PRRT and Y-90: Patient Selection, Treatment Decisions, and Upcoming Research

Peptide receptor radionuclide therapy (PRRT) is a potential therapy option for patients with metastatic neuroendocrine tumor, but questions remain about patient selection and treatment decisions in conjunction with arterial therapy, particularly Y-90. Dan Brown, MD, FSIR, an interventional radiologist from Vanderbilt University in Tennessee, spoke about PRRT and Y-90 at the 2019 Society for Interventional Radiology meeting in Austin, Texas. In the Q&A below, he answers more questions about treatment decisions with PRRT and different options for patients with short- versus long-term projected survival.

What is peptide receptor radionuclide therapy (PRRT) and which patients benefit the most from it?

PRRT is a systemically-administered radionuclide using lutetium-177, which targets somatostatin receptors. Metastases from neuroendocrine tumor often have somatostatin receptors, and the concept behind PRRT is that the agent goes to the Sandostatin receptors and treats the tumors effectively. The therapy is administered in 4 separate intravenous injections.

The NETTER-1 trial was a randomized controlled trial that was recently published in the New England Journal of Medicine and showed that the lutetium-177 improved overall survival and progression-free survival compared to monthly Sandostatin, which has been the gold standard for managing those patients.

A second study was published in the Journal of Clinical Oncology examining time to clinical decline. It appeared that the effects of the therapy would last for about two years before people started experiencing clinical symptoms again.

Y-90 has been used for neuroendocrine metastases for over a decade now, and it is quite effective. How do we decide which of these therapies would go first in people who have neuroendocrine tumors?  We need to understand how much radiation the liver can tolerate before being damaged by radiation from either PRRT or Y-90 or some combination of the two.

At our institution, medical oncologists are not using PRRT as first-line therapy. They tend to recommend it as a salvage therapy for patients who have a life expectancy of a couple of years but are unlikely to survive to experience any long-term radiation effects of PRRT.

What do we know about the long-term effects of treatment?

The effects of PRRT and Y-90 together are still largely unknown, though there were some small papers on long-term Y-90 consequences  in the last couple years. Ultimately, there can be imaging changes, but the amount of people going into clinical liver failure is very small. Northwestern had 154 patients undergo treatment. They followed those patients and found that there were only long-term complications in two patients, and those patients had treatment of the entire liver.

A paper from Oregon Health Sciences University looked at changes in liver function following Y90. The study involved a very small number of people who had been followed for four years. Results revealed some significant changes in liver function, but the absolute values in terms of serum changes were not tremendously concerning. Changes occur very slowly, so Y-90 should not be a problem for someone with a 1- or 2-year life expectancy.

Based on this finding, patients with high-grade and intermediate-grade neuroendocrine cancer will probably succumb to their disease before any changes from Y-90 would occur. The low-grade patients could live 10 to 12 years though, and we need to better understand how they may be affected when considering both Y90 and PRRT.

What do we currently know about how patients with low-grade cancer may be affected?

There are a few small papers, but we do not yet have good data. The University of Pennsylvania did a retrospective study with 17 patients who underwent PRRT after Y-90 or chemotherapy in bulk, and PRRT appeared to be relatively toxic in that setting. The most significant adverse effect was ascites, often with concomitant shrinkage of the liver, often in the setting of normal liver functions.

One of the confounding variables in evaluating liver toxicity is that patients frequently have progression of their disease, so  changes such as ascites could be related to metastatic disease or from systemic therapy used to treat the new tumors.  We still need to determine how to separate the treatment effect from the worsening of the disease in order to properly evaluate PRRT.

In your own practice, how are you approaching treatment decisions?

If a patient with neuroendocrine cancer potentially may receive PRRT in next few years, we are currently recommending chemoembolization as a bridge to limit the potential toxicity. This approach is not the definitive answer, but it is one way we are handling the question.

I also suggest that PRRT should not be a first option for low-grade patients because they are going to live longer than the benefits of the therapy. I’m concerned about future scenarios for patients who are treated with first-line PRRT and have disease progression in the liver. If we are assessing the case at tumor board and see declining liver functions, we may not be able to provide more help to that patient, either with Y90 or with chemoembolization.

If patients have many symptoms accompanied by other comorbidities, we focus on keeping them comfortable, and perhaps they will survive long enough to be treated with PRRT. We’ll still discuss treating such patients with Y-90 though.

Sometimes we’ll perform chemoembolization on a small piece of the liver to see how well the patient tolerates treatment. If the patient struggles, we can confer with the medical oncologist and say, “This was really hard for the patient. If she’s not going to get PRRT, why don’t we try Y-90 next so that she can recover more easily?” 

How long is the typical wait list for PRRT?

At our institution, the wait list is about 6 months, though I’ve heard of it being up to 2 years at other institutions. PRRT is resource-intensive. There are only so many resources available at centers where chemotherapy and other infusions also take place. We currently can treat only have 1 patient per day due to limited resources. After PRRT, patients need to be monitored closely in a separate room before they are released, because the radiation emission after the injection is high. Patients need to be below a certain threshold before they are released to go home.

Can you tell me about any upcoming research in this area? 

I’m in charge of a large registry run by Sirtex Medical. We have 1,300 patients enrolled, and this includes several hundred neuroendocrine patients. We are including patients who have had PRRT, and I think this approach will help us obtain more information.

Ultimately, I hope we can gain a clearer picture of the right course of action and the right patient selection. One of the questions I have about the NETTER trial, which was done well, is whether lower uptake in the liver is more likely to lead to liver damage. If the treatment is not necessarily going to the receptors with high affinity, then it’s going throughout the whole body, and some of it would end up in the normal liver. Is that a group of people that might be better treated with arterial delivery?  

Do you have any technical tips for IRs in centers that are performing PRRT?

PRRT is a complex procedure that is mostly being performed at academic centers, though there are some private practices offering it as well. Whether or not you are personally treating these patients, it’s crucial that IRs obtain the radiation records of patients who have had PRRT when considering Y90. We need to review the radiation records to ensure that we understand the total liver exposure and then treat the patients as safely as possible in any future procedures.

What do you want your colleagues to take away from this article?

The most important takeaway is that neuroendocrine tumors are complicated and there is no one answer that solves all the problems. Some people are going to live less than a year, but other people are going to live 15 years. My hope is that IRs can work with our clinical colleagues at different institutions to make the best decisions for patients. Reference

1. Strosberg J, El-Haddad G1, Wolin E, et al. Phase 3 Trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135.