Quality Improvement Guidelines for Transhepatic Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic Malignancy

Article Outline

• Preamble
• Methodology
• Introduction
• Definitions
• Indications
  • General Indications
    • HCC
    • Neuroendocrine Malignancy
    • Colorectal Carcinoma
    • Other metastases
  • Preprocedural Considerations
  • Procedural Considerations
  • Chemoembolization versus Embolization
  • Chemoembolization versus Chemotherapeutic Infusion
  • Postprocedural Considerations
  • Postprocedural Imaging
  • Repeat Treatment
• Success Rates
  • Technical Success
  • Clinical Success
• Complications
• Overall Procedure Threshold
• Acknowledgments
• Appendix 1. SIR Standards of Practice Committee Classification of Complications by Outcome
• Appendix 2. Consensus Methodology
• Appendix 3. Evidence Table
• References
• Copyright

Abbreviation: HCC, hepatocellular carcinoma

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Preamble 

THE membership of the Society of Interventional Radiology (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.

Technical documents specifying the exact consensus and literature review methodologies as well as the institutional affiliations and professional credentials of the authors of this document are available upon request from SIR, 3975 Fair Ridge Dr, Suite 400 North, Fairfax, VA 22033.

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Methodology 

SIR produces its Standards of Practice documents with use of the following process. Standards documents of relevance and timeliness are conceptualized by the Standards of Practice Committee members. A recognized expert is identified to serve as the principal author for the standard. Additional authors may be assigned depending on the magnitude of the project.

An in-depth literature search is performed with use of 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 (Appendix 3; this appendix can be viewed at the Journal's Web site, www.jvir.org), which is used to write the document such that it contains evidence-based data with respect to content, rates, and thresholds.

Appendix 3. EVIDENCE TABLE

Note.—AFP = α-fetoprotein; AST = aspartate aminotransferase; CEA = carcinoembryonic antigen; DSA = digital subtraction angiography; ECOG = Eastern Cooperative Oncology Group; HACE = hepatic arterial chemoembolization; HCC = hepatocellular carcinoma; LDH = lactate dehydrogenase; LHA = left hepatic artery; MELD = Model for End-Stage Liver Disease; NA = not applicable; PEI = percutaneous ethanol injection; PES = postembolization syndrome; PV = portal vein; PVA = polyvinyl alcohol; RHA = right hepatic artery; TACE = transhepatic arterial chemoembolization; WHO = World Health Organization.

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 according to a modified Delphi Consensus Method (Appendix 2). 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 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 membership for further input/criticism during a 30-day comment period. These comments are discussed by the Standards of Practice Committee and appropriate revisions made to create the finished standards document. Before its publication, the document is endorsed by the SIR Executive Council.

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Introduction 

Chemoembolization of hepatic malignancy represents an important therapeutic procedure in individuals with liver-dominant neoplasms. These include primary hepatic malignancies and certain other cancers in which the liver is the dominant site of disease. A variety of different cancers are amenable to treatment (1, 2, 3, 4). Hepatocellular carcinoma (HCC) has been successfully treated with chemoembolization. Nearly 500,000 patients worldwide are diagnosed with HCC annually and the incidence in the United States is increasing dramatically (5, 6). Most patients with HCC are not candidates for surgical treatment at the time of referral to an interventional radiology department. Radiation therapy and systemic chemotherapy are ineffective at prolonging survival (7) and transplantation remains the only curative option. The demand for donated organs far outstrips supply (8). Many patients require some kind of image-guided therapy as a bridge to transplantation or as palliative therapy (9).

The liver is the dominant site of metastatic disease for a number of malignancies, including colorectal cancer, neuroendocrine tumors, and ocular melanoma. Fewer than 20% of patients with metastatic disease are candidates for curative surgical resection (10). Chemotherapy has provided some improvement in survival with colorectal metastases but has limited benefit for the majority of patients with metastatic neuroendocrine tumors (11, 12, 13). Patients who are not surgical candidates often have diffuse disease, and chemoembolization can play an important role in the treatment of these patients.

These guidelines are written to be used in quality improvement programs to assess chemoembolization. The most important processes of care are (i) patient selection, (ii) performance of the procedure, and (iii) monitoring of the patient. The outcome measures or indicators for these processes are indications, success rates, and complication rates. Outcome measures are assigned threshold levels.

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Definitions 

Chemoembolization, embolization, and chemotherapeutic infusion are performed after catheterization of the proper, lobar, or segmental hepatic arteries with use of standard angio-graphic principles as described in the SIR quality improvement guidelines for diagnostic angiography (15). Unless otherwise stated, references in this document will specifically refer to chemoembolization, as the majority of the existing literature has reported on the use of this technique.

Although practicing physicians should strive to achieve perfect outcomes (eg, 100% success, no complications), in practice all physicians will fall short of this ideal to a variable extent. Therefore, indicator thresholds may be used to assess the efficacy of ongoing quality improvement programs. For the purposes of these guidelines, a threshold is a specific level of an indicator that should prompt a review. “Procedure thresholds” or “overall thresholds” reference a group of indicators for a procedure, such as major complications. Individual complications may also be associated with complication-specific thresholds. When measures such as indications or success rates fall below a (minimum) threshold, or when complication 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 abscess formation is one measure of the quality of chemoembolization, values in excess of the defined threshold (in this case, 2%) 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 complication. Thresholds may vary from those listed here; for example, patient referral patterns and selection factors may dictate a different threshold value for a particular indicator at a particular institution. Therefore, 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 quality improvement program needs.

Complications can be stratified on the basis of outcome. Major complications result in admission to a hospital for therapy (for outpatient procedures), an unplanned increase in the level of care, prolonged hospitalization, permanent adverse sequelae, or death. Minor complications result in no sequelae; they may require nominal therapy or a short hospital stay for observation (generally overnight; Appendix 1). The complication rates and thresholds listed herein refer to major complications.

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Indications 

General Indications 

Chemoembolization is indicated in patients with liver-dominant hepatic malignancies who are not candidates for curative resection. All patients should undergo preprocedural contrast material– enhanced CT or MR imaging to ensure that the disease is liver-dominant. The main portal vein should be patent or collateral flow should be present with hepatopetal flow (16, 17). If there is a question of adequate portal perfusion on cross-sectional imaging, confirmation can be obtained with catheter angiography immediately preceding chemoembolization. Preprocedural evaluation also includes laboratory evaluation including complete blood count, prothrombin time, and evaluation of liver and kidney function. Exclusion criteria based on laboratory values are not definitively established. However, the constellation of more than 50% liver replacement with tumor, bilirubin level greater than 2 mg/dL, lactate dehydrogenase level greater than 425 mg/dL, and aspartate aminotransferase level greater than 100 IU/L has a strong anecdotal association with increased postprocedural mortality (18). Individual abnormalities of these four parameters have not been shown to predict adverse outcomes of chemoembolization (19). Laboratory values and scoring systems have been used differently by other authors. Commonly used scoring systems are outlined in Table 1, Table 2, Table 3. A bilirubin cutoff level of 3 mg/dL has been described (20). The Child-Pugh scoring system is superior to the Model for End-Stage Liver Disease system in predicting long-term survival in HCC (19). Patients with Child-Pugh class A disease or class B disease with an albumin level of at least 3.4 g/dL have improved survival. Another group found that Model for End-Stage Liver Disease scores greater than 10 and a Cancer of the Liver Italian Program score greater than 2 constituted a negative predictor of survival (21).

Table 1. Child-Pugh Scoring System

Note.—Child-Pugh Score: A = 5–6; B = 7–9; C = 10–15.

Table 2. Model for End-stage Liver Disease Scoring System

Table 3. Cancer of the Liver Italian Program Scoring System

Note.—NA = not applicable

As a result of underlying cirrhosis, fewer than 20% of patients with HCC are candidates for surgical resection (7). Transplantation remains the only curative option for patients with HCC, and individuals with limited disease (1 tumor <5 cm or three tumors <3 cm each) should be evaluated for transplantation during work-up as part of a multidisciplinary effort. Initial randomized trials evaluating chemoembolization versus symptomatic treatment had disappointing results (22, 23, 24, 25). However, three recent well-constructed randomized trials (1, 2, 26), two of which were prospectively randomized (1, 2), have demonstrated significantly improved survival with chemoembolization. Poor outcomes from the initial trials can be directly linked to treatment of patients with advanced disease and to administration of excessive therapy. These outcomes reinforce the need to treat patients with well-compensated cirrhosis and to repeat therapy only when viable tumor is present on cross-sectional imaging (27). Patients with small tumors may also be considered for percutaneous ablative therapies alone or in combination with chemoembolization (28, 29, 30). The choice between therapies should be based on the overall size, number, and location of the tumors. In some situations, chemoembolization and tumor ablation may be appropriate alone or in combination.

Initial control of symptoms is usually performed with short- or long-acting somatostatin agents. Most patients with symptomatic disease have diffuse metastases, which are a contraindication to surgery. The frequent presence of diffuse metastases also limits the number of patients who are candidates for percutaneous ablative therapies. Chemoembolization and embolization of patients with hepatic metastases from neuroendocrine tumors can result in durable elimination of hormonal symptoms (3, 31). A number of patients with hormonally active liver metastases also have extrahepatic disease at the time of diagnosis. However, because chemoembolization can still reduce or eliminate symptoms, treatment should not be withheld from these patients.

Fewer than 20% of patients with colorectal metastases are candidates for curative resection (10). Survival rates with systemic chemotherapy have improved, with mean survival times approaching 2 years (11). A gold standard chemotherapeutic regimen has not been determined, limiting studies comparing systemic chemo-therapy with chemoembolization. Chemoembolization for hepatic metastases may be considered as a salvage option when other systemic chemotherapy options have been exhausted. Other treatment methods, such as yttrium Y 90 sphere infusion, are being investigated and may play an increasing role over time (32).

Other tumors that may present with liver-dominant metastases include ocular melanoma and soft-tissue sarcoma. These tumors have been successfully treated with chemoembolization. Patient survival appears to be improved compared with historical controls, but randomized prospective data are not available (33, 34, 35, 36).

Participation by the radiologist in patient follow-up in the hospital and at imaging follow-up is an integral part of chemoembolization and will limit the incidence of postprocedural complications and ensure appropriate scheduling of follow-up therapy. Close follow-up with monitoring and management of the patient by the interventional radiologist is appropriate. Regarding indications for chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy, the threshold is 95% for the presence of liver-dominant malignancy with preserved hepatic function. When fewer than 95% of procedures are for these indications, the department will review the process of patient selection.

Preprocedural Considerations 

Premedication before chemoembolization is standard. Hydration is essential with intravenous administration of 150–300 mL/h of normal saline solution. Other premedications include antiemetics and steroids. Many operators administer antibiotic coverage for gram-negative enteric organisms, even though this practice is not universal or prospectively proven to be beneficial for all patients (37, 38). In patients without an intact sphincter of Oddi from earlier surgery, sphincterotomy, or biliary drainage, the risk of infection after embolization is significantly increased (39). The risk of postembolization infection appears to be reduced by the performance of bowel preparation the night before treatment (40). In patients with carcinoid tumors, pretreatment with octreotide 150 μg subcutaneously is important to limit carcinoid crisis caused by hormonal dumping from tumor necrosis after embolization (3).

Procedural Considerations 

Given the frequency of variant hepatic arterial anatomy, initial angiography should include study of the superior mesenteric and celiac arteries (41). Imaging should be performed through the portal venous phase to ensure patency of the main portal vein or reconstitution via collateral vessels with hepatopetal flow. Practice patterns for level of catheter selection range from superselective to lobar embolization depending on the type and number of tumors to be treated, as well as the philosophy of the individual performing the procedure. Treatment of the entire liver in one session is associated with an increase in mortality (31). When treatment leads to permanent occlusion of the native hepatic arteries, several collateral pathways have been treated with clinical success, including the inferior phrenic, internal mammary, and intercostal arteries (42, 43, 44). If these collateral arteries have potential communication with cutaneous vessels, embolization without chemotherapy should be performed to limit the risk of cutaneous ischemic ulceration (45). Treatment should avoid the cystic artery if possible. If treatment of the tumor is not feasible without including the cystic artery in the infused area, chemoembolization may still be performed. The principal risk of treatment of the cystic artery is pain, which may potentially lengthen the posttreatment hospital stay but does not result in significant risk to the gallbladder itself (46). Intermittent infusion of 1% lidocaine between aliquots of the chemotherapeutic agent/Ethiodol slurry decreases postembolization pain (47, 48).

Chemoembolization versus Embolization 

Randomized trials for treatment of HCC comparing protocols with and without chemotherapy are limited. A prospective randomized trial with three arms comparing survival with chemoembolization versus embolization versus symptomatic treatment resulted in a significant survival benefit for chemoembolization versus symptomatic treatment, and the trial was halted (2). At the time the trial was terminated, embolization without chemotherapy was associated with similar survival rates as chemoembolization. The trial was not continued to determine whether embolization without chemotherapy would lead to a survival benefit versus symptomatic treatment alone. A separate meta-analysis did not reveal any clear-cut benefit from the addition of chemo-therapy to embolization (49). A complicating factor in determining the gold standard arterial infusion therapy is that chemotherapy regimens vary significantly among trials. No ideal chemotherapeutic agent has been identified. A definitive statement regarding treatment with or without chemotherapy can not be made without an adequately powered prospective trial.

Chemoembolization versus Chemotherapeutic Infusion 

Few comparisons of chemoembolization versus chemotherapeutic infusion are available. Infusion without embolization appears to result in a lower percentage of tumor necrosis compared with chemoembolization, particularly in HCCs larger than 3 cm in diameter (50). However, toxicity to the surrounding liver may be lower with infusion alone (51). Chemotherapeutic infusion may be considered an option in patients with severe hepatic dysfunction.

Postprocedural Considerations 

Many practitioners recommend administration of antibiotics for 3–7 days after chemoembolization to cover gram-negative enteric pathogens. Data regarding the need for routine antibiotic prophylaxis are mixed, without definitive evidence of benefit (38). If a patient has a disrupted sphincter of Oddi, it has been suggested that antibiotics should be administered for 14 days (40). Even with extended administration of antibiotics, data for this group of patients are limited and the operator should proceed with caution in the setting of any biliary abnormality. Antibiotics may be converted to oral administration as soon as patients can tolerate a normal diet to facilitate expedient discharge. Antiemetics should be continued as long as needed. Narcotics should be available. One method preferred by many inter-ventionalists to control pain is to administer narcotics via a patient-controlled analgesia pump.

Postprocedural Imaging 

Follow-up imaging should be performed 4–6 weeks after all tumor-bearing areas have been treated. If treatment of both lobes of the liver is planned, imaging between sessions may be performed based on operator preference. Signs of tumor necrosis on CT include Ethiodol uptake and absence of arterial-phase enhancement when it was present before chemoembolization (52, 53). Disappearance of arterial enhancement is the principal determinant of tumor necrosis on MR imaging (54). There is a paucity of literature regarding follow-up of lesions after chemoembolization without arterial phase enhancement. Gross enlargement of a lesion or nodular enhancement in portal vein or delayed-phase imaging has been described as evidence of residual or recurrent tumor after radiofrequency ablation of lesions without initial arterial phase enhancement (55). Similar findings may be present in the setting of residual or recurrent tumor after chemoembolization. Patients without active disease at follow-up should undergo follow-up imaging every 3–4 months.

Repeat Treatment 

Individuals with HCC or metastases from nonneuroendocrine tumors require further treatment when new or residual disease is detected (27). Patients with liver metastases from neuroendocrine tumors should be treated again if the initial treatment does not result in symptomatic improvement or when symptoms recur. Before additional chemoembolization sessions, liver function tests and complete blood count should be performed again to ensure the patient is still an appropriate candidate.

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Success Rates 

Technical Success 

Successful chemoembolization is defined as successful catheter placement and administration of selected agents. The threshold is 95% for technical success of chemoembolization.

Clinical Success 

Clinical success is defined as successful tumor necrosis resulting in effective palliation. Effective palliation is tumor-dependent, with survival as the primary outcome for tumors such as HCC and colorectal carcinoma. To reach this success, individual operators should have survival rates comparable to those in the established literature. Thresholds are set at less than 100% because operators will encounter patients in practice who require therapy who have clinical presentations worse than allowed in clinical trials. In patients with symptomatic neuroendocrine malignancy, clinical success is defined as the elimination of hormonal symptoms (Table 4) (3, 19, 26, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65).

Table 4. Thresholds for Median Survival after Chemoembolization of Hepatocellular and Colorectal Carcinomas (3, 19, 26, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65)

Disease	Median Survival (months), Reference	Threshold (%)
Hepatocellular carcinoma	20(19, 26, 56, 57)	50
Colorectal carcinoma	10(58, 59, 60, 61, 62, 63)	50
Neuroendocrine tumors	26(3, 64, 65)	50
Ocular melanoma	11(33)	50
Metastatic sarcoma	19(34, 35)	50

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Complications 

Complications occur in approximately 10% of patients. Published complication rates and suggested thresholds include the following:

Postembolization syndrome (fever, pain, increased white blood cell count) by itself is not considered a complication but rather an expected outcome of embolotherapy (46). As noted earlier, a small percentage of patients will have prolonged symptoms that require a greater level of postprocedural care (56). Published rates for individual types of complications are highly dependent on patient selection and are based on series comprising several hundred patients, which is a volume larger than most individual practitioners are likely to treat. Therefore, we recommend that complication-specific thresholds should usually be set higher than the complication-specific reported rates listed herein. It is also recognized that a single complication can cause a rate to cross above a complication-specific threshold when the complication occurs in a small volume of patients, eg, early in a quality improvement program. In this situation, the overall procedure threshold is more appropriate for use in a quality improvement program.

In Table 5 (39, 56, 66, 67, 68, 69), all values are supported by the weight of literature evidence and panel consensus except those shown with an asterisk (weak literature evidence, but 80% Delphi consensus), or dagger (weak literature evidence and no Delphi consensus).

Table 5. Thresholds for Major Complications of Hepatic Arterial Chemoembolization (39, 56, 66, 67, 68, 69)

Specific Major Complication	Reported Rate (%)	Suggested Threshold (%), Reference
Liver failure	2.3	4(56)
Abscess with functional sphincter of Oddi	<1	2(39, 66)
Post-embolization syndrome requiring extended stay or readmission	4.6	10(56)
Abscess with biliary-enteric anastomosis/biliary stent/sphincterotomy	25	25(39, 67)
Surgical cholecystitis	<1	1(66, 68, 69)
Biloma requiring percutaneous drainage	<1	2(68)
Pulmonary arterial oil embolus	<1	1(69)
Gastrointestinal hemorrhage/ulceration	<1	1(69)
Iatrogenic dissection preventing treatment	<1	1(68)
Death within 30 days	1	2(68, 69)

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Overall Procedure Threshold 

The threshold is 15% for all major complications resulting from chemoembolization, embolization, or chemo-therapeutic infusion.

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Acknowledgments 

Dr. Daniel B. Brown authored the first draft of this document and served as topic leader during the subsequent revisions of the draft. Dr. John F. Cardella is chair of the SIR Standards of Practice Committee. Dr. David Sacks is Councilor of the SIR Standards Division. All other authors are listed alphabetically: John “Fritz” Angle, MD, Stephen Balter, PhD, Timothy W.I. Clark, MD, MSc, Patricia E. Cole, PhD, MD, Peter Drescher, MD, Neil J. Freeman, MD, Jeffrey D. Georgia, MD, Ziv Haskal, MD, David M. Hovsepian, MD, Neil M. Kilnani, MD, Sanjoy Kundu, MD, Patrick C. Malloy, MD, Louis G. Martin, MD, J. Kevin McGraw, MD, Steven G. Meranze, MD, Philip M. Meyers, MD, Steven F. Millward, MD, Kenneth Murphy, MD, Calvin D. Neithamer, Jr., MD, Reed Ali Omary, MD, MS, Nilesh H. Patel, MD, Anne C. Roberts, MD, Marc S. Schwartzberg, MD, Gary P. Siskin, MD, Harry R. Smouse, MD, Timothy L. Swan, MD, Patricia E. Thorpe, MD, Thomas M. Vesely, MD, Louis K. Wagner, PhD, Bret N. Wiechmann, MD, Curtis W. Bakal, MD, Curtis A. Lewis, MD, MBA, Albert A. Nemcek, Jr., MD, Kenneth S. Rholl, MD.

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Appendix 1. SIR Standards of Practice Committee Classification of Complications by Outcome 

Minor Complications

Major Complications

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Appendix 2. Consensus Methodology 

Reported complication-specific rates in some cases reflect the aggregate of major and minor complications. Thresholds are derived from critical evaluation of the literature, evaluation of empirical data from Standards of Practice Committee members' practices, and, when available, the SIR HI-IQ^™ System national database.

Consensus on statements in this document was obtained with use of a modified Delphi technique (70, 71).

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Appendix 3. Evidence Table 

Appendix 3 is available online at www.jvir.org.

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