Radioembolization of Hepatic Malignancies: Background, Quality Improvement Guidelines, and Future Directions

STANDARDS OF PRACTICE

Radioembolization of Hepatic Malignancies: Background, Quality Improvement Guidelines, and Future Directions Siddharth A. Padia, MD, Robert J. Lewandowski, MD, Guy E. Johnson, MD, Daniel Y. Sze, MD, PhD, Thomas J. Ward, MD, Ron C. Gaba, MD, Mark O. Baerlocher, MD, Vanessa L. Gates, MS, Ahsun Riaz, MD, Daniel B. Brown, MD, Nasir H. Siddiqi, MD, T. Gregory Walker, MD, James E. Silberzweig, MD, Jason W. Mitchell, MD, MPH, MBA, Boris Nikolic, MD, MBA, and Riad Salem, MD, MBA, for the Society of Interventional Radiology Standards of Practice Committee ABBREVIATIONS AFP = α-fetoprotein, ECOG = Eastern Cooperative Oncology Group, EASL = European Association for Study of the Liver, FDA = Food and Drug Administration, FDG = fluorodeoxyglucose, HCC = hepatocellular carcinoma, MAA = macroaggregated albumin, mRECIST = modified Response Evaluation Criteria In Solid Tumors, QI = quality improvement, RECIST = Response Evaluation Criteria In Solid Tumors, REILD = radioembolization-induced liver disease, SPECT = single-photon emission computed tomography, 3D = three-dimensional

PREAMBLE The mission of the Society of Interventional Radiology (SIR) is to improve patient care through image-guided therapy. The Society was founded in 1973, and is recognized today as the primary specialty society for physicians who provide minimally invasive image-guided therapies. The Standards Division of SIR writes a number of different types of standards documents to reflect the current clinical paradigm and evolution in the treatment of a specific disease state or a procedure. The Standards Division currently produces four different types of documents. A Position Statement document reflects the viewpoints of SIR on a specific disease state or procedure. A Reporting Standards document attempts to codify the key elements required for future research on a specific procedure or disease process. A Quality Improvement (QI) Guideline attempts to provide clinical guidelines on the application of a specific procedure or treatment of a disease process when a significant body of literature is available. A Credentialing From the Division of Interventional Radiology (S.A.P.), Department of Radiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Division of Interventional Radiology (D.Y.S.), Stanford University School of Medicine, Stanford, California; Section of Interventional Radiology, Department of Radiology (R.J.L., V.L.G., A.R., R.S.), Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois; Department of Radiology, Division of Interventional Radiology (R.C.G.), University of Illinois Hospital and Health Sciences System, Chicago, Illinois; Section of Interventional Radiology, Department of Radiology (G.E.J.), University of Washington, Seattle, Washington; Section of Interventional Radiology, Department of Radiology (T.J.W.), Florida Hospital, Orlando, Florida; Department of Radiology, Vanderbilt University School of Medicine (D.B.B.), Nashville, Tennessee; Division of Interventional Radiology (T.G.W.), Massachusetts General Hospital, Boston, Massachusetts; Interventional Radiology, P.C. (J.E.S.), New York, New York; Department of Radiology (B.N.), Stratton Medical Center, Albany, New York; Department of Diagnostic Radiology and Nuclear Medicine (J.W.M.), Division of Vascular & Interventional Radiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Medical Imaging, Royal Victoria Hospital (M.O.B.), Barrie, Ontario Canada; and Department of Radiology, King Faisal Specialist Hospital & Research Center (N.H.S.), Riyadh, Saudi Arabia. Received August 16, 2016; final revision received September 18, 2016; accepted September 20, 2016. Address correspondence to S.A.P., c/o Debbie Katsarelis,

document describes the knowledge base, technical skills, and experience required to perform a specific procedure. A QI Guideline is produced by the Standards of Practice Committee. The membership of the SIR Standards of Practice Committee represents experts in a broad spectrum of interventional procedures from the private and academic sectors of medicine. Generally, Standards of Practice Committee members dedicate the vast majority of their professional time to performing interventional procedures; as such, they represent a valid broad expert constituency of the subject matter under consideration for standards production.

DOCUMENT METHODOLOGY SIR produces its QI Guidelines documents by using the following process. Topics of relevance and timeliness are conceptualized by the Standards of Practice Committee members, Service Lines, SIR SIR, 3975 Fair Ridge Dr., Suite 400 N., Fairfax, VA 22033; E-mail: spadia@ gmail.com S.A.P. is a paid consultant for and serves on the advisory board of BTG International (Ottawa, Ontario, Canada) and Guerbet (Roissy, France). R.J.L. serves on the advisory boards for BTG International and Boston Scientific (Marlborough, Massachusetts) and is a paid consultant for Cook (Bloomington, Indiana). D.Y.S. receives personal fees from BTG International, Sirtex (North Sydney, Australia), Boston Scientific, EmbolX (Los Altos, California), Cook, Covidien (Dublin, Ireland), Amgen (Thousand Oaks, California), and Codman (Raynham, Massachusetts). M.O.B. is a paid consultant for Boston Scientific. D.B.B. is a paid consultant for Cook, Vascular Solutions (Minneapolis, Minnesota), and Onyx Pharmaceuticals (South San Francisco, California). R.S. receives grants and personal fees from BTG International and personal fees from Boston Scientific, Merit Medical (South Jordan, Utah), Terumo (Tokyo, Japan), Siemens (Munich, Germany), and Bayer (Leverkusen, Germany). None of the other authors have identified a conflict of interest. & SIR, 2016 J Vasc Interv Radiol 2016; XX:]]]–]]] http://dx.doi.org/10.1016/j.jvir.2016.09.024

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Quality Improvement Guidelines for Hepatic Radioembolization

members, or the Executive Council. A recognized expert or group of experts is identified to serve as the principal author or writing group for the document. Additional authors or societies may be sought to increase the scope, depth, and quality of the document depending on the magnitude of the project. An in-depth literature search is performed by using electronic medical literature databases. Then, a critical review of peer-reviewed articles is performed with regard to the study methodology, results, and conclusions. The qualitative weight of these articles is assembled into an evidence table, which is used to write the document such that it contains evidence-based data with respect to content, rates, and thresholds. Threshold values are determined by calculating the standard deviation of the weighted mean success and adverse event reported in all relevant trials with a sample size of approximately 50 patients or greater. Calculated threshold values represent two standard deviations above or below the mean for adverse event and success rates, respectively. When the evidence of literature is weak, conflicting, or contradictory, consensus for the parameter is reached by a minimum of 12 Standards of Practice Committee members by using a modified Delphi consensus method (Appendix A). For purposes of these documents, consensus is defined as 80% Delphi participant agreement on a value or parameter. The draft document is critically reviewed by the writing group and Standards of Practice Committee members by telephone conference calling or face-to-face meeting. The finalized draft from the Committee is sent to the SIR Operations Committee for approval. The document is then posted on the SIR Web site for SIR membership to provide further input/criticism during a 30-day comment period. These comments are discussed by the Standards of Practice Committee, and appropriate revisions are made to create the finished standards document before its publication.

INTRODUCTION Locoregional therapies have an important role in the management of hepatic malignancies. Percutaneous ablation and transarterial therapies are the two main tools available to interventional radiologists for the treatment of liver tumors. Yttrium-90 (90Y) radioembolization is a transarterial catheter-based technique that is increasingly being used in the management of primary and secondary liver malignancies. This document serves as a guide on hepatic artery radioembolization for the treatment of primary and secondary liver malignancies. The readers are also referred to the Research Reporting Standards for Radioembolization of Hepatic Malignancies (1) with recommendations on presenting data regarding radioembolization. Throughout this document, the procedure under discussion will be referred to as “radioembolization.” Many other terms have been used to describe the same procedure in the literature, including selective internal radiation therapy (or “SIRT”) and transarterial radioembolization (or “TARE”).

PRIMARY HEPATIC MALIGNANCIES There were an estimated 782,500 new primary liver cancer cases and 645,500 liver cancer–related deaths globally in 2008 (2). Hepatocellular carcinoma (HCC) constitutes approximately 85%–90% of all primary hepatic malignancies (2–4). Liver resection, liver transplantation, and ablation are considered potentially curative therapies in select patients with HCC (5,6). Systemic therapy, including the use of sorafenib, has had a limited impact in the management of HCC, and is primarily indicated in patients with advanced or metastatic disease (7,8). Transarterial-based therapies such as bland embolization, chemoembolization, and radioembolization have an established role in the management of HCC (9,10). Radioembolization has an accepted role in the treatment of HCC in several scenarios, and is endorsed by national guidelines for hepatobiliary malignancies (11). This includes “bridging” patients to liver transplantation by delaying disease progression,

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downstaging disease to meet transplantation criteria, controlling disease while simultaneously inducing hypertrophy of the future liver remnant before surgical resection, and treating patients with macrovascular invasion, and as primary/definitive therapy in patients with tumors located within a single liver segment (10,12–17). Several prospective and retrospective studies have demonstrated the safety and efficacy of radioembolization in patients with primary hepatic malignancies (Table 1) (10,13–25). Studies comparing radioembolization versus surgery and percutaneous ablation techniques have not been performed because these procedures are typically done in different patient populations. Several studies comparing chemoembolization versus radioembolization in HCC demonstrated longer times to progression, better quality of life, slightly improved toxicity profiles, and fewer days of hospitalization among patients treated with radioembolization compared with patients treated with chemoembolization (26–29). However, a significant survival benefit has not been demonstrated. Multiple prospective studies are under way comparing radioembolization versus systemic chemotherapy in advanced-stage hepatic malignancy. Cholangiocarcinoma represents the other subset of primary hepatic malignancy. The accepted systemic chemotherapy regimen for unresectable cholangiocarcinoma has a limited survival benefit (30). Radioembolization has demonstrated efficacy in the setting of intrahepatic cholangiocarcinoma (Table 1), and can therefore play a role in improving long-term survival. In survival assessments, several factors were found to be good prognostic indicators, specifically patient performance status, tumor burden, and peripheral tumor type. Conversely, factors deemed to be poor prognostic indicators were multifocal tumor, infiltrative tumor, and higher tumor burden (18–20).

SECONDARY (METASTATIC) HEPATIC MALIGNANCIES The treatment of cancers metastatic to the liver includes surgical resection and/or systemic chemotherapy. Radioembolization has been shown to be safe and effective in patients with liver metastases from primary cancers such as colorectal carcinoma and neuroendocrine tumors. Radioembolization for the treatment of metastatic cancer to the liver has been evaluated primarily in the setting of colorectal cancer metastases, often for chemotherapy-refractory disease (ie, “salvage therapy”). Several studies have evaluated the efficacy of radioembolization for this indication (Table 2) (31–50). In a multicenter prospective randomized phase III trial, the addition of radioembolization to salvage chemotherapy showed a trend toward prolonged overall survival compared with chemotherapy alone (10.0 vs 7.3 mo; P = .8) (36). Radioembolization as first-line therapy for colorectal metastases has recently been evaluated, with preliminary results showing no significant improvement in progression-free survival when radioembolization is added to systemic chemotherapy compared with systemic chemotherapy alone (37). However, an advantage in hepatic progression-free survival was identified in the radioembolization arm. Prospective trials assessing the effectiveness of radioembolization in the second-line setting are currently under way. Radioembolization for neuroendocrine tumors metastatic to the liver has repeatedly shown excellent tumor response rates with significant improvement in survival. A retrospective study of 148 patients demonstrated a median survival of 70 months (32). In the setting of multifocal disease, bland embolization and chemoembolization have also shown efficacy with acceptable safety profiles. A systematic review of chemoembolization and radioembolization for the treatment of neuroendocrine metastases demonstrated similar response rates and survival (51). However, the heterogeneity of the study populations makes this comparison challenging to draw firm conclusions. Debate therefore continues as to the optimal transarterial treatment regimen for this indication. Radioembolization has also been studied for several other metastatic tumors, including breast cancer, uveal melanoma, renal-

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Table 1 . Outcomes of Radioembolization for Primary Liver Cancer ([10,13–25) Y Device

No. of Pts.

CTP Score (No. of Pts.)

BCLC Stage (No. of Pts.)

OR (%)

Median (95% CI) TTP*

Survival

Glass

65

NR

NR

NR

NR

649 d (Okuda I), 302 d

Lewandowski et al, 2009 (14) Riaz et al, 2011 (15)

Glass Glass

43 84

A (24), B (19), C (0) A (41), B (42), C (1)

A (0), B (34), C (9), D (0) A (27), B (25), C (31), D (1)

61 81

33.3 mo (17.8– 33.8 mo) 13.6 mo (9.3–18.7 mo)

35.7 mo 26.9 mo

Salem et al, 2010 (10)

Glass

291

A (131), B (152), C (8)

A (48), B (83), C (152), D (8)

57

7.9 mo (6–10.3 mo)

17.2 mo (Child–Pugh class A),

Sangro et al, 2011 (23)

Resin

325

A (268), B (57), C (0)

A (52), B (87), C (183), D (3)

NR

NR

7.7 mo (Child–Pugh class B) 12.8 mo

2016

Hepatocellular carcinoma Carr, 2004 (13)

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Study, Year

(Okuda II)

Padia et al, 2014 (16)

Glass

20

A (11), B (8), C (1)

A (2), B (2), C (15), D (1)

95

319 d

90% at 1 y

Mazzaferro et al, 2013 (22) Kokabi et al, 2015 (24)

Glass Glass

52 30

A (43), B (9), C (0) A (20), B (10), C (0)

A (0), B (17), C (35), D (0) A (0), B (0), C (30), D (0)

40 NR

11 mo 9 mo (6.2–13.1 mo)

15 mo 13 mo

Saxena et al, 2014 (25)

Resin

40

A (30), B (10), C (1),

NR

48

NR

27.7 mo

Resin

63

unknown (4) A (58), B (5), C (0)

A (0), B (26), C (37), D (0)

73

5 mo

13.2 mo

Saxena et al, 2010 (18) Hoffman et al, 2012 (19)

Resin Resin

25 33

NR NR

NR NR

24 36

NR 9.8 mo

9.3 mo 22 mo

Mouli et al, 2013 (20)

Glass

46

NR

NR

73

NR

14.6 mo

Gramenzi et al, 2015 (21) Cholangiocarcinoma

BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; CTP ¼ Child–Turcotte–Pugh; NR ¼ not reported; OR ¼ objective response; TTP ¼ time to progression. *TTP is presented as overall time to progression unless otherwise stated.

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Table 2 . Outcomes of Radioembolization for Metastatic Disease to the Liver (31,33–50) 90

Study, Year

Y Regimen

Previous Chemotherapy

No. of Pts.

Objective Response

Survival

Colorectal cancer metastases van Hazel et al, 2016 (37) Gray et al, 2001 (31) Sharma et al, 2007 (33)

Resin þ FOLFOX

No

267

76.4%

10.7 mo (PFS)

Resin þ chemotherapy Resin þ FOLFOX

No No

35 20

44% 90%

72% (1 y) 9.3 mo (PFS)

Glass

Yes

72

40%

14.5 mo

Resin þ 5-FU Resin

No Yes

11 12

91% 0%

29.4 mo 4.5 mo

Mulcahy et al, 2009 (34) Van Hazel et al, 2004 (35) Murthy et al, 2005 (39) Abbott et al, 2015 (40)

Glass

Yes

68

NR

11.6 mo

Hendlisz et al, 2010 (36) Kalva et al, 2014 (41)

Resin Resin

Yes Yes

21 45

9.5% 2%

10 mo 186 d

Saxena et al, 2015 (42)

Resin

Yes

302

39%

10.5 mo

Kennedy et al, 2015 (43) Lewandowski et al, 2014 (44)

Resin Glass

Yes Yes

606 214

NR NR

9.6 mo 10.6 mo

Resin or glass Resin þ 5-FU

No 15% of patients

42 34

52% 50%

25 mo 24.2 mo

Neuroendocrine metastases Rhee et al, 2008 (45) King et al, 2008 (46)

Resin

NR

148

63.2%

70 mo

Saxena et al, 2010 (47) Breast cancer metastases

Kennedy et al, 2008 (32)

Resin

52% of patients

48

54%

35 mo

Gordon et al, 2014 (48)

Glass

Yes

75

35%

6.6 mo

Saxena et al, 2014 (49) Uveal melanoma

Resin

Yes

40

31%

13.6 mo

Gonsalves et al, 2011 (38)

Resin

No

32

6%

10 mo

Klingenstein et al, 2013 (50)

Resin

77% of patients

13

62%

7 mo

5-FU ¼ 5-fluorouracil; FOLFOX ¼ leucovorin/5-fluorouracil/oxaliplatin; NR ¼ not reported; PFS ¼ progression-free survival. cell carcinoma, and sarcoma (38,48–50,52,53). Current evidence supports consideration of the use of radioembolization for these malignancies in the salvage setting. The incidence of liver-dominant metastases is relatively low with these cancers; therefore, large-scale prospective randomized trials are not feasible.

DEFINITIONS/TERMINOLOGY Although practicing physicians should strive to achieve perfect outcomes (eg, 100% success, 0% adverse events), all physicians will fall short of this ideal to a variable extent. Therefore, indicator thresholds may be used to assess the efficacy of ongoing QI programs. For the purposes of these guidelines, a threshold is a specific level of an indicator that should prompt an internal review. “Procedure thresholds” or “overall thresholds” reference a group of indicators for a procedure, eg, major adverse events. Individual adverse events may also be associated with adverse events–specific thresholds. When measures such as indications or success rates fall below a (minimum) threshold, or when adverse event rates exceed a (maximum) threshold, a review should be performed to determine causes and to implement changes, if necessary. For example, if the incidence of gastrointestinal ulceration is one measure of the quality of radioembolization, values in excess of the defined threshold (in this case 3%) should trigger a review of policies and procedures within the department to determine the causes and to implement changes to lower the incidence of the adverse events. Thresholds may vary from those listed; for example, patient referral patterns and selection factors may dictate a different threshold value for a particular indicator at a particular institution. Thus, setting universal thresholds is very difficult, and each department is urged to alter the thresholds as needed to higher or lower values to meet its own QI program needs. Primary liver cancers are those malignancies that originate from the hepatic tissue. These include HCC and cholangiocarcinoma.

Cholangiocarcinoma can present initially as intrahepatic or extrahepatic. Radioembolization has been studied for HCC and intrahepatic cholangiocarcinoma. Secondary liver cancers are those malignancies that originate at an extrahepatic site and then metastasize to the liver. Examples include metastases from colorectal cancer, neuroendocrine tumors, breast cancer, lung cancer, uveal melanoma, other gastrointestinal carcinomas, renal-cell carcinoma, and sarcoma. Activity is the amount of radiation that is emitted per unit time. The SI unit for activity is the becquerel, which is one nuclear disintegration per second. Absorbed dose refers to the amount of energy deposited (in Joules per kilogram) in matter by radiation, and should not be confused with the unit of radioactive activity (becquerels) of the radiation source. Exposure to radiation will result in a radiation absorbed dose, which is dependent on many factors, such as the activity of the source, volume of exposed tissue, duration of exposure, energy of the emitted radiation, and distance from the source. The SI unit for absorbed radiation dose is the Gray. C-arm computed tomography (CT; also commonly referred to as cone-beam CT) is a three-dimensional (3D) CT-like filtered backprojection reconstruction after a rotational angiogram is obtained with the use of a flat-panel detector. Potential advantages of c-arm CT include improved tumor detection and extrahepatic perfusion detection, 3D vascular mapping, and real-time 3D guidance during angiographic procedures (54). Nontarget embolization is defined as the unintended delivery of an embolic agent to a vascular territory outside the target region. In the liver, this includes portions of the liver, possibly free of disease, that were not the intended target. Gallbladder, duodenum, stomach, anterior abdominal wall, and lungs are examples of extrahepatic nontarget regions. Nontarget embolization can result in radiationinduced damage to these areas and produce symptoms of abdominal

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pain, bleeding, or dyspnea with the possibility of temporary or permanent disability. It should be recognized that, depending on the angiographic anatomy, gallbladder, anterior abdominal wall, and lung deposition within limits may be clinically acceptable. However, nontarget deposition involving the duodenum and stomach are never clinically acceptable. Postembolization syndrome is the occurrence of abdominal pain, low-grade fever, nausea, vomiting, loss of appetite, and/or malaise in the first few days after radioembolization. Although this is an expected part of recovery, its frequency and severity may be lower than seen with chemoembolization. This process should not be considered an adverse event of radioembolization unless unplanned medical therapy or hospitalization is required. Technical success is the administration of 90Y microspheres into the target artery supplying the intended region of treatment. On occasion, a patient may not be a candidate for 90Y infusion based on nonsuitable vasculature identified on the mapping angiogram or because of a high lung shunt fraction. This should not be considered a technical failure because the treatment plan changed before the infusion procedure. Radioembolization-induced liver disease (REILD; often described as “radiation-induced liver disease” because of subtle differences caused by external-beam irradiation) consists of a constellation of symptoms related to radiation-induced liver dysfunction in the absence of objective tumor progression. These include jaundice and/or ascites, usually with associated increases in serum alkaline phosphatase and bilirubin levels (unlike radiation-induced liver disease from conventional external-beam radiation, which is often associated with normal bilirubin levels). REILD usually occurs 1–2 months after radioembolization, but its onset is highly variable, making the diagnosis often challenging (55).

PATIENT SELECTION A comprehensive understanding of the patient’s oncologic stage, performance status, laboratory test results, treatment history, and potential future treatment options is critical in patient selection. Interventional radiologists should be aware of (i) clinical parameters such as the Eastern Cooperative Oncology Group (ECOG) performance status; (ii) laboratory assessment of liver function, coagulation status, renal function, and tumor markers; and (iii) radiologic staging of disease, including distribution, number, and size of tumors and the presence of vascular invasion or extrahepatic metastases. The Couinaud liver segment classification system is preferred for describing the anatomic location of hepatic tumors. A thorough clinical history, including previous therapies (surgical/ medical/interventional), should be obtained. The previous administration of certain systemic chemotherapy agents (especially patients receiving biologic agents such as bevacizumab) is relevant because of the association with hepatic vasculature adverse events, such as vasospasm, dissection, or inability to deliver the microspheres. Other systemic agents may cause subclinical hepatic toxicity and compromise liver reserve. Finally, the interventional radiologist should decide whether to proceed with radioembolization in the context of other available therapies (eg, surgical resection, ablation, external-beam radiation, systemic chemotherapy, chemoembolization). In patients who are already receiving systemic chemotherapy, the interventional radiologist should also assess whether radioembolization should be performed concurrently or during a chemotherapy “holiday” (56).

Disease Staging Oncologic staging should be performed by using accepted staging systems for the particular malignancy. In the case of HCC, in which there is often coexisting liver cirrhosis, assessment of liver function with the Child–Turcotte–Pugh score should be calculated. Some commonly used staging systems for HCC include the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, Okuda, United Network

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for Organ Sharing tumor/node/metastasis, and Hong Kong staging systems. Although one study suggested that the Cancer of the Liver Italian Program system outperformed other staging systems in HCC, no single staging system can be recommended in view of the limited data comparing the various staging systems (57–59). Given the numerous types of liver metastases that may be treated with radioembolization, it is impractical to mandate a specific staging system based on all tumor types (eg, Dukes/tumor/node/metastasis staging for colorectal cancer). However, baseline data regarding presence of extrahepatic metastases should be obtained.

Indications and Contraindications If feasible, therapy selection is recommended by consensus in a multidisciplinary team, for example, including hepatologists (in the case of primary liver cancer), medical oncologists, radiation oncologists, surgeons, and interventional radiologists. For HCC, size, number, and distribution of tumors play pivotal roles in patient selection. Other locoregional options should also be considered, including transarterial chemoembolization and ablation. There is considerable overlap in the indications and patient selection of each treatment modality. The choice of therapy must take multiple factors into consideration, such as best potential tumor response, lowest degree of toxicity, patient preference, and availability of local expertise. Degree of cirrhosis (measured by Child–Turcotte–Pugh class) must be considered, as well as trends in patients’ liver function over time. The albumin-bilirubin grade is being investigated as an adjunct to the Child–Pugh score (60). In general, radioembolization may be safely offered to patients with borderline liver function if performed in a more selective (ie, segmental) fashion, even though this depends on stability of the patient’s liver function over time, goals of treatment (eg, palliation vs downstaging to transplantation), and the expertise and experience of the performing interventional radiologist. For intrahepatic cholangiocarcinoma, patients should have surgically unresectable disease at the time of treatment. Presence of extrahepatic metastases should not be considered an absolute contraindication, as several studies have shown promising overall survival in this scenario (18,20). Rather, efforts at combining radioembolization with systemic chemotherapy should be considered in this situation. Caution should be taken in patients with biliary obstruction or in patients with a history of biliary manipulation, even though this does not represent an absolute contraindication and is associated with a lower risk for hepatic abscess formation than seen with chemoembolization (61). There is currently no role for radioembolization in the setting of hilar/extrahepatic cholangiocarcinoma. In the setting of hepatic metastases, indications vary widely and are often institution-dependent. For colorectal cancer metastases, the metastases should be considered unresectable and not amenable to ablation. However, the timing of radioembolization with regard to a patient’s chemotherapy regimen remains controversial. Most centers do not perform radioembolization as first-line therapy, but rather in a salvage setting. It is unclear when the maximum benefit from radioembolization may be derived, such as after failure of first-line or second line chemotherapy. Although survival times tend to be longer in patients receiving radioembolization earlier in the disease course, this may reflect selection and lead-time bias. In certain situations when a patient has exhibited toxicity from systemic chemotherapy, radioembolization can allow for a chemotherapy holiday while controlling tumor growth. Patients with metastatic disease to the liver should have acceptable performance status, ie, ECOG performance status 0 or 1. Poor performance status should be addressed before treatment, as this may reflect a patient whose condition is rapidly declining. In these cases, radioembolization would be of no benefit, and could even be potentially harmful by accelerating the decline in performance status. Hepatic function should be within normal limits, and any liver function abnormality before treatment must be addressed and managed. Abnormal liver function is often a sign of toxicity from systemic chemotherapy or

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rapid tumor infiltration. In these situations, radioembolization would be contraindicated. This is in contrast to patients with HCC, who usually have underlying cirrhosis, typically resulting in some baseline decline in performance status and/or hepatic function abnormality. Furthermore, trends in hepatic function should be reviewed if available, as patients with declining liver function may still have laboratory values that are considered within normal limits. Isolated elevation of alkaline phosphatase is typically not of concern and is more a marker of metastatic foci in the liver rather than hepatic dysfunction. The absolute contraindications to radioembolization for any malignancy include severely compromised hepatic function, poor performance status (ECOG 4 2), active hepatic infection, significant extrahepatic metastases, and pregnancy. After mapping angiography, the inability to administer 90Y microspheres without nontarget embolization to the bowel is also considered an absolute contraindication. A high lung shunt fraction (LSF) that would lead to a greater than 30-Gy dose to the lungs with a single treatment is an absolute contraindication for radioembolization. Relative contraindications to radioembolization include uncorrectable coagulopathy, severe radiographic contrast medium allergy, and renal impairment, all of which can often be medically addressed. Increased bilirubin level and significant ascites are relative contraindications; individualized patient decision-making is recommended in these settings.

DEVICES There are two types of 90Y microspheres commercially available. TheraSphere (BTG International, Ottawa, Ontario, Canada) consists of 20–30-mm-diameter glass microspheres with 90Y integrated into the glass structure. This device received US Food and Drug Administration (FDA) approval in 1999 under a Humanitarian Device Exemption as radiation treatment or as a neoadjuvant therapy to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters, or in patients with HCC with partial or branch portal vein thrombosis/ occlusion, when clinical evaluation warrants the treatment. In the European Union and Canada, it is approved for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. SIR-Spheres (Sirtex, North Sydney, Australia) are biodegradable resin 20–60-mm-diameter microspheres onto which 90Y is adsorbed to the surface. This device received FDA approval in 2002 for the treatment of metastatic colorectal cancer with concomitant use of intraarterial floxuridine. In the European Union, SIR-Spheres are indicated for the treatment of patients with inoperable liver tumors. Despite the relatively narrow FDA-approved indications for both devices, both are often used on an off-label basis based on several medical practice guidelines (62,63). There are other radiopharmaceutical agents (ie, radionuclide/carrier combinations) available, but there are limited data available on their safety and efficacy (64–67).

TECHNIQUE Multiple factors may influence technique of radioembolization, such as tumor distribution, choice of 90Y device, and goals of therapy.

Preprocedure Angiography Pretreatment (ie, planning) angiography is an integral step before radioembolization (68–72). Meticulous mapping of the vascular anatomy allows the interventional radiologist to (i) identify the vascular supply of the liver and the tumor, (ii) identify and embolize vessels that may lead to nontarget deposition of the radioembolic material, and (iii) to quantify LSF. The choice to perform prophylactic embolization of extrahepatic vessels (eg, gastroduodenal artery, right gastric artery) is largely operator-dependent and varies considerably across institutions. It is recommended that new users have a low threshold to perform prophylactic embolization of extrahepatic vessels before radioembolization. However, many experienced, high-volume centers have moved

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away from routine prophylactic embolization of the gastroduodenal artery and right gastric artery (73). Many cases of collateral vessel formation have been observed following gastroduodenal and right gastric artery embolization, and these collateral vessels are exceedingly difficult to embolize (74,75). The degree of anticipated arterial stasis during radioembolization is an important consideration when deciding if prophylactic embolization is necessary. Several techniques (in addition to coil embolization) have been used to decrease the incidence of extrahepatic microsphere deposition. A thorough evaluation of the technetium-99m (99mTc) macroaggregated albumin (MAA) images should be performed to assess for extrahepatic uptake. Free technetium should be excluded as a cause of uptake in the stomach. In certain cases, a second mapping angiogram may be necessary if scintigraphic findings are concerning. The concept of vascular redistribution (ie, occluding intrahepatic vessels before radioembolization to induce redistribution of flow) has been developed to simplify treatment and potentially avoid gastric vessels (76,77). For example, in the case of a replaced left hepatic artery originating from a left gastric artery, the gastrohepatic trunk is embolized to redistribute flow to the left from the right hepatic artery. This is commonly done for radioembolization with higher particle loads. Finally, antireflux catheters (eg, Surefire, Surefire, Westminster, Colorado) have played an increasing role in preventing reflux of particles. C-arm cone-beam CT is now routinely used intraprocedurally in addition to digital subtraction angiography to determine vascular supply to the tumor and detect potential extrahepatic vessels (78–82). It allows for visualization of tumors as well as intraprocedural guidance to position microcatheters in the appropriate vessels for targeting (54). This intraprocedural imaging technique is strongly recommended and may become the standard of care, but is currently not mandated as a result of the lack of universal availability.

Imaging with

99m

Tc MAA

Technetium-99m MAA scintigraphy is performed at the time of the pretreatment angiography to quantify the LSF and identify nontarget flow. It is important to recognize that the gold standard for assessment of extrahepatic arterial flow is angiography (with or without cone-beam CT) and not 99mTc-MAA scintigraphy. However, improved imaging protocols and implementation of single-photon emission CT (SPECT) will continue to play a role in confirming the lack of extrahepatic deposition of 99mTc-MAA (83).

Choosing Hepatic Target Volume The decision to use whole-liver, lobar, or selective (ie, two or fewer hepatic segments perfused) approaches is dependent on the patient’s baseline laboratory values, clinical characteristics, tumor distribution, and vascular anatomy. In general, patients with better performance status, adequate liver function, and lack of previous treatment tend to tolerate treatment of larger hepatic target volumes. Targeting is principally accomplished with angiography, use of c-arm cone-beam CT, and correlation with preprocedural imaging. This allows an appropriate level of vessel selection. Lobar infusion is the most common approach for multifocal disease. For whole-liver therapy, sequential lobar injections (typically separated by 4–8 wk) are the most common method. In select situations, especially in the setting of metastatic liver tumors in which no underlying liver disease is present, whole-liver infusion can be performed (via separate lobar injections in a single session). Selective multivessel infusions can potentially avoid nontarget deposition in proximal extrahepatic vessels (eg, cystic artery, supraduodenal artery). Segmental radioembolization, whereby one or two hepatic segments are treated, can be considered in patients with isolated tumor burden, and may allow higher administered dose because most segments of the liver would remain unaffected by treatment (15,16,84).

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DOSIMETRY Standard dosimetric formulas are presented as follows:

Dose Calculation for Glass Microspheres Dose calculations require the use of 3D-reconstructed cross-sectional imaging to calculate the volume of the targeted liver tissue to be infused. The volume (in milliliters) is then used to calculate the mass (in grams) by multiplying it by a factor of 1.03 (conversion factor that represents liver parenchymal density). The activity (A in Equation 1) in gigabecquerels administered to the target area of the liver, assuming uniform distribution of microspheres, is calculated using the following the Medical Internal Radiation Dose formula as follows: A¼D  m=50

[Eq 1]

Where D is the dose administered in Grays and m is the mass in kilograms of the perfused tumor-bearing liver tissue. The dose delivered to the treated mass also depends on the percent residual activity (R in Eq 2) in the vial and tubing after treatment and the LSF, which is calculated beforehand by using 99mTc-MAA scintigraphy. These factors are accounted for in the following formula: D¼A  50  ð1LSFÞ  ð1RÞ=m

[Eq 2]

Although it is noted that this dosimetry model is independent of tumor burden, for a given dose, different number of microspheres can be administered to account for larger tumor size.

the same imaging modality and temporal follow-up; if possible, standardization is recommended. Radiologic response has been shown to correlate with survival (94). Tumor response can be measured strictly based on size by using the World Health Organization criteria and Response Evaluation Criteria In Solid Tumors (RECIST). In cases of enhancing tumors (ie, HCC), the European Association for Study of the Liver (EASL) and modified RECIST (mRECIST) guidelines (measuring change in the amount of enhancing, ie, viable, tumor only) are commonly used (95,96). The use of EASL guidelines and mRECIST for HCC has numerous advantages over conventional size measurements, and has been shown in multiple studies to be a better predictor of progression and survival (97–99). Combining size and enhancement criteria has been shown to improve the prediction of complete pathologic necrosis at explant (100). Recently, use of the “primary index tumor” to assess response following locoregional therapy in HCC has been reported, thereby simplifying and standardizing response evaluation methodology in HCC (101). The use of quantitative 3D imaging assessment is a developing tool that may prove to have better accuracy and correlation with outcomes (102,103). Fluorodeoxyglucose (FDG) positron emission tomography is a metabolic imaging technique that has a role in response assessment following radioembolization of some metastatic hepatic tumors, but is rarely used in the setting of HCC because HCC is not typically FDGavid (104–108).

Changes in Tumor Markers Dose Calculation for Resin Microspheres The model of dosimetry for SIR-Spheres is based on whole-liver infusion. The calculated activity of the whole liver is multiplied by the percentage of the target site as a proportion of the whole liver. The formula for dosimetry of SIR-Spheres is as follows:
A¼body surface area–0:2 þ % tumor burden=100 Where A is the activity in gigabecquerels, body surface area is measured in meters squared, and “% tumor burden” is the percentage of the liver that is involved by tumor. For treatment of less than the whole liver, the dose is adjusted according to the proportion of liver treated. A lower number of microspheres per activity can now be administered when infused 1 day early relative to its calibration date. Several drawbacks to both dosimetry models exist, leading many experienced users to modify their approach to dosimetry with the intent of maximizing tumor response and minimizing liver toxicity (85). For example, many centers have adopted partition modeling for resin microsphere dosimetry, which involves calculating tumor versus nontumor distribution of dose (86,87). Other centers have adopted quantitative SPECT/CT after 99mTc-MAA injection to adjust dosimetry for glass microspheres (88–90). This area is still under investigation.

FOLLOW-UP AND OUTCOME ASSESSMENT The response to radioembolization may be evaluated by using (i) imaging findings, (ii) changes in tumor markers, and (iii) pathologic findings (91–93). The clinical impact should be assessed as well, such as change in energy levels and pain palliation. A clinic visit is recommended with laboratory workup (including liver function tests) within 1 month of treatment. Radiologic evaluation is recommended at 1–3 months following treatment and at 3–6-month intervals thereafter. Although early follow-up imaging at 1 month is often performed, one should interpret tumor response with caution at such an early time period, as the effects of radioembolization occur over several months.

Radiologic Response The imaging modality (ie, CT vs magnetic resonance imaging) should be consistent throughout the patient’s care to best assess response to therapy. It may be difficult in some situations to have patients receive

Posttreatment changes in tumor markers, such as α-fetoprotein (AFP) in HCC and carcinoembryonic antigen in colorectal metastases, correlate to response to treatment. Recent studies support the use of tumor markers following locoregional therapies (92). In many cases in which response for HCC is challenging to assess with imaging, the use of AFP trends can help direct future therapy. In cases of solitary HCC and elevated baseline AFP level (4 200 ng/mL), AFP assessment may outperform imaging in predicting long-term outcomes (109).

Tumor Progression It is important to be able to recognize progression following treatment. RECIST, mRECIST, World Health Organization, and EASL guidelines define progression distinctly. Progression should incorporate development of new tumor, development or expansion of vascular invasion, and development of extrahepatic metastases. As staged therapy has become more accepted for liver malignancy, the differentiation of local tumor progression and overall tumor progression is vital in defining treatment success. In addition, the pattern of extrahepatic disease should be well-understood, particularly in HCC, to avoid premature discontinuation of effective treatment (110).

Patient Mortality Patient mortality unrelated to the intervention is expected as a result of (i) cancer, (ii) progression of underlying liver disease (particularly in the case of HCC), and (iii) other comorbidities. Mortality rates should not be confused with survival. Mortality rates are represented by the percentage of patients who have died at a specific time, whereas survival data represent extrapolated medians calculated by using the Kaplan–Meier method.

ADVERSE EVENTS Published rates for individual types of adverse events (Appendix B) are highly dependent on patient selection and may be based on series comprising several hundred patients, which is a volume larger than most individual practitioners are likely to treat. Generally, the adverse event–specific thresholds should therefore be set higher than the adverse event–specific reported rates listed here earlier. It is also recognized that a single adverse event can cause a rate to cross above an adverse event–specific threshold when the adverse event

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occurs within a small patient volume, (eg, early in a QI program). In this situation, the overall procedure threshold is more appropriate for use in a QI program. All values in Table 3 were supported by the weight of literature evidence and panel consensus. Adverse events following radioembolization may occur as a result of (i) a toxic dose to normal hepatic parenchyma, (ii) a toxic dose to extrahepatic tissue, (iii) adverse events of angiography (eg, puncture site adverse events, vessel dissection), and (iv) systemic side effects. It is recommend to actively track additional clinical and biochemical toxicities representing liver function abnormalities, such as bilirubin toxicity and ascites. Adverse events secondary to treatment delivery should be defined by using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (111). These criteria are designed to be applied to all treatment modalities.

Hepatic Adverse Events Hepatic adverse events include liver failure, portal hypertension (caused by hepatic fibrosis), liver abscess, intrahepatic bilomas, and liver infarction (112–117). Worsening ascites, jaundice, and laboratory test results (eg, elevated total bilirubin) may indicate postprocedural liver dysfunction. The incidence of hepatic adverse events in the literature is highly variable as a result of diverse patient selection, duration of patient follow-up to assess for toxicities, and definitions for grading toxicities. The presence of underlying cirrhosis (in the case of HCC) further complicates this picture, as the natural history of cirrhosis progression may be confounded with liver toxicity from radioembolization. This is especially the case in patients with Child–Pugh class B and C disease, as well as patients with rapidly deteriorating liver function before treatment. Multiple factors have been identified that place patients at increased risk of hepatic dysfunction, especially the presence of preexisting liver disease. For this reason, patients with Child–Pugh class C disease are at markedly increased risk of further hepatic toxicity, and radioembolization should be performed with extreme caution. Patients with elevated baseline bilirubin levels, low albumin levels, or the presence of ascites are not ideal candidates for radioembolization. Patients with metastatic liver tumors should have normal background hepatic parenchyma, and therefore any hepatic laboratory abnormality should raise concern. This often occurs when patients have received numerous lines of systemic chemotherapy, some of which may be hepatotoxic. Although several guidelines on absolute values of acceptable liver function are available, one must also assess trends in a patient’s liver function tests over time to assess their candidacy for radioembolization. REILD can present at any time after radioembolization, but usually occurs at least 1 month after treatment. REILD is characterized by abnormal liver function test results (including elevated alkaline

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phosphatase and bilirubin levels), ascites, and fatigue in the absence of tumor progression. Although the incidence of REILD is relatively low (typically less than 4%), it can progress to liver failure and death (114). Previous radioembolization, multiple lines of chemotherapy, abnormal baseline liver function, single-session whole-liver therapy, and empiric model dosimetry with resin microspheres have been identified as risk factors for the development of REILD (55,114). Biliary adverse events from radioembolization have been reported, but are relatively uncommon compared with other intraarterial therapies, likely because of the minimally embolic effect of radioembolization (112). Patients with biliary stents, obstructed bile ducts, or previous manipulation of the ampulla of Vater are at increased risk of cholangitis and bilomas. Such a history tends to be more prevalent in the setting of intrahepatic cholangiocarcinoma, as many of these patients initially present with biliary obstruction. However, these should not be considered an absolute contraindication to radioembolization. Instead, a thorough assessment of competing therapies and discussion with the patient regarding risks should be undertaken. The use of prophylactic antibiotic agents, as per the SIR antibiotics guidelines (116), may lower the rate of infection and should be considered. Hepatic abscess is a known adverse event associated with all intraarterial therapies, including radioembolization. Its incidence is relatively low, likely because of the minimally embolic effect of 90Y microspheres. Management is usually conservative, but percutaneous drainage may be required occasionally. Hepatic fibrosis can be observed months to years after radioembolization, and may manifest clinically as portal hypertension. Several case series demonstrating hepatic volume reduction and splenic enlargement after radioembolization have been published (118–120). Repeat treatments have been associated with an increased incidence of fibrosis, and, in these cases, alternative therapies should again be evaluated. Refinements in dosimetry may help to reduce the incidence in the future, as the fibrosis likely occurs from microsphere deposition into the normal hepatic parenchyma. In some scenarios, the development of fibrosis in a treated lobe may be beneficial, as contralateral lobar hypertrophy may occur, facilitating an eventual surgical resection (119).

Extrahepatic Adverse Events Extrahepatic adverse events can be separated into adverse events resulting from systemic effects of radioembolization (eg, lymphopenia) and extrahepatic deposition of injected material (ie, nontarget embolization). The latter includes radiation pneumonitis and radiationinduced pulmonary fibrosis, radiation cholecystitis, and gastrointestinal ulcers. When these adverse events occur, reevaluation of relevant details of the vascular anatomy from angiography and 99mTc-MAA is recommended for QI purposes.

Table 3 . Adverse Events Reported Rate (%)

Suggested Threshold (%)

Radiation-induced liver disease

Adverse Event

1–4

5

Biloma requiring percutaneous drainage Abscess with functional sphincter of Oddi

o1 o1

2 2

Postembolization syndrome requiring extended stay or readmission

1–2

4

GI ulceration Radiation-induced skin injury

0–5 o1

3 4

Radiation-induced cholecystitis Radiation pneumonitis Radiation-induced pulmonary fibrosis Iatrogenic dissection preventing treatment Death within 30 d

2

5

o1 o1

1 1

1

5

0–2

4

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Gastrointestinal ulceration remains one of the most concerning sequela of extrahepatic deposition of 90Y microspheres. This occurs from unintentional 90Y embolization to arteries supplying the stomach or duodenum, such as the gastroduodenal artery, right gastric artery, supraduodenal artery, left gastric artery, or accessory left gastric artery. The consequences of gastrointestinal ulceration are potentially severe. In the setting of metastatic disease, the use of biologic agents is not recommended if gastrointestinal ulceration occurs. In addition, it may be necessary to withhold systemic chemotherapy agents to allow for healing. Because patients may have difficulty eating, weight loss and poor nutritional status become a major concern, which may lead to fatigue and decrease in performance status. Many patients may require long-term proton pump inhibitors, intravenous nutrition, and narcotic pain control. Overall quality of life is markedly affected in patients with gastrointestinal ulceration, and symptoms may last for years. In some cases, it may not be technically possible to safely administer 90Y without a significant risk of nontarget embolization to the bowel. In such cases, alternative therapies (eg, systemic chemotherapy, chemoembolization, bland particle embolization) should be considered. A recent series (121) has shown that stasis during injection of resin microspheres, a proximal injection location, and a distal origin of the gastroduodenal artery (even if coil embolization has been performed) are the greatest risk factors for ulceration. Infusion should never be performed from the region of the common or proper hepatic artery, and, at the very least, lobar (eg, right hepatic artery) injections should be performed. In the case of whole-liver infusions, a multivessel 90Y approach to cover the entire liver should be chosen instead of infusion from a proximal position. Radiation-induced skin injury has been reported from microsphere deposition in the falciform artery (122,123). Severe cases can manifest in dermatitis or even skin ulceration. Many patients report symptoms of superficial abdominal pain, which is thought to result from falciform artery deposition. Because of the exceedingly low incidence of severe adverse events from falciform artery uptake of 90 Y, it may not routinely require prophylactic embolization. In many cases, the origin of the falciform artery is in a distal second- or thirdorder left hepatic artery branch, and attempted catheterization may cause spasm or dissection of the left hepatic artery. Therefore, risks of coil embolization in these instances may exceed the potential benefits. Inclusion of the falciform artery in the treated distribution is not an absolute contraindication to radioembolization. Radiation-induced cholecystitis is a well-known adverse event when infusion is performed proximal to the cystic artery, and occurs in as many as 2% of cases. Not uncommonly, the gallbladder wall may enhance at follow-up imaging as a result of exposure to 90Y. This finding is most commonly clinically innocuous. Several studies have assessed the impact of prophylactic embolization (eg, gelatin, coils) of the cystic artery, but a decrease in the rate of cholecystitis has not been observed with these maneuvers (124). It is likely that cases of cholecystitis after prophylactic embolization may be ischemic in nature. Most instances of radiation-induced cholecystitis can be managed conservatively with hydration, pain control, and antibiotic therapy. In rare cases, cholecystectomy or percutaneous cholecystostomy may be required; however, these measures should be reserved as a last option (125). Prevention by administration of microspheres distal to the cystic artery should be attempted whenever feasible. Radiation pneumonitis is rare and likely occurs from hepatic arterial–hepatic venous shunting, resulting in particle deposition to the lungs. Its incidence can be controlled by appropriate dose reduction in cases of elevated LSF. Elevated lung shunting is often seen with infiltrative disease, high tumor burden, and portal vein invasion (126). However, the presence of these factors should not preclude mapping angiography, as many tumors with these features do not exhibit a high degree of lung shunting. For glass microspheres, dose should be reduced to keep a single-session pulmonary dose under 30 Gy (in a patient with normal pulmonary function). Resin microspheres may be dose-modified in the same manner, or can be reduced based on shunt

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fractions exceeding 10% as recommend by the manufacturer. Interestingly, a recent study of resin microspheres for HCC (21) reported two deaths (among a total of 63 patients) secondary to radiation-induced lung injury. In both these cases, large tumors with arterial–venous fistulae were prophylactically embolized to lower the shunt fractions to less than 20%, but were hypothesized to reform fistulae by the time of treatment. Although chemotherapy was not administered in these two cases, systemic chemotherapy may also play a role in predisposing patients to radiation pneumonitis (127).

Vascular Adverse Events Systemic chemotherapeutic agents may render blood vessels fragile. Hence, vascular adverse events may occur more often following systemic chemotherapy for secondary liver tumors. Biologic agents have been widely known to cause vascular adverse events during arteriography. The most common agent associated with vascular adverse events is bevacizumab, a monoclonal antibody to vascular endothelial growth factor commonly used in metastatic colon and breast cancer. Arterial dissection, vasoconstriction, and poor vascular flow have been reported (128,129). Therefore, it is recommended that radioembolization proceed at least 4–6 weeks after the last dose of bevacizumab. Careful selection and manipulation of microcatheters and wires are mandatory in these situations.

Systemic Side Effects Systemic side effects are frequent consequences of radioembolization, but rarely result in substantial morbidity. The most common side effect is a postradioembolization syndrome that consists of a combination of fatigue and anorexia, occasionally with nausea, vomiting, fever, and abdominal discomfort. Analgesic agents with or without oral steroids may be considered. Patients may be given antiemetic agents such as ondansetron on the day of treatment. Gastrointestinal prophylaxis with H2 receptor blockers or proton pump inhibitors and may be considered. Postradioembolization syndrome is less severe than that observed after other embolic therapies (such as chemoembolization) in which fatigue and constitutional symptoms predominate (39,130,131). Mild abdominal pain may be experienced following radioembolization. Rare cases of significant pain during infusion have been reported. This is often accompanied by nausea and diaphoresis, occasionally with alterations in blood pressure and heart rate. It has been attributed to an idiosyncratic reaction, often to resin microspheres (39).

FUTURE DIRECTIONS Future developments in radioembolization will continue to refine the therapy, with the goal of expanding appropriate indications, improving tumor response (and hence survival), and minimizing adverse events. It is imperative that robust data be obtained for new indications of radioembolization. For example, further research is needed to appropriately define its role in the treatment of hepatic metastases from uveal melanoma, sarcoma, renal-cell carcinoma, lung cancer, pancreatic cancer, and prostate cancer. The challenge in obtaining data is the relatively low incidence of liver-only or liver-dominant metastases in these situations. For example, patients with liver metastases from renal-cell carcinoma often present with concurrent pulmonary and osseous metastases. Although radioembolization is not commonly recommended in this setting, there may be instances in which extrahepatic metastases are being well-controlled by systemic chemotherapy. This is especially true in breast cancer. In this scenario, radioembolization may result in improved time to progression and patient survival. It is widely believed that hepatic tumor progression in many of these cancers represents the limiting factor in patients’ survival. Comparative data of radioembolization versus other locoregional therapies are important to collect, especially for primary liver cancer. Several studies comparing chemoembolization and radioembolization have shown no significant superiority of any one therapy in overall

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survival (26–28,132). However, many of these studies had broad inclusion criteria and included patients across the spectrum of Barcelona Clinic Liver Cancer staging. In several studies, even within the same tumor stage, radioembolization was often offered to patients who were not candidates for chemoembolization. Further work is needed to compare these therapies based on tumor stage. For example, comparing chemoembolization and radioembolization when performed in a segmental fashion would be a fair comparison. Finally, many of the previously published studies compared radioembolization versus chemoembolization when the authors were experienced with chemoembolization but were early in their experience with radioembolization. As the radioembolization technique continues to be refined and improved, comparative studies may indeed reveal differences in the future. The combination of systemic chemotherapy and radioembolization continues to be debated for primary and metastatic disease. In the case of HCC, patients with certain features that portend a high likelihood of future metastatic disease (eg, high AFP level, vascular invasion) may benefit from the addition of a systemic agent in addition to local arterial-based therapy. In the case of metastatic disease, the safety of systemic agents may be potentially compromised by the addition of radioembolization. Future studies should continue to focus on the safety and efficacy of combined strategies, as this will likely become the new paradigm for liver cancer treatment. With further evolution and refinement of technology and techniques, the efficacy of radioembolization will continue to improve for primary and secondary hepatic malignancy. A wide range of tumor response rates following radioembolization has been published. Further research is needed to identify factors that could result in higher tumor response rates without raising rates of hepatic toxicity. For example, there has been significant work in improving dosimetry models for resin and glass microspheres, acknowledging the limitations of the currently accepted dosimetry formulas. Several publications on non–FDG positron emission tomography–based dosimetry and quantified single photon-emission CT dosimetry may help to create threshold doses to achieve higher tumor response rates (133,134). Further studies are needed to assess factors that result in hepatic toxicity, especially radiation-induced liver disease. Refinements in dosimetry can play a large role in reducing hepatic toxicity. In many cases, this is unavoidable, especially when multifocal tumor is present. However, refinements in dosimetry, use of segmental infusions, and use of ancillary devices may help to improve rates of hepatic toxicity. Several series have shown extraordinarily low rates of hepatic toxicity from segmental radioembolization (15,16), as most of the hepatic parenchyma is spared exposure to radiation. Future directions in dosimetric quantification from the mapping 99mTc-MAA study may further help to refine the dosimetry model. Nontarget embolization of microspheres to the gastrointestinal tract must be minimized, as radiation-induced ulcers represent a significant cause of patient morbidity and can severely limit quality of life. Future studies looking at various techniques to minimize nontarget deposition are needed. Finally, cost–benefit analyses are lacking in this arena. This is becoming increasingly important as the trend to reduce overall health care expenditures continues. Although many believe radioembolization can be a costly procedure, cost–benefit comparisons of radioembolization versus other techniques must take into account costs over specified time periods (ie, cost per patient year of survival) as well as quality of life (eg, number of days of hospitalization, days of work lost) (135).

CONCLUSIONS Radioembolization has an established role in the management of hepatic malignancies. Ongoing research will help to refine the technology and techniques, further validate indications, and help determine its exact place among other therapies for primary and secondary liver cancer.

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APPENDIX A. CONSENSUS METHODOLOGY Reported adverse event–specific rates in some cases reflect the aggregate of adverse events of varying severities. Thresholds are derived from critical evaluation of the literature, evaluation of empirical data from Standards of Practice Committee members, and, when available, the National Benchmarks from the National Quality Registry for Interventional Radiology. Modified Delphi technique may be used to enhance effective decision-making (136,137).

APPENDIX B. ADVERSE EVENT CLASSIFICATION Adverse Event Description A. Description narrative of adverse event (including sedation and anesthesia) B. Adverse event severity assessment*: escalation of level of care. 1. Mild adverse event: No therapy or nominal (non-substantial) therapy (post-procedural imaging performed and fails to show manifestation of adverse event); near miss (e.g., wrong site of patient prepped, recognized and corrected prior to procedure, wrong patient information entered for procedure, etc.); 2. Moderate adverse event: moderate escalation of care, requiring substantial treatment, e.g., intervention (description of intervention and result of intervention) under conscious sedation, blood product administration, extremely prolonged outpatient observation or overnight admission post outpatient procedure not typical for the procedure (excludes admission or hospital days unrelated to adverse event); 3. Severe adverse event: marked escalation of care, i.e. hospital admission or prolongation of existing hospital admission for > 24 h hospital admission that is atypical for the procedure, inpatient transfer from regular floor/telemetry to ICU or complex intervention performed requiring general anesthesia in previously non-intubated patient (generally excludes pediatrics or in circumstances where GA would primarily be used in lieu of conscious sedation, e.g., in mentally challenged or severely uncooperative patients); 4. Life-threatening or disabling event, e.g. cardiopulmonary arrest, shock, organ failure, unanticipated dialysis, paralysis, loss of limb or organ; 5. Patient death or unexpected pregnancy abortion n The SIR Adverse event Severity Scale is intended to approximate the surgical Clavien-Dingo scale and the NCI CTCAE scale. The SIR scale is tailored towards the procedures and adverse events encountered in IR practices. The grading of interventional oncology adverse events can selectively incorporate relevant adverse event grading definitions published in the current CTCAE for oncological interventions, which may be particularly relevant in the context of research publications. All adverse events occurring within 30 days of a procedure should be included in the adverse event description and analysis, regardless of causality, in the interest of objectivity. The adverse event scale itself does not assess operator performance.

Modifier: M = multiple adverse events, each of which is counted and evaluated separately if possible; The preceding part refers to adverse event description and severity characterization. It is suitable for scientific use (presentations, publications etc.) as well as for adverse event reviews within a practice, practice group, facility or specialty. The following part pertains to adverse event analysis. It is designed to enable a confidential and constructive review of any adverse event within an IR practice or practice group. Applicability for scientific publications is limited and there is none for other public use. The following content is meant to provide a strictly confidential, legally

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non-discoverable, non-punitive, objective, consistent and clinically constructive analytic guide that may result in quality improvement measures to advance the quality of patient care in interventional radiology.

Adverse Event Analysis A. Causality Category 1. Adverse event not caused by the procedure Category 2. Unknown whether adverse event was caused by the procedure Category 3. Adverse event caused by the procedure B. Patient and procedural risk modifier: Risk modifier: Category 1. High risk patient AND technically challenging procedure Category 2. High risk patient (e.g. ASA 4, uncorrectable coagulopathy, poor functional status (ECOG 3 & 4), polypharmacy/polyintravenous therapy and transfusion, septicemia, hemodynamic instability, recent catastrophic event/ICU admission/major surgery or interventions) etc. OR low risk patient and technically challenging procedure (e.g. TIPS with occluded portal vein, percutaneous biliary drain placement in nondilated biliary system, etc.) Category 3. No modifier C. Adverse event preventability Category 1: Rarely preventable: i.e. well described and “typical” for the procedure and occurring despite adequate precautionary and preventive measures Category 2: Potentially preventable Category 3: Consistently preventable: e.g. inappropriateness of procedural indication (may use checklist, see appendixn) D. Adverse event Management Category 1: Most operators would have handled the adverse event similarly; Category 2: Some operators would have handled the adverse event differently; Category 3: Most operators would have handled the adverse event differently.

Consistently Preventable Events  Wrong patient  Absolute contraindication for procedure  Wrong side for procedure  Wrong procedure  Wrong

medication/contrast administration route)

agent/blood

product

(dose/

 Exposure to known allergens  Intraarterial placement of catheter meant to be intravenous or

nonvenous placement of inferior vena cava filter

 Ferromagnetic devices contraindicating performance of mag-

netic resonance imaging  Failure to follow up or communicate laboratory, pathology, or

radiology results  Use

of known monitor system

malfunctioning

equipment

or

patient

 Lack or inappropriate use of monitoring equipment during

sedation

Billing, Coding, and Reimbursement The most current coding updates are available in the member area of the SIR Web site at www.sirweb.org.

ACKNOWLEDGMENTS Siddharth A. Padia, MD, authored the first draft of this document and served as topic leader during the subsequent revisions of the draft. T. Gregory Walker, MD, and James E. Silberzweig, MD, are co-chairs of the SIR Standards of Practice Committee. Boris Nikolic, MD, MBA, is Councilor of the SIR Standards Division. All other authors are listed alphabetically. Other members of the Standards of Practice Committee and SIR who participated in the development of this guideline are (listed alphabetically): J. Fritz Angle, MD, Bulent Arslan, MD, Stephen Balter, PhD, Kevin Baskin, MD, Olga Brook, MD, Drew Caplin, MD, Michael Censullo, MD, Abbas Chamsuddin, MD, Christine Chao, MD, Marco Cura, MD, Mandeep S. Dagli, MD, Sean R, Dariushnia, MD, Jon Davidson, MD, A. Michael Devane, MD, Eduardo Eyheremendy, MD, Florian Fintelmann, MD, Suvranu Ganguli, MD, Joseph J. Gemmete, MD, Vyacheslav Gendel, MD, Kirk Giesbrandt, MD, Jennifer Gould, MD, Tara Graham, MD, John Hancock, MD, Mark Hogan, MD, Bertrand Janne d’Othee, MD, MPH, Ahmed Kamel Abdel Aal, MD, MSc, PhD, Sanjeeva Kalva, MD, Baljendra Kapoor, MD, Maureen P. Kohi, MD, Naganathan B. Mani, MD, Gloria Martinez‑Salazar, MD, Mehran Midia, MD, Donald L. Miller, MD, John Moriarty, MD, Christopher Morris, MD, Waleska Pabon‑Ramos, MD, MPH, Indravadan Patel, MD, Anil Pillai, MD, Uei Pua, MD, Ellen Redstone, MD, Anne C. Roberts, MD, Tarun Sabharwal, MD, Cindy K. Saiter, NP, Marc Sapoval, MD, PhD, Brian J. Schiro, MD, Samir Shah, MD, Paul Shyn, MD, Nasir Siddiqi, MD, LeAnn Stokes, MD, Rajeev Suri, MD, Timothy L. Swan, MD, Naciye Turan, MD, Ulku Turba, MD, Aradhana Venkatesan, MD, Jeffrey L. Weinstein, MD, and Joan C. Wojak, MD.

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SIR DISCLAIMER The clinical guidelines of the Society of Interventional Radiology attempt to define principles that generally should assist in producing high quality medical care. These guidelines are voluntary and are not rules. A physician may deviate from these guidelines, as necessitated by the individual patient and available resources. These guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care that are reasonably directed towards the same result. Other sources of information may be used in conjunction with these principles to produce a process leading to high quality medical care. The ultimate judgment regarding the conduct of any specific procedure or course of management must be made by the physician, who should consider all circumstances relevant to the individual clinical situation. Adherence to the SIR Quality Improvement Program will not assure a successful outcome in every situation. It is prudent to document the rationale for any deviation from the suggested guidelines in the department policies and procedure manual or in the patient’s medical record.