ACR Appropriateness Criteria Radiologic Management of Hepatic Malignancy

ACR Appropriateness Criteria Radiologic Management of Hepatic Malignancy Brian E. Kouri, MDa, Brian S. Funaki, MDb, Charles E. Ray Jr, MD, PhDc, Ghassan K. Abou-Alfa, MDd,e, Charles T. Burke, MDf, Michael D. Darcy, MDg, Nicholas Fidelman, MDh, Frederick L. Greene, MDi,j, Stephen A. Harrison, MDk,l, Thomas B. Kinney, MDm, Jon K. Kostelic, MDn, Jonathan M. Lorenz, MDo, Ajit V. Nair, MDp, Albert A. Nemcek Jr, MDq, Charles A. Owens, MDr, Wael E. A. Saad, MB, BChs, George Vatakencherry, MDt

Management of hepatic malignancy is a challenging clinical problem involving several different medical and surgical disciplines. Because of the wide variety of potential therapies, treatment protocols for various malignancies continue to evolve. Consequently, development of appropriate therapeutic algorithms necessitates consideration of medical options, such as systemic chemotherapy; surgical options, such as resection or transplantation; and locoregional therapies, such as thermal ablation and transarterial embolization. The authors discuss treatment strategies for the 3 most common subtypes of hepatic malignancy treated with locoregional therapies: hepatocellular carcinoma, neuroendocrine metastases, and colorectal metastases. The ACR Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a wellestablished consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Key Words: Appropriateness criteria, hepatocellular carcinoma, liver metastases, ablation, chemoembolization, radioembolization J Am Coll Radiol 2012;9:919-925. Copyright © 2012 American College of Radiology

Management of hepatic malignancy remains a challenging problem. Depending on the clinical scenario, tradi-

tional therapies such as resection, systemic chemotherapy, and external-beam radiation are either unavailable or ineffective. To help fill this void, a number of tech-

a

n

SUMMARY OF LITERATURE REVIEW

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina. b The University of Chicago, Chicago, Illinois. c University of Colorado, Denver, and Health Sciences Center, Aurora, Colorado. d Memorial Sloan-Kettering Cancer Center, and Weill Medical College at Cornell University, New York, New York. e American Society of Clinical Oncology, Alexandria, Virginia. f University of North Carolina Hospital, Chapel Hill, North Carolina. g Mallinckrodt Institute of Radiology, St Louis, Missouri. h University of California, San Francisco, San Francisco, California. i Carolinas Medical Center, Charlotte, North Carolina. j American College of Surgeons, Chicago, Illinois. k Brooke Army Medical Center, San Antonio, Texas. l American Gastroenterological Association, Bethesda, Maryland. m University of California, San Diego, Medical Center, San Diego, California. © 2012 American College of Radiology 0091-2182/12/$36.00 ● http://dx.doi.org/10.1016/j.jacr.2012.09.002

o

Central Kentucky Radiology, Lexington, Kentucky. University of Chicago Hospital, Chicago, Illinois.

p q r s

Kaiser Permanente Modesto Medical Center, Modesto, California.

Northwestern Memorial Hospital, Chicago, Illinois.

University of Illinois College of Medicine, Chicago, Illinois.

University of Virginia Health System, Charlottesville, Virginia.

t

Kaiser Permanente Los Angeles Medical Center, Los Angeles, California. The ACR seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document. Corresponding author and reprints: Brian E. Kouri, MD, American College of Radiology, 1891 Preston White Drive, Reston, VA 20191; e-mail: bkouri@ wakehealth.edu.

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920 Journal of the American College of Radiology/ Vol. 9 No. 12 December 2012

Variant 1. Hepatocellular carcinoma: solitary tumor ⬍ 3 cm Treatment/Procedure Rating Comments Systemic chemotherapy Resection Transplantation Chemical ablation Thermal ablation Transarterial embolization Transarterial chemoembolization Selective internal radiation therapy

3 8 9 6 8 5 5 5

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

niques 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 90 Y. 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 [1]. Unfortunately, the number of patients awaiting transplantation far outstrips the number of available organs. Patients aged ⬍ 65 years with limited tumor burden (conventionally defined by the Milan criteria as 1 tumor measuring ⱕ5 cm or up to 3 tumors all measuring ⬍3 cm) should undergo evaluation for transplantation [2]. Patients with adequate hepatic reserve may undergo resection if obtaining a margin does not leave too small a remnant [3]. 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 [4,5] (see Variant 1). Chemotherapy and external-beam radiation have traditionally been ineffective in treating HCC. A recent double-blind randomized study of chemotherapy with

sorafenib versus placebo in patients with HCC demonstrated a statistically significant difference in median overall survival: 10.7 months for those taking sorafenib compared with 7.9 months for those on placebos. However, this study found significant benefit only in patients with mild underlying liver disease [6]. Because 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 comprise two groups: chemical and thermal. Chemical ablation is accomplished by the injection of a tumoricidal agent, typically absolute alcohol, directly into the tumor under imaging guidance. Thermal ablation commonly refers to radiofrequency ablation (RFA), but includes other techniques like 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 for treating HCC. However, percutaneous ethanol injection may still have a legitimate role for treating tumors adjacent to critical structures that would be at higher risk for injury with RFA [7,8]. Microwave ablation has also shown promise for this indication [9]. Justification for the use of cryotherapy in treating HCC is currently not as well supported [10]. Ablative therapies are typically most effective at treating small HCCs (ⱕ5 cm in diameter) [11-13]. Moderate success has also been described with tumors ⱕ7 cm in diameter [14]. Additionally, although 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 [15-17]. Ablative therapies are also now commonly used as a neoadjuvant therapy intended to “downstage” or bridge patients to transplantation or resection. In this role, ablative therapies have been found to effectively decrease the dropout rate for liver transplantation, but published evidence is inconclusive as to whether this effectively improves patient survival [18] (see Variant 2).

Variant 2. Hepatocellular carcinoma: solitary tumor ⱕ 5 cm Treatment/Procedure Rating Systemic chemotherapy Resection Transplantation Chemical ablation

3 8 9 3

Thermal ablation Transarterial embolization Transarterial chemoembolization (TACE) Selective internal radiation therapy TACE combined with thermal ablation

5 6 7 7 7

Comments

The tumor is too large for chemical ablation. May use it instead of or in addition to thermal ablation depending on tumor location.

Especially applicable in portal vein thrombosis or extensive bilobar disease.

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

Kouri et al/Radiologic Management of Hepatic Malignancy 921

Variant 3. Hepatocellular carcinoma: more than one tumor, at least one of them ⬎ 5 cm Treatment/Procedure Rating Comments Systemic chemotherapy Resection Transplantation Chemical ablation Thermal ablation Transarterial embolization (TAE) Transarterial chemoembolization (TACE) Selective internal radiation therapy TACE combined with thermal ablation

6 5 1 2 3 7 8 7 6

Consider for patients not amenable to other localized therapies. Consider resection after neoadjuvant TAE or TACE in noncirrhotic patients.

Depends on local expertise.

Early evidence is promising. More data needed.

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

As tumor number or size increases, the operator may want to focus on arterial-based therapies as adjuvant or neoadjuvant therapy [19]. 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 [20]. Surprisingly, given the theoretical risk for rendering the liver globally ischemic, hepatic arterial embolization techniques tend to be well tolerated in the setting of portal vein thrombosis [21,22]. Several trials have demonstrated a significant survival benefit with the use of TACE for HCC compared with no treatment [23-25]. There is limited evidence that TAE may have similar efficacy as TACE [26]. TACE has also been studied as a neoadjuvant therapy to transplantation or resection. As with RFA, TACE has been shown to decrease transplantation list dropout rates, but the survival benefit of this technique is still debated [2730]. 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 [31,32].

SIRT with ␤-emitting 90Y beads is emerging as another treatment option for patients with HCC [33-35]. Outcomes with this new agent are similar to those described with TACE and TAE, with the possible advantage of less patient discomfort and toxicity [36,37]. SIRT has also shown the ability to effectively downstage patients for potential transplantation or resection [38,39]. Therapeutic regimens using different combinations of ablative techniques, TAE, chemotherapy, and surgical treatments are also commonly used, given the theoretical benefits of a multifaceted treatment regimen compared with monotherapy. Efforts to assess the efficacy of these combined approaches are still in their infancy [40-44] (see Variant 3). 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 become symptomatic only 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 [45].

Variant 4. Metastatic liver disease: multifocal metastatic neuroendocrine tumor (includes carcinoid tumors as well as islet cell tumors of the pancreas) Treatment/Procedure Rating Comments Long-acting octreotide Systemic chemotherapy Resection Transplantation Chemical ablation Thermal ablation Transarterial embolization Transarterial chemoembolization (TACE) Selective internal radiation therapy TACE combined with thermal ablation

9 3 3 2 1 3 8 8 7 5

If If If If

patient patient patient patient

is is is is

symptomatic symptomatic symptomatic symptomatic

and and and and

control control control control

with with with with

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

medication medication medication medication

fails. fails. fails. fails.

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Variant 5. Metastatic liver disease: multifocal colorectal carcinoma (liver dominant or isolated), ⱖ5-cm tumors Treatment/Procedure Rating Comments Systemic chemotherapy Resection Transplantation Chemical ablation Thermal ablation Hepatic arterial chemotherapy infusion Transarterial embolization Transarterial chemoembolization (TACE) Selective internal radiation therapy TACE combined with thermal ablation

9 7 1 1 2 5

Colorectal Cancer Metastases to the Liver

5 5 5 5

Depends on tumor burden.

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

For patients with hormonally active disease, treatment typically focuses initially on controlling symptoms with medical therapy [46]. However, many tumors will become refractory to medical therapy [47]. 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 [48-50]. Transplantation is uncommonly performed for neuroendocrine metastases [51,52]. Systemic chemotherapy also has a limited role [53,54]. 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 them [55]. Image-guided ablation, however, can still play a meaningful role as an adjunctive intraoperative therapy or as an alternative treatment for poor surgical candidates [56-58]. Arterial therapies often play a significant role in management. TAE and TACE have been shown to decrease hormonal symptoms and improve survival. Debate reVariant 6. Solitary colorectal liver metastasis Treatment/Procedure Rating Systemic chemotherapy Resection Transplantation Chemical ablation Thermal ablation Hepatic arterial chemotherapy infusion Transarterial embolization Transarterial chemoembolization (TACE) Selective internal radiation therapy TACE combined with thermal ablation

mains 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) [5961]. There has also been increasing research into the use of SIRT in this patient population, with early small studies suggesting therapeutic equivalency with more traditional arterial embolization techniques [62-64] (see Variant 4).

9 9 1 2 8 4 3 6 6 6

The gold standard in the management of colon cancer metastatic to the liver is resection [65,66]. Unfortunately, most of these patients are not candidates for surgery because of either disease bulk or the presence of extrahepatic metastases [67]. 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 [68,69]. The role of chemotherapy is still being refined as promising agents such as bevacizumab and cetuximab are being incorporated into treatment protocols [70]. 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 [71]. 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 [72]. However, this remains a controversial issue that because of significant logistical hurdles remains very difficult to study conclusively [73]. Arterial therapies such as TACE and SIRT, either as monotherapy or in combination with other therapeutic regimens, have also shown survival benefit [74,75]. Patients without extrahepatic disease survive longer than

Comments

Appropriate alone and with resection.

If tumor ⬍ 3-5 cm. Depends on local expertise. May be especially useful for down-staging patients for more definitive therapies. May be especially useful for down-staging patients for more definitive therapies. Early evidence is promising. More data needed. May be especially useful for down-staging patients for more definitive therapies.

Note: Rating scale: 1, 2, and 3 ⫽ usually not appropriate; 4, 5, and 6 ⫽ may be appropriate; 7, 8, and 9 ⫽ usually appropriate.

Kouri et al/Radiologic Management of Hepatic Malignancy 923

those with extrahepatic disease [76]. As with HCC and metastatic neuroendocrine tumors, published evidence suggests that TACE and SIRT provide similar survival benefit [77]. Primarily because of the development of more effective chemotherapy agents, hepatic artery infusion therapy has also been shown to be potentially beneficial for unresectable disease as well as in a neoadjuvant role [7881]. However, this technique remains relatively unpopular because of the added cost and complexity of arterial pump placement as well as concerns over liver toxicity [82] (see Variants 5 and 6). SUMMARY ●

●

● ●

● ●

Management of primary and secondary hepatic malignancy remains a complex issue because of 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. Because of the development of improved chemotherapy options, protocols focusing on the proper combination and sequence of therapies may benefit from reexamination.

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