Clinical UM Guideline

This document addresses locally ablative therapies to treat primary or metastatic liver cancer. Treatment goals can be curative, palliative, as a bridge to liver transplantation or downstaging (become eligible for liver transplantation following initial treatment). Locoregional therapies may include any of the following ablative therapies:

• Cryosurgical ablation, or cryotherapy
• Microwave ablation (MWA)
• Percutaneous ethanol injection (PEI)
• Radiofrequency ablation (RFA)

Note: For criteria related to arterially directed therapy to treat solid tumors in the liver, refer to applicable guidelines used by the plan.

Note: For related topics, please see the following:

• CG-SURG-61 Cryosurgical, Radiofrequency, Microwave or Laser Ablation to Treat Solid Tumors Outside the Liver
• SURG.00126 Irreversible Electroporation
• SURG.00165 Histotripsy
• TRANS.00008 Liver Transplantation

Medically Necessary:

A.  Treatment of Hepatic Tumors (Primary or Metastatic)

Any of the following locally ablative techniques are considered medically necessary for individuals with any of the following conditions when all of the criteria below have been met:

1. Techniques
   1. Cryosurgical ablation; or
   2. Microwave ablation (MWA); or
   3. Percutaneous ethanol injection (PEI); or
   4. Radiofrequency (RFA);
      and
2. Conditions
   1. Hepatocellular carcinoma; or
   2. Liver metastases from colorectal cancer; or
   3. Functioning neuroendocrine tumors;
      and
3. Criteria
   1. A poor candidate for surgical resection or unwilling to undergo surgical resection; and
   2. Each lesion measures no more than 5 cm in diameter; and
   3. No or minimal extra-hepatic metastases; and
   4. All foci of disease are amenable to ablative therapy or surgical resection.

​​​​​​​​​​​​​​B. Bridge to Liver Transplantation

Any of the following locally ablative techniques (MWA, PEI, RFA) is considered medically necessary as a bridge to liver transplantation, when all of the following criteria are met:

1. Preserved liver function defined as Childs-Turcotte-Pugh Class A or B; and
2. Three or fewer encapsulated nodules and each nodule is less than or equal to 5 centimeters in diameter; and
3. No evidence of extra-hepatic metastases; and
4. No evidence of portal vein occlusion.

C.  Hepatocellular Carcinoma in Individuals Who May Become Eligible for Liver Transplantation (Downstaging)

Any of the following locally ablative techniques (PEI, RFA) is considered medically necessary for the treatment of an individual when both of the following criteria are met:

1. May become eligible for liver transplantation except that the hepatic lesion(s) size is greater than 5 centimeters in maximal diameter; and
2. It can be reasonably expected that treatment will result in tumor size reduction to less than or equal to 5 centimeters in maximal diameter.

Not Medically Necessary:

Locally ablative techniques are considered not medically necessary when the criteria above are not met.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Cryosurgical ablation
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for situations designated in the Clinical Indications section as not medically necessary.

Radiofrequency, Microwave, Percutaneous Ethanol Injection ablation
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary
For the procedure and diagnosis codes listed above when criteria are not met.

Description and Prevalence of Disease

According to the American Cancer Institute (ACS), there will be an estimated 42,240 new cases of primary liver cancer and intrahepatic bile duct cancer diagnosed in the United States (U.S.) in 2024 and approximately 30,090 deaths associated with the disease. Since 1980, the incidence of hepatic cancer has more than tripled and the increasing incidence attributed to high rates of hepatitis C (HCV), nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome (Heimbach, 2017).

Primary hepatocellular carcinoma (HCC) pertains to malignancies arising from the liver, while hepatobiliary cancers originate from bile ducts and/or gallbladder. These groups of malignancies are collectively known as intrahepatic and extrahepatic cholangiocarcinoma. Hepatic carcinoma can arise either as primary liver cancer or by metastasis to the liver from other tissue origins. Malignancies of the liver are comprised primarily of adenocarcinomas classified by hepatocellular and cholangiocarcinoma cell types (National Cancer Institute [NCI], 2024). Hepatocellular carcinoma is the most common form of hepatic malignancies and makes up 90% of the cases. Gallbladder cancer is the most common type of biliary tract malignancies. Cholangiocarcinoma occurs throughout the biliary tree (National Comprehensive Cancer Network^® [NCCN], V6.2024).

Neuroendocrine tumors may also involve the liver, where hormone production can cause systemic symptoms. The most common neuroendocrine tumor is the carcinoid tumor where excessive hormone production is associated with the carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea. Pancreatic endocrine tumors that produce gastrin, insulin or other pancreatic hormones are unusual types of neuroendocrine tumors. Pancreatic endocrine (i.e., islet cell) tumors differ from the more common pancreatic epithelial tumors that arise from the exocrine portion of the pancreas. Surgical resection is typically not possible for neuroendocrine tumors, and treatment tends to focus on palliation of specific systemic symptoms.

There is no universal staging system utilized by all facilities within the US. In addition, the potential presence of an underlying liver disease complicates the treatment of HCC (NCCN, V4.2024). More than 80% of the individuals diagnosed with HCC are found to have pre-existing cirrhosis (Marrero, 2018).

Extrahepatic Disease

At initial diagnosis, extrahepatic metastases are detected in 13-36% of HCC cases. At autopsy, approximately 68% of cases are found to have extrahepatic disease, imaging is underestimating the extent of disease or metastases are developing during or following treatment. Post-instrumentation seeding of HCC can occur following biopsies or percutaneous ablation. Also, tumors may rupture or slough off cells during arterially directed therapies, resulting in extrahepatic spread (Arora, 2021). There is no specific definition of oligometastatic disease, but for this guideline it is defined as up to 5 lesions extrahepatic lesions (Lievens, 2020).

Liver metastases can develop from any type of cancer, but metastases from colorectal cancer (CRC) are the most common. Metastases develop in approximately 50-60% of those diagnosed with CRC and 80-90% of those individuals present with unresectable metastatic liver disease. Stewart and associates (2018) analyzed survival times and palliation in those with CRC metastases. The median survival of individuals with unresectable metastases to the liver is 13 months. The median survival of individuals with extrahepatic metastases ranges from a low of 19 months in bone metastases to 36 months in brain metastases. Metastases to the liver largely determine the length of survival in CRC. Over 70% of individuals with unresectable liver metastatic disease will die from liver metastases. The authors note the following for individuals with CRC metastases:

Disease specific survival is also significantly shorter for those who die of liver metastasis, compared to patients who die from other metastatic sites. Thus, addressing liver metastases initially is the most clinically relevant, since this is the most life limiting. Currently, patients who do not undergo surgical treatment of liver metastases typically live less than 18 months, with no 5-year survivors. By comparison, those who are resected but recur have a median survival of 40 months, and have a 17% 5-year survival. As such, liver directed therapies shift the cause of death to other sites at a later time point. For this reason, having metastases at other sites does not change survival for patients with liver metastases, as long as they are candidates for surgery.

The NCCN clinical practice guideline (CPG) for HCC (V4.2024) includes both ablation techniques and arterially directed therapies as options for HCC with minimal or uncertain extrahepatic, if surgery is not an option. While early reports indicated that the use of locoregional techniques in individuals with extrahepatic are associated with poorer prognostic outcomes (Wong, 2009), locoregional techniques appear to provide improved survival times in individuals with extrahepatic metastasis when hepatic lesions are treated.

Ablative Techniques (Cryoablation, RFA, MWA or PEI)

Local ablative therapy for hepatic metastasis is generally indicated when there is no extrahepatic disease or when all sites of disease can be treated, criteria that predominantly apply to  individuals with colorectal carcinoma or certain neuroendocrine malignancies. Currently, surgical resection with adequate margins or liver transplantation are considered the treatments of choice and are viewed as potentially curative. Ablative therapy may be considered as a curative therapy in individuals with small lesions (NCCN, V4.2024). Ablative therapy may also be an option for individuals who are not candidates for surgical resection due to the location or tumor load, inadequate liver reserve or comorbid conditions. Common complications of ablative therapies include abscess formation, infection, hemorrhage and injury to adjacent anatomical organs. There have also been reports of death associated with the ablative procedures.

Cryosurgery, also called cryotherapy or cryoablation, is the use of extreme cold to destroy abnormal tissue. Cryosurgical ablation is performed by inserting a cryoprobe into the lesion followed by injection of a coolant such as liquid nitrogen or argon gas, freezing and killing the surrounding tissue. The dead tissue is then naturally absorbed by the body. Cryosurgery does have side effects; however, they may be less severe than those associated with conventional surgery or radiation therapy.

Radiofrequency ablation (RFA) involves inserting a probe into the center of the tumor to deliver an alternating electric current causing an increase in temperature and coagulative necrosis of the cell and death. RFA can be performed as an open surgical procedure, laparoscopically, or percutaneously with ultrasound or computed tomography (CT) guidance. The NCCN CPG for HCC (V4.2024) notes that although individuals with HCC should first be considered for surgical curative therapy, RFA may be considered a potential curative therapy in select individuals in early-stage disease who are not surgical candidates.

Microwave ablation (MWA) is a form of thermal ablation, along with cryoablation and RFA, in which probes, inserted into the tumor, deliver microwave energy that heats and kills surrounding tissue. One purported advantage of MWA over RFA is the ability to achieve higher temperatures and obtain a larger ablation zone (Abdelaziz, 2015; Veltri, 2015). For this reason, MWA has generated some interest as a potential therapy for larger lesions although the evidence does not currently support that use.

Percutaneous ethanol injection uses the injection of ethanol directly into tumor tissue, where it destroys the tumor tissue due to its dehydrative and protein degenerative effects. The relative hypervascularity of HCC ensures good penetration of the tumor with minimal spillover of ethanol into normal liver tissue.

The NCCN CPG for HCC (V4.2024) states the following with Category 2A recommendations in the Principles of Locoregional Therapy-Ablation section:

• Locoregional therapy should be considered in patients who are not candidates for surgical curative treatments, or as a part of a strategy to bridge patients for other curative therapies.
• All tumors should be amenable to ablation such that the tumor and, in the case of thermal ablation, a margin of normal tissue is treated. A margin is not expected following percutaneous ethanol injection.
• Tumors should be in a location accessible for percutaneous/laparoscopic/open approaches for ablation.
• Caution should be exercised when ablating lesions near major vessels, major bile ducts, diaphragm and other intra-abdominal organs.
• Ablation alone may be curative in treating tumors less than or equal to 3 cm. In well-selected patients with small properly located tumors, ablation should be considered as definitive treatment in the context of a multidisciplinary review. Lesions 3 to 5 cm may be treated to prolong survival using arterially directed therapies, or with combination of an arterially directed therapy and ablation as long as tumor location is accessible for ablation. Unresectable/inoperable lesions greater than 5 cm should be considered for treatment using arterially directed therapy, systemic therapy, or EBRT.

The 2023 recommendations by the AASLD (Singal, 2023) addressing treatment of HCC with ablative therapies include the following recommendations:

• Patients with solitary tumors ≤5 cm should be treated with curative intent using local ablative therapies if they are ineligible for or decline surgical therapy (Level 1, Strong Recommendation).
• Thermal ablation (radiofrequency or microwave ablation) should be considered the treatment of choice for patients with early stage HCC ≤3 cm who are ineligible for or decline surgery (Level 1, Strong Recommendation).
  a. AASLD does not advise one thermal ablative modality over another.

In a position statement for the Society of Interventional Radiology (SIR), Gervais and colleagues (2009) noted “HCCs 5 cm or less in diameter have a higher probability of having complete ablation compared to those greater than 5 cm in diameter.” The authors also noted superior results with tumors smaller than 3 cm, acceptable (intermediate) results with tumors 3 to 5 cm, and “fairly dismal results for tumors larger than 5 cm.”

Feng and colleagues (2015) conducted a meta-analysis to compare percutaneous RFA and surgical resection as treatments of small HCC. A total of 15,482 individuals from 3 randomized controlled trials (RCTs) and 20 retrospective studies were included in the efficacy and safety analysis. There were 7524 individuals treated with surgical resection of the liver, and 7958 treated with RFA. At 1, 3 and 5 years, surgical resection had higher OS and recurrence-free rates compared to RFA. There was no difference in mortality between the two groups, but the RFA group had a significantly lower morbidity rate compared to the surgical resection group.

Chong and associates (2020) compared the safety and efficacy outcomes of RFA and MWA in individuals with unresectable HCC (n=93) in a prospective randomized study. Participation was limited to those with lesions 3 or less, a maximum tumor diameter of 5 cm or less and an absence of extrahepatic metastasis. Participants were randomized to receive either RFA (n=46) or MWA (n=47). The MWA versus RFA 1-year, 3-year, 5-year OS rates were 97.9%, 67.1%, 42.8% and 93.5%, 72.7% and 56.7% respectively (p=0.899). There were no cases of treatment related mortality at 30 days. The authors concluded that both procedures were equally safe and effective in treating small HCC. MWA did show shorter ablation times and no risk of burn injury. Other studies support the finding that MWA and RFA therapy produce similar clinical outcomes in a comparable population (Kamal, 2019; Vietti Violi, 2018; Yu, 2017; Zhang, 2008).

In a systematic review, Shen and associates (2013) assessed clinical outcomes of each therapy, including survival, recurrence and major complications in individuals with HCC lesions less than 3 cm. While RFA was shown to have a higher 3-year OS rate and a lower rate of local recurrence, there was no difference between the therapies in terms of distant intrahepatic recurrence. RFA was associated with a higher rate of complications. RFA and PEI appear to have similar outcomes in individuals with early HCC (three or less lesions which are 5 cm or smaller) (Ikeda, 2001; Giorgio, 2011; Lencioni, 2003; Livraghi, 1999). Response to the initial treatment appears to be a significant predictor in survival rather than the type of ablation therapy (RFA versus PEI) used (Morimoto, 2007). Other studies evaluating PEI therapy have shown that hepatic function, Child-Pugh classification, and tumor size affect survival rates and individuals with tumors 3 cm or less with improved survival rates compared to larger tumors (Bruix, 2005; Lermite, 2006; Luo, 2005; Taniguchi, 2008).

Lencioni and colleagues (2003) published a randomized comparison of RFA and PEI in 102 individuals with hepatocellular cancer. Tumors were fully ablated in 91% of the participants treated with RFA and 85% of the individuals treated with PEI; however, an average of 5.4 sessions were required for PEI versus 1.1 for RFA. Additionally, there was a significant difference in the local recurrence-free survival rate at 1 year of 83% and 62% at 2 years for the PEI group. In comparison, the RFA group had a local recurrence-free survival rate at 1 year of 96% and 95% at 2 years. The overall 2-year survival was similar in both groups. Additional nonrandomized comparative studies reporting survival data also support the equivalency of these two options (Ikeda, 2001; Livraghi, 1999).

In a study of 153 enrolled individuals with newly diagnosed HCC, Morimoto and colleagues (2007) described two cohorts of participants. A total of 110 individuals received RFA ablation while 43 participants received PEI. Of those, 102 participants had single HCC tumors and 51 participants had two or three HCC nodules with a maximum diameter of 5 cm or less. The OS at 3 years was 75% and 59% at 5 years. No local tumor growth at 6 months following initial treatment was reported in 125 (82%) individuals. Twenty-eight (18%) participants had residual tumor and were retreated. There was no significant difference in successful initial treatment outcomes between the treatment modalities; 90 (82%) of the 110 individuals treated with RFA, and 35 (81%) of 43 individuals treated with PEI, had no residual tumor by contrast enhanced computerized tomography (CT) at 6 months. Median follow-up of 34 months revealed 58 (53%) of 110 individuals treated with RFA and 25 (58%) of 43 individuals treated with PEI had tumor recurrence. Twenty-three participants died and 3 participants were lost to follow-up. Tumor size was one of the pre-treatment factors associated with survival. Overall, the significant predictor of survival was the response to initial treatment.

The current RFA devices are capable of producing a lesion of 5 cm or more in one session. This is sufficient to allow for the full ablation of a 3cm tumor with adequate margins (Peng, 2013; Tovoli, 2016). Ablation of larger tumors was more technically challenging as overlapping fields were required to ensure adequate ablation. Radiographic studies present challenges when used to accurately determine the defining margins for overlap. There have been several prospective or retrospective studies have shown some promising results in the treatment of larger lesions with locoregional therapies such as MWA or RFA (Abdelaziz, 2015; Dai, 2015; Veltri, 2015). However, at this time, the use of ablative therapies have not been shown in studies to be clinically appropriate in the treatment tumors larger than 5 cm.

Neuroendocrine tumors with a high incidence of distant metastases frequently involve the liver (Bacchetti, 2013). Treatment of neuroendocrine cancers is primarily palliative in nature, to reduce levels of functioning hormones, which may result in significant morbidity. There is considerable literature regarding the use of ablative techniques, which support an increase in survival times when compared to conservative treatment in select individuals or to reduce levels of functioning hormones (Adam, 2002; Bacchetti, 2013; Henn, 2003; Saxena, 2012). Overall, the studies do not show that a specific ablative technique is superior. While RFA appears to be the most common modality used in this country, the choice of ablative technique is often based on individual physician and institution experience and preference. Locally ablative techniques are frequently used with resective surgery.

Retrospective studies and case series using a locally ablative technique to treat liver metastases from primaries other than colorectal and neuroendocrine tumors generally report the feasibility of the procedure and suggest improved progression-free survival (Bleicher, 2003; Fairhurst, 2016; Kümler, 2015; Seidensticker, 2015; Xiao, 2018). However, because of the limited data and heterogeneous clinical presentations, optimal selection criteria have not been identified and uniformly adopted. Various authors noted prospective trials are needed to confirm the results. Recommendations for routine local ablation of hepatic metastases are included in the NCCN CPGs for colorectal cancer and neuroendocrine cancers. However, the treatments are not recommended for other metastatic tumors to the liver.

In a retrospective review of 110 individuals, Shady and colleagues (2018) compared the local tumor progression free survival (LTPFS) in individuals who underwent either RFA or MWA to treat colorectal liver metastases. A total of 62 individuals with 85 tumors underwent RFA in 72 sessions, and 48 individuals with 60 tumors underwent microwave ablation in 52 sessions. The median tumor size was 1.8 cm and 1.7 cm in the RFA and microwave ablation groups respectively. Complete ablation or no evidence of residual disease on the first post-ablation contrast enhanced CT (6 weeks), was used as the basis for monitoring for local tumor progression. Complete ablation was reported in 93% (79/85) of the RFA group and 97% (58/60) of the MWA group. The LTPFS rate for RFA versus MWA at 12 months was 69% versus 75%, at 18 months 66% versus 66%, and at 24 months 61% versus 60% respectively. An ablation margin of 5 mm or less was a predictor of shorter LTPFS in both groups while the presence of peri-vascular tumors was a predictor of LTPFS in only the RFA group. The authors noted that while the heat sink effect is a limitation of RFA, MWA might be relatively resistant to the heat sink effect. There were no differences in complication rates between the two modalities.

Intrahepatic Cholangiocarcinoma (CCA)

CCAs are tumors originating in the epithelium of the bile ducts and can be classified as intrahepatic or extrahepatic tumors. Extrahepatic tumors are more common than intrahepatic tumors, but the incidence of intrahepatic tumors has increased more quickly than extrahepatic tumors. Intrahepatic CCAs are often diagnosed at a late stage due to the nonspecific symptoms associated with early-stage disease. Surgical resection is considered the only potentially curative treatment although most individuals are not candidates for surgical resection at the time of diagnosis (NCCN, V6.2024). At the time of diagnosis, approximately 15 to 30% of individuals are considered to have surgically resectable disease (Mosconi, 2021). For individuals with unresectable disease, the NCCN recommends various potential locoregional options including arterially directed therapy. The studies supporting this recommendation consist primarily of smaller, retrospective studies. Due to the relative rarity of intrahepatic CCA, larger randomized studies may not be feasible (Mosconi, 2021).

Bridge to Liver Transplantation

As the incidence of HCC continues to rise and availability of donor organs remains low, the waiting time for potentially curative therapy with orthotopic liver transplantation (OLT) increases. Heckman (2008) noted the incidence of disease progression while listed for transplant was 10-23%. Various technologies have been explored to maintain transplant eligibility by controlling disease progression, of which transcatheter arterial chemoembolization (TACE) and RFA were the most frequently studied. A “bridge” to liver transplant involves ablative techniques to minimize and control disease progression to allow individuals with limited HCC to remain eligible on the OLT waitlist. The goal of bridging is to prevent drop-off from the waiting list and to improve post-transplant survival (DuBay, 2011; Lee, 2020).

Bridge therapy is typically recommended when predicted liver transplant times are likely to exceed 6 months. The majority of studies include a combination of therapies rather than a sole therapy. A number of locoregional therapies have been recognized as successful bridging techniques to maintain transplant eligibility and there is no evidence to support the superiority of any one technique in those studied. In those individuals who are able to achieve a complete response from locoregional therapy prior to transplant, bridging therapy may improve post-transplant survival (Agopian, 2017; Braat, 2016; Bauschke, 2020; Cheng, 2005b; Kulik, 2018; Lee, 2017; Lewandowski, 2009; Obed, 2007).

The current Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) allocation policy (2024) provides incentives to use loco-regional therapies to downsize tumors to T2 status and to prevent progression while on the transplant wait list. In addition, the OPTN/UNOS policy implicitly recognizes the role of loco-regional therapy in the pre-transplant setting. These indications are in part related to the current OPTN/UNOS liver allocation scoring system referred to as the Model for End-Stage Liver Disease (MELD), for adults ages 12 and older, and the Pediatric End-stage Liver Disease (PELD) scoring system for candidates younger than 12 years of age. The MELD score is a continuous disease severity scale incorporating serum bilirubin, prothrombin time (for example, international normalized ratio-INR), and serum creatinine into an equation, producing a number ranging from 6 (less ill) to 40 (gravely ill). The MELD score estimates how urgently the individual needs a liver transplant within the next 3 months. PELD is similar to MELD but uses additional factors to recognize the specific growth and development needs of children. PELD scores may also range higher or lower than the range of MELD scores. The PELD scoring system includes measures of serum bilirubin, INR, albumin, growth failure, and whether the child is less than 1 year old. Candidates that meet the staging and imaging criteria specified in the OPTN/UNOS Allocation of Livers and Liver-Intestines Policy, Candidates with Hepatocellular Carcinoma (HCC) sections 9.3.G.iv-v may receive extra priority on the "Waiting List." A candidate with an HCC tumor that is stage T2 may be registered at a MELD/PELD score equivalent to a 15% risk of candidate death within 3 months if additional criteria are also met. OPTN/UNOS defines Stage T2 lesions as:

• One lesion greater than or equal to 2 cm and less than or equal to 5 cm; or,
• Two or three lesions each greater than or equal to 1 cm and less than or equal to 3 cm in size.

The largest dimension of each tumor is used to report the size of HCC lesions. Nodules less than 1 cm are indeterminate and cannot be considered for additional priority. Past loco-regional treatment for HCC (OPTN Class 5 [T2] lesion or biopsy proven prior to ablation) are eligible for automatic priority.

The NCCN CPG for hepatocellular carcinoma (V4.2024) states:

Bridge therapy is used to decrease tumor progression and the dropout rate from the liver transplantation waiting list. A number of studies have investigated the role of locoregional therapies as a bridge to liver transplantation in patients on a waiting list. These studies included RFA/microwave ablation (MWA), transarterial embolization (TAE), TACE, including conventional TACE and TACE with drug-eluting beads (DEB-TACE), selective internal radiotherapy (SIRT) or radioembolization (TARE) with Y-90 microspheres, EBRT, and TACE followed by EBRT as “bridge” therapies.

Limitations of these studies include size and heterogeneity of the study populations; however, the NCCN CPG states, “Nevertheless, the use of bridge therapy in this setting is increasing, and it is administered at most NCCN Member Institutions, especially in areas where there are long wait times for a transplant.”

The 2023 AASLD guidelines on HCC (Singal, 2023) include locoregional therapy recommendations for bridging therapy:

• AASLD advises the use of pre-transplant locoregional bridging therapy for patients being evaluated or listed for liver transplantation, if they have adequate hepatic reserve, to reduce the risk of waitlist dropout in the context of anticipated prolonged wait times for transplant (Level 3, Strong Recommendation).
• AASLD does not advise one LRT over another for bridging therapy. The choice of locoregional modality should be based on tumor size, location, and center expertise (Level 3, Weak Recommendation).

Hepatocellular Carcinoma in Individuals Who May Become Eligible for Liver Transplantation

Downstaging therapy is defined as treatment used to reduce the tumor burden in individuals without distant metastasis but do have more advanced HCC whose tumor characteristics are beyond the accepted transplant criteria (NCCN, V4.2024). The choice of technique used is influenced by multiple factors, such as tumor size/number, location, liver function, and individual center experience (Kulik, 2018). A number of studies support the use of locoregional therapies as a downstaging technique, with TACE being the most widely studied method (Chapman, 2008; Heckman, 2008).

In 2020 retrospective study, Lee and colleagues evaluated the long-term outcomes of individuals who underwent liver transplantation with or without downstaging or bridging therapy. Individuals with HCC without extrahepatic metastasis who underwent TACE (n=409), RFA (n=50), resection (n=13) radiation (n=5) or combination therapy (n=211) treatment were included in the review. An individual was considered to achieve a successful downstaging (SD) when there was a reduction in the number and size of viable tumors to within the Milan criteria. SD outcomes were associated with improved recurrence-free survival (RFS) and OS when compared to those who experience downstaging failure or disease progression. Individuals with SD prior to liver transplantation achieved better RFS when compared to individuals who did not undergo downstaging prior to liver transplantation.

Yao and associates (2015) compared the long-term outcomes of individuals with HCC who underwent downstaging to prior to liver transplantation (n=118) to individuals who did not require downstaging prior to liver transplantation (n=488). Tumor downstaging was not successful in 41 individuals (34.7%) Individuals who underwent successful downstaging achieved similar Kaplan-Meier 1- and 5-year post-transplant survival compared to those who did not undergo downstaging (93.4% and 77.8% versus 94.3% and 81%, respectively; p=0.69). While the study did include individuals with 4-5 lesions (n=14), the size of this group precludes drawing firm conclusions about the efficacy of downstaging in this subgroup. The authors reported successful post-transplant outcomes following downstaging but noted “We believe that there are upper limits in tumor size and number beyond which down-staging is not likely to be successful and the outcome may be significantly worse.”

The NCCN CPG for hepatocellular cancers (V4.2024), principles of surgery, includes the following recommendation:

Patients meeting the UNOS criteria [(AFP level ≤1000 ng/mL and single lesion ≥2cm and ≤5 cm, or 2 or 3 lesions ≥1cm and ≤3cm)] should be considered for transplantation (cadaveric or living donation).

The Model for End-Stage Liver Disease (MELD) score is used by UNOS to assess the severity of liver disease and prioritize the allocation of the liver transplants. There are patients whose tumor characteristics are marginally outside of the UNOS guidelines who should be considered for transplant. Furthermore, there are patients who are downstaged to within criteria that can also be considered for transplantation.

The 2024 OPTN and UNOS allocation policy (2024) notes that lesions which are eligible for downstaging protocols must meet one of the following criteria:

1. One lesion greater than 5 cm and less than or equal to 8 cm
2. Two or three lesions that meet all of the following:
   • at least one lesion greater than 3 cm
   • each lesion less than or equal to 5 cm, and
   • a total diameter of all lesions less than or equal to 8 cm
3. Four or five lesions each less than 3 cm, and a total diameter of all lesions less than or equal to 8 cm

For individuals who have meet the downstaging criteria and subsequently undergo local-regional therapy, any residual therapy must meet the definition for T2 lesions in order to be eligible for a standardized MELD or PELD exception.

Ablation: The destruction of a body part or tissue or its function, which may be achieved by surgery, hormones, drugs, radiofrequency, heat, or other methods.

Adenocarcinoma: Cancer which arises from glandular epithelial cells within internal organs. The majority of breast, lung, esophagus, stomach, colon, rectum, pancreas, prostate, and uterus cancers are classified as adenocarcinomas.

Bridge Therapy: Therapy considered for those who meet transplant criteria, used slow tumor progression in order to decrease the liver transplantation dropout rate.

Childs-Turcotte-Pugh (CTP): A scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, candidates can be classified into 1 of 3 categories:

• Childs A (5-6 points): 10 year survival 80-90%
• Childs B (7-9 points): 5 year survival 60-80%
• Childs C (10-15 points): 2 year survival less than 50%

Cancer of the Liver Italian Program (CLIP): A tumor classification system from Italy that includes scoring for 8 clinical parameters for HCC, combining the Child-Turcotte-Pugh scoring system with tumor criteria including tumor morphology, portal invasion, and alpha fetoprotein levels.

Cholangiocarcinoma: A type of cancer developing in cells that line the bile ducts in the liver.

Encapsulated nodules: Any group of abnormal cells confined to a specific area, surrounded by a covering of specialized cells called a capsule.

Extra-hepatic disease: Cancer that is located outside of the liver.

Hepatic metastases: Cancer that has spread from its original location to the liver.

Metastasis: The spread of cancer from one part of the body (the origin of the cancer) to another part of the body. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Neuroendocrine tumor: Tumors arising from cells that produce hormones that can cause systemic symptoms such as flushing or wheezing. Examples of neuroendocrine tumors include, but are not limited to carcinoid tumors, islet cell tumors, medullary thyroid carcinoma, and pheochromocytoma.

Palliative treatment: Treatment given for relief of symptoms and pain rather than effecting a cure.

Primary hepatocellular cancer: A cancer that originates within liver cells.

Unresectable: Refers to a tumor that cannot safely be removed surgically due to size or location.

Peer Reviewed Publications:

1. Abdelaziz AO, Nabeel MM, Elbaz TM, et al. Microwave ablation versus transarterial chemoembolization in large hepatocellular carcinoma: prospective analysis. Scand J Gastroenterol. 2015; 50(4):479-484.
2. Adam R, Hagopian EJ, Linhares M, et al. A comparison of percutaneous cryosurgery and percutaneous radiofrequency for unresectable hepatic malignancies. Arch Surg. 2002; 137(2):1332-1339.
3. Agopian VG, Harlander-Locke MP, Ruiz RM, et al. Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within Milan criteria undergoing liver transplantation: analysis of 3601 patients from the US Multicenter HCC Transplant Consortium. Ann Surg. 2017; 266(3):525-535.
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Colorectal Cancer
Cryoablation
Hepatic Metastases
Hepatic Tumors
Hepatocellular Carcinoma
Liver Tumors
Metastatic Liver Tumors
Microwave Ablation
Percutaneous Ethanol Injection (PEI)
Radiofrequency Ablation (RFA)
Surgical Ablation

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