Radioembolization for the Treatment of Unresectable Liver Cancer: Initial Experience at a Single Center

Diagn Interv Radiol 2010; 16:70–78 INTERVENTIONAL RADIOLOGY © Turkish Society of Radiology 2010 ORIGINAL ARTICLE

Radioembolization for the treatment of unresectable liver cancer: initial experience at a single center

Bora Peynircioğlu, Barbaros Çil, Fani Bozkurt, Ece Aydemir, Ömer Uğur, Ferhun Balkancı

PURPOSE nresectable liver cancer from primary or metastatic cancer causes Radioembolization with yttrium-90 microsphere (Y-90) ther- significant suffering and eventual death in many patients world- apy with SIR-Spheres® (Sirtex Medical, Lane Cove, Australia) was approved by the Turkish Ministry of Health in April 2008. Uwide each year. Yttrium-90 microsphere (Y-90) therapy for he- In this study, we present the preliminary experience at a terti- patic tumors—so-called radioembolization—has been increasingly used ary care center with early follow-up results of Y-90 therapy, as in the last decade, although its first clinical trials date back to the early well as a review of the related literature. 1960s (1). Transarterial treatment of liver tumors has been performed MATERIALS AND METHODS for 30 years all over the world. Chemoembolization was first introduced Complete evaluation for radioembolization was performed in 10 patients (8 males, 2 females; mean age, 52.3 years) during in the late 1970s; today, transarterial chemoembolization (TACE) is a an 8-month period at a single center, of which 9 were actually widely accepted treatment technique for patients with uncontrolled treated with SIR-Spheres®. All patients underwent meticulous pre- and post-procedural imaging studies to document the hepatocellular cancer (HCC) or metastatic liver cancer primarily caused therapy response. by colo-rectal carcinoma. Radioembolization, a new form of transarte- RESULTS rial therapy involving infusion of radioactive microparticles, has shown In order to isolate the target hepatic arterial circulation, fol- promise for the treatment of patients with unresectable liver tumors (2– lowing branches were embolized as they were considered 7). The therapeutic advantage of the hepatic arterial approach is based as potential gastrointestinal shunts: the gastroduodenal artery (n = 5), right gastric artery (n = 1), and supraduode- on the unique dual vascular supply of the liver. It is known that hepatic nal artery (n = 1). Radioembolization therapy could not be tumors receive 80–100% of afferent blood exclusively from the hepatic performed only in one patient because of a hepatogastric artery (8). Radioembolization takes advantage of this to provide liver-di- shunt of unknown origin. No significant hepatopulmonary shunting was identified (maximum, 9% shunting). The rected transarterial therapy. There are two distinct aspects of the proce- body surface area method was used to calculate the Y-90 dure: the first being the injection of embolic particles (“embolization”) dose in all patients (mean dose, 1.24 GBq). All patients had at least partial response of the targeted liver lesions, as the vehicle and the second being the delivery and administration, via according to RECIST (Response Evaluation Criteria in Solid this embolic vehicle, of radiation (“radio”). Tumors). The Y-90 microsphere therapy with SIR-Spheres® (Sirtex Medical, Lane CONCLUSION Cove, Australia) was approved by the Turkish Ministry of Health in April In comparison to chemoembolization, radioembolization has 2008. Since then, increasing numbers of patients are receiving this treat- less systemic toxicity and can be performed as an outpatient procedure, which makes it more attractive to both patients ment in an effort to control or stabilize liver involvement of several and physicians. From our limited experience, the radioem- different inoperable cancers. In this study, we present the preliminary bolization procedure is a promising first-line treatment in experience at a single center with early follow-up results of Y-90 therapy, unresectable liver cancer; randomized controlled multi-center studies, however, are needed. as well as the review of the related literature.

Key words: • therapeutic embolizations • yttrium radioisotopes Materials and methods • liver neoplasms In this study, complete evaluation for radioembolization procedure was performed in 10 patients (8 males, 2 females; mean age, 52.3 years) who were selected to be treated with radioembolization using SIR- Spheres during an 8-month period between April 2008 and January 2009 at a tertiary care hospital. However, 9 out of 10 patients did receive the actual treatment. In one patient, the radioembolization procedure could not be performed due to a hepatogastric shunt of unknown origin. Liver diseases of all selected patients were inoperable primary or metastatic From the Departments of Radiology (B.P.  borapeynir@gmail. com, B.Ç., E.A., F.Balkancı), and Nuclear Medicine (F.Bozkurt, liver malignancies, including hepatocellular carcinoma (n = 1), cholan- Ö.U.), Hacettepe University School of Medicine, Ankara, Turkey. giocarcinoma (n = 3), colorectal carcinoma metastases (n = 1), pancreatic

Received 24 February 2009; revision requested 5 April 2009; revision adenocarcinoma metastases (n = 1), gastric adenocarcinoma metastases received 6 April 2009; accepted 15 April 2009. (n = 1), neuroendocrine tumor metastases (n = 1), breast cancer metastases (n = 1), and metastatic adenocarcinoma of unknown origin (n = Published online 16 February 2010 DOI 10.4261/1305-3825.DIR.2693-09.1 1). All patients had undergone other treatments of liver disease prior to

70 radioembolization, including different zation; the only concern is the risk of Once hepatic arterial anatomy is chemotherapy regimens and surgical radiation exposure of the surgery team well documented, selective arteriogra- resection. Initial hepatic arteriography during the transplantation, which can phy is performed in the expected loca- with/without visceral artery emboliza- be significantly reduced by waiting at tion of the Y-90 treatment. To avoid tion and Technetium-99m-macroaggre- least a month for the surgery after the catheter/wire induced vasospasm that gated albumin (Tc-99m-MAA) infusion last radioembolization session. There may preclude optimal evaluation or prior to Y-90 treatment was performed was no transplant candidate patient treatment, microcatheter injections in all patients primarily for isolation of in our study group. For SIR-Spheres are recommended, particularly if the the hepatic artery circulation and to which were used in all patients in this vessels are small in caliber or demon- prevent extrahepatic shunting to the study, infusion is limited by the lung strate significant tortuosity. Following lungs and gastrointestinal tract. SIR- shunt fraction (contraindicated above the positioning of the catheter at the Spheres treatment was used in all pa- 20% shunting). Activity of SIR-Spheres desired location, the presence of lung tients; the TheraSphere (MDS Nordion, infused is adjusted based on tumor vol- shunting through the tumor must be Ottawa, Canada) is not yet available ume and lung shunt fraction (11). For determined. The lung-shunt fraction in our country. All patients had F-18 TheraSphere, which is not available in is calculated as the fraction of Tc-99m- fluorodeoxyglucose-positron emission our country yet, the limitation of what MAA observed in the lungs relative tomography-computed tomography can be administered to the lungs is to the total Tc-99m-MAA activity ob- (FDG-PET-CT) and dynamic CT scans based on cumulative dose, irrespective served, and can be determined by in- before and after Y-90 therapy to deter- of lung shunt (12). fusing 5 mCi of Tc-99m labeled MAA mine the cross-sectional and metabolic particles through the catheter (Fig. 1). responses to the treatments. Initial angiographic evaluation MAA particles range in size from 10 to An initial angiographic evaluation is 60 nm, with a mean diameter of 35 Patient selection a routine practice once a patient has nm. The Tc-99m-MAA scan is also use- In general, patient selection criteria been selected as a candidate for radi- ful to demonstrate the presence of any for radioembolization are very similar oembolization. The hepatic arterial gastrointestinal flow. As we did, it is to those for chemoembolization (9). anatomy is to be evaluated primarily recommended that MAA injection be Adequate coagulation parameters and to identify the anatomic variants, and performed after all vessels of concern non-compromised pulmonary func- isolate the hepatic circulation by oc- have been embolized. The so-called tions to undergo arterial catheteriza- cluding extrahepatic vessels (13). The single photon emission computed to- tion and selective visceral catheteriza- technique includes standard visceral mography (SPECT-CT) fusion images, tion, and adequate liver function as angiography using a 4 or 5 French the fusion of the images of SPECT after in chemoembolization were sought diagnostic catheter. Following an ab- the infusion of the Tc-99m-MAA with in all patients. Pre-procedural intrave- dominal aortogram, a superior me- the diagnostic CT images, allow us to nous hydration with N-acetyl cysteine senteric artery injection is performed better localize any suspicious foci of ac- was administered in patients with im- to assess for the presence of accessory tivity (Fig. 2). The shunting evaluation paired renal function (10). Adequate or replaced hepatic arteries arising allows the physician to minimize any liver function in primary liver tumors from the superior mesenteric artery. uncertainty in microsphere distribu- was necessary. Additional inclusion A venous phase is also obtained to tion at the time of treatment. criteria were tumor less than 70% of evaluate the status/patency of the por- Although it was not the case in our the total liver volume; no evidence of tal vein. The celiac trunk is selectively patients, intratumoral arteriovenous infiltrative disease or complete por- catheterized to evaluate the hepatic shunting resulting in a significant lung tal vein thrombosis; total bilirubin arterial supply. Subsequent to celiac shunting, particularly in bilobar HCC level less than 2 mg/dL, and alanine injection, it is imperative that selec- cases, may be taken care of by unilobar or aspartate amino-transferase levels tive right and left hepatic angiography approach (10). Injection of MAA is per- less than five times the upper limit of with power injection angiography be formed and only one lobe is assessed at normal. Patients with metastatic liver performed, usually with a microcath- any one time. A repeat MAA injection disease should have normal liver func- eter system (Progreat 2.7 F, Somerset, is performed at a later session when the tion tests and acceptable performance New Jersey, USA). This will allow for second treatment site requires treat- status. Portal vein thrombosis has been the identification of variant mesenter- ment. It is also important to note that regarded as a relative contraindication ic anatomy and subsequent prophy- in patients with variant hepatic arterial for such treatments as TACE; however, lactic embolization of extrahepatic anatomy the MAA can and should be it is not necessarily a contraindication vessels such as the right gastric, gas- fractionated in order to evaluate the for radioembolization because relative troduodenal, or falciform artery. Other entire liver in one angiography setting percentage of obliteration is small and vessels that may be identified and may (10). overall embolic effect is minimal (10). require prophylactic embolization in- Other exclusionary criteria include im- clude the supraduodenal, retroduode- Embolization of extrahepatic vasculature mediate life-threatening extrahepatic nal, left inferior phrenic, accessory left The identification and isolation of disease, non-correctable flow to the gastric, and inferior esophageal artery. the hepatic vasculature are critical gastrointestinal tract, and hepatopul- Detailed technical protocol for map- when performing radioembolization. monary lung shunting. Being a candi- ping mesenteric angiography prior to One devastating complication is ex- date for liver transplantation is not a radioembolization has already been trahepatic delivery of Y-90 particles, contraindication for liver radioemboli- described in the literature (10). most commonly to the gastrointesti-

Volume 16 • Issue 1 Radioembolization of unresectable liver cancer • 71 a b undergo endoscopy for confirmation of ulceration, location of injury, and assessment of the size of the ulcer (10). As opposed to standard gastrointestinal ulcers, radioembolization-induced ulceration arises from the serosal surface, possibly decreasing the ability for the ulcer to heal or be seen using endoscopy. Hence, every effort should be made to minimize the risk of non- target Y-90 administration. The largest extrahepatic vessel in the area of concern is the gastroduodenal artery (GDA), which is expected to provide branches to the duodenum, pan- creas, and stomach. It is recommended that the GDA be embolized routinely to protect the gastrointestinal tract from reflux of Y-90 microspheres during hepatic artery injection (Fig. 3). The next most important vessel to identify is the right gastric artery (Fig. 4). Although the Figure 1. a, b. Gamma camera scan (a) after Tc-99m-MAA delivered intra-arterially suggesting origin of this vessel is variable and may that all activity is accumulated within the liver with no extra-hepatic shunting. Bremsstrahlung arise from any site in the hepatic artery, scan (b) within an hour after Y-90 microspheres delivered intra-arterially in the same patient. the left hepatic artery is the most common origin of the right gastric artery. Embolization of the right gastric is also recommended to prevent catastrophic stomach ulcers. If antegrade catheterization of the right gastric artery cannot be performed, continuous anastomosis with the left gastric artery can be seen in some patients, for which retrograde catheterization can be accomplished from the left gastric artery (Fig. 5). There are many other hepatic arterial variants and accessory vessels that may interfere with the radioembolic treatment (10, 13). Extensive initial patient work-up is essential in the treatment of liver tumors with Y-90 microspheres. The falciform artery, supraduodenal artery, and cystic artery must also be identified during the initial arterio- grams (Fig. 6). The blood supply to the gallbladder comes not only from the cystic artery, but also from perforators to the body of the gallbladder, the hepatic parenchyma, and the GDA (13). In the context of radioembolization, although infusion of Y-90 distal to the cystic artery is ideal, it is often not possible. Although the incidence of radiation-induced cholecystitis is very low, Figure 2. SPECT-CT fusion images showing the distribution of the Tc-99m-MAA in prophylactic embolization may be concordance to CT images which were obtained for PET-CT study. considered (10).

Imaging studies nal tract, invariably leading to severe surgical intervention is sometimes re- Imaging of the patients was planned gastritis and possibly even ulceration quired. When gastrointestinal ulcera- as in the literature (3). All patients were (2). Although some gastric and duo- tion or radiation gastritis is suspected evaluated via chest, abdomen, and denal ulcers can be treated medically, as an adverse event, patients should pelvis CT scans (magnetic resonance

72 • March 2010 • Diagnostic and Interventional Radiology Peynircioğlu et al. a b

Figure 3. a, b. Common hepatic artery injection angiogram (a) showing standard hepatic arterial anatomy with a very short proper hepatic artery. Also note the diminutive filling of the right gastric artery (arrows, a) off the left hepatic artery. The same injection immediately after proximal coil embolization of the gastroduodenal artery (b) to prevent non-target Y-90 embolization in case of reflux.

a b

Figure 4. a, b. Superselective catheterization of the right gastric artery (a) off the left hepatic artery of the patient in Fig. 1. Digital subtraction angiography image right after successful deployment of the coils into the proximal part of the right gastric artery (b).

imaging [MRI] was also used only for a few patients) to detect extrahepatic metastases and determine liver tumor location, size, and number. All scans of the abdomen were 3 phase, performed with oral and IV contrast, with a slice thickness 5 mm through the abdomen. All of our patients underwent FDG-PET-CT scanning before and after treatment. “Response evaluation criteria in solid tumors” (RECIST) were used to assess the patients before and after treatment (14). Unlike RECIST criteria, FDG-PET-scan response criteria are not yet uniform, but were typically used to evaluate response Figure 5. The retrograde right gastric artery filling by power injection from the left 6–8 weeks after treatment, compared gastric artery. with a pretreatment scan performed

Volume 16 • Issue 1 Radioembolization of unresectable liver cancer • 73 a b

Figure 6. a, b. Superselective supraduodenal artery injection (a) arising off directly from the proper hepatic artery. Note the coils within the gastroduodenal artery. Common hepatic artery injection (b) after proximal embolization of the gastroduodenal and supraduodenal arteries.

procedure bremsstrahlung scans were obtained within an hour in all our patients to document that there was no extrahepatic activity on the MAA scan (Fig. 1).

Postprocedure management and follow-up Radioembolization is generally performed on an outpatient basis in the United States. However, our patients were admitted to the hospital for close overnight observation for arterial puncture and post-embolic syndrome, as is done in many European countries. Because Y-90 microspheres are export- ed to our country via Australia-Ger- many-Turkey flight route, procedure timing has to be arranged according to the flight hours to avoid radioactive decay of Y-90, which has a half-life of 64 hours. The radioactive vial is rou- Figure 7. Plexiglass delivery box for radioembolization. After appropriate positioning of the tinely brought to our hospital at noon, microcatheter to the desired location of the hepatic artery, the delivery of the Y-90 loaded which causes a delay for an outpatient microspheres is done by using the syringes attached to the box as a clean (not sterile) transarterial procedure. Following the procedure. procedure, hemostasis was obtained by manual compression. After overnight observation at the hospital, all within 4 weeks before the treatment. used at arteriography for therapy plan- patients were discharged home. All pa- FDG-PET-CT may have limitations in ning. Radioactive microspheres that tients were placed on a proton pump tumors known to have low glucose have the pre-calibrated activity are inhibitor (omeprazole 20 mg) for 7–10 metabolism, such as HCC. However, suspended in sterile water inside a vial days before and after treatment. Oral decrease in standardized uptake value that is housed in a shielded container methylprednisolone therapy may be (SUV) of the known high metabolic le- (Fig. 7). Although it is a relatively com- given to non-diabetic patients for the sions and absence of new lesions indi- plex delivery system, an experienced next 6 days to relieve the fatigue that cates good metabolic response and is a interventional radiologist can easily ensues in most patients. Patients may good indicator of outcome. get used to it. A three-way stopcock receive 7–10 days of a fluoroquinolone allows sequential infusion of the Y-90 or cefuroxime if the entire right lobe Radioembolization procedure microspheres and contrast material in- is to be treated and the cystic artery The catheter is usually positioned in jection for monitoring the progress of was thought to be perfused with mi- essentially the same location as that infusion (15). As recommended, post- crospheres. Tumor markers (AFP, CEA,

74 • March 2010 • Diagnostic and Interventional Radiology Peynircioğlu et al. CA-19-9), complete blood count, liver anatomy. From our limited experience, shunting was determined (maximum function tests, and routine biochemi- as long as the proper hepatic artery is 9% shunting). The body surface area cal tests are obtained 4–6 weeks post- long enough to prevent reflux, MAA (BSA) method was used to calculate procedure. This is also the time recom- infusion can be done at a desired loca- the Y-90 dose in all patients. The mean mended for cross-sectional (triphasic tion for right lobe treatment, avoiding dose of Y-90 was 1.24 GBq (range, CT, dynamic gadolinium-enhanced unnecessary occlusion of an impor- 1.11–2 GBq). Post-procedure bremsst- MRI, perfusion imaging) and func- tant mesenteric blood supplier like the rahlung scans were obtained in all tional imaging (FDG-PET-CT) tests to GDA (similar to the radioembolization patients (Fig. 1b). There were no com- assess the results of therapy. The op- technique from the replaced right he- plications related to initial hepatic ar- posite lobe is to be treated shortly fol- patic artery taking off from the SMA). teriograms or Y-90 treatment sessions. lowing assessment of response and the If a gastrointestinal shunt is suspected Post-procedural mild to moderate fa- demonstration of lack of diffuse pro- on the subsequent MAA scan, the GDA tigue was noted for the next 7 days gression. None of our patients had op- and right gastric arteries must be em- in all patients, with mild to moderate posite lobe treatment in the 8-month bolized to ensure that the most com- fever and abdominal pain in some pa- follow-up because they had a prior mon sources of extrahepatic shunts tients (all were self-limited, with com- hepatectomy or low tumor volume at are controlled. Because non-target plete resolution within 4 weeks). Liver the opposite lobe. embolization may lead to catastrophic function tests during the 8-month complications such as gastrointestinal follow-up period (range, 1–8 months) Results ulcer and perforation, it is strongly were stable in all patients. All patients Initial hepatic arteriography with recommended that all potential extra- had at least partial response of the tar- visceral artery embolization and Tc- hepatic feeders be embolized initially get lesions at the treated liver lobes ac- 99m-MAA infusion prior to Y-90 treat- (before the first MAA injection) until cording to the RECIST criteria. ment was performed in all patients the operator becomes really comfort- In the early follow-up at 4–6 weeks primarily for isolation of the hepatic able with the procedure. Of note, the post-therapy, FDG-PET-CT showed artery circulation and to prevent ext- GDA was surgically ligated in our one decrease in number and metabolic rahepatic shunting to the lungs and patient, in which the posterior branch activity of the lesions in the treated gastrointestinal tract (Fig. 1a). As a of the right gastric artery was used for liver regions in all nine patients. FDG- result of the various hepatic arterial the final Y-90 injection. As most of the PET-CT displayed new lesions in the anatomic variations like the replaced patients in this study group under- non-treated liver segments in three right hepatic artery arising from the went right lobe treatment, and there patients and new extrahepatic foci in superior mesenteric artery, or previ- was no evidence of gastric shunting at four patients. One patient with color- ous surgical arterial ligations, coiling MAA scan, the right gastric artery was ectal cancer died of disease recurrence, of arteries as potential shunts to gas- occluded only in 1 patient. Five mCi which caused multisystem failure, ap- trointestinal system were not needed Tc-99m-MAA delivered intra-arterially proximately 6 months after Y-90 mi- in all patients. Besides, after having in all patients after the embolizations crosphere therapy. All other patients some experience with radioemboliza- were performed, and shunting was de- are alive and being followed up with tion procedure, coiling of each an- termined by SPECT-CT fusion images regressed/ stable disease of the treated giographically visible potential shunt (Fig. 7). In the patient with pancre- lobes as of January 2009. may not be considered in every single atic adenocarcinoma metastases, the patient depending on the hepatic arte- source of the existing hepatogastric Discussion rial anatomy, target lobe to treat and shunt could not be depicted and em- Radioembolization, a form of intra- the experience of the interventional bolized despite the repetitive hepatic arterial brachytherapy, is a technique radiologist. However, the gastroduode- angiographies; so the Y-90 therapy was in which particles of glass or resin, im- nal artery (n = 5), right gastric artery given into a segmental branch of the pregnated with the isotope Y-90, are (n = 1), and supraduodenal artery (n right hepatic artery instead of a lobar infused through a catheter directly into = 1) were embolized with microcoils treatment. SIR-sphere radioemboliza- the hepatic arteries. Y-90 is a pure  to prevent possible gastrointestinal tion therapy could not be performed emitter and decays to stable Zr-90 with shunts in our patients (Figs. 3–6). The in one patient because of hepatogastric a physical half-life of 64.1 h. The aver- major blood supplying vessel of hyper- shunting, despite coil embolization of age energy of the  particles is 0.9367 vascular tumors was determined, and the GDA. MeV, has a mean tissue penetration selective catheterization of the right One of our patients developed shakes of 2.5 mm, and has a maximum pen- hepatic artery (n = 7), posterior branch and chills immediately after the proce- etration of 10 mm. There are currently of the right hepatic artery (n = 1), and dure, which lasted less than 1 hour. two commercially available agents: SIR- the left hepatic artery (n = 1) was per- Both the onset of symptoms and their Spheres and TheraSphere. SIR-Spheres formed. After getting familiar with the resolution were quite rapid. No medi- are resin-based particles, approximately radioembolization infusion technique cation was needed to relieve the pa- 29–35 nm in diameter, in which the Y- and treating a number of patients, we tient’s self-limiting symptoms. 90 and resin are intimately bound. The felt that the embolization of the each Only one patient underwent two ses- standard activity vial is 3 GBq, of which potential shunt (including the GDA sions of radioembolization, in which a predetermined amount is decanted in and right gastric artery) was not neces- the entire residual left lobe was com- the nuclear medicine pharmacy from sary in every patient depending on the promised by numerous HCC metas- the vial for injection into the patient. A target lobe to treat or hepatic arterial tases. No significant hepatopulmonary 3-GBq activity vial contains between 40

Volume 16 • Issue 1 Radioembolization of unresectable liver cancer • 75 million and 80 million microspheres. BSA method (4). The BSA method was ent tumor types has shown promising Each microsphere contains 50 Bq of proposed to account for body and liver results in metastatic disease from color- activity at the time of calibration (11). size differences and was the preferred ectal cancer (3, 6), hepatoma (20), neu- Radioembolization refers to the use of method for dose calculation in our pa- roendocrine tumors (21), breast cancer TheraSphere, SIR-Spheres, or other mi- tients. BSA and the percentage of tu- (22), and other tumor types (4). crosphere agents that have the emis- mor to the liver (TLR, tumor liver ratio) External radiotherapy at doses above sion of radiation as their primary and values were used (dose of Y-90 = BSA − 50 Gy is effective in destroying colorec- microembolization as their secondary 0.2 + TLR) in our study (16). tal tumors. The limitation in this treat- modes of action (10). Although much of the early clini- ment is the tolerance of normal liver Radioembolization, as a kind of cal experience with Y-90 involved parenchyma to radiation; the maxi- brachytherapy, has a different treat- whole-liver infusion, this treatment mum acceptable dose of 35 Gy for the ment mechanism from embolization. paradigm is no longer recommended. whole liver is far below that required Microspheres laden with the -emit- Enhancements in microcatheter tech- to destroy adenocarcinoma metastases, ting isotope Y-90 are used; they are nology have decreased the use of sur- estimated at 70 Gy or more. Micro- small enough to pass deep into the tu- gically implanted pumps for the treat- sphere implantation within the tumor mor vasculature but too large to pass ment of liver tumors. Furthermore, while sparing the adjacent normal liver through the capillary bed and reach ve- there exists significant extrahepatic is the key to its importance: liver toler- nous circulation, preventing deposition flow, described throughout this ar- ance to microsphere therapy is excel- in the lungs (4). On the other hand, ticle, through small vessels that can lent, although tumor destruction, even fluoroscopic guidance, angiographic only be avoided using lobar/segmen- in large tumors, is observed. The actual end points of embolization and stasis, tal infusions. For radioembolization, dose given to each lobe or segment, or and the need to modify this based on a treatment paradigm that parallels to the whole liver, is dependent upon angiographic findings make this treat- TACE is recommended, i.e., lobar or the tumor vasculature capacity. Both ment a true embolization procedure. subsegmental infusions (10). the embolic-related and the radiation- There is a spectrum of radioembolic Percutaneous interventions have related edema effects in the liver and effects that exists with this therapy: been widely used in the treatment of the intensity of liver radiation during with TheraSphere, there is high specific liver tumors worldwide. Radiofrequen- this time are stressful on the body and activity and a small number of micro- cy ablation, cryoablation, and percu- counteracted by a short burst of steroid spheres (mild radioembolic effect); with taneous ethanol ablation have been therapy (3). The results of a study of 208 SIR-Spheres, there is low specific activ- shown to be effective for the treatment patients with colorectal cancer showed ity and a large number of microspheres of small liver tumors (10, 17). Similarly, that CT partial response of 35%, posi- (moderate/high radioembolic effect) liver-directed transarterial techniques, tron emission tomography response of (10). It is this varying number of mi- such as TACE and transcatheter arterial 91%, and reduction in carcinoembry- crospheres, embolic effect, and possible bland embolization, have shown clini- onic antigen of 70% were achieved (3). vascular saturation that makes fluoro- cal benefit in selected patients (18). Combining the newest and most effec- scopic observation necessary. Compar- It has been shown that the TACE tive chemotherapy agents for colorectal ing the two commercially available Y- procedure itself is a safe and efficient cancer with microspheres is the logical 90 microspheres, Sato et al. reported no procedure when selection criteria are next step, now that the effectiveness identifiable change in angiography af- applied strictly, particularly in terms of and safety have been established in mi- ter treatment, based on blinded review liver function tests. Although the same crosphere-alone–treated patients (3). of before and after glass microsphere patient selection criteria are applied for Neuroendocrine tumors are an un- radioembolization (5). Conversely, sta- radioembolization, it appears that radi- common, heterogeneous group of dif- sis of hepatic arterial flow represents oembolization may be undertaken in ferent slow growing, hormone-secret- the major reason for stopping delivery the setting of abnormal/elevated liver ing malignancies. Transcatheter bland of resin microspheres before the full function if a segmental infusion can be embolization and TACE are known to planned activity has been given. Stasis performed, without significant impact be effective treatment options in the is not desired, in part, because of the on liver functions (19). This is a criti- palliation of neuroendocrine tumors, shunting of microspheres into the nor- cal assumption, depending on the fact particularly for symptom-free survival mal liver, creating tumor hypoxia (5). that the transarterial treatments are (23). Internal radiotherapy has also be- Because of their higher embolic poten- generally applied after several chemo- ing used to control, eradicate, or sim- tial, SIR-Spheres are contraindicated therapy regimens, which usually com- ply debulk hepatic metastases, often in the setting of complete portal vein promise the liver functions because to palliate carcinoid syndrome or lo- thrombosis, as the number of particles of toxicity. Applying radioemboliza- cal pain from liver capsular stretching. in a typical vial may result in embolic tion as a first-line treatment in select Selective uptake by carcinoid tumors occlusion of the patent vessel. Hence, if patients with widespread liver disease provides the proximity needed for  SIR-Spheres are to be used in the setting may act like radiofrequency ablation radiation cell killing (21). of portal vein thrombosis, dose frac- in the setting of relatively limited dis- HCC, as the most common primary tionation should be considered (10). ease. Multicenter randomized control- tumor of the liver, is chemotherapy Although there are different meth- led studies are warranted to determine resistant, and—because of low liver ods for calculating activity in Y-90 the actual role of radioembolization in reserve in most patients and compro- microspheres, those most frequently liver tumor therapy algorithm. Several mised portal vein flow in approxi- used are the empiric method and the clinical studies of this therapy in differ- mately 25%—unresectable HCC has

76 • March 2010 • Diagnostic and Interventional Radiology Peynircioğlu et al. a dismal prognosis. Tumor burden in higher than was initially thought with tiveness, careful steps should be taken the liver is a major threat to patient commonly accepted doses of radioem- in parallel to the studies published in survival and well-being; and because bolization, which lead up to 20% off the literature. systemic chemotherapy is ineffective, the calculated dose in current prac- local liver-directed therapies including tice. High doses of corticosteroids tra- References hepatic arterial therapies have been de- ditionally are administered in an at- 1. Ariel IM. Radioactive isotopes for adjuvant veloped to reduce tumor burden, pro- tempt to decrease intrahepatic inflam- cancer therapy. Arch Surg 1964; 89:244– viding palliation and the potential for mation. Treatment results are variable 249. 2. Yip D, Allen R, Ashton C, Jain S. Radiation- increased survival. Y-90 microsphere and mostly unsuccessful, as the condi- induced ulceration of the stomach second- treatment appears to be well tolerated tion progresses in some patients to he- ary to hepatic embolization with radioac- and can be used safely in carefully se- patic insufficiency of various degrees tive yttrium microspheres in the treatment lected patients (7). (15). For enhanced patient safety, the of metastatic colon cancer. J Gastroenterol Hepatol 2004; 19:347–349. Idiosyncratic reaction has also been dose calculation and patient selection 3. Kennedy AS, Coldwell D, Nutting C, et al. described immediately after radioem- must be done carefully. Resin 90Y-microsphere brachytherapy for bolization, which is very similar to Non-standard chemotherapeutic re- unresectable colorectal liver metastases: that of urokinase (10). Although it is lease and local concentrations deliv- modern USA experience. Int J Radiat Oncol reported to be a rare and unusual reac- ered by conventional TACE techniques Biol Phys 2006; 65:412–425. 4. Kennedy AS, McNeillie P, Dezarn WA, et tion, radioembolization with Y-90 may have mostly been replaced by drug- al. Treatment parameters and outcome in cause a short-lived idiosyncratic reac- eluting beads, which have predictable 680 treatments of internal radiation with tion with symptoms of shakes, chills, pharmacokinetics and can achieve resin (90)Y-microspheres for unresectable and alterations in hemodynamics and higher doses of the chemotherapeu- hepatic tumors. Int J Radiat Oncol Biol Phys 2009; 74:1494–1500. vital signs. Contrast material reaction tic agent and prolonged contact time 5. Sato K, Lewandowski RJ, Bui JT, et al. should be included in the differential with cancer cells (26). However, sys- Treatment of unresectable primary and diagnosis. As with urokinase reaction, temic effects of locally given chemo- metastatic liver cancer with yttrium-90 management is supportive, including therapy are unavoidable in TACE. microspheres (TheraSphere): assessment of fluids if hypotensive, as well as anti- When comparing radioembolization hepatic arterial embolization. Cardiovasc Intervent Radiol 2006; 29:522–529. histaminic medications. Although it with TACE, radioembolization has 6. Gulec SA, Fong Y. Yttrium 90 microsphere is difficult to predict which patients less systemic toxicity and can be done selective internal radiation treatment of will have this reaction, it has been seen as an outpatient procedure, making it hepatic colorectal metastases. Arch Surg commonly in patients with arteriopor- attractive to both patients and physi- 2007; 142:675–682. 7. Geschwind JF, Salem R, Carr BI, et al. tal shunting who undergo radioembol- cians. Post-embolic syndrome is usual- Yttrium-90 microspheres for the treat- ization (10). ly milder after radioembolization than ment of hepatocellular carcinoma. Patient selection, tumor response, after chemoembolization. Another key Gastroenterology 2004; 127:S194–205. treatment techniques, and complica- point is the PET-CT monitoring of the 8. Breedis C, Young G. The blood supply of tions including acute and late onset treatment response. Although the cost neoplasms in the liver. Am J Pathol 1954; 30:969–984. radiation toxicity have been reported increases significantly with numerous 9. Gates J, Hartnell GG, Stuart KE, Clouse ME. in the literature. Radiation-induced PET-CT scans, it allows clearer evalua- Chemoembolization of hepatic neoplasms: liver disease (RILD) was initially de- tion of the metabolic responses with safety, complications, and when to worry. scribed as radiation hepatitis after ex- unclear survival contribution. Radiographics 1999; 19:399–414. 10. Lewandowski RJ, Sato KT, Atassi B, et al. ternal beam radiation and is widely From our limited experience, the ra- Radioembolization with 90Y microspheres: acknowledged to be a clinical entity dioembolization procedure promises angiographic and technical considera- that can present with ascites 2 weeks to be a first-line treatment in unresect- tions. Cardiovasc Intervent Radiol 2007; to 4 months after hepatic radiation able liver cancer. However, there is a 30:571–592. (24). RILD is now known to be a re- need for randomized controlled mul- 11. SIRTeX MedicalSIR-Spheres yttrium-90 microspheres package insert. Lane Cove, sult of veno-occlusive disease rather ticenter studies to document cost-ef- Australia. SIRTeX Medical 2004. than hepatitis. RILD seems to be the fectiveness. Technical aspects of radi- 12. MDS Nordion TheraSphere yttrium-90 mi- most severe toxicity of microspheres, oembolization are almost entirely an crospheres package insert. Kanata, Canada. but there is no identified relation- interventional radiology procedure. MDS Nordion 2004. 13. Covey AM, Brody LA, Maluccio MA, ship between toxicity and tumor type However, because oncology patients Getrajdman GI, Brown KT. Variant hepatic (4). Clinically, patients develop rapid should always be evaluated in a multi- arterial anatomy revisited: digital subtrac- weight gain, increased abdominal disciplinary fashion for the maximal tion angiography performed in 600 pa- girth, liver enlargement, jaundice, benefit for the patient, radioemboli- tients. Radiology 2002; 224:542–547. and increased liver enzymes, particu- zation should be implemented to the 14. Therasse P, Verweij J. RECIST revisited: a review of validation studies on tumour larly alkaline phosphatase, occurring treatment algorithms of hospital dy- assessment. Eur J Cancer 2006; 42:1031– before 90 days post-treatment (4, 25). namics. Institutional policies, hospital 1039. Most of these patients survive RILD radiation safety committees, interven- 15. Murthy R, Nunez R, Szklaruk J, et al. but may require aggressive vascular tional radiologists, oncologists, gen- Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, tech- intervention or therapy to control eral surgeons, and nuclear medicine nical considerations, and potential com- symptoms from abdominal ascites, physicians should function in a colle- plications. Radiographics 2005; 1:41–55. including transjugular portosystemic gial manner. Because of the relatively shunt. Furthermore, it is now believed short history of radioembolization that the incidence of RILD might be and the lack of evidence on cost-effec-

Volume 16 • Issue 1 Radioembolization of unresectable liver cancer • 77 16. Sanjeeva P, Kalva AT, Stephan W. Recent 20. Ibrahim SM, Lewandowski RJ, Sato KT, et 24. Lawrence TS, Robertson JM, Anscher MS, advances in transarterial therapy of pri- al. Radioembolization for the treatment et al. Hepatic toxicity resulting from can- mary and secondary liver malignancies. of unresectable hepatocellular carcinoma: cer treatment. Int J Radiat Oncol Biol Phys Radiographics 2008; 28:101–117. a clinical review. World J Gastroenterol 1995; 31:1237–1248. 17. Buscarini L, Buscarini E, Di Stasi M, Vallisa 2008; 14:1664–1669. 25. Fajardo LF, Berthrong M, Anderson RE. D, Quaretti P, Rocca A. Percutaneous ra- 21. Kennedy AS, Dezarn WA, McNeillie P, et al. Radiation pathology. 1st ed. New York: diofrequency ablation of small hepato- Radioembolization for unresectable neu- Oxford University 2001; 249–257. cellular carcinoma: long-term results. Eur roendocrine hepatic metastases using resin 26. Malagari K. Drug-eluting particles in the Radiol 2001; 11:914–921. 90Y-microspheres: early results in 148 pa- treatment of HCC: chemoembolization 18. Llovet JM, Real MI, Montana X, et al. tients. Am J Clin Oncol 2008; 31:271–279. with doxorubicin-loaded DC Bead. Expert Arterial embolization or chemoemboli- 22. Coldwell DM, Kennedy AS, Nutting CW. Rev Anticancer Ther 2008; 8:1643–1650. zation versus symptomatic treatment in Use of yttrium-90 microspheres in the patients with unresectable hepatocellular treatment of unresectable hepatic metas- carcinoma: a randomized controlled trial. tases from breast cancer. Int J Radiat Oncol Lancet 2002; 359:1734–1739. Biol Phys 2007; 69:800–804. 19. Gray BN. Use of SIR-Spheres in patients 23. Ruutiainen AT, Soulen MC, Tuite CM, et with impaired liver function. Safety al. Chemoembolization and bland emboli- Notice. 2003; Sirtex Medical, Lane Cove, zation of neuroendocrine tumor metastas- Australia. es to the liver. J Vasc Interv Radiol 2007; 18:847–855.

78 • March 2010 • Diagnostic and Interventional Radiology Peynircioğlu et al.