Are We Ready to Change Management Based on Next-Generation Imaging? YES: APCCC 2022 Presentation - Jason Efstathiou

August 9, 2022

At the 2022 Advanced Prostate Cancer Consensus Conference, Jason Efstathiou presents why we are ready to change management based on next-generation imaging.

Biographies:

Jason Efstathiou, MD, Radiation Oncologist Professor of Radiation Oncology, Harvard Medical School, Vice-Chair, Faculty & Academic Affairs, and Director, Genitourinary Service, Department of Radiation Oncology, Clinical Co-Director, The Claire and John Bertucci Center for Genitourinary Cancers, Boston, MA


Read the Full Video Transcript

Neha Vapiwala: Now we'll move on to our debate, are we ready to change management based on next generation imaging, and to give the perspective from yes viewpoint is Dr. Jason Efstathiou you from Massachusetts General Hospital.

Jason Efstathiou: Thank you, Neha. Thank you, Aurelius, Silke. Phenomenal meeting. I'm arguing in the affirmative, and I'm ready to debate. I think we can all agree, we're living in a state of gizmo idolatry. We're beholden by our gizmos, and PET is our new gizmo. Many of us in the GU community felt like Jonah Hill, this includes physicians and patients, "Oh my God, oh my God." Giddy with anticipation for the arrival, especially if PSMA PET. And truly, a picture is worth a thousand words. There you see nothing, and on the right, you see it. Amazing.

You can apply PET imaging to Gartner's Hype Cycle. A technique is introduced, a celebrity is treated, it's the best thing since sliced bread, then you wouldn't give it to a dog. Eventually you figure out appropriate use. It's very hard to have a smooth adoption curve, so we just have to accept that. And indeed, the replacement of conventional imaging with PET imaging reminds me of IMRT replacing 3-D conformal radiation within a matter of 7 years. It just happened. And that was without a randomized controlled trial, and as I'm going to argue today, there's lots of data to support PET-based imaging.

So indeed, there is unmet clinical needs and prostate staging. Conventional imaging underestimates disease burden. We need more sensitive, specific imaging to inform, ideally, clinically relevant tumor burden to inform prognosis and treatment planning, and PET can help do that. It's highly sensitive for nodal and osseus metastases. We've seen good data for it to support that statement. It's useful in initial diagnosis and staging. It can guide targeted biopsies and find clinically significant disease. The proPSMA randomized trial proved that it has superior sensitivity and specificity compared to conventional imaging. So indeed, PSMA PET is a suitable replacement for conventional imaging in men with biopsy-proven, treatment naive prostate cancer, and it's FDA approved.

It changes upfront management. It helps us assess lymph node involvement to inform surgical planning. There is a caveat, though, there's only moderate sensitivity, so a negative PET doesn't rule out the presence of nodal met, so it doesn't mean you shouldn't do a lymph adenectomy, for example. Radiation is dependent on accurate localization of disease and adequate dose delivery to targets. And we have lots of data saying that PET leads to changes in radiation therapy planning, PET alters our radiation fields and plans in about 40-50% of cases.

PET is also useful in biochemical recurrence and the accurate localization of such recurrences is important to inform salvage therapies. In this setting, we've seen that it's highly accurate, and about 20-30% of patients will have at least one PSMA positive lesion that is not covered by consensus salvage radiation fields. Prospective studies have shown that clinicians change their management in about two-thirds of patients. Here's one of those studies with a very low PSA level, less than 1. 20% of PSMA lesions were outside of consensus CTVs, many of them extrapelvic. Here's another study showing nearly one-third of men had PSMA disease outside of standard radiation fields. And indeed, that just doesn't apply to PSMA PET.

The LOCATE trial showed this with fluciclovine in the biochemically recurrent setting. It showed that 60% of the time PET led to changes in management, and almost 80% of the time, those were major changes. Indeed, if we look in that study, the subset of patients that had salvage radiation after prostatectomy failure, 42% had fluciclovine avid lesions, 48% had a management change. It's changing management.

Not only is it better in terms of accuracy than conventional imaging, not only is it changing management, but it actually improves outcomes. Everyone has said, "There's no data to show improved outcomes." Well, look at this EMPIRE-1 phase II/III randomized trial of salvage radiation. The radiation design was directed by conventional imaging, and there was a randomization to getting a PET or not. If you got a PET, 3-year event-free survival was better, 75% versus 63%. It improved outcomes. Indeed, there's lots of future studies that will be randomizing between fluciclovine and PSMA PET and allowing dose escalation. The PATRON study, the INDICATE study, these are all looking at intensification of therapy based on PET-based imaging.

Now let's go to the oligometastatic setting. PET identifies oligometastatic disease also at initial diagnosis. In this UCSF study, PET detected N1 or M1 disease, PET only detected N1 or M1 disease, occurred 56% of the time. There's been the expansion of this oligometastatic disease state. It has grown. And indeed, if you look at oligometastatic prostate cancer patients undergoing metastasis-directed therapy using findings from PET imaging, they have improved outcomes. Look at the STOMP trial, a randomized trial. If you did metastasis directed therapy of the PET detected lesions, you improved ADT-free survival.

And if you go to the ORIOLE study, which was comparing SBRT, SABR versus observation, SABR improved progression at 6 months, we know that. So it improved progression-free survival as shown on this curve. It did so with no grade 3 or higher adverse events. But look at this in this ORIOLE study. In the SABR arm, total consolidation of all PSMA radiotracer-avid lesions improved progression-free survival. Not only that, total consolidation decreased the incidence of new metastases, look at those numbers, very significantly. So, total consolidation improved distant met-free survival.

Lots of future studies looking at intensifying SABR by adding on things like radium. There's also studies looking at the de novo oligometastatic setting, and with definitive radiation adding on SABR to sites of PET avid disease. And there's even a study looking at, if you do SABR with hormone therapy, do you still need to treat whole pelvic radiation, or can you just do SABR with hormone therapy? Lots of studies to look forward to.

Lastly, what about in theranostics. Lutetium PSMA targeting radioligand therapy is effective targeted therapy for metastatic castrate-resistant prostate cancer. We know that from the TheraP trial, the VISION trial, and lutetium is now being evaluated with all kinds of other systemic agents. But PSMA PET may serve as a useful biomarker to predict response to lutetium therapy, with high PET uptake correlating with longer survival, perhaps. We need more study of this and looking at which patients are most likely to respond to lutetium-based therapy when looking at pretherapeutic PET imaging and how disease burden might affect dosing.

In conclusion, I hope I've shown that there is a clinical unmet need for better imaging, PET can help with this. Many studies demonstrate superior diagnostic accuracy of PET compared to conventional imaging. PET imaging certainly changes clinical decision making, it leads to management changes, and it personalizes therapy. PET integrated into radiation decision making, planning, significantly improved biochemical event-free survival in the EMPIRE trial, and consolidation of oligometastatic PET avid lesions with metastasis-directed therapy improves ADT-free, survival progression-free survival, even metastasis-free survival. Do you know how hard it is to have an imaging study with these kinds of survival endpoints? This never happened. It never happened for MRI, it never happened for CT, ultrasound. This is incredible data. As such, we are ready. Not only are we ready, we have already changed management based on PET imaging, and you're going to see that in the consensus questions that are going to be presented today.

The stage is really set for wide-spread use of PSMA PET. It's becoming the standard of care for imaging in prostate cancer. It is disruptive and transformative. That, of course, doesn't say we have all the data we need. We need a lot of things.

We need more perspective studies with integrated imaging correlates. Ideally, we need to have more randomized trials proving long-term clinical benefits. But recruitment to those studies are going to become near impossible, certainly very challenging, if it's becoming the standard of care. We need to reconcile PET findings with trial eligibility study endpoints and systemic therapy indications. We have to interpret prior therapeutic trials in a post-PSMA PET setting. We have to explore PET as a biomarker to predict therapy response in select patients. We have to reconcile PET findings with other biomarkers, such as genomic classifiers, Dr. Feng will be talking about genomic classifiers later in the meeting. We have to explore artificial intelligence and radiomics-based machine learning analysis of PET metrics to further predict disease features. And we have to really promote standardized imaging interpretation and reporting guidelines. There's a lot that we need to do, but that doesn't mean we aren't ready to change management. Thank you.