Combining targeted Holmium-166 radioembolization with systemic therapy improves response rates in bulky liver disease patients

Marnix Lam

This article is sponsored by Terumo.

The first prospective study on the combination of peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and Holmium-166 (166Ho) radioembolization has shown that significant tumour reduction can be achieved in patients with bulky liver disease, a significant advancement considering the liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Just published in Lancet Oncology, Arthur Braat (University Medical Center Utrecht, The Netherlands) et al conclude that the additional radiation boost provided by 166Ho-radioembolization following PRRT leads to a high objective response rate with acceptable side effects and only temporary changes in quality of life.

The HEPAR PLuS study (Holmium Embolization Particles for Arterial Radiotherapy Plus 177Lu-DOTATATE in Salvage NET [neuroendocrine tumour] patients) was a phase 2, single centre, non-randomised, noncomparative, open label study. Patients received additional 166Ho-radioembolization within 20 weeks after the fourth cycle of 177Lu-DOTATATE. Senior author Marnix Lam speaks about the study’s implications, highlighting the investigators’ use of Quiremspheres (Quirem/ Terumo Europe), and how these particles are helping to usher in a new era of more individualised treatment planning when it comes to selective internal radiation therapy (SIRT):

How is this data breaking new ground?

In my opinion, the phase 3 NETTER-1 trial in patients with grade 1 and 2 gastrointestinal neuroendocrine neoplasms was a landmark study, showing that PRRT has a huge benefit for patients in terms of progression-free survival [PFS] and overall survival [OS]. However, objective response rate after PRRT was limited to only 18%. In addition, a subanalysis showed that 68% of patients in the NETTER-1 study had bulky disease, and of those patients, 70% had bulky disease in the liver. The outcomes in terms of progression-free survival are much worse: most patients with bulky disease did not reach the median PFS of >40 weeks of the NETTER-1 trial. In other words, for patients with bulky liver disease, there is definitely room for improvement.

I was discussing this with Dik Kwekkeboom (Rotterdam, The Netherlands), one of the founders of PRRT, and a friend and colleague of mine who sadly passed away in 2017. He told me he had a fantastic new treatment for neuroendocrine tumours, but that improvements were needed for patients with bulky liver disease. At the time, we were developing 166Ho-radioembolization for liver disease, so we joined forces and came up with the design of the HEPAR PLuS study, which combines the treatments: four cycles of PRRT followed by additional 166Ho-radioembolization, which provides a radiation boost. While PRRT is a systemic treatment, 166Ho-radioembolization is a local treatment, targeting the liver metastases.

With this method, we were able to improve that 18% response rate. Total hepatic objective response rate at six months was 47% in HEPAR PLuS—a huge increase. Of course, we always have to keep in mind that response rates do not necessarily translate into improved PFS or OS, and that is definitely the next step that we want to take: conduct a randomised controlled trial to evaluate whether the increased response rate translates into a better outcome for patients with bulky liver disease.

The timing of this publication is significant. PRRT is now the standard of care, as a lot of hospitals around the world have been performing this therapy for six to 12 months. They have gained experience with PRRT, which is great, but have also found that the response rate for patients with bulky liver disease is limited.

What do you think is the future of SIRT?

I think the future of SIRT is individualised treatment planning. The HEPAR PLuS study shows that it is safe to combine PRRT and 166Ho-radioembolization. However, when combining two treatment modalities that involve radiation doses, dosimetry is essential. You have to calculate the absorbed dose coming from PRRT and from radioembolization, so combining these modalities is a call for improved treatment planning.

This is where the benefit of the 166Ho-microspheres comes in: we can use the exact same particles (QuieremScout) in the test procedure as in the treatment (QuieremSpheres). During the test, we only administer a small fraction of the microspheres to the patients for diagnostic purposes—a scout dose. We evaluate the biodistribution of the microspheres, and then draw an individualised treatment plan. This is possible because, even at low activities, 166Ho-microspheres are fit for imaging, unlike Yttrium-90 (90Y)-microspheres, which can only be properly imaged at high activities. Therefore, when using 90Y-microspheres, you have to use a surrogate for the pre-treatment testing, and this is not always predictive enough for the final outcome.

Having an individual treatment plan in place is crucial when combining treatments. This is not only true for PRRT, but also if we start combining immunotherapy or chemotherapy with radioembolization. This is really where the benefit of 166Ho-microspheres lies in comparison to the 90Y-microspheres.

How can other centres benefit from this combined treatment approach?

As with all innovation, study results need to be translated into clinical guidelines for reimbursement. In Germany and Belgium, 166Ho-radioembolization is already reimbursed specifically in the treatment of neuroendocrine tumours and liver metastases.

In the most recent US guidelines for neuroendocrine neoplasm patients with liver disease, PRRT is the standard of care. Radioembolization is listed as an option following the failure of systemic treatment such as PRRT, but is also considered investigational. We want to change that. This is the first step: we have shown that the combination is safe and effective in a prospective study; now we have to conduct a randomised controlled trial. If the outcomes of this concord with those of our present study, then I am convinced we will be able to change the guidelines and offer this combined treatment approach to patients with bulky liver disease.

Preliminary experience with 166Ho-radioembolization

Irene Bargellini (University of Pisa, Pisa, Italy) shares her early experience using 166Ho-microspheres (Quirem/ Terumo): “The initial cases we have performed have confirmed that there is something really interesting going on here that deserves more attention. 

What drew you to 166Ho-microspheres?

Several interesting features attracted us to 166Ho-microspheres. Our physicists and nuclear medicine physicians in particular were very interested in the dosimetry—the idea of the scout dose (QuiremScout) was intriguing to them. The concept of being able to evaluate the distribution of the microspheres with MRI was also interesting to us.

How was incorporating 166Horadioembolization into your practice?

Initially, we had to set up a specific acquisition protocol for MRI and SPECT [Single photon emission computed tomography].

What therapeutic feedback have you got from using 166Homicrospheres?

We have treated 15 patients so far. In our limited experience, we have seen the majority of our patients responding much quicker than what we are used to seeing with 90Y microspheres. The lesions were already shrinking just 45 days post-procedure. In fact, two of our patients originally deemed to be non-surgical candidates had a resection and a transplant, respectively, after radioembolization with QuiremSpheres. The response might be so quick because 166Ho has a shorter half-life than 90Y, so the dose is deposited much quicker. This is the reason why we are currently using 166Ho-microspheres for patients that could be resected or transplanted after an adequate and fast tumour downstaging. In five patients, the Holmium scout dose (QuiremScout) was performed after an initial 99mTc-MAA diagnostic work-up, whose findings would have excluded the patients from treatment, due to high lung shunting in one patient and to heterogeneous 99mTc-MAA distribution within the tumours in the remaining four cases. In all 99mTccases, the scout dose provided different information that allowed us to safely and effectively perform Holmium radioembolization. We also try to use 166Ho-microspheres in patients with colorectal metastases, because so far we have not had very good results with 90Y in this cohort.


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