Can PRRT Be Made More Effective Against NET Liver Metastases? An interesting hybrid approach using 177Lu-DOTATATE

Researchers and clinicians are actively exploring multiple strategies to enhance Peptide Receptor Radionuclide Therapy (PRRT) and make it more effective and personalised for neuroendocrine tumour (NET) patients. Key areas of improvement currently being studied include:

Moving PRRT Earlier in Treatment

Novel Radioisotopes and Radiosensitizers: Scientists are investigating alternative radioisotopes with different particle ranges and emission profiles (such as Terbium-161 and alpha-emitters like Actinium-225) alongside targeted radiosensitizers and PARP inhibitors to help sensitize cancer cells and expand treatment to patients with lower somatostatin receptor expression.

Advanced Imaging and Radiomics: Studies are utilizing multi-lesion PET/CT imaging and radiomic feature analysis to better predict individual patient response, account for tumor heterogeneity, and tailor dosing more accurately.

But I wanted to talk about the latest initiative based on a small trial involving a ‘hybrid’ approach to delivering the payload to different areas making it even more targeted. Keep reading ….

Background

Many neuroendocrine cancer patients will already be familiar with peptide receptor radionuclide therapy (PRRT), particularly 177Lu-DOTATATE (Lutathera). But could an established PRRT treatment be made more effective against liver-dominant NET metastases simply by changing how some of it is delivered? That’s the interesting question behind a study from Memorial Sloan Kettering Cancer Center (MSK) in New York. The study is particularly noteworthy because the research team includes Professor Lisa Bodei, a name that will be familiar to many people who follow PRRT and theranostics research.

Standard 177Lu-DOTATATE PRRT is administered intravenously where it has a systemic effect. The radiopharmaceutical circulates around the body and binds to somatostatin receptors expressed by NET cells. This systemic delivery is one of PRRT’s major advantages because it allows treatment to reach receptor-positive disease at multiple sites. But some patients have a particularly heavy burden of metastatic disease in the liver. The MSK investigators wanted to determine whether they could increase the radiation delivered specifically to those liver metastases without giving up the whole-body treatment provided by intravenous PRRT.

Their answer was a hybrid approach.

The investigators tested a different strategy of using different therapy routes to deliver the Lutathera. One via via an intra-arterial route (direct into the hepatic artery) where it would go direct to the liver; and the other the conventional route using an arm catheter where it is given systemically. Importantly, activity during the intra-arterial treatment was adjusted according to the volume being targeted.

This was spread across all four cycles with the first two cycles of 177Lu-DOTATATE directly through the arteries supplying the liver, then give the remaining two cycles in the conventional intravenous way.

The results are preliminary, and this was a very small study involving only 10 patients. Nevertheless, the findings are interesting and may lead to further studies.

The idea of using PRRT intra-arterial route is not new – I once wrote about a study from Netherlands in 2019 where this has been done (although I cannot see any results from that). Click here to read about that trial.

Did more radiation actually reach the liver metastases?

Dosimetry indicated that intraarterial administration during the first cycle delivered more than three times the radiation dose to liver metastases compared with intravenous administration during cycle three. Imaging with 68Ga-DOTATATE PET also showed an 86% increase in median uptake within liver lesions following intraarterial administration. In very simple terms, delivering 177Lu-DOTATATE through the hepatic arteries resulted in substantially more of the radiopharmaceutical reaching the liver metastases.

What about tumour response?

The early response figures were also encouraging. At the first follow-up, three months after completion of treatment, 67% of evaluable patients had achieved a partial response. At the second follow-up, six months after treatment, the reported partial-response rate was 87%, according to the study’s response assessments.

But …….. There were only 10 patients.

And ……there was no randomised comparison against another group receiving four cycles of conventional intravenous PRRT.

Consequently, it’s not safe to assume we can take an 87% response figure from this small study and assume that the same result would occur in the wider NET population. Nor does it establish that hybrid intraarterial/intravenous PRRT is superior to conventional PRRT. The researchers themselves point out an important nuances e.g. The comparison was between intraarterial cycle 1 and intravenous cycle 3. By cycle three, the tumours had already been exposed to treatment, so an interim treatment response might have influenced the subsequent comparison. In other words, even that impressive >3-fold figure needs to be interpreted carefully.

What it does provide, however, is an intriguing early clinical signal that may be worthy of exploring further.

Was it safe?

The researchers reported that intraarterial administration was technically feasible in all 10 patients. Radiation exposure to patients and staff remained within regulatory limits and there were no reported contamination events. The treatment regimen was generally well tolerated.

Again, however, 10 patients is far too small a group to establish the complete safety profile of a treatment strategy, larger studies would be required.

Why is this of interest?

There’s understandably enormous interest in the next generation of PRRT.

I’m regularly writing about new radionuclides, alpha emitters, different somatostatin receptor-targeting compounds, combinations with other treatments and other attempts to improve radioligand therapy. This MSK research approached the problem from another direction.

It’s another example of adding different approaches, different routes to target or using combination treatments – a recent example I wrote about includes a trial of PRRT plus PARP inhibitors as an enhancement.

The dosimetry for the dominant liver metastases is also interesting but there is not enough evidence to suggest this can make improvements. But that >3-fold difference in absorbed radiation dose to liver metastases is therefore of interest.

Summary

I find this research genuinely interesting because the basic concept is relatively easy to understand. But we would need larger studies, appropriate comparisons and longer follow-up before knowing whether the impressive dosimetry translates into a meaningful improvement in how long patients’ disease remains controlled. For now, I’d put this firmly into the category of ‘Interesting, innovative and definitely worth watching’. I’ll keep this blog live if anything transpires from this study.

Sources

Bodei L, Ziv E, Mauguen A, et al. Optimizing the Therapeutic Index: Sequential Intraarterial–Intravenous PRRT with Personalized Volumetric-Adjusted Dosing. Journal of Nuclear Medicine. 2026;67(11):1781–1788. DOI: 10.2967/jnumed.126.272710. Click here.

Society of Nuclear Medicine and Molecular Imaging. Hybrid Radionuclide Therapy Intensifies Treatment of NET Liver Metastases while Maintaining Whole-Body Coverage. November 2026. Click here.

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