA, DCFPyL is being developed by Progenics, PSMA-1007 is being developed by ABX Chem. There is a whole family of PSMA compounds coming to market on the back of the experience of PSMA-11. There are questions as to which is better, and although there is not a lot of head-to-head literature published, it’s fairly clear that PSMA 11 is better than, for example, the choline radiotracers and fluciclovine. The question is: how do these other PSMA tracers rate against one another? In my mind, they’re much better overall as a class, but I’m not sure there is a huge difference between them in terms of detection activity. We’ll find more about that as things progress.

You said the PSMA compound is widely available because it was not under the auspices of a specific company but that it is not approved everywhere. Does that mean that patients can get access to it, but it is not necessarily covered by their insurance?

Dr. Hope: You have to go country by country, so it gets complicated. In the United States, for example,

PSMA-11 is not owned by a company, and there’s no company paying for clinical trials. Centers like ours are running trials through Investigational New Drug (IND) authorization, which means it’s being studied in clinical trial aiming to get FDA approval. In the United States, everything is done under a clinical trial. There are a couple of methods to pay for the studies. There are a few insurance companies that will pay for these imaging studies under a trial setting. But I would say that the majority do not, and patients end up having to pay out of pocket.

The FDA allows you to use a cost recovery mechanism if you are acquiring data to eventually support an NDA application, and that’s how the majority of these studies are paid for. There are other institutions that use research funds in order to have a small number of studies performed. The two major institutions in the United States are UCSF and UCLA, and each uses cost recovery mechanisms and billing patients’ insurance companies directly in order to perform the study.

Are the studies expensive?

Dr. Hope: Yes. I would say they range between $3,000 to $5,000 apiece, so they’re quite expensive. There is clearly an ethical dilemma in having patients pay for an imaging study that’s not FDA-approved. What do you do with that? I think it is a reasonable approach as long as the institutions are actually using that data in the way that they state they are, which means that it’s up to us to use the data to get the agent approved. If the data isn’t used productively to get the drug approved so that insurance companies will pay for it, then I have an issue with the ethical aspect of it. As long as I’m doing the work, then it may be reasonable, although different people might disagree.

I’m sure there is a wide range of opinions.

Dr. Hope: There’s no right answer. For example, two weeks ago, we went to the FDA for our pre- NDA meeting and presented all of our data, which we are doing in collaboration with UCLA. The FDA was very positive and said that we had enough clinical data to support an NDA application, which is pretty exciting. Hopefully, we can get the drug approved within the next 6 to 12 months.

How have these newer imaging techniques impacted how we treated prostate cancer? We’re detecting smaller and smaller amounts of cancer earlier and earlier. What do we do with that information? How is it changing how we treat patients?

Dr. Hope: These newer techniques are changing current patient care. But is that actually improving the outcome? For example, if you have a low PSA, and your PSA is 0.2 after radical prostatectomy, the standard treatment is to radiate the prostate bed and maybe the pelvic nodes. Now you get a PSMA PET, and it shows a node somewhere over here. So, now the radiation oncologist zaps that PSMA-positive node. Everyone thinks we did a good job, and maybe we did. But we just don’t know.

What we don’t understand fully is whether or not PSMA PET is the tip of the iceberg. If you have a PSMA positive node, are there many nodes we do not see, or does it mean that those nodes are the extent of the patient’s disease, which we can potentially cure if we hit it? Right now, the care is changed in maybe over 50 percent of patients who get a PSMA PET, but whether that change in care or treatment planning has improved outcomes, no one has a handle on that yet. There are some clinical trials starting that use varying radiotracers. The question in the community is: how does PSMA PET impact this care, and does that change improve the outcome of the patient who we’re imaging?

Is it just a matter of time before we answer this question?

Dr. Hope: Yes, but it is not that straightforward. You cannot take a cohort of patients who got PSMA PETs, check what happens to them, and conclude that things got better. You have to do it in a trial setting with a cohort of patients who do not get PSMA PETs and a cohort who did, and see if there’s a difference between the two. Otherwise, there are a lot of biases if you have a one arm study. You cannot tell if the patients have improved outcomes for other reasons or even how you compare the data. You really do need a randomized trial in order to demonstrate this improvement in outcomes.

That will come, but those trials will take a very long time to perform. These drugs will all be approved well before the length of time that these trials take to perform. This becomes a big issue. If you have an imaging agent, and we all believe it’s better than the previously existing ones, how do you randomize patients to not get it once it is FDA-approved? We are going to face difficulty showing that PSMA PET improves patient outcomes because we are going to be bottlenecked based on the availability of agents in the near future.

That’s an interesting position to be in.

Dr. Hope: It has happened in imaging over the years. Take sodium fluoride PET, which was never approved. It was grandfathered into FDA approval. No one ever did any clinical trials showing impact and outcome, and that is why Medicare has chosen not to reimburse sodium fluoride PET CT. This has happened over and over again.

It is mainly because imaging trials are unique. Drug trials must have outcome benefits as the endpoint in order to obtain approval. Imaging trials only need to show that we saw something we thought we would see. For example: “I think there is prostate cancer, I looked at a cohort of patients, I biopsied them, and the biopsies came back as prostate cancer. Therefore, this imaging study is good.” But that doesn’t work in a therapy world. Therapy data is a lot stronger.

Do you have any thoughts for men considering travel to get one of these newer imaging techniques or participating in a clinical trial if it’s not available in their community?

Dr. Hope: That is a hard position to be in right now. Think about it in a different setting. Let’s say you were at your institution, and you were thinking about participating in a clinical trial for an investigational therapeutic agent. Most men would not travel too far outside their institution for that therapy. With PSMA PET, patients are traveling all across the country for this agent and paying out of pocket for it. It’s an unusual circumstance. Two years ago, it would not have occurred to people to do this.

I think in the United States, you have to think about the cost and the marginal benefit. It really depends on your PSA. It depends on discussions with your oncologist or urologist in terms of where you are and what type of therapies you are thinking of. Outside of imaging studies, there are therapeutic aspects of PSMA targeted radionuclide therapy. That becomes a much bigger issue. Outside of the United States, the vast majority of sites that offer it do so outside of trial settings.

There are potential huge ethical issues with doing that. Sites are treating patients with therapies that have significant toxicities, and that data is not being collected prospectively, is not being reported, and the trial is not being done in a way that will lead to data that will help us determine what to do with patients moving forward. Centers should run clinical trials and publish results so that we learn, but there’s a large number of centers around the world offering some of these agents out there to treat patients with limited to no follow-up.

It’s really important that, if we’re going to treat patients with a non-approved drug, the trial or the setting where it’s administered does so in a way that leads to actionable, usable information for the community at large, and not just the individual institution or patient.

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Should You Travel For Prostate Cancer Imaging?

This month, Prostatepedia is talking about newer imaging techniques for prostate cancer. As our ability to image prostate cancer becomes ever more precise, controversy over what to do with this newer information is coming to the forefront. Also at stake are whether or not American insurance companies will pay for newer scans. When a man’s insurance doesn’t cover an imaging study, many patients with the financial means are paying for the scans themselves and often traveling to sites within and outside of the United States.

When your PSA begins to rise after initial treatment, you have what is called a biochemical recurrence. If you’re scanned with one of these newer imaging techniques—the Gallium-68 PSMA, for example—and discover 1 or 2 spots of metastases, you have what is called oligometastatic disease.

Prostate cancer experts are divided on how to treat men with only a few metastases. Traveling—and paying out of pocket—for a scan when doctors are still grappling over what to do with any information such a scan would reveal—may not be the wises course of action. Unless, of course, you understand that the scan results may just be interesting information for you and your doctor to consider and will not necessarily change your course of treatment immediately.

Drs. Thomas Hope and Stefano Fanti help us place PSMA imaging and the controversies mentioned above within the context of conventional prostate cancer imaging and treatment. Dr. Fanti’s offers us the European perspective: imaging has been more widely available in the United Kingdom and continental Europe. Many Americans are now traveling to these countries to obtain newer imaging studies. Dr. Nina Tunariu, of the United Kingdom, talks about whole body MRI as a way of staging prostate cancer. She also offers a note of caution for Americans traveling abroad for scanning.

Dr. Rodney Ellis talks about how newer imaging techniques are changing the treatment landscape at the community level. UsToo offers the support group network and patient advocacy’s view of how imaging impacts prostate cancer diagnosis, staging, and treatment.

And finally, Mr. John Moore talks about his prostate cancer journey and the experience of traveling from his home in North Carolina to California for imaging studies.

The bottom line is that more information is always useful. Newer imaging techniques are detecting cancer in smaller and smaller amounts. How to treat these small amounts of cancer is still under debate, especially since the side effects of prostate cancer treatment can be particularly difficult for many men. If you have the means to obtain a newer scan, do so: but understand that there are controversies over the meaning of their results within the global prostate cancer community. A frank and open discussion with your doctor about what you’ll do with any information you learn before you get scanned is the wisest course of action.

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Imaging Prostate Cancer

In November, we’re talking about imaging prostate cancer.


Dr. Snuffy Myers frames this month’s discussion for us.

Our ability to image prostate cancer metastases has improved dramatically over the past few years. CT and bone scans, which have been the standards for decades, typically image a cancer mass larger than 1 cm (0.4 inches). Newer imaging techniques have lower limits that approach 1-4 mm. Dramatic changes like these have a way of disrupting the status quo.

The current guidelines for the treatment of metastatic prostate cancer are based on clinical trials where metastases were detected with CT or bone scans. Do these treatment guidelines still hold for metastases too small to be found by CT or bone scan, but detectable with the newer, more sensitive imaging techniques? There are reasons to suspect we might begin to detect prostate cancer at a different stage in its evolution.

The concept of cancer dormancy is commonly used to explain a long interval between initial treatment with surgery or radiation and subsequent appearance of metastatic disease. For both breast and prostate cancers, more than 10 years can pass between treatment with curative intent and the appearance of detectable metastatic disease.

Several mechanisms have been identified that can lead to cancer dormancy. Two of these mechanisms might result in cancer masses potentially detectable by the newer imaging techniques. First, cancer dormancy can result when the cancer mass fails to attract a blood supply and thus is starved of both oxygen and food. The second is that cancer dormancy can result from ongoing immune attack on the cancer. Both mechanisms can allow cancer masses above 1 mm that overlap with the lower limit of the newer scans.

Cancer dormancy is associated with greater resistance to cytotoxic chemotherapy and hormonal therapy. The implication is that we may increasingly detect prostate cancer metastases that pose no immediate threat to the patient because they are dormant. Additionally, these metastases may respond poorly to standard treatment options. All of these factors would argue for caution in making treatment decisions based on the newer generation of scans.

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