Role of Radioembolization in Neuroendocrine Liver Metastases Treatment: History
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Contributor:
Khalil Ramdhani
,
Arthur J. A. T. Braat

Neuroendocrine neoplasms (NEN) consist of a very heterogenous group of tumors, contributing to large differences in patients’ disease burden, symptomatology, clinical and objective responses to different treatments, and prognosis. Liver-directed treatments for NELM can be divided into two categories: ablative localized treatments, e.g., radiofrequency ablation (RFA) or microwave ablation (MWA); or trans-arterial treatments, e.g., trans-arterial (bland) embolization (TAE), trans-arterial chemoembolization (TACE) and trans-arterial radioembolization (TARE). The latter technique is also known as selective internal radiation therapy (SIRT). Radioembolization is a more commonly used and simplified term but also a misnomer. Contrary to TAE and TACE, the primary effect is not to embolize vasculature and induce ischemia but to deliver high doses of radiation to tumor tissue via trans-arterial implantation. 

  • NEN
  • radioembolization
  • SIRT
  • neuroendocrine tumor

1. Introduction

In accordance with the most recent WHO/ENETS criteria, tumor grading is the most common denominator for survival: grade 1 and 2 neuroendocrine tumors (G1-/G2NET) are regarded as well- to moderately differentiated tumors with a low Ki67 index (<3% and 3–20%, respectively); grade 3 NET (G3NET) as well- or moderately differentiated NET with high Ki67 index >20%; and neuroendocrine carcinomas (NEC) as poorly differentiated and with highly proliferative tumors (Ki67 index is most commonly >55%) [1][2][3]. However, within its heterogeneity, a well-established negative factor for survival for NEN patients is the presence of neuroendocrine liver metastases (NELM) [4]. Unfortunately, at diagnosis, 21% of all G1NET, 30% of all G2NET and 50% of all G3NET already have distant metastases, of which the liver is the most commonly affected [5][6]. In the presence of NELM, Frilling et al. provided an easy method to categorize liver involvement into three groups, based on tumor distribution in the liver [7]: from a ‘simple pattern’ (NELM involves 1–2 liver segments) to a ‘complex pattern’ (extensive unilobar disease with limited disease in the contralateral lobe) to a ‘diffuse pattern’ (bilobar or miliary disease). Whereas these ‘simple’ and ‘complex’ patterns allow surgical resection, the ‘diffuse’ pattern does not. Unfortunately, 60–70% of patients with NELM reside in the ‘diffuse pattern’ group, illustrating the clinical need for liver-directed treatments in light of the limited systemic options for NENs.

Within trans-arterial treatments for NELM, radioembolization has gained a lot of attention over the last decade and reports high tumor objective response rates and limited toxicities [8]. As illustrated by the European Neuroendocrine Tumor Society (ENETS) guideline from 2016 and the European Society for Medical Oncology (ESMO) guideline from 2020, the role of radioembolization has extended, including early application as a tumor debulking treatment or as a salvage treatment in selected cases, after the failure of systemic treatments [4][9]. As NEN and NELM development are highly variable between individuals, the application of radioembolization needs to be determined on a case-by-case basis through discussions by multidisciplinary tumor boards (MDT).

2. How Is Radioembolization Performed?

Pre-radioembolization work-up is quite similar to other (minimally) invasive treatments, including clinical assessment, laboratory testing and imaging investigations. The minimal requirements and additional assessments that could be considered during the work-up for NELM are depicted in Table 1.
Table 1. Pre-radioembolization work-up.
Clinical Assessment Laboratory Testing Imaging Work-Up
Minimal    
ECOG performance score Bilirubin, ALP, AST, ALT, albumin gdMRI/CECT for intrahepatic tumor load 1
Signs of hepatic dysfunction (Child–Pugh score) Creatinine, eGFR Early-phase CECT for arterial vasculature
NET hormone-related symptoms Tumor markers (e.g., CgA, gastrin)  
Additional    
In selected cases, Fibroscan or gastroscopy to assess esophageal varices Hb, hematocrit, WBC, platelets SSTR-PET/CT for total body tumor load 1
Coagulation (e.g., Prothrombin time or INR) FDG-PET/CT for tumor grade distinction, excluding aggressive disease.
Legend: ECOG = Eastern Cooperative Oncology Group, NET = neuroendocrine tumor, eGFR = estimated glomerular filtration rate; ALP = alkaline phosphatase, AST = aspartate aminotransferase, ALT = alanine aminotransferase, CgA = chromogranin A, Hb = hemoglobin, WBC = white blood cell count, INR = international normalized ratio, gdMRI = gadolinium-enhanced magnetic resonance imaging, CECT = contrast-enhanced computed tomography, SSTR = somatostatin receptor; PET/CT = positron emission tomography/computed tomography, FDG = fluorodeoxyglucose. 1 tumor load = fractional tumor involvement.
Radioembolization is a multidisciplinary treatment (involving an interventional radiologist and nuclear medicine physician) and always consists of a two-step approach (Figure 1). Firstly, a treatment simulation is performed, also known as a scout-procedure, with the administration of scout particles, either technetium-99 m macroaggregated albumin (99 mTc-MAA) or a small amount of holmium-166 microspheres (166Ho-scout dose, QuiremScout®, Quirem Medical, Deventer, the Netherlands), followed by imaging. Secondly, the actual radioembolization procedure with the administration of the therapeutic activity of particles can be used with one of three commercially available particles: yttrium-90 (90Y)-loaded glass (Theraspheres®, Boston Scientific, Marlborough, MA, USA), resin microspheres (SirSpheres®, SIRTex medical, Woburn, MA, USA), or 166Ho-microspheres (QuiremSpheres®, Quirem Medical, Deventer, the Netherlands). Thereafter, clinical, laboratory and imaging evaluation is performed for at least 6 months [10].
/media/item_content/202209/632ad817bd159cancers-14-03415-g001.png
Figure 1. Graphical representation of a radioembolization treatment.
To date, no evidence is available on the use of prophylactic medication in NELM. Based on clinical experience, standard octreotide infusion is not recommended, except in patients experiencing several carcinoid syndromes [10]. Prophylactic antibiotics should be considered in patients with a bilidigestive anastomosis but not in the general population [11]. Prophylactic proton pump inhibitors, anti-emetics and dexamethasone were commonly used at the start of radioembolization, but most experienced centers refrain from using any prophylactic medications [12].

3. SIRT in NEN: Salvage Setting

Table 2 summarizes the most important scientific evidence available to date for salvage radioembolization.

Table 2. Landmark papers on salvage radioembolization in NEN.
  Year N ORR * DCR * PFS OS REILD
    % % Months Months n (%)
Devcic et al. † [8] 2014 435 50 86 NR 28.5 NR
Peker et al. [13] 2015 38 46 83 NR 39 0
Barbier et al. [14] 2016 54 54 94 NR 34.8 1 (1.8)
Braat et al. [10] 2019 244 16 91 NR 31 2 (0.8)
43 91
Schaarschmidt et al. [15] 2022 297 41.3 83.5 15.9 30.6 2 (0.8)
Wong et al. [16] 2022 170 36 69 25 33 1 (0.6)
Legend: NR = not reported, n = number of procedures, ORR = objective response rate, defined as complete + partial response, DCR = disease control rate, defined as ORR + stable disease, PFS = median or mean progression free survival, OS = median or mean overall survival, REILD = radioembolization-induced liver disease. * Response within or at 3 months according to RECIST 1.1 in regular font and in italics according to mRECIST. † Only meta-analyses on data before 2014, and other studies presented are original articles.
Interestingly, together, these studies report over 1200 patients with quite similar findings, illustrating some degree of robustness of data and confirming the safety and efficacy of the radioembolization of NELM in a salvage setting (Table 2). In addition to similar results for objective endpoints (imaging-based response and overall survival), all studies show a positive correlation with low tumor grading, obtaining DCR at first evaluation and limited intrahepatic tumor burden with OS. Several differences can also be noticed: the most interesting was the influence of the presence of extrahepatic disease. Braat et al. found a significant negative correlation with OS, whilst Schaarschmidt et al. and Wong et al. did not. However, the majority of the patients the study of Braat et al. had more extensive extrahepatic disease (66%). To date, only Braat et al. reported clinical outcomes, indicating the reduction in or resolution of hormone-related complaints in 44% and 34% of patients, respectively [10][15][16].

4. Radioembolization in Earlier Lines or Combinations Treatments

As the liver is the most commonly affected organ for NEN metastases, independent of tumor origin and often the only affected organ after the resection of a primary tumor, the application of radioembolization in an earlier line of the disease is increasingly debated. As shown in the current ENETS and ESMO guidelines, liver-directed treatments should be considered in specific cases [4][9]. Schaarschmidt et al. showed a median hepatic PFS of 18.6 months and median global PFS of 18.8 months, which is slightly better than the results obtained in a salvage setting (Table 2). Logically, prolonged median OS was found (44.8 vs. 30.6 months) in the group treated in the second-line compared to the salvage setting group [15].
The mainstay in the treatment of metastatic disease resides in the use of systemic treatments, most commonly somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT) and chemotherapy [4][9]. In patients with significant intrahepatic tumor burden or aggressive disease, systemic treatments tend to have less prolonged effects [17][18]. Combining a systemic and/or targeted treatment with a liver-directed treatment seems logical to boost the benefit for patients suffering from high intrahepatic tumor burden or patients with mainly NELM (liver-only or so-called “liver dominant disease”).
The most recent study by Braat et al. (“HEPAR PLuS”) combined PRRT with 166Ho-radioembolization, by adding radioembolization within 20 weeks after the fourth cycle of PRRT [19]. The scholars concluded that the combination was safe and effective. REILD was encountered in one patient. However, due to the heterogeneity of the group and the selection bias introduced by patient inclusion after the completion of PRRT, a patient population with a poor prognosis was selected. Five out of thirty-one (17%) of the included patients already failed PRRT (with only intrahepatic progressive disease). Nonetheless, high ORR, both RECIST 1.1 and mRECIST, and durable responses during the first year in follow-up were reported, thus the combination seems promising, and no loss in quality of life was reported (Figure 2).
/media/item_content/202209/632ad83a05bedcancers-14-03415-g004.png
Figure 2. Patient with a grade 1 pNET with liver metastases, who participated in the HEPAR PLuS trial. (A) Baseline CT prior to PRRT with 4 cycles of 7.4 GBq 177Lu-DOTATATE. (B) CT 3 months after PRRT depicting evident progressive intrahepatic disease. (C) CT 3 months after additional 166Ho-radioembolization showing increased necrosis, size reduction and reduced enhancement of neuroendocrine liver metastases, and stable disease according to RECIST 1.1 (−22%). (D) CT 12 months after additional 166Ho-radioembolization showing advancing partial response according to RECIST 1.1 (−44%) and tumor reduction.

5. Conclusions

Hepatic radioembolization is safe and effective as a monotreatment in NEN. Based on current evidence, the exact application of radioembolization in NEN care remains unknown, and the scientific debate on suggested long-term toxicities remains unresolved. The application of radioembolization should be considered on a case-by-case basis through multidisciplinary discussion. Upcoming clinical and technical developments in the field will ensure a more promising role for radioembolization in NEN care.

This entry is adapted from the peer-reviewed paper 10.3390/cancers14143415

References

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