This is the current release of the guideline.

This guideline updates a previous version: Brown DB, Bakal CW, Weintraub JL, Bass JC, Dickey KW, Gemery JM, Klyde DP, Millward SF, Patel AA, Salem R, Selby JB Jr, Silberzweig JE, Expert Panel on Interventional Radiology. Hepatic malignancy. [online publication]. Reston (VA): American College of Radiology (ACR); 2007. 7 p.

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Hepatic malignancy, including hepatocellular carcinoma, neuroendocrine tumors, and colorectal metastases to the liver

To evaluate the appropriateness of interventional radiologic (ablative and endovascular) procedures/treatments for hepatic malignancy

Patients with hepatic malignancies: hepatocellular carcinoma, neuroendocrine tumors, colorectal metastases to the liver

Effectiveness of interventional radiologic (ablative and endovascular) procedures/treatments for hepatic malignancy

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

1. Articles that have abstracts available and are concerned with humans.
2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
3. May restrict the search to Adults only or Pediatrics only.
4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

The total number of source documents identified as the result of the literature search is not known.

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis, and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid, but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the ACR Appropriateness Criteria® Evidence Table Development document (see the "Availability of Companion Documents" field).

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Radiologic Management of Hepatic Malignancy

Variant 1: Hepatocellular carcinoma: Solitary tumor <3 cm.

Variant 2: Hepatocellular carcinoma: Solitary tumor 5 cm.

Variant 3: Hepatocellular carcinoma: More than one tumor, at least one of the tumors >5 cm.

Variant 4: Metastatic liver disease: Multifocal metastatic neuroendocrine tumor (includes carcinoid tumors as well as islet cell tumors of the pancreas).

Variant 5: Metastatic liver disease: Multifocal colorectal carcinoma (liver dominant or isolated), ≥5 cm tumors.

Variant 6: Solitary colorectal liver metastasis

Summary of Literature Review

Management of hepatic malignancy remains a challenging problem. Depending on the clinical scenario, traditional therapies such as resection, systemic chemotherapy, and external beam radiation are either unavailable or ineffective. To help fill this void a number of techniques have been developed by interventional radiologists to treat hepatic malignancy. These treatments include direct tumor ablation via chemical or thermal means and endovascular techniques such as embolization, chemoembolization, and radioembolization with Yttrium-90 (Y90). The role of these treatments in the management of hepatic malignancy is reviewed below.

Hepatocellular Carcinoma

Despite marked advances in interventional oncology over the past decade, the most successful cure for hepatocellular carcinoma (HCC) remains liver transplantation. Unfortunately, the number of patients awaiting transplant far outstrips the number of available organs. Patients younger than 65 with limited tumor burden (conventionally defined by the Milan criteria as one tumor measuring ≤5 cm or up to three tumors all measuring <3 cm) should undergo evaluation for transplantation. Patients with adequate hepatic reserve may undergo resection if obtaining a margin does not leave too small a remnant. Preoperative portal vein embolization with the intent of inducing hypertrophy of the residual future liver remnant has served to expand the pool of potential candidates for potentially curative resection.

Chemotherapy and external beam radiation have traditionally been ineffective in treating HCC. A recent double-blinded randomized study of chemotherapy with sorafenib versus placebo in patients with HCC, demonstrated a statistically significant difference in time: 10.7 months for those taking sorafenib compared to 7.9 months for those on placebos. However, this study only found significant benefit in patients with mild underlying liver disease. Since many patients are not candidates for surgery, and in light of the ineffectiveness of other treatments, percutaneous therapies often play a central role in the management of HCC.

Ablative therapies are broken into two groups: chemical and thermal. Chemical ablation is accomplished by injection of a tumoricidal agent, typically absolute alcohol, directly into the tumor under imaging guidance. Thermal ablation commonly refers to radiofrequency ablation (RFA), but other techniques include cryoablation and microwave ablation. Ablative therapies can be performed either percutaneously or surgically, using open or laparoscopic methods. Two recent meta-analyses support RFA as being a more effective ablative therapy than percutaneous ethanol injection (PEI) for treating HCC. However, PEI may still have a legitimate role for treating tumors adjacent to critical structures that would be at higher risk of injury with RFA. Microwave ablation has also shown promise for this indication. Justification for the use of cryotherapy in treating HCC is currently not as well supported.

Ablative therapies are typically most effective at treating small HCCs (≤5 cm in diameter). Moderate success has also been described with tumors ≤7 cm in diameter. Additionally, while ablative therapies have traditionally been viewed as only palliative, recent research has demonstrated their potential to offer equivalent opportunities for cure, relative to surgical resection, in certain clinical scenarios. Ablative therapies are also now commonly used as a neoadjuvant therapy intended to "downstage" or bridge patients to transplant or resection. In this role, ablative therapies have been found to effectively decrease the dropout rate for liver transplant, but published evidence is inconclusive as to whether this effectively improves patient survival.

As tumor number and/or size increases, the operator may want to focus on arterial-based therapies and adjuvant or neoadjuvant therapy. A variety of endovascular techniques have been developed to treat HCC with this intent. These include transarterial embolization (TAE) with embolic particles alone, transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT). Exclusion criteria for these techniques often focus on the extent of underlying liver disease and tumor burden. Surprisingly, given the theoretical risk of rendering the liver globally ischemic, hepatic arterial embolization techniques tend to be well tolerated in the setting of portal vein thrombosis.

Several trials have demonstrated a significant survival benefit with the use of TACE for HCC compared to no treatment. There is limited evidence that TAE may have similar efficacy as TACE. TACE has also been studied as a neoadjuvant therapy to transplantation or resection. As with RFA, TACE has been shown to decrease transplant list dropout rates, but the survival benefit of this technique is still debated. Recently, TACE has been further refined through the development of drug-eluting beads as the embolic agent. Several studies have suggested that this agent may be more efficacious with less systemic toxicity than the established TACE technique of direct infusion of chemotherapeutic agents followed by bland embolization.

SIRT with beta-emitting Y90 beads is emerging as another treatment option for patients with HCC. Outcomes with this new agent are similar to those described with TACE and TAE with the possible advantage of less patient discomfort and toxicity. SIRT has also shown the ability to effectively downstage patients for potential transplant or resection.

Therapeutic regimens using different combinations of ablative techniques, TAE, chemotherapy, and surgical treatments are also commonly utilized, given the theoretical benefits of a multifaceted treatment regimen compared to monotherapy. Efforts to assess the efficacy of these combined approaches are still in their infancy.

Neuroendocrine Tumors

Neuroendocrine tumors include carcinoid tumors that arise from the small bowel, appendix, lung, bronchi, and pancreas, as well as pancreatic islet cell malignancies with related hormonal symptoms from glucagon, vasoactive intestinal peptide, insulin, and gastrin secretion. These tumors tend to follow a relatively indolent course and often only become symptomatic when the liver is involved with extensive metastatic disease. Consequently, many patients initially present with widespread liver involvement. Management of these tumors focuses on controlling tumor growth as well as managing symptoms related to tumor bulk and hormonal syndromes.

For patients with hormonally active disease, treatment typically focuses initially on controlling symptoms with medical therapy. However, many tumors will become refractory to medical therapy.

With respect to managing tumor burden, resection of hepatic metastases can be beneficial in appropriate cases. In properly selected patients, resection confers a survival advantage over other treatment modalities. Transplantation is uncommonly performed for neuroendocrine metastases. Systemic chemotherapy also has a limited role.

As with resection, thermal or chemical ablation may be feasible in certain cases; however, most patients present with multiple bilobar metastases, making ablation a suboptimal option for most patients. Image-guided ablation, however, can still play a meaningful role as an adjunctive intraoperative therapy or as an alternative treatment for poor surgical candidates.

Arterial therapies often play a significant role in management. TAE and TACE have been shown to decrease hormonal symptoms and improve survival. Debate remains over which method of embolization is most effective, with some published studies arguing that bland hepatic artery embolization (TAE) produces essentially equivalent results as chemoembolization (TACE). There has also been increasing research into the use of SIRT in this patient population, early small studies suggesting therapeutic equivalency with more traditional arterial embolization techniques.

Colorectal Cancer Metastases to the Liver

The gold standard in management of colon cancer metastatic to the liver is resection. Unfortunately, most of these patients are not candidates for surgery due to either disease bulk or the presence of extrahepatic metastases. However, as with HCC, preoperative portal vein embolization can potentially increase the number of candidates for surgical resection.

Systemic chemotherapy is often used with the goal of improving survival as well as potentially converting the patient into a candidate for resection. The role of chemotherapy is still being refined as promising agents such as bevacizumab and cetuximab are being incorporated into treatment protocols. Nevertheless, many patients with liver metastases will progress after chemotherapy options are exhausted or toxicity from systemic therapy limits chemotherapy options. These patients are potential candidates for palliative ablative or arterial interventions.

Ablation is most successful in patients with a limited number of smaller tumors. Larger tumors may be treated with a combination of ablation and TAE or TACE. As with HCC, recent data have suggested that, for properly selected patients, ablative techniques may approach equivalency with resection with respect to survival. However, this remains a controversial issue that due to significant logistical hurdles remains very difficult to study conclusively.

Arterial therapies such as TACE and SIRT, either as monotherapy or in combination with other therapeutic regimens have also shown survival benefit. Patients without extrahepatic disease survive longer than those with extrahepatic disease. As with HCC and metastatic neuroendocrine tumors, published evidence suggests that TACE and SIRT provide similar survival benefit.

Primarily due to the development of more effective chemotherapy agents, hepatic artery infusion (HAI) therapy has also been shown to be potentially beneficial for unresectable disease as well as in a neoadjuvant role. However, this technique remains relatively unpopular due to the added cost and complexity of arterial pump placement as well as concerns over liver toxicity.

Summary

• Management of primary and secondary hepatic malignancy remains a complex issue due to the multitude of treatment options. For that reason, a multidisciplinary approach offers the best hope for optimal treatment with respect to any individual patient.
• Resection and transplantation remain the best options for cure in properly selected patients; however, the role of RFA as a primary treatment option is worthy of future research.
• SIRT may be as effective as TACE or TAE.
• The choice between percutaneous ablative techniques and arterial methods will vary from institution to institution depending on operator expertise.
• Combining ablative and arterial treatments may be better than arterial treatments alone.
• Due to the development of improved chemotherapy options, protocols focusing on the proper combination and sequence of therapies may benefit from reexamination.

Algorithms were not developed from criteria guidelines.

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate interventional radiologic (ablative and endovascular) procedures/treatments for hepatic malignancy

The American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Interventional Radiology

Panel Members: Brian E. Kouri, MD (Principal Author); Brian S. Funaki, MD (Panel Chair); Charles E. Ray, Jr, MD, PhD (Panel Vice-chair); Ghassan Abou-Alfa, MD; Charles T. Burke, MD; Michael D. Darcy, MD; Nicholas Fidelman, MD; Frederick L. Greene, MD; Stephen A. Harrison, MD; Thomas B. Kinney, MD; Jon K. Kostelic, MD; Jonathan M. Lorenz, MD; Ajit V. Nair, MD; Albert A. Nemcek Jr, MD; Charles A. Owens, MD; Wael E. A. Saad, MB, BCh; George Vatakencherry, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Brown DB, Bakal CW, Weintraub JL, Bass JC, Dickey KW, Gemery JM, Klyde DP, Millward SF, Patel AA, Salem R, Selby JB Jr, Silberzweig JE, Expert Panel on Interventional Radiology. Hepatic malignancy. [online publication]. Reston (VA): American College of Radiology (ACR); 2007. 7 p.

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following are available:

• ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.
• ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.

None available

This NGC summary was completed by ECRI Institute on November 13, 2007. This NGC summary was updated by ECRI Institute on February 22, 2012.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .