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Radionuclide Therapy of Tumors of the Liver and Biliary Tract

  • Giuseppe BoniEmail author
  • Federica Guidoccio
  • Duccio Volterrani
  • Giuliano Mariani
Living reference work entry

Abstract

The liver represents a frequent site for both primary cancer and metastatic disease, In these circumstances, liver-directed therapies as cytoreduction via surgery or in situ ablative techniques may influence the natural history of the disease progression and improve clinical outcomes.

Radioembolization (RE) is a selective internal radiotherapy technique in which 131I-lipiodol or 90Y microspheres are infused through the hepatic arteries. It is based on the fact that primary and secondary hepatic tumors are vascularized mostly by arterial blood flow whereas the normal liver perfusion is mostly from the portal network. This enables high radiation doses to be delivered, sparing the surrounding non-malignant liver parenchyma.

Although there are some clinical evidences that RE may play an important role in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors, further randomised clinical trials are mandatory to better assess the potential beneficial and harmful outcomes of trans-arterial radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies.

In this chapter we discuss some technical aspects, patient selection, current clinical evidence, and future directions of radioembolisation for primary and secondary liver cancer.

Keywords

Hepatocellular carcinoma Selective internalradiation therapy Radioembolization Liver Neoplasm Metastasis 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

5-FU

5-Fluorouracil, a chemotherapy agent

68Ga-DOTANOC

68Ga-DOTA-1-Nal3-octreotide

99mTc-HSA

99mTc-human serum albumin

99mTc-MAA

99mTc-macroaggregated albumin

99mTcO4

99mTc-pertechnetate

AFP

Alpha-fetoprotein, a circulating serum marker of hepatocellular carcinoma (and of testicular germ-cell cancer as well)

Bq

Becquerel unit

BSA

Body surface area

CA 19–9

Carbohydrate antigen 19–9, a tumor-associated serum marker

ce-CT

Contrast-enhanced x-ray computed tomography

CI

Confidence interval

CR

Complete response

CRC

Colorectal cancer

CT

X-ray computed tomography

DEB

Drug-eluting bead

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

EASL

European Association for the Study of the Liver

ECOG

Eastern Cooperative Oncology Group

eV

Electron volt

GBq

Giga-Becquerel (109 Becquerel)

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HCC

Hepatocellular carcinoma

HDD

4-Hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol, a chelating agent

ICC

Intrahepatic cholangiocarcinoma

IRE

Irreversible electroporation

keV

Kiloelectron volt (103 eV)

LSF

Lung shunt fraction

MBq

Mega-Becquerel (106 Becquerel)

MeV

Megaelectron volt (106 eV)

MIP

Maximum intensity projection

MIRD

Medical Internal Radiation Dose

MR

Magnetic resonance

MRI

Magnetic resonance imaging

NET

Neuroendocrine tumor

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PFS

Progression-free survival

PR

Partial response

PVT

Portal vein thrombosis

RE

Radioembolization

RECIST

Response evaluation criteria in solid tumors

RFA

Radiofrequency ablation

RILD

Radiation-induced liver diseases

ROI

Region of interest

SD

Stable disease

SIRT

Selective internal radiation therapy

SPECT/CT

Single-photon emission computed tomography/computed tomography

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

TACE

Transcatheter arterial chemoembolization

TARE

Transarterial radioemobilization

VIPoma

Neuroendocrine tumor producing vasoactive intestinal peptide

WHO

World Health Organization

Introduction

Both primary tumors and metastatic malignancies can arise in the liver. Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is rising [1]. In addition, the liver is one of the most common sites for hematogenous metastases from different solid tumors primarily arising in other tissues/organs, most importantly colorectal cancer (CRC). About 15–25% of all CRCs may present synchronous hepatic metastases or develop metachronous metastatic involvement of the liver disease during the course of the disease [2].

Although significant survival benefit can be achieved with curative resection or liver transplantation in selected cases [3], less than 15% of the patients with newly diagnosed HCC are candidates for surgical procedures with curative intents. Although various treatments have been proposed for the remaining patients, definite agreement has not been reached on which option offers the greatest survival benefit associated with the least toxicity.

External beam radiation therapy has a limited role in the treatment of HCC due to the relatively high radiosensitivity of normal hepatic tissue [4]. In fact, exposure of the liver to radiation doses greater than 40 Gy may result in a clinical syndrome called “radiation-induced liver disease ” (RILD) or radiation hepatitis. This syndrome, which occurs weeks to months following therapy, includes elevated liver enzymes, anicteric hepatomegaly, and ascites [4, 5].

Minimally invasive, percutaneous ablative treatments include radiofrequency ablation (RFA), microwave ablation, cryoablation, and irreversible electroporation (IRE) that have become widely accepted as potentially curative therapies for either HCC or metastatic liver disease [6]. In particular, these ablative techniques are useful for treating patients who do not meet the criteria for surgery but in whom curative treatment is desired.

Transcatheter arterial chemoembolization (TACE) is the mainstay of catheter-based locoregional therapies for unresectable primary liver cancer; its use is expanding and includes liver metastatic disease from other malignancies [7]. Conventional TACE typically involves the injection of chemotherapeutic agents mixed with lipiodol and embolic particles into the branch of the hepatic artery that feeds the tumor [8]. TACE with drug-eluting beads (DEB) involves the injection of DEBs into the tumor-feeding artery, offering simultaneous delivery of chemotherapy and embolization with sustained and controlled drug release over time [9]. Both TACE and DEB-TACE are effective as palliative treatments for primary and metastatic liver cancers [10, 11].

There are substantial differences in the treatment strategies for primary or metastatic malignancies of the liver. While locoregional treatments are a mainstay in primary liver cancers [12], transcatheter techniques such TACE or DEB-TACE are not commonly used for patients with metastatic liver disease.

The recent successful development of trans-arterial radioembolization (TARE) with 90Y-labeled particles has revived interest in an approach to locoregional treatment of liver tumors with radionuclides that had been introduced earlier with the use of lipiodol containing 131I but had shown little benefit for long-term survival (see further below). This technique is also defined as “selective internal radiation therapy ” (SIRT); therefore, the acronyms TARE and SIRT can be employed in an interchangeable manner.

Rationale of Radioembolization Therapy for Liver Tumors

In order to deliver the highest possible therapeutic doses to the tumor while sparing normal liver parenchyma, techniques based on minimally invasive intra-arterial administration of therapeutic radionuclides have been developed, an approach that takes advantage of the dual blood supply to the liver. Normal hepatic tissue derives greater than 70% of its blood supply from the portal system, whereas blood to malignant tissue is preferentially supplied by the arterial system. High tumoricidal doses can thus be selectively delivered to the tumor lesions (more than 70 Gy, usually 200–300 Gy) through locoregional administration of agents emitting β particles (labeled with either 131I, 90Y, 188Re, or 166Ho), with low levels of associated damage for the non-affected liver and therefore a minimal risk of inducing RILD [13, 14, 15, 16, 17].

Radioactive Lipiodol

Upon injection into the hepatic artery of patients with HCC, the iodinated oil 131I-lipiodol (a suspension of lipidic particles) follows the preferential blood flow toward the tumor; the radiolabeled micellae are then retained by pinocytosis both in the tumor cells and in the endothelial cells of the arteries feeding the tumor [18]. Following this route of administration (which is performed under angiographic monitoring), more than 75% of the injected 131I-lipiodol remains in the liver, while the remainder distributes mainly to the lungs. Release of free radioiodine results in some accumulation of radioactivity in the thyroid gland. Dose to the thyroid galnd can be minimized by pretreatment with sodium iodide. Tumor/non-tumor uptake ratios in the liver are generally higher than 5, and more than 10% of the injected radioactivity remains within the tumor with an effective half-life greater than 6 days, longer than in the normal liver tissue [14, 15, 19]. Administered activity can be either a fixed amount of 2.4 GBq (65 mCi) or defined on the basis of patient-specific dosimetric estimates. Due to the long half-life of 131I-lipiodol in the tumor, current legislation in some countries requires hospitalization for about 1 week, for the purpose of radioprotection of the general population.

Treatment is in general well tolerated, and serious adverse effects are very rare, while generic asthenia is commonly reported; hematologic toxicity is exceptionally rare, although blood cell counts may be altered due to the cirrhosis-related hypersplenism often present in these patients. Interstitial pneumopathy due to trapping and retention of the radiolabeled particle suspension is reported as the main risk of this treatment [20].

Both retrospective studies [21, 22, 23] and prospective trials [21, 24, 25] have demonstrated the safety of 131I-lipiodol therapy, while the objective response rate is reported in the 40–50% range. In particular, a randomized controlled trial comparing 131I-lipiodol therapy versus best supportive care in a group of 27 HCC patients with portal thrombosis demonstrated that survival at 3 months was 71% in the treatment arm versus 10% in the best supportive care arm (with median overall survivals of 26 weeks and 10 weeks, respectively) [24].

In the adjuvant setting, the efficacy of 131I-lipiodol therapy was tested in a phase II study involving 28 patients [26]. Median time to recurrence was 28 months (range 12–62 months) in the 16 patients who were apparently disease-free at follow-up; overall survival in the responding patients was 86% at 3 years and 65% at 5 years. In a recently published phase III study, 21 patients without evidence of residual disease after potentially curative resection for HCC received 1,850 MBq of 131I-lipiodol intra-arterially as adjuvant therapy, while 22 patients treated with surgery alone served as the control group [27]. The recurrence rate in the patients treated with surgery alone was 63.6%, while it was 47.6% in those receiving adjuvant radioembolization. The 5-year, 7-year, and 10-year disease-free survivals were 61.9%, 52.4%, and 47.6%, respectively, in the adjuvant therapy group, significantly higher than the values in the corresponding control group (31.8% with P = 0.0397, 31.8% with P = 0.0224, and 27.3% with P = 0.0892, respectively). Also, overall survivals in the treated group (66.7% at both 5 and 7 years, 52.4% at 10 years) were higher than in the control group (36.4% with P = 0.0433 at 5 years, 31.8% with P = 0.0243 at 7 years, and 27.3% with P = 0.0905 at 10 years, respectively). When compared with chemoembolization, embolization with 131I-lipiodol has yielded similar results in terms of efficacy but better tolerance [23].

More recently lipiodol labeled with 188Re using 4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD) as the chelating agent [28] was shown to be a promising agent for radioembolization in patients with inoperable large and/or multifocal HCCs. 188Re has potentially favorable physical characteristics, such as a shorter half-life than 131I (16.9 h versus 8 days), a β emission of high energy with ensuing good tumoricidal effect (E max = 2.1 MeV), and a 155-keV γ emission favorable for gamma-camera imaging (for the purpose of dosimetric estimates). Furthermore, the relatively short-lived 188Re can be obtained through a generator system based on its parent radionuclide (188W) that has a physical half-life of 69 days, suitable for distribution logistics.

Therapy of HCC with 188Re-HDD-lipiodol results in higher tumor-killing efficacy than 131I-lipiodol, yet combined with lower toxicity. The 188Re-labeled agent represents therefore an excellent alternative to the 131I-labeled agent [29].

Promising results of both safety and clinical response following therapy with 188Re-HDD-lipiodol were obtained in a multicenter study performed in 93 patients with inoperable HCC [30]. Treatment was well tolerated, and an objective response (including either tumor regression of some degree or stabilization of disease that was in progression prior to therapy) was observed in 66/93 patients (71%); out of these 66 objective responses, there were 5 cases with complete ablation of the tumor mass, 17 cases of partial response, and 23 cases with stabilization of disease.

90Y-Microspheres

Intra-arterial radioembolization with 90Y-labeled particles was approved in 2002 for the treatment of liver tumors, both primary malignancies and metastatic lesions originated by other tumors [31]. 90Y is a pure β emitter that decays to stable 90Zr and has a physical half-life of 64.2 h. The average energy of β emission is 0.936 MeV, with a mean tissue penetration of 2.5 mm and a maximum tissue range of 10 mm. The physical properties of 90Y allow the delivery of high-radiation doses to hepatic malignancies, when administered with this technique, while minimally affecting the non-affected surrounding liver parenchyma.

Two types of microspheres labeled with 90Y are currently available, made, respectively, of glass (TheraSphere®, MDS Nordion, Ottawa, Ontario, Canada) and of resin (SIR-Spheres®, Sirtex Medical, Sydney, Australia). These two preparations differ in some important respects [32]. TheraSphere® consists of particles 20–30 μm in diameter, each one carrying 2,500 Bq of 90Y (high specific activity); about 1.2 million microspheres is injected intra-arterially for a single treatment, corresponding to a total administered activity of about 3 GBq (81 mCi). SIR-Spheres® consists instead of particles 20–60 μm in diameter, each one carrying 50 Bq of 90Y (low specific activity); 40–80 million microspheres are injected for a single treatment to achieve a similar total administered activity of 3 GBq [32].

Patient Selection

After the diagnosis of inoperable liver tumor has been made on the basis of proper imaging and biopsy, the pretreatment functional status of the liver is evaluated by routine blood chemistry workup. Patients with an ECOG performance status of greater than two are not considered ideal candidates for this treatment.

An inadequate liver function reserve with total bilirubin >2.0 mg/dL and serum albumin <3 g/dL is considered a contraindication to treatment with 90Y-microspheres. In case of concomitant renal failure, care must be taken to avoid or minimize the use of iodinated contrast medium during angiography (see further below).

Pretreatment evaluation for TARE/SIRT with 90Y-microspheres is based on cross-sectional imaging and arteriograms in the individual patient, with the fundamental prerequisite that the patient has liver-dominant unresectable disease. The workup should include CT or MR imaging of the liver for assessment of tumoral and non-tumoral volume, portal vein patency, and extent of extrahepatic disease. Distribution of the tumor disease is typically characterized as unilobar or bilobar; however, the correlation of tumor lesions with hepatic arterial supply is variable and can only be ascertained through arteriography. Ascites indicates poor hepatic reserve or peritoneal metastasis, both of which bear poor prognosis.

The final decision-making about treatment with 90Y-microsphere TARE/SIRT for each individual patient should be achieved after careful consideration of all functional and anatomic parameters within a multidisciplinary team involving interventional radiologists, surgical oncologists, medical oncologists, nuclear medicine physicians, radiation oncologists, medical physicists, and radiation safety experts.

Assessment of Arterial Anatomy

Pretreatment angiography (an essential requisite for the therapeutic procedure) is performed to assess the vascular anatomy of the liver, patency of the portal vein, and presence of artero-portal shunting and/or shunting to extrahepatic territories, the most important of which is the liver-to-lung shunt (see further below). Abnormal blood flow spreading the radiolabeled microspheres outside the liver vasculature is prevented by prophylactic embolization of some vessels identified during angiography, such as the gastroduodenal artery and the right gastric artery [5]. This is a safe and effective procedure to minimize the risks of hepato-enteric flow. Mesenteric angiography is necessary to ensure that blood supply to the lesions has been adequately identified, as incomplete/inaccurate definition of the pattern of blood supply to the tumor may lead to incomplete/ineffective targeting of the tumor lesion.

Pretreatment Imaging with 99mTc-MAA

During pretreatment angiography, 99mTc-macroaggregated serum albumin ((99mTc-MAA) or alternatively 99mTc-HSA-microspheres) is injected into the hepatic artery to confirm that the radiolabeled particles home in the tumor lesion(s), as well as to assess for the presence of shunting to the splanchnic and/or pulmonary vascular bed. To this purpose, scintigraphy of the lung and upper abdomen by either planar and/or SPECT/CT imaging (i.e., the optimal imaging technique) is routinely performed (Figs. 1, 2, and 3) [33]. Images can be acquired within 4 h of the administration of 99mTc-HSA-microspheres, while the optimal time window for imaging after administration of 99mTc-MAA is within 1 h post-administration. In fact, albumin macroaggregates undergo a relatively fast intrahepatic degradation, with possible redistribution of radioactivity (constituted either by smaller fragments and/or free 99mTcO4 ) from the capillary bed of the liver to the capillary bed of the lung. As a consequence, the liver-to-lung shunt fraction can be overestimated at later time points after administration [34], or radioactivity accumulation at other sites (e.g., free 99mTcO4 accumulating in the stomach) can be misinterpreted as shunting to extrahepatic sites. In order to avoid such occurrence, sodium perchlorate is administered orally about 30 min before 99mTc-MAA injection [35].
Fig. 1

Angiographic and scintigraphic pretreatment evaluation of a 67-year-old patient with a large, infiltrating hepatocellular carcinoma (HCC) candidate to radioembolization therapy with 90Y-microspheres. (a) Left panel shows contrast-enhanced CT demonstrating massive infiltration of segment 1 by a large HCC, with extension to the adjacent liver segments. Right panel shows an early phase of digital subtraction angiography through the hepatic artery (catheter indicated by black arrow); there is intense diffuse enhancement of the left branches of the portal vein, with a wide-lumen artero-portal fistula (indicated by white arrows). (b) Left panel shows planar scintigraphy acquired after trans-arterial injection of 99mTc-MAA (anterior view) demonstrating widespread diffusion of the injected particles to virtually the entire liver. Right panel shows the fused axial SPECT/CT image, which better defines the intrahepatic distribution of 99mTc-MAAs, mostly to both the right and the left lobes of the liver, while there is minimal perfusion of the main site of the tumor. On the basis of the angiographic and scintigraphic characterization, this patient was excluded from trans-arterial radioembolization with 90Y-microspheres, because this treatment would have exposed the non-tumor liver parenchyma to excessive, unjustified radiation doses without actually an expected benefit for what concerns tumor therapy

Fig. 2

Angiographic and scintigraphic pretreatment evaluation of a 75-year-old man with metastasis from an urothelial carcinoma in both lobes of the liver, with posttreatment PET/CT acquisition based on internal pair production during decay of 90Y. Selective angiography was performed by injecting contrast medium separately into the right, the median, and the left branches of the hepatic artery. (a) Left panel shows digital subtraction angiography obtained upon injection into the median hepatic artery, revealing a thin branch (indicated by the white arrow) identified as a patent falciform artery. Right panel shows the corresponding contrast-enhanced CT phase (falciform artery indicated by white arrow). (b) Scintigraphy acquired after trans-arterial 99mTc-MAA injection clearly demonstrate the abnormal arterial branch (indicated by arrows) in the planar anterior view (upper left panel) as well as in the fused SPECT/CT images (coronal in upper right, sagittal in lower left, axial in lower right panels, respectively). During the subsequent trans-arterial treatment phase, an ice pack was positioned on the cutaneous projection of the falciform artery before injecting the 90Y-microspheres, in order to induce vasoconstriction and thus reduce as much as possible inadvertent deposition of the radiolabeled particles in the periumbilical region, which would have caused delivery of a high-radiation dose to this region. The procedure was uneventful, and the posttreatment PET/CT acquisition based on internal pair production of 90Y (c) showed excellent tumor targeting without visualization of the area fed by the patent falciform artery (fused coronal image in left panel, fused sagittal image in right panel)

Fig. 3

Scintigraphic pretreatment evaluation (fused axial SPECT/CT images at various levels) of a 72-year-old patient with a tumor lesion between segments 5 and 6 of the liver. Trans-arterial 99mTc-MAA injection results in satisfactory distribution to the tumor lesion but also in scintigraphic visualization of the gallbladder wall, due to flow of the radiolabeled particles through the cholecystic artery. Therapy with 90Y-microsperes was not performed, because of the fear of causing necrotizing radiation-induced cholecystitis. In patients with vascular patterns similar to this (as those regarding the mesenteric artery feeding the gastric wall), further attempt to 90Y-microsphere radioembolization therapy must be preceded by coil embolization of the arteries feeding extrahepatic territories

It is crucial to correlate the 99mTc-MAA scintigraphic images to the angiography pattern, as topographic proximity of the duodenum and stomach to the liver may decrease the ability to identify extrahepatic shunting by scintigraphy alone, especially if based solely on planar imaging. Based on ROI technique, the lung shunt fraction (LSF) is calculated and employed to estimate the radiation dose delivered to the lungs for any given amount of radioactivity, so that appropriate adjustments in the administered activity can be made to minimize the risk of radiation pneumonitis (see further below).

Radiodosimetric Aspects

The choice of the most appropriate 90Y activity to be delivered into the tumor target and to the normal liver parenchyma requires adequate knowledge of many factors, mainly the liver function and reserve, that are frequently influenced by concomitant pathologies (i.e., cirrhosis) or by prior chemotherapy and/or external beam radiation therapy.

The main complications possibly linked to 90Y-microsphere radioembolization are caused by excessive irradiation of nontarget tissue. In this regard, the key limiting factor is the lower tolerance to radiation of normal liver parenchyma relative to the dose required to destroy the tumor target. The maximum external beam acceptable cumulative dose to the whole liver is 35 Gy (based on prior experience with external beam radiation therapy) [36], while the estimated dose to destroy a solid tumor is more than 70 Gy. Above the 35 Gy threshold radiation dose to the liver parenchyma, the risk of liver failure rises sharply.

The other absolute and relative contraindications for the procedure are related to the possible flow/reflux of part of the 90Y-microspheres to arteries feeding the wall of the gastrointestinal tract and to excessive lung radiation due to a high hepato-pulmonary shunt, frequently observed in HCC as well as in metastatic disease with a large tumor burden. In this case, the administration of therapeutic amounts of 90Y-microspheres increases the risk of clinically relevant radiation pneumonitis.

To warrant the safety of the procedure, it is crucial to quantify the lung shunt fraction (LSF) as detected in the pretreatment evaluation with the 99mTc-MAA scan, in order to calculate the expected radiation dose to the lungs. Previous data extrapolated from the large body of experience accumulated with external beam radiation therapy indicate that the highest tolerable dose to the lungs is 30 Gy for a single administration and less than 50 Gy as the cumulative dose for multiple treatments [36].

The LSF value is routinely calculated by ROI analysis of the planar scans acquired after 99mTc-MAA administration in the pretreatment phase, using the geometric mean of the lung and liver counts, respectively, in the anterior and posterior views, according to the following equation:
$$ L S F\left(\%\right)=\frac{\mathrm{Lung}\ \mathrm{Counts}}{\mathrm{Lung}\ \mathrm{Counts}+\mathrm{Liver}\ \mathrm{Counts}}\times 100 $$
Radioembolization with 90Y-microspheres has no restrictions for any LSF value <10%, whereas an LSF value >20% constitutes per se an absolute contraindication to treatment. Activity adjustments can be adopted for LSF values between 10% and 20%, that is, a 20% reduction in administered activities for LSF values included between 10% and 15% and a 40% reduction for LSF values included between 15% and 20% (see Fig. 4).
Fig. 4

Representative examples in three different patients of estimation of the lung shunt fraction (LSF) as derived from planar gamma-camera imaging after trans-arterial injection of 99mTc-MAA. For each patient, the anterior and posterior views are displayed, with delineation of regions of interest (ROI) for the liver and for the lung fields, respectively; each ROI is first manually drawn on the anterior view, and then it is flipped on the horizontal axis to match the posterior view. The geometric means of the ROI counts from the two orthogonal views are utilized to calculate the LSF value according to the equation described in the text. The LSF value calculated for the patient in left panel resulted to be 6.4%; the 90Y-microsphere activity injected in this patient was therefore the full amount planned on the basis of the dosimetric estimate. A 20% reduction for administered 90Y-microsphere activity was instead applied to the patient in the center panel (whose LSF was 12%), while the patient represented in right panel was excluded from treatment because of a LSF exceeding 20%

Different models have been proposed and can be employed to calculate the 90Y activity to be administered that would allow delivery of the highest dose to the tumor while sparing normal liver tissue. The so-called partition model (based on the MIRD approach) takes into account three different compartments for radiation dose estimates, i.e., the liver tumor, the non-tumoral liver, and the lungs [37]. The basic assumption is that the LSF and the relative distribution of 99mTc-MAAs in the tumor and non-tumor liver compartments (expressed as T/N ratio) reliably predicts distribution of the 90Y-microspheres that will be administered during another interventional radiology procedure performed a few days later by the same radiologist trying to replicate exactly the same position of the intra-arterial catheter as during 99mTc-MAA administration. The activity of 90Y-microspheres to be administered can be estimated using the LSF derived from the 99mTc-MAA scintigraphic images. This approach is adopted routinely when administering the glass 90Y-microspheres and has been shown to yield safe and reproducible estimates regarding expected toxicity and clinical outcomes.

When using the resin 90Y-microspheres, two additional methods can be employed to estimate the activity to be administered, i.e., empiric method and the body surface area (BSA) method. The empiric method is based on the volume of the liver occupied by the tumor tissue expressed as a fraction of the overall liver volume, as estimated by cross-sectional imaging (either CT or MRI). A 90Y-microsphere activity of 2 GBq is recommended for a tumor/liver fraction <0.25, increasing to 2.5 GBq for tumor fractions between 0.25 and 0.5 and increasing further to 3 GBq for tumor fractions >0.5 (keeping in mind that a value above 0.7 constitutes per se an absolute contraindication to treatment).

The body surface area (BSA, expressed in square meters) method uses the following equation to calculate the 90Y-microsphere activity (A) to be administered:
$$ A(GBq)=\left( BSA-0.2\right)+\frac{\mathrm{tumor}\ \mathrm{volume}}{\mathrm{total}\ \mathrm{liver}\ \mathrm{volume}} $$

Although these two methods based on clinically derived data of intraoperative activity calculations are routinely used in some centers, they are not optimal in certain situations, in particular when the target is well identified and the total volume of the three compartments is accurately known. Moreover, it has been demonstrated that both the BSA method and the empiric method frequently overestimate the activity to be administered to the patient [38, 39]. Therefore, the use of the MIRD partition model should be recommended when administering the resin 90Y-microspheres.

Patient-specific dosimetry requires accurate evaluation of the liver and tumor mass (usually derived from anatomic imaging such as CT) and of 99mTc-MAA biodistribution based on scintigraphic imaging. However, the predictive value of 99mTc-MAA scintigraphy as to the distribution of 90Y-microspheres in the liver is still a matter of debate [40, 41, 42]. Parameters that may induce some discordance between the distribution of 99mTc-MAAs and that of the 90Y-microspheres include interval differences in catheter position during injection in the two separate occasions, physiologic changes in hepatic blood flow, tumor histopathology, and tumor load, size, and morphology differences between the 99mTc-MAA particles and the 90Y-microspheres [42]. These factors may all limit the concordance between 99mTc-MAA distribution as assessed in the pretreatment procedure and actual distribution of the 90Y-microspheres administered for therapy [41].

Although the ability of 99mTc-MAA to predict radiation dosimetry expected from 90Y-microsphere administration is far from ideal, most of the retrospective studies based on 99mTc-MAA scintigraphy for these estimates have shown a definite dose-response correlation with a threshold value from 120 to 205 Gy [43, 44] and even up to 500 Gy [45]. However, no prospective studies have confirmed these observations, and no single cutoff value that ensures tumor response has been identified as yet.

The dosimetry-based methods utilized to calculate the activity to be administered during radioembolization are described in detail in Chap. 13 of this book (“Radiobiology and Radiation Dosimetry in Nuclear Medicine”).

90Y-Microsphere Administration

During the radioembolization session, the vessel perfusing the tumor is reached under fluoroscopic guidance, and the 90Y-microsphere suspension is injected into the artery feeding the target lesion. A delivery system that allows the administration in a step-by-step manner is useful to avoid early full embolization of the vasculature that prevents infusion of the total estimated activity. The infusion is usually done with alternating injections of iodinated contrast medium and sterile water/glucose solution when using the resin 90Y-microspheres or of saline solution during infusion of the glass 90Y-microspheres. Continuous fluoroscopy monitoring ensures that no stasis occurs during infusion and also serves to confirm that the flow of microspheres is similar to that observed during the prior angiographic workup.

According to topography of the tumor, treatment can be either selective (i.e., directed to one liver lobe) or super-selective (directed to one liver segment).

Posttreatment Scan

Early posttreatment assessment of the pattern of 90Y-microsphere deposition by high-quality imaging is necessary to exclude radioactivity accumulation in gastrointestinal tract and to evaluate the radiation-absorbed dose delivered to the tumor.

A post-therapy planar and SPECT/CT scan based on the bremsstrahlung emission generated by the high-energy β particles of 90Y helps to confirm correct deposition of the radiolabeled microspheres in the tumor lesions [46]. However, the low-resolution and poor-quality imaging obtained from the bremsstrahlung emission does not allow an accurate quantification of microsphere distribution, especially when dealing with small lesions.

More recently imaging with 90Y PET has been used to assess the distribution of the microspheres [47] (Fig. 5). PET imaging is made possible by the fact that, despite the commonly held notion that 90Y is a pure β emitter, in reality, a certain fraction of 90Y decays (even if extremely small, i.e., 32 per million) occur through internal pair production that generates 511 keV annihilation photons. The annihiliation radiation generated from these emissions can be imaged by PET. In the case of radioembolization of liver tumors with 90Y-microspheres, the therapeutic agent remains concentrated in a relatively small volume at the administration site; therefore, even the extremely small fraction of 90Y decays occurring through internal pair production are sufficient to acquire clinically useful PET images for validation and dosimetric purposes [48, 49, 50, 51]. The better resolution images provided by PET may allow easy detection of extrahepatic distribution of 90Y-microspheres and assessment of the absorbed dose delivered during the radioembolization procedure [47, 48].
Fig. 5

Good correspondence in the patterns of intrahepatic distribution of radiolabeled particles injected into the right hepatic artery between pretreatment 99mTc-MAA SPECT/CT (left) and posttreatment 90Y-PET/CT (right). For SPECT/CT, the MIP image is displayed in upper right panel, the axial CT image in upper left panel, the fused axial SPECT/CT image in lower left panel, and the 3D surface volumetric rendering in lower right panel. Similar displays for PET/CT: MIP image in upper right panel, axial CT image in upper left panel, fused PET/CT image in lower left panel, and 3D surface volumetric rendering in lower right panel

Radioembolization with 90Y-microspheres can be performed as an outpatient procedure, and the patient can be discharged from the hospital on the same day of treatment or on the following day.

Patient Follow-Up and Assessment of Response to Therapy

Tumor response to radioembolization is monitored both clinically and radiologically. Routine follow-up includes blood chemistry to monitor possible toxicity due to treatment; in the case of HCC, measurement of the serum levels of the tumor-associated marker AFP serves to assess evolution of the malignant disease. Contrast CT is performed at 1 month posttreatment, while additional CT scans are performed every 3 months to assess response to treatment or progression of disease. Although tumor response to therapy can be assessed by classical RECIST criteria, specific criteria set by the World Health Organization (WHO) and by the European Association for the Study of the Liver (EASL) based on size parameters and on necrosis parameters, respectively, are employed to assess response in the target lesions [13, 52].

In metabolic assessment with [18F]FDG-PET provides useful prognostic information in response of either primary or metastatic liver tumors to trans-arterial radioembolization with 90Y-microspheres [40, 53, 54, 55]. The superiority of functional metabolic imaging with PET versus the conventional morphology-based criteria such as RECIST for early assessment of tumor response to radioembolization with 90Y-microspheres has been demonstrated in different clinical settings such as HCC [56, 57], intrahepatic cholangiocellular carcinoma [55] (Fig. 6), metastatic CRC [58, 59] (Figs. 7 and 8), and liver metastases from breast cancer [60] and metastatic neuroendocrine malignancies (the latter using 68Ga-DOTANOC as the PET tracer) [61] (Fig. 9).
Fig. 6

Left panel: response to trans-arterial therapy with 90Y-microspheres in a patient with intrahepatic cholangiocarcinoma. (a) Axial fused pre-therapeutic [18F]FDG-PET/CT image; (b) corresponding slice of diagnostic CT; (c) axial fused post-therapeutic [18F]FDG-PET/CT image; (d) corresponding slice of diagnostic CT. The SUVmax declined by 70% 3 months after radioembolization, and the serum levels of CA 19-9 fell from 85.2 to 49.2 U/mL; the patient was still alive 12 months after radioembolization without evidence of progression within the liver. Right panel: Kaplan-Meier survival curves as a function of ΔSUV2SD. Responders (blue line) had a significantly (P < 0.05) longer survival than nonresponders (green line) (Modified and reproduced with permission from: Haug et al. [55])

Fig. 7

Left panel: coronal PET (left), axial fused [18F]FDG-PET/CT images (a, c), and axial contrast-enhanced CT (ce-CT) images (b, d) in a patient with metastatic colorectal cancer before and 6 weeks after radioembolization with 90Y-microspheres. (a) Baseline PET/CT shows increased [18F]FDG uptake in metastases in segments I, II, IVa, VII, and VIII. (b) The ce-CT image before radioembolization shows some of the metabolically active metastases as low-attenuation lesions, but several of them are isointense compared to the liver parenchyma and are difficult to delineate, such as the lesions in segment VIII (arrow). (c) PET/CT after radioembolization shows an excellent partial response (PR) with marked reduction in the intensity and extent of uptake in the metastatic lesions. (d) Post-radioembolization ce-CT shows multiple new low-attenuation lesions, which are more apparent as they have become necrotic, such as the metastasis in segment VIII (arrow). This ce-CT image was incorrectly reported as showing disease progression. Right panel: Kaplan-Meier plots of progression-free survival (PFS) in relation to responses seen on [18F]FDG-PET/CT. Patients who had a PR or stable disease on [18F]FDG-PET/CT had median PFS of 12 and 5 months, respectively (Modified and reproduced with permission from: Zerizer et al. [58])

Fig. 8

Left panel: axial fused [18F]FDG-PET/CT images before (a) and 4 weeks after (b) trans-arterial radioembolization with 90Y-microspheres of a patient with metastatic colorectal cancer; the marked metabolic response was associated with a survival of 12 months after treatment. Center panel: Axial fused [18F]FDG-PET/CT images before (a) and 4 weeks after (b) trans-arterial radioembolization with 90Y-microspheres of a patient with metastatic colorectal cancer; this metabolic nonresponder survived 5 months after treatment (Modified and reproduced with permission from: Sabet et al. [59])

Fig. 9

Left upper panel: (a) 68Ga-DOTANOC PET axial slice acquired before trans-arterial radioembolization with 90Y-microspheres shows intense tracer accumulation in a patient with a large metastasis from a neuroendocrine neoplasm in the right hepatic lobe (arrow). (b) Fused unenhanced CT slice and 90Y PET axial slice acquired after administration of 90Y-microspheres shows radioactivity accumulation in the tumor mass with a necrotic core surrounded by a hot circular region. (c) 68Ga-DOTANOC PET axial slice acquired 6 weeks after radioembolization shows significant reduction of tracer uptake in the tumor uptake (arrow), consistent with a molecular response (ΔT/S was −73.4%); overall survival was 34 months. Left lower panel: (a) 68Ga-DOTANOC PET axial slice acquired before trans-arterial radioembolization with 90Y-microspheres shows intense tracer accumulation in a patient with a metastasis from neuroendocrine neoplasm in hepatic segment IV (arrow). (b) Fused unenhanced CT slice and 90Y-PET slice acquired after administration of 90Y-microspheres shows radioactivity accumulation in the tumor mass. (c) 68Ga-DOTANOC PET/CT axial slice acquired 6 weeks after treatment shows substantially unchanged tumor uptake (arrow), consistent with no response (ΔT/S was −24.6%). Overall survival was 23 months. Right panel: Kaplan-Meier survival analysis in relation to ΔT/S measured 6 weeks after radioembolization. Patients with ΔT/S less than −50% (dashed line) had significantly lower (P < 0.001) survival than those with ΔT/S more than −50% (solid line) (Modified and reproduced with permission from: Filippi et al. [61])

90Y-Microsphere Radioembolization Combined with Other Therapies

Radioembolization with 90Y-microspheres is a valid therapeutic option per se, preferably in patients with early stage inoperable liver-predominant malignancies. Nevertheless, it can be used also in combination with systemic molecular/chemotherapies in patients presenting with an intermediate or even advanced stage of HCC [62] or with unresectable liver-predominant metastases from colorectal cancer. Moreover, thanks to its ability to downsize/downgrade the disease, SIRT/TARE may be used as neoadjuvant therapy also in patients with HCC not meeting the criteria for resection, percutaneous ablation, or transplantation.

The clinical situations in which patients with nonresectable/ablatable HCC can be used with radioembolization combined with other therapies can be summarized as follows:
  • Before planned resection or transplantation [63], radioembolization may be considered as a neoadjuvant treatment to reduce the tumor burden and simplify surgery or to stop/slow down tumor progression in order to keep patients on the transplant waiting list or to improve the long-term outcome – even achieving in some cases downstaging of the disease [64]. In selected clinical situations where the non-tumoral liver is too small in terms of functional reserve (thus hindering any type of resection), lobar or segmental selective radioembolization may lead to ipsilateral lobar of segmental parenchymal hypotrophy and contra-lobar hypertrophy (ranging from 21% to 35%) allowing subsequent surgery [65].

  • As an alternative option when other ablative treatments cannot be applied. 90Y-microsphere radioembolization as well trans-arterial chemoembolization may improve the survival in patients with poor prognosis with portal vein occlusion, who are often excluded from a targeted therapy [66].

  • In combination with systemic therapies. Although preliminary data suggest a synergistic beneficial effect of 90Y-microsphere radioembolization when combined with sorafenib (with associated tolerable toxicity) [67, 68, 69, 70], large-scale multicenter trials are still ongoing to confirm these data and to define the safety profile and the impact of the combination on survival of this combination regimen.

  • In patients with unresectable liver-predominant metastases from colorectal cancer, preliminary results of the SIRFLOX study indicate that radioembolization combined with systemic therapy as first-line treatment can lead to downstaging of the disease in a significant proportion of cases and to improved PFS for the liver lesions (but not overall PFS, while the follow-up phase is ongoing for overall survival) [71].

  • As a second-line treatment and in the salvage setting for liver-predominant metastatic colorectal cancer, there are clinical evidences that combination of radioembolization and systemic chemotherapy using radiosensitizing drugs (i.e., oxaliplatin, 5-FU, and irinotecan) is safe, with preliminary results indicating a 79% response rate [72].

Clinical Indications

Radioembolization with 90Y-microspheres has shown to be an effective procedure with significant impact on survival of patients with either primary or secondary liver malignancies.

Primary Liver Tumors

Hepatocellular Carcinoma

Radioembolization as a treatment option has been extensively investigated for the most common primary liver malignancy, i.e., HCC, especially after Geschwind and coworkers published their landmark comprehensive analysis on the use of 90Y-microspheres for HCC. Besides demonstrating overall clinical safety and benefit of this therapy, the study also indicated better survival as treatment was employed earlier in the course of disease, i.e., in Okuda stage I (63% for 1-year survival and 628-day median survival) rather than in Okuda stage II patients (51% for 1-year survival and 384-day median survival, with P = 0.02) [73].

The response rates to radioembolization with 90Y-microspheres may vary widely not only because of variable tumor biology but also because of differences in evaluation times or in treatment intensity. Tumor shrinkage after therapy may take months to occur, with a median time to response of approximately 6 months according to WHO criteria [74]. Nevertheless, response in tumor size is not an adequate parameter to define all the antitumor effects of therapy. When combining different response criteria, such as tumor size and arterial contrast enhancement with the EASL response criteria, the overall tumor response rates vary between 40% and 90%, with a disease control rate in targeted lesion of 80–100%. According to changes in vascular enhancement, time to response occurs in the treated tumor lesions earlier than response in tumor size, around 2 months after 90Y-microsphere radioembolization [74].

Surgery is the optimal standard of care with curative intents for patients with HCC; however, resection is possible only for lesions limited in size and number and if the liver function is well preserved; the latter is not a frequent condition considering that most HCCs originate in patients with liver cirrhosis. On the other hand, patients with a single lesion <5 cm in diameter, or with ≤3 lesions, all <3 cm without extrahepatic metastases or portal vein thrombosis (PVT), are eligible for liver transplantation. Nevertheless, orthotopic liver transplantation has had a limited role in the management of patients with HCC due both to limited availability of donor organs and to dropout of patients because of tumor progression. Since radioembolization has been shown to slow the progression of HCC, this procedure may allow patients more time to wait for donor organs and thus increases their chance of undergoing liver transplant [75, 76, 77].

Patients whose disease is too advanced to meet transplant criteria, but do not have malignant PVT or metastatic HCC, are good candidates for radioembolization. In fact, radioembolization has been shown to downstage the disease so that 56% of the patients who were initially stratified as non-eligible for transplant according to Milan criteria then become eligible for transplant after therapy; 8 out of 34 downstaged patients actually underwent subsequent liver transplantation, with 84%, 54%, and 27% overall survivals, respectively, at 1, 2, and 3 years. In addition to downstaging, radioembolization also prolongs overall survival of these patients [75, 76, 77].

Survival benefit following radioembolization has been observed also in patients with malignant vascular involvement, with a 70% response rate according to EASL criteria [78]. The presence of distant metastases contraindicates treatment, as a survival benefit has not been demonstrated for this subset of patients.

Intrahepatic Cholangiocarcinoma

Resection has a modest survival benefit in patients who have resectable intrahepatic cholangiocarcinoma (ICC). Some improvement in survival has been observed after trans-arterial chemoembolization, but toxicity associated with this treatment remains high. On the other hand, while radioembolization has been shown to be an effective treatment for HCC, its role in the management of ICC patients has not been extensively investigated. Nevertheless, a pilot study in 24 patients with biopsy-proven ICC has shown favorable tumor response and favorable survival outcomes following therapy with 90Y-microspheres, especially for patients with better ECOG performance status [79].

A recent systematic review on the use of TARE in the treatment of ICC identified 12 studies including a total of 73 patients. PR and SD at 3 months were reported in 28% and 54% of patients, respectively. In a pooled analysis, the overall weighed median survival was 15.5 months, and downstaging to surgery was achieved in seven patients [80]. The combination of TARE and chemotherapy as a strategy for downstaging ICC to achieve resectability has recently been proposed, with encouraging initial data [81]. However, when comparing different locoregional treatments for ICC, TARE may not be the most effective approach. In a comparative analysis, TARE performed second in terms of tumor response to intra-arterial chemotherapy but was more effective than TACE or DEB-TACE both in terms of tumor response and in terms of overall survival. In fact, overall survival was 22.8 months for intra-arterial chemotherapy, 13.9 months for TARE, 12.4 months for TACE, and 12.3 months for DEB-TACE. Nevertheless, intra-arterial chemotherapy had the highest toxicity [82]. Despite the lack of randomized controlled trials, locoregional treatments appear to be somewhat more effective than the current standard chemotherapy regimens with oxaliplatin and gemcitabine [83]. For patients with unresectable ICC, trans-arterial radioembolization with 90Y-microspheres seems to be best suited for patients who are not eligible for intra-arterial chemotherapy.

[18F]FDG-PET is the best independent predictor for patient outcome after radioembolization treatment, based on reduction in the metabolically active tumor volume at 3 months after therapy [55].

Metastatic Liver Tumors

Extrahepatic metastasis and comorbidities limit the role of surgical resection in patients with secondary liver tumors [84]. The use of radioembolization in these patients has been extensively investigated, either as a single treatment or in adjunct to systemic chemotherapy.

Metastatic Colorectal Carcinoma

Liver metastases from colorectal carcinoma (CRC) are resectable in less than 10% of the patients [84]. Radioembolization has been shown to be effective in the treatment of metastatic CRC to the liver. Candidates for radioembolization are those patients who have unresectable liver metastases and are on systemic chemotherapy or have failed to respond to first- or second-line chemotherapy. In these patients, [18F]FDG-PET has been shown to be more sensitive than CT for assessing tumor response to radioembolization [54, 85]. Furthermore, reduction of the hepatic metastatic load can be assessed quantitatively by [18F]FDG-PET, by evaluating the percent change of total liver SUV after treatment [53, 54].

Most of the studies on 90Y-microsphere TARE reported so far have been conducted in patients with chemorefractory liver-predominant metastatic CRC. A systematic review of 20 studies including a total of 979 patients treated with resin 90Y-microspheres has demonstrated the overall safety and efficacy of TARE for unresectable, chemorefractory metastatic CRC, with a median time to intrahepatic progression of 9 months and overall survival of 12 months [86].

In a randomized controlled clinical trial involving 74 patients, the combination of systemic therapy with radioembolization resulted in significantly better tumor response (44% objective response versus 17.6% in the control group), longer time to progression, and longer survival than systemic chemotherapy alone [87]; furthermore, the safety profile of the combined regimen was acceptable [87], and dose escalation studies have shown improved tumor response with increasing doses [88].

Several prospective trials have investigated the efficacy of TARE in combination with systemic chemotherapy versus systemic chemotherapy alone. In an early study, TARE combined with systemic 5-fluorouracil (5-FU) induced better objective response rates than 5-FU alone: 73% versus 0%, with time to progression of 18.6 months versus 3.6 months and overall survival of 29.4 months versus 12.8 months [89]. More recent prospective studies have evaluated chemotherapy regimen more up-to-date than 5-FU. In a first-line setting, TARE combined with FOLFOX4 achieved a 90% PR rate [90], while TARE with irinotecan in a second-line setting after failure of previous chemotherapy reported an overall 87% response rate, with 48% PR and 39% SD [91]. In the SIRFLOX study, a randomized clinical trial including 530 patients, the results of mFOLFOX 6 with or without bevacizumab were compared with TARE + mFOLFOX 6 with or without bevacizumab. While there was no difference in progression-free survival, there was a significant difference in progression-free survival in the liver, favoring the combination with TARE (20.5 months) over chemotherapy alone (12.6 months, with P = 0.002). Objective response rates were somewhat better with the combination therapy than with chemotherapy alone (76.4% versus 68.1%, but without reaching statistical significance, with P = 0.113) [92].

Also the recently published results obtained by Hong and coworkers show that radioembolization is safe and effective as a salvage therapy in the management of metastatic CRC when compared with chemoembolization [93].

A recent systematic review on TARE in unresectable, chemorefractory metastatic CRC includes 20 studies for a total of 979 patients enrolled after failure of two to five lines of chemotherapy. TARE achieved CR, PR, and SD in 0% (range 0–6%), 31% (range 0–73%), and 40.5% (range 17–76%) of patients, respectively. The median time to intrahepatic progression was 9 months (range 6–16), and median overall survival was 12 months (range 8.3–36) [94]. In a large multicenter trial, overall survival was strongly dependent on previous treatments; in particular, median survival after 90Y-microsphere radioembolization was 13 months (95% CI 10.5–14.6) when TARE was performed as second-line treatment, 9 months (95% CI 7.8–11.0) for third-line treatment, and 8.1 months (95% CI 6.4–9.3) for fourth-line treatment and over, respectively, with P < 0.001 [95].

Metastatic Neuroendocrine Tumors

Several neuroendocrine tumors , such as carcinoids, VIPomas, gastrinomas, and somatostatinomas, metastasize to the liver. These lesions are often well arterialized and represent a target for trans-arterial therapies, similarly to patients with HCC. The goals of treatment in these patients are both control of symptoms and survival. Systemic chemotherapy and ablative procedures have all been shown to produce modest benefit in these patients. Patients with unresectable disease are considered candidates for radioembolization. The results obtained in a multicenter study including 148 patients have shown that radioembolization of metastatic neuroendocrine tumors to the liver is safe and effective, with very high response rates: any response in 95.1% of patients and progressive disease in only 4.9% of the patients. Response rates were even longer than 2 years, especially in non-pancreatic NETs [96, 97].

Absolute and Relative Contraindications

Two absolute contraindications exist for therapy with 90Y-microspheres intra-arterially. The main contraindication is represented by a pretreatment 99mTc-MAA scan demonstrating significant hepato-pulmonary shunting. This occurrence would in fact result in the delivery of a radiation dose to the lungs greater than 30 Gy with a single infusion or as much as 50 Gy for multiple infusions. The second contraindication is the inability to prevent deposition of the radiolabeled microspheres in the gastrointestinal tract. Relative contraindications include reduced pulmonary function, inadequate functional liver reserve, serum creatinine >2.0 mg/dL, and platelet count <75 × 109/L. When such relative contraindications exist, clinical judgment should be exercised for determining whether or not a patient is appropriate to undergo the procedure, taking into consideration either 90Y-microspheres or 131I-lipiodol [98].

Early and Late Toxicities

The most common clinical toxicity observed with 90Y-microsphere therapy is a mild post-embolic syndrome. Similarly as observed with other embolic treatments such as trans-arterial chemoembolization, this syndrome includes fatigue, vague abdominal discomfort, pain, and fever [99, 100]. Other toxicities that can occur as a result of nontarget radiation (and should therefore be avoided by adequate pre-therapy procedures and by accurate treatment planning) include the following: cholecystitis, gastric ulceration, gastroduodenitis, pancreatitis, radiation pneumonitis, and RILD [75, 78, 79, 101]. By adopting meticulous planning, careful selection of patients, and proper techniques, the majority of these toxicities can be mitigated. Finally, a common hematologic toxicity observed in the immediate post-radioembolization period is represented by lymphopenia, not an unexpected finding considering the sensitivity of lymphocytes to radiation. Despite this possible occurrence, no infectious complications have been reported [13, 33, 52, 53, 54, 99, 100, 101, 102].

Perspectives on Radioembolization for Primary and Metastatic Liver Tumors

A growing body of evidence supports the use of TARE with 90Y-microspheres as an effective monotherapy in patients with HCC. Future avenues to be explored concern the scenario of combination therapies with systemic and locoregional agents, specifically sorafenib and TARE, in the adjuvant or neoadjuvant setting. Although the mechanisms of action for the two therapeutic approaches can in principle be considered as complementary one to the other from the pathophysiologic point of view, there are currently scarce data confirming the actual clinical benefit of regimens based on this combination.

In the only prospective study so far reported for combination therapy of TARE with sorafenib, the rate of objective responses was 25%, somewhat disappointing with respect to that expected on the basis of the underlying rationale. Moreover, 39% of the patients could not complete the prescribed dose of sorafenib due to important side effects [67]. On the other hand, initial safety results in the first 40 patients enrolled in a randomized controlled clinical trial comparing TARE with resin 90Y-microspheres followed by sorafenib with sorafenib only indicate a similar tolerance for the two treatment arms [69]. Long-term outcome data from ongoing randomized controlled clinical trials such as SORAMIC, SARAH, or SIRveNIB (based on the use of resin 90Y-microspheres) or STOP-HCC (using glass 90Y-microspheres) have not been published yet.

Regarding treatment of metastatic disease, there is the need of randomized controlled clinical trials comparing TARE with up-to-date chemotherapy regimens, since the few data so far available have been obtained in studies comparing the efficacy of therapy with resin 90Y-microspheres versus chemotherapeutic regimen that are now obsolete or the studies lack survival data. An ongoing randomized controlled clinical phase III trial evaluates treatment with glass 90Y-microspheres and second-line chemotherapy after failure of first-line chemotherapy in comparison to second-line chemotherapy alone for metastatic CRC; 360 patients have been enrolled in this trial, and the first results of the analysis are expected to be released soon.

The FOXFIRE global is an international phase III study assessing the value of additional resin 90Y-microspheres in the setting of first-line treatment with FOLFOX6m (NCT01721954). Enrollment of 530 patients has been completed, and the preliminary results are encouraging, with significantly prolonged PFS in the liver by competing risk analysis, from a median of 12.6 months for control patients to 20.5 months (P = 0.002) for patients receiving resin 90Y-microspheres; this translates into a 31% reduction in the risk of disease progression in the liver. Pooling the data of studies with similar designs (SIRFLOX, FOXFIRE, and FOXFIRE global) from over 1,100 patients will provide sufficient statistical power to assess the survival benefit derived from the addition of resin 90Y-microspheres to current chemotherapy regimens. Survival data from the three combined studies are expected to be released in 2017.

Further ongoing studies evaluate the role of TARE in uveal melanoma with liver metastasis (SIRUM trial, NCT01473004) or the combination of TARE and pasireotide and everolimus in liver metastatic neuroendocrine tumors (NCT01469572) [103].

References

  1. 1.
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    van der Pool AE, Damhuis RA, Ijzermans JN, de Wilt JH, Eggermont AM, Kranse R, Verhoef C. Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series. Colorectal Dis. 2012;14:56–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation hepatitis. Am J Roentgenol Radium Ther Nucl Med. 1965;93:200–8.PubMedGoogle Scholar
  5. 5.
    Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys. 1995;31:1237–48.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu H, Burke CT. Comparison of percutaneous ablation technologies in the treatment of malignant liver tumors. Semin Interv Radiol. 2014;31:129–37.CrossRefGoogle Scholar
  7. 7.
    Stuart K. Chemoembolization in the management of liver tumors. Oncologist. 2003;8:425–37.PubMedCrossRefGoogle Scholar
  8. 8.
    Geschwind JFH. Chemoembolization for hepatocellular carcinoma: where does the truth lie? J Vasc Interv Radiol. 2002;13:991–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Kettenbach J, Stadler A, Katzler IV, et al. Drug-loaded microspheres for the treatment of liver cancer: review of current results. Cardiovasc Intervent Radiol. 2008;31:468–76.PubMedCrossRefGoogle Scholar
  12. 12.
    European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASLEORT clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.CrossRefGoogle Scholar
  13. 13.
    Salem R, Lewandowski RJ, Atassi B, et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol. 2005;16:1627–39.PubMedCrossRefGoogle Scholar
  14. 14.
    Raoul JL, Bourguet P, Bretagne JF, et al. Hepatic artery injection of I-131-labelled lipiodol. I. Biodistribution study results in patients with hepatocellular carcinoma. Radiology. 1988;168:541–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Nakajo M, Kobayashi H, Shimabukuro K, et al. Biodistribution and in vivo kinetics of iodine-131 lipiodol infused via the hepatic artery of patients with hepatic cancers. J Nucl Med. 1988;29:1066–77.PubMedGoogle Scholar
  16. 16.
    Smits ML, Nijsen JF, van den Bosch MA, Lam MG, Vente MA, Huijbregts JE, et al. Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial. J Exp Clin Cancer Res. 2010;29:70.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Nowicki ML, Cwikla JB, Sankowski AJ, Shcherbinin S, Grimmes J, Celler A, et al. Initial study of radiological and clinical efficacy radioembolization using 188Re-human serum albumin (HSA) microspheres in patients with progressive, unresectable primary or secondary liver cancers. Med Sci Monit. 2014;20:1353–62.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bhattacharya S, Dhillon AP, Winslet MC, et al. Human liver cancer cells and endothelial cells incorporate iodised oil. Br J Cancer. 1996;73:877–81.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Madsen MT, Park CH, Thakur ML. Dosimetry of iodine-131 ethiodol in the treatment of hepatoma. J Nucl Med. 1988;29:1038–44.PubMedGoogle Scholar
  20. 20.
    Monsieurs MA, Bacher K, Brans B, et al. Patient dosimetry for 131I-lipiodol therapy. Eur J Nucl Med Mol Imaging. 2003;30:554–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Bhattacharya S, Novell JR, Dusheiko GM, Hilson AJ, Dick R, Hobbs KE. Epirubicin-lipiodol chemotherapy versus 131iodine-lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma. Cancer. 1995;76:2202–10.PubMedCrossRefGoogle Scholar
  22. 22.
    Yoo HS, Park CH, Lee JT, et al. Small hepatocellular carcinoma: high dose internal radiation therapy with superselective intra-arterial injection of I-131-labeled Lipiodol. Cancer Chemother Pharmacol. 1994;33:S128–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Leung WT, Lau WY, Ho S, et al. Selective internal radiation therapy with intra-arterial iodine-131-lipiodol in inoperable hepatocellular carcinoma. J Nucl Med. 1994;35:1313–8.PubMedGoogle Scholar
  24. 24.
    Raoul JL, Guyader D, Bretagne JF, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med. 1994;35:1782–7.PubMedGoogle Scholar
  25. 25.
    Boucher E, Garin E, Guillygomac’h A, Olivie D, Boudjema K, Raoul JL. Intra-arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma. Radiother Oncol. 2007;82:76–82.PubMedCrossRefGoogle Scholar
  26. 26.
    Partensky C, Sassolas G, Henry L, Paliard P, Maddern GJ. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study. Arch Surg. 2000;135:1298–300.PubMedCrossRefGoogle Scholar
  27. 27.
    Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Ann Surg. 2008;247:43–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee YS, Jeong JM, Kim YJ, et al. Synthesis of 188Re-labelled long chain alkyl diaminedithiol for therapy of liver cancer. Nucl Med Commun. 2002;23:237–42.PubMedCrossRefGoogle Scholar
  29. 29.
    De Ruyck K, Lambert B, Bacher K, et al. Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma. J Nucl Med. 2004;45:612–8.PubMedGoogle Scholar
  30. 30.
    Kumar A, Srivastava DN, Chau TT, et al. Inoperable hepatocellular carcinoma: transarterial 188Re HDD-labeled iodized oil for treatment. Prospective multicenter clinical trial. Radiology. 2007;243:509–19.PubMedCrossRefGoogle Scholar
  31. 31.
    Sato K, Lewandowski RJ, Bui JT, et al. Treatment of unresectable primary and metastatic liver cancer with yttrium-90 microspheres (TheraSphere): assessment of hepatic arterial embolization. Cardiovasc Intervent Radiol. 2006;29:522–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol. 2006;17:1251–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Hamami ME, Poeppel TD, Müller S, Heusner T, Bockisch A, Hilgard P, Antoch G. SPECT/CT with 99mTc-MAA in radioembolization with 90Y microspheres in patients with hepatocellular cancer. J Nucl Med. 2009;50:688–92.PubMedCrossRefGoogle Scholar
  34. 34.
    Grosser OS, Rufi J, Kupitz D, Pethe A, Ulrich G, Genseke P, et al. Pharmacokinetics of 99mTc-MAA- and 99mTc-HSA microspheres used in preradioembolization dosimetry: influence on the liver–lung shunt. J Nucl Med. 2016;57:925–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Sabet A, Ahmadzadehfar H, Muckle M, Haslerud T, Wilhelm K, Biersack HJ, et al. Significance of oral administration of sodium perchlorate in planning liver-directed radioembolisation. J Nucl Med. 2011;52:1063–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Dale RG. Dose-rate effects in targeted radiotherapy. Phys Med Biol. 1996;41:1871–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Ho S, Lau WY, Leung TW, Chan M, Chan KW, Lee WY, et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumors. Eur J Nucl Med. 1996;23:947–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Kennedy AS, Dezarn WA, McNeillie P, Overton C, England M, Sailer SL. Fractionation, dose selection, and response of hepatic metastases of neuroendocrine tumors after 90Y-microsphere brachytherapy. Brachytheraphy. 2006;5:103–4.Google Scholar
  39. 39.
    Kennedy AS, Dezarn WA, McNeillie P, Overton C, England M, Sailer SL. Dose selection of resin 90Y-micrspheres for liver brachytherapy: a single center review. Brachytheraphy. 2006;5:104.Google Scholar
  40. 40.
    Flamen P, Vanderlinden B, Delatte P, Ghanem G, Ameye L, Van Den Eyden M, et al. Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolisation therapy with yttrium-90 labeled resin microspheres. Phys Med Biol. 2008;53:6591–693.PubMedCrossRefGoogle Scholar
  41. 41.
    Jiang M, Fischman A, Nowakowski FS, et al. Segmental perfusion differences on paired Tc-99m macroaggregated albumin (MAA) hepatic perfusion imaging and yttrium-90 (Y-90) bremsstrahlung imaging studies in SIR-sphere radioembolization: associations with angiography. J Nucl Med Radiat Ther. 2012;3:122.CrossRefGoogle Scholar
  42. 42.
    Wondergem M, Smits MLJ, Elschot M, de Jong HWAM, Verkooijen HM, van den Bosch MAAJ, Nijsen JFW, Lam MGEH. 99mTc-Macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization. J Nucl Med. 2013;54:1294–301.PubMedCrossRefGoogle Scholar
  43. 43.
    Lau WY, Sangro B, Chen PJ, Cheng SQ, Chow P, Lee RC, et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology. 2013;84:311–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Garin E, Lenoir L, Rolland Y, Edeline J, Mesbah H, Laffont S, et al. Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results. J Nucl Med. 2012;53:255–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi C, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology. 2013;57:1826–37.PubMedCrossRefGoogle Scholar
  46. 46.
    Ahmadzadehfar H, Muckle M, Sabet A, Wilhelm K, Kuhl C, Biermann K, et al. The significance of bremsstrahlung SPECT/CT after yttrium-90 radioembolisation treatment in the prediction of extrahepatic side effects. Eur J Nucl Med Mol Imaging. 2011;39:309–15.CrossRefGoogle Scholar
  47. 47.
    Lhommel R, Goffette P, del Eynde V, Jamar F, Pauwels S, Bilbao JI, et al. Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT. Eur J Nucl Med Mol Imaging. 2009;36:1696.PubMedCrossRefGoogle Scholar
  48. 48.
    Lhommel R, van Elmbt L, Goffette P, et al. Feasibility of 90Y TOF PET-based dosimetry in liver metastasis therapy using SIR-spheres. Eur J Nucl Med Mol Imaging. 2010;37:1654–62.PubMedCrossRefGoogle Scholar
  49. 49.
    Kao YH, Tan EH, Lim KY, Eng CE, Goh SW. Yttrium-90 internal pair production imaging using first generation PET/CT provides high resolution images for qualitative diagnostic purposes. Br J Radiol. 2012;85:1018–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Wright CL, Zhang J, Tweedle MF, Knopp MV, Hall NC. Theranostic imaging of yttrium-90. Biomed Res Int. 2015;2015:481279.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Gnesin S, Canetti L, Adib S, Cherbuin N, Silva-Monteiro M, Bize P, et al. Partition model based 99mTc-MAA SPECT/CT predictive dosimetry compared to 90Y TOF PET/CT post treatment dosimetry in radioembolisation of hepatocellular carcinoma: a quantitative agreement comparison. J Nucl Med. 2016 Jun 15 [Epub ahead of print].Google Scholar
  52. 52.
    Riaz A, Memon K, Miller FH, et al. Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic-pathologic correlation. J Hepatol. 2011;54:695–704.PubMedCrossRefGoogle Scholar
  53. 53.
    Wong CY, Qing F, Savin M, et al. Reduction of metastatic load to liver after intraarterial hepatic yttrium-90 radioembolization as evaluated by [18F]fluorodeoxyglucose positron emission tomographic imaging. J Vasc Interv Radiol. 2005;16:1101–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Miller FH, Keppke AL, Reddy D, Huang J, Jin J, Mulcahy MF, Salem R. Response of liver metastases after treatment with yttrium-90 microspheres: role of size, necrosis, and PET. AJR Am J Roentgenol. 2007;188:776–83.PubMedCrossRefGoogle Scholar
  55. 55.
    Haug AR, Heinemann V, Bruns CJ, Hoffmann R, Jakobs T, Bartenstein P, Hacker M. 18F-FDG PET independently predicts survival in patients with cholangiocellular carcinoma treated with 90Y microspheres. Eur J Nucl Med Mol Imaging. 2011;38:1037–45.PubMedCrossRefGoogle Scholar
  56. 56.
    Sabet A, Ahmadzadehfar H, Bruhman J, Sabet A, Meyer C, Wasmuth JC, et al. Survival in patients with hepatocellular carcinoma treated with 90Y-microsphere radioembolization. Prediction by 18F-FDG PET. Nuklearmedizin. 2014;53:39–45.PubMedCrossRefGoogle Scholar
  57. 57.
    Hartenbach M, Weber S, Albert NL, Hartenbach S, Hirtl A, Zacherl MJ, et al. Evaluating treatment response of radioembolization in intermediate-stage hepatocellular carcinoma patients using 18F-fluoroethylcholine PET/CT. J Nucl Med. 2015;56:1661–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Zerizer I, Al-Nahhas A, Towey D, Tait P, Ariff B, Wasan H, et al. The role of early 18F-FDG PET/CT in prediction of progression-free survival after 90Y radioembolization: comparison with RECIST and tumour density criteria. Eur J Nucl Med Mol Imaging. 2012;39:1391–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Sabet A, Meyer C, Aouf A, Sabet A, Ghamari S, Pieper CC, et al. Early post-treatment FDG PET predicts survival after 90Y microsphere radioembolization in liver-dominant metastatic colorectal cancer. Eur J Nucl Med Mol Imaging. 2015;42:370–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Haug AR, Tiega Donfack BP, Trumm C, Zech CJ, Michl M, Laubender RP, et al. 18F-FDG PET/CT predicts survival after radioembolization of hepatic metastases from breast cancer. J Nucl Med. 2012;53:371–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Filippi L, Scopinaro F, Pelle G, Cianni R, Salvatori R, Schillaci O, et al. Molecular response assessed by 68Ga-DOTANOC and survival after 90Y microsphere therapy in patients with liver metastases from neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2016;43:432–40.PubMedCrossRefGoogle Scholar
  62. 62.
    Fidelman N, Kerlan Jr RK. Transarterial chemoembolization and 90Y radioembolization for hepatocellular carcinoma: review of current applications beyond intermediate-stage disease. AJR Am J Roentgenol. 2015;205:742–52.PubMedCrossRefGoogle Scholar
  63. 63.
    Braat AJ, Huijbregts JE, Molenaar IQ, Borel Rinkes IH, van den Bosch MA, Lam MG. Hepatic radioembolization as a bridge to liver surgery. Front Oncol. 2014;4:199.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lewandowski RJ, Donahue L, Chokechanachaisakul A, Kulik L, Mouli S, Caicedo J, et al. 90Y radiation lobectomy: outcomes following surgical resection in patients with hepatic tumors and small future liver remnant volumes. J Surg Oncol. 2016;114:99–105.PubMedCrossRefGoogle Scholar
  65. 65.
    Teo JY, Allen Jr JC, Ng DC, Choo SP, Tai DW, Chang JP, et al. A systematic review of contralateral liver lobe hypertrophy after unilobar selective internal radiation therapy with Y90. HPB (Oxford). 2016;18:7–12.CrossRefGoogle Scholar
  66. 66.
    Johnson GE, Monsky WL, Valji K, Hippe DS, Padia SA. Yttrium-90 radioembolization as a salvage treatment following chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2016;27:1123–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Chow PK, Poon DY, Khin MW, Singh H, Han HS, Goh AS, Asia-Pacific Hepatocellular Carcinoma Trials Group, et al. Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma. PLoS One. 2014;9(3), e90909.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kulik L, Vouche M, Koppe S, Lewandowski RJ, Mulcahy MF, Ganger D, et al. Prospective randomized pilot study of Y90 +/− sorafenib as bridge to transplantation in hepatocellular carcinoma. J Hepatol. 2014;61:309–17.PubMedCrossRefGoogle Scholar
  69. 69.
    Ricke J, Bulla K, Kolligs F, Peck-Radosavljevic M, Reimer P, Sangro B, et al. Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC. Liver Int. 2015;35:620–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Lorenzin D, Pravisani R, Leo CA, Bugiantella W, Soardo G, Carnelutti A, et al. Complete remission of unresectable hepatocellular carcinoma after combined sorafenib and adjuvant yttrium-90 radioembolization. Cancer Biother Radiopharm. 2016;31:65–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Sangha BS, Nimeiri H, Hickey R, Salem R, Lewandowski RJ. Radioembolization as a treatment strategy for metastatic colorectal cancer to the liver: what can we learn from the SIRFLOX trial? Curr Treat Options Oncol. 2016;17:26.PubMedCrossRefGoogle Scholar
  72. 72.
    Dutton SJ, Kenealy N, Love SB, Wasan HS, Sharma RA, FOXFIRE Protocol Development Group and the NCRI Colorectal Clinical Study Group. FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal cancer. BMC Cancer. 2014;14:497.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Geschwind JF, Salem R, Carr BI, et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology. 2004;127:S194–205.PubMedCrossRefGoogle Scholar
  74. 74.
    Salem R, Lewandowsky RJ, Mulcahy MF, et al. Radioembolisation for hepatocellular carcinoma using Yttrium-90 microspheres. a comprehensive report of long term outcomes. Gastroenterology. 2010;138:52–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere®) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. 2006;94:572–86.PubMedCrossRefGoogle Scholar
  76. 76.
    Tohme S, Sukato D, Chen HW, Amesur N, Zajko AB, Humar A, et al. Yttrium-90 radioembolization as a bridge to liver transplantation: a single-institution experience. J Vasc Interv Radiol. 2013;24:1632–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Abdelfattah MR, Al-Sebayel M, Broering D, Alsuhaibani H. Radioembolization using yttrium-90 microspheres as bridging and downstaging treatment for unresectable hepatocellular carcinoma before liver transplantation: initial single-center experience. Transplant Proc. 2015;47:408–11.PubMedCrossRefGoogle Scholar
  78. 78.
    Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2007;41:71–81.CrossRefGoogle Scholar
  79. 79.
    Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer. 2008;113:2119–28.PubMedCrossRefGoogle Scholar
  80. 80.
    Al-Adra DP, Gill RS, Axford SJ, Shi X, Kneteman N, Liau SS. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol. 2015;41:120–7.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Rayar M, Sulpice L, Edeline J, Garin E, Levi Sandri GB, Meunier B, et al. Intra-arterial yttrium-90 radioembolization combined with systemic chemotherapy is a promising method for downstaging unresectable huge intrahepatic cholangiocarcinoma to surgical treatment. Ann Surg Oncol. 2015;22:3102–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Boehm LM, Jayakrishnan TT, Miura JT, Zacharias AJ, Johnston FM, Turaga KK, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111:213–20.PubMedCrossRefGoogle Scholar
  83. 83.
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.PubMedCrossRefGoogle Scholar
  84. 84.
    Welsh JS, Kennedy AS, Thomadsen B. Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2006;66:S62–73.PubMedCrossRefGoogle Scholar
  85. 85.
    Wong CY, Salem R, Raman S, Gates VL, Dworkin HJ. Evaluating 90Y-glass microsphere treatment response of unresectable colorectal liver metastases by [18F]FDG PET: a comparison with CT or MRI. Eur J Nucl Med Mol Imaging. 2002;29:815–20.PubMedCrossRefGoogle Scholar
  86. 86.
    Van den Eynde M, Flamen P, El Nakadi I, Liberale G, Delatte P, Larsimont D, Hendlisz A. Inducing resectability of chemotherapy refractory colorectal liver metastasis by radioembolization with yttrium-90 microspheres. Clin Nucl Med. 2008;33:697–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12:1711–20.PubMedCrossRefGoogle Scholar
  88. 88.
    Goin JE, Dancey JE, Hermann GA, Sickles CJ, Roberts CA, MacDonald JS. Treatment of unresectable metastatic colorectal carcinoma to the liver with intrahepatic Y-90 microspheres: a dose-ranging study. World J Nucl Med. 2003;2:216–25.Google Scholar
  89. 89.
    Van Hazel G, Blackwell A, Anderson J, Price D, Moroz P, Bower G, Cardaci G, Gray B. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88:78–85.PubMedCrossRefGoogle Scholar
  90. 90.
    Sharma RA, Van Hazel GA, Morgan B, Berry DP, Blanshard K, Price D, Bower G, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25:1099–106.PubMedCrossRefGoogle Scholar
  91. 91.
    van Hazel GA, Pavlakis N, Goldstein D, Olver IN, Tapner MJ, Price D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009;27:4089–95.PubMedCrossRefGoogle Scholar
  92. 92.
    Gibbs P, Heinemann V, Sharma NK, Findlay MPN, Ricke J, Gebski V, SIRFLOX Study Group, et al. SIRFLOX: randomized phase III trial comparing firstline mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33(Suppl):3502.Google Scholar
  93. 93.
    Hong K, McBride JD, Georgiades CS, et al. Salvage therapy for liver-dominant colorectal metastatic adenocarcinoma: comparison between transcatheter arterial chemoembolization versus yttrium-90 radioembolization. J Vasc Interv Radiol. 2009;20:360–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Saxena A, Bester L, Shan L, Perera M, Gibbs P, Meteling B, et al. A systematic review on the safety and efficacy of yttrium-90 radioembolization for unresectable, chemorefractory colorectal cancer liver metastases. J Cancer Res Clin Oncol. 2014;140:537–47.PubMedCrossRefGoogle Scholar
  95. 95.
    Kennedy AS, Ball D, Cohen SJ, Cohn M, Coldwell DM, Drooz A, et al. Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres. J Gastrointest Oncol. 2015;6:134–42.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008;247:1029–35.PubMedCrossRefGoogle Scholar
  97. 97.
    Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in patients. Am J Clin Oncol. 2008;31:271–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Giammarile F, Bodei L, Chiesa C, Flux G, Forrer F, Kraeber-Bodere F, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging. 2011;38:1393–406.PubMedCrossRefGoogle Scholar
  99. 99.
    Shepherd FA, Rotstein LE, Houle S, Yip TC, Paul K, Sniderman KW. A phase I dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma. Cancer. 1992;70:2250–4.PubMedCrossRefGoogle Scholar
  100. 100.
    Yan ZP, Lin G, Zhao HY, Dong YH. An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer. Cancer. 1993;72:3210–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Lau WY, Leung WT, Ho S, Cotton LA, Ensminger WD, Shapiro B. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study. Br J Cancer. 1994;70:994–9.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Andrews JC, Walker SC, Ackermann RJ, Cotton LA, Ensminger WD, Shapiro B. Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up. J Nucl Med. 1994;35:1637–44.PubMedGoogle Scholar
  103. 103.
    Mahnken AH. Current status of transarterial radioembolization. World J Radiol. 2016;8:449–59.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Giuseppe Boni
    • 1
    Email author
  • Federica Guidoccio
    • 1
  • Duccio Volterrani
    • 1
  • Giuliano Mariani
    • 1
  1. 1.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly

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