<p>Researchers are exploring alternative radionuclides and novel approaches to help patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). At the <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong>, several speakers highlighted research aiming to further optimize and individualize PRRT during a joint SNMMI and North American Neuroendocrine Tumor Society (NANETS) session on theranostics in NETs.</p> <p><br></p> <p><em>Following these presentations, featured expert Daniel M. Halperin, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Halperin on these findings are presented here.</em></p>

Experts in different areas of the world have different degrees of reliance on dosimetry for ¹⁷⁷Lu-dotatate. In the United States, it is commonly given as a flat dose and is not in any way adjusted based on dosimetry. And, for me, a key takeaway from the “Theranostics in NETs – Joint SNMMI and NANETS Session” at the 2025 SNMMI Annual Meeting was that, while we can think about ways in which dosing and administration might be adjusted for efficacy or for toxicity risk, we do not yet have any high-level evidence that tells us that we should do this or even how, specifically, we might do this.

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In the presentation, “Progress Toward Meeting the Evidentiary Standard for Dosimetry-Guided PRRT,” by Stephen A. Graves, PhD, DABR, during the joint session, we saw a case-based illustration of radionuclide administration with a discussion of the cumulative dose to the kidneys and its potential to induce nephrotoxicity. It is known that there are certain limits to how much of an aggregate dose of radiation that organs such as the kidneys can safely receive. The bone marrow is a major consideration as well.

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One of the things that I have been trying to learn more about lately is how the dose measurements may not be exactly the same as the true dose that is absorbed from one radionuclide to another, even though the measurements may be the same. ⁹⁰Y and ¹⁷⁷Lu are the classic examples of differences in particle energy, range, and other characteristics leading to differences in actual toxicity to specific target organs. In that respect, I think that the simple fact that ⁹⁰Y is likely to have a higher rate of nephrotoxicity than ¹⁷⁷Lu at equivalent aggregate kidney doses tells us that we cannot cleanly and simply extrapolate across radiation sources. There can be a big gap between what we might measure and what the measurement might mean (eg, for a specific organ).

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We did see schemas for dose escalation studies in the presentation by Dr Graves, and there is interest in potentially achieving greater efficacy through dose escalation. Moreover, in observational analyses involving patients with GEP-NETs, we saw dose-response relationships. We generally agree that if we radiate enough in total, that should kill cancer cells. However, I think that the jury is still deliberating on what exactly to do for an individual patient.

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I have seen experts at different institutions apply different measurement strategies, and much of it is currently research oriented, more so than guiding standard management. There may also be different practice styles of individual clinicians involved, and there can be robust debates about whether and how we should be performing dosimetry. One school of thought is that there is no point in doing the measurements when it would not lead to a different course of action for the patient. Another is that dosimetry should be performed with every dose.

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How different radionuclides may differ in their radiotoxicity profiles is also an interesting question. Acknowledging my own involvement in work on targeted alpha-particle therapy, I think that we can hypothesize that the radiobiology might one day prove to have significant clinical implications (for example, that the very high linear energy transfer of alpha particles should be better able to cause double-strand breaks, leading to greater lethality in tumor and adjacent cells, resulting in lower rates of bystander cells that survive to accumulate mutations). And that makes me wonder whether the myelotoxicity could be lower with targeted alpha-particle therapy. I need to emphasize that I have absolutely no evidence to assert that this hypothesis is true, but such a thought experiment makes me wonder whether there could be important differences between radionuclides in this regard.

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During his presentation at the 2025 SNMMI Annual Meeting, Dr Graves noted the need for level I evidence in personalized dosimetry. When looking back over decades of data, one of the remarkable things in the neuroendocrine field is that there was a period of years after the US Food and Drug Administration (FDA) approval of octreotide in the late 1980s until the evidence base started to pick up again in the late 2000s. I think that this was, at least in part, because of the belief that the right clinical trials could not be done. But when people worked together and did the hard work of figuring out how to run randomized trials across centers, those studies began to have meaning. It was not easy, but that is what led to a cascade of high-level evidence for systemic therapy.

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One of the concluding points from the presentation by Dr Graves was that a single positive randomized clinical trial might catalyze additional advancements and lead to the implementation of a new paradigm. It really does sometimes take just 1, or perhaps 2, successful randomized clinical trial(s) to complete and give an answer for people to really be willing to invest in a new approach.