PET/CT–Guided Postprostatectomy Salvage Radiotherapy for Prostate Cancer - Episode 2

Prostate Cancer: Clinical Implications From the EMPIRE-1 Trial


Drs Brian Helfand and Steven Finkelstein share key takeaways and clinical pearls from the phase 2/3 EMPIRE-1 trial for prostate cancer.

Steven Finkelstein, MD, FACRO: Welcome to this Cancer Network® discussion of today’s featured article. We’ll be talking about fluciclovine F 18 fluciclovine PET [positron emission tomography]/CT imaging vs conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer, EMPIRE-1, a single-center, open-label, phase 2/3 randomized controlled trial. I’m Steven Finkelstein at Florida Cancer Affiliates, US Oncology Network at Panama City, Florida. I’m joined by Brian Helfand at NorthShore University in Chicago, Illinois. We’ll be talking about this article and focusing on discussion where we’ll be going through these questions. We’ll start by talking about what are some of the key takeaways from this paper.

Brian Helfand, MD, PhD: To remind everyone, the results of this paper on the EMPIRE trial was performed at Emory University in Atlanta, Georgia, when fluciclovine PET/CT imaging was first coming into play. They had the foresight to see if the results of fluciclovine imaging added any additional value to further oncologic control, meaning that if we plan our subsequent radiotherapy for men who have had a biochemical progression or progression after radical prostatectomy, did fluciclovine influence that treatment plan? Did that treatment plan influence outcomes? What the papers ultimately showed was that yes, it did. At 3½ years’ follow-up, there was an absolute difference of about 12% of men, which is significantly greater. In multivariable analysis that was a 2-point over a 2-fold higher hazard ratio or likelihood that men who underwent fluciclovine were less likely to experience a disease progression following salvage or adjuvant radiotherapy. Importantly, this additional oncologic control, which was guided by the fluciclovine, did not offer or provide additional toxicities, meaning that men who underwent radiotherapy based on fluciclovine vs men who underwent radiotherapy, based on conventional imaging, did not experience increased urinary or bowel issues or other toxicities, suggesting that we got improved oncologic control but didn’t have worsened issues, toxicities following fluciclovine imaging. That’s really the takeaway point. Steven, as you previously pointed out, there are few if any imaging modalities that have led to improved oncologic control such as PET/CT imaging.

Steven Finkelstein, MD, FACRO: Yes. As we talk about some of the interesting questions, we have to think about the context this study was initiated in. In 2011 when this trial was initiated, the conventional way we approached trying to find prostate cancer when we felt that there was a recurrence was with technetium-99 bone scans. Technetium-99 bone scans were not approved because they could improve cancer outcome. They were approved for use based on the ability to detect disease, as most imaging agents are approved for an improvement in sensitivity, specificity, and ultimately maybe positive predicted value, negative predicted value. But this was a unique trial in which this agent had suggested an improved diagnostic accuracy against standard imaging like bone scan, CT, or MRI.

The investigators had the intestinal fortitude to structure a trial to try to improve upon cancer control outcome. In the context of postprostatectomy, rising PSA [prostate-specific antigen], could they change the radiation therapy fields? We could talk a little about how radiation therapy is delivered in the postprostatectomy salvage setting. In this setting, where people are doing conventional imaging, the patients who getting radiation and conventional imaging was determined by the individual investigators. Whether patients got radiotherapy to the prostate bed, or radiation therapy was going to be delivered to the prostate bed and to the pelvis, or radiation therapy was not to be delivered at all.

In that world that we live in, that’s based on conventional imaging. In this trial, in EMPIRE-1, for the first time they had a algorithmic approach based on the PET imaging. If there was extra-pelvic or skeletal uptake—disease outside what would have been a normal radiation therapy field—then no radiotherapy was given to the patients in this trial. They were excluded from the intent-to-treat analysis. If there was pelvic nodal uptake seen, then radiotherapy was delivered to the pelvis in doses that we would standardly give that’s between 45 and 50.4 gray and 1.8 gray fractions. Plus, they would get radiotherapy to the prostate bed in the typical doses of 64.8 to 70.2 gray and 1.8 gray fractions. If there was uptake in the prostate bed alone, then you’d radiate the prostate bed alone. That would be 64.8 to 70.2 gray. What if there was no uptake? You’d still do radiotherapy in this trial and radiate the prostate bed. It’s interesting to see that if you didn’t find uptake, which is pretty much what we classically do, we’d radiate the prostate bed alone. An algorithmic approach based on PET as the determining factor of what was to be treated. Brian, what do you think about that with respect to a radiation approach?

Brian Helfand, MD, PhD: It’s brilliant. Certainly having lived through the years and talked to many radiation oncologists whom I consider close colleagues and friends, a lot of times it was an overall gestalt. “I think we should do this. We’re going to try to justify it in some way.” Once we have a true system in place to stratify patients and then understand where that disease may be coming from, we’ll understand how it has changed the field. Here we see in a prospective fashion that it does influence the way that we can—our outcomes, at least the 12% advantage. That’s huge and very exciting. Ultimately in the same spirit, as you said, this came out and developed in the year 2011. That was very advanced for the time. In the short decade since, we now have improved our understanding of fluciclovine. Radiologists’ experience have also improved. Now we have even newer and some FDA-approved technologies, PSMA [prostate-specific membrane antigen] PET imaging. If those are more sensitive, we still don’t know, and how they react or influence we’re still unveiling, but that will add to this algorithm. Would you agree?

Steven Finkelstein, MD, FACRO: I would. Those are all excellent points. One of the things I occasionally hear is, ”You’re potentially expanding the areas that were radiated.” Is that a bad thing? Is that going to lead to increased toxicity? First let’s look: did we actually expand the volumes that we would’ve been treating? In the conventional group in this trial, 56 patients of 81 got prostate bed radiation alone; 25 got radiation to the bed plus an additional field to the pelvic nodes. What about the PET/CT group? Only 41 of 80 patients who were in the study group received prostate bed alone; 35 got radiation to the prostate bed and to the additional pelvic field. There was a larger radiation field delivered in this group of patients when you think about the 80 patients. But did they have more toxicity? When we think about the toxicity analysis, you look at the significant grade 3 or higher AEs [adverse events], and there was no difference between the toxicity between the conventional group and the PET group, even though the fields were large. This was extremely well tolerated. For those who may say ”You don’t want to do more radiation because more radiation is going to be more toxic,” this group was PET-driven radiation. It was larger fields in many patients. But the toxicity was not significantly higher. From a urology standpoint, is that something you think urologists will say “I’m excited that we can deliver targeted, PET-targeted radiotherapy and keep the toxicity about the same”?

Brian Helfand, MD, PhD: That’s important. I hope you’re not offended, but sometimes urologists have this impression that we live in a silo and a lot of the subsequent events are not necessarily recognized by the radiation oncologists. When we study and document it, it becomes very important. This is something that we can expand our fields, continue that collaboration, and have the patients come back and not worry that we’re giving them increased risk by irrigating their bladder out or sending them to GI [gastrointestinal] for coiling or control of their proctitis. This is very exciting for us because we can do all this without the toxicity, but improve oncologic control. One of the things and questions for you to comment on that I always get is, in the absence of a positive fluciclovine scan, if we can’t figure out where it’s coming from because the disease is presumably so small, why do we radiate anything? Or should we just wait until the PSA is higher and we can identify a target? I have my own answers, but it’s important to verbalize because I do get from a lot of urologists and oncologists the question of ”Why don’t we just wait?”

Steven Finkelstein, MD, FACRO: Yes, that’s an excellent point. I always bring up…that Willie Sutton is a famous bank robber. They said, “Willie, why did you rob banks?” He said “that’s where the money is.” Classically, when we didn’t know where a potential cancer recurrence was, we radiated where we thought the money was. If you radiate the prostate bed in 40% to 70% of the cases, then you’ll never have another problem from prostate cancer. But the question is, can you improve on that? If only half the time you’re right, could you use something to determine the places you needed to be radiating? Nationally, I’ve talked about this for the last decade. As we developed next-generation imaging, whether it was C11 or Axumin scans or now PSMA, the idea to find the targets and then radiate them is much more appealing than just “I’m going to radiate where the money potentially is,” because we’re only right half the time. As a surgeon who became a radiation oncologist, I was very attracted to the idea of next-generation imaging guiding this and EMPIRE-1 for the first time using a PET agent in a randomized fashion to determine these things. It does have its downsides. It’s a single-institution paper done at the place that developed the PET agent. Their acumen is obviously extremely high. Does this translate to the same effects in the community? We need to test that. In addition, there are other pieces of information, such as the uses of androgen deprivation. The use of this approach in a community setting will translate into the same improvements with the same toxicity outcomes. We don’t know. We can learn from this paper and try to think about employing this into our practices.

Brian Helfand, MD, PhD: What would you say about the types of radiotherapy employed here, or some of the newer, more stereotaxic-guided therapies? Is there a difference? Have we improved? Is that going to offer potentially yet even more improved oncologic outcomes?

Steven Finkelstein, MD, FACRO: Those are great questions for next steps. This has been a very algorithmic, classic approach, but the question is if you didn’t find the actual disease in the pelvis, could you not radiate those patients and wait? We don’t know but with the new next-generation imaging agents coming down the pike, I can see the next 10 years developing approaches where we start to stratify these things. For the first time, we can use a PET imaging agent, a next-generation agent, and have an improvement using radiation therapy to improve oncologic outcomes.

Brian Helfand, MD, PhD: Agreed. It’s very exciting. From the medical oncology perspective and androgen deprivation therapy, it becomes even more exciting and complex with newer androgen deprivation agents, androgen receptor inhibitors, and combined therapies to stratify who needs it and who doesn’t. Some of that decision is going to be based on the findings from many of these next-generation androgen scans, whether it’s Axumin, the fluciclovine as shown, PSMA, or a combination. There are many exciting questions that continue to arise, but will need to be addressed over the next upcoming years.

Steven Finkelstein, MD, FACRO: Thank you for joining us for this Cancer Network® presentation. We hope you’ve learned a lot from this paper on EMPIRE-1.

Transcript Edited for Clarity