Background

Liver transplantation

Recipients

Liver transplantation is now routinely performed as a treatment of last resort for patients with end-stage liver disease. Liver transplantation may be performed with liver donation after a brain or cardiac death or with a liver segment donation from a living donor. Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by Organ Procurement and Transplantation Network and United Network of Organ Sharing. The liver allocation system adopted included the Model for End-stage Liver Disease (MELD) and Pediatric End-stage Liver Disease (PELD) scales. Scoring on the MELD and PELD uses a continuous disease severity scale based entirely on objective laboratory values. In 2013, the Organ Procurement and Transplantation Network and United Network of Organ Sharing updated its allocation system. Status 1A patients have an acute liver failure with a life expectancy of fewer than seven days without a liver transplant. Status 1A patients also include primary graft nonfunction, hepatic artery thrombosis, and acute Wilson disease. Status 1A patients must be recertified every seven days. Status 1B patients are pediatric patients (age range, 0-17 years) with chronic liver disease, which may include the following: fulminant liver failure, primary nonfunction, hepatic artery thrombosis, acute decompensated Wilson disease, chronic liver disease; and nonmetastatic hepatoblastoma. Pediatric patients move to status 1A at age 18 but still qualify for pediatric indications.

Following status 1, donor livers are prioritized to those with the highest scores on MELD or PELD. These scales have been found to be highly predictive of the risk of dying from liver disease for patients waiting on the transplant list. The MELD score incorporates bilirubin, prothrombin time (i.e., international normalized ratio), and creatinine into an equation, producing a number that ranges from 6 to 40. The PELD score incorporates albumin, bilirubin, INR growth failure, and age at the listing. Waiting time will only be used to break ties among patients with the same MELD or PELD score and blood type compatibility.^1,Status seven describes patients who are temporarily inactive on the transplant waiting list due to being temporarily unsuitable for transplantation. Pediatric patients who turn 18 are status X.

Donors

Due to the scarcity of donor livers, a variety of strategies have been developed to expand the donor pool. For example, a split graft refers to dividing a donor liver into two segments that can be used for two recipients. Living donor liver transplantation (LDLT) is now commonly performed for adults and children from a related or unrelated donor. Depending on the graft size needed for the recipient, either the right lobe, left lobe, or the left lateral segment can be used for LDLT. In addition to addressing the problem of donor organ scarcity, LDLT allows the procedure to be scheduled electively before the recipient's condition deteriorates or serious complications develop. LDLT also shortens the preservation time for the donor liver and decreases disease transmission from donor to recipient.

Management
Management of acute rejection of liver transplant using intravenous immunoglobulin or plasmapheresis is discussed separately in 'Intravenous Immunoglobulin (IVIG) Therapy' (Policy #016 in the Drugs Section) and 'Plasma Exchange' (Policy #056 in the Treatment Section), respectively. Also, the role of chemoembolization or radiofrequency ablation as a bridge to transplant in patients with hepatocellular cancer is addressed separately in 'Transcatheter Arterial Chemoembolization To Treat Primary or Metastatic Liver Malignancies' (Policy #034 in the Surgery Section) and 'Radiofrequency Ablation of Primary or Metastatic Liver Tumors' (Policy #079 in the Surgery Section), respectively.

Regulatory Status

Liver and liver-kidney transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Liver transplants are included in these regulations.

Related Policies

• None

I. A liver transplant, using a cadaver or living donor, is considered medically necessary for carefully selected members with end-stage liver failure due to irreversibly damaged livers.

Etiologies of end-stage liver disease include, but are not limited to, the following:
A. Hepatocellular diseases:
• Alcoholic liver disease
• Viral hepatitis (either A, B, C, or non-A, non-B)
• Autoimmune hepatitis
• Alpha-1 antitrypsin deficiency
• Hemochromatosis
• Non-alcoholic steatohepatitis
• Protoporphyria
• Wilson disease
B. Cholestatic liver diseases:
• Primary biliary cirrhosis
• Primary sclerosing cholangitis with development of secondary biliary cirrhosis
• Biliary atresia
C. Vascular disease:
• Budd-Chiari syndrome
D. Primary hepatocellular carcinoma (see Policy Guidelines section for patient selection criteria)

E. Inborn errors of metabolism

F. Trauma and toxic reactions

G. Miscellaneous:

• Familial amyloid polyneuropathy

• primary graft non-function
• hepatic artery thrombosis
• chronic rejection
• ischemic type biliary lesions after donation after cardiac death
• recurrent non-neoplastic disease causing late graft failure

• Members with intrahepatic cholangiocarcinoma
• Members with neuroendocrine tumors metastatic to the liver
  

• Members with hepatocellular carcinoma that has extended beyond the liver (see Policy Guidelines section for patient selection criteria)
• Members with ongoing alcohol and/or drug abuse. (Evidence for abstinence may vary among liver transplant programs, but generally a minimum of 3 months is required.)

General
Potential contraindications for solid organ transplant are subject to the judgment of the transplant center and include the following:

· Known current malignancy, including metastatic cancer
· Recent malignancy with high risk of recurrence
· Untreated systemic infection making immunosuppression unsafe, including chronic infection
· Other irreversible end-stage disease not attributed to liver disease
· History of cancer with a moderate risk of recurrence
· Systemic disease that could be exacerbated by immunosuppression
· Psychosocial conditions or chemical dependency affecting ability to adhere to therapy.

Patients with liver disease related to alcohol or drug abuse must be actively involved in a substance abuse treatment program.

Tobacco consumption is a contraindication.

Patients with polycystic disease of the liver do not develop liver failure but may require transplantation due to the anatomic complications of a hugely enlarged liver. The MELD and PELD score may not apply to these cases. One of the following complications should be present:

· Enlargement of liver impinging on respiratory function
· Extremely painful enlargement of liver
· Enlargement of liver significantly compressing and interfering with function of other abdominal organs.

Hepatocellular Carcinoma
Criteria used for patient selection of hepatocellular carcinoma (HCC) patients eligible for liver transplant include the Milan criteria, which is considered the criterion standard, the University of California, San Francisco expanded criteria, and United Network of Organ Sharing (UNOS) criteria.

Milan Criteria
A single tumor 5 cm or less or 2 to 3 tumors 3 cm or less.

University of California, San Francisco Expanded Criteria
A single tumor 6.5 cm or less or up to 3 tumors 4.5 cm or less, and a total tumor size of 8 cm or less.

UNOS Stage T2 Criteria
A single tumor 2 cm or greater and up to 5 cm or less or 2 to 3 tumors 1 cm or greater and up to 3 cm or less and without extrahepatic spread or macrovascular invasion. UNOS criteria were updated in 2018 (https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_09)

Patients with HCC are appropriate candidates for liver transplant only if the disease remains confined to the liver. Therefore, the patient should be periodically monitored while on the waiting list, and if metastatic disease develops, the patient should be removed from the transplant waiting list. Also, at the time of transplant, a backup candidate should be scheduled. If locally extensive or metastatic cancer is discovered at the time of exploration before hepatectomy, the transplant should be aborted, and the backup candidate scheduled for transplant.

Note that liver transplantation for those with T3 HCC is not prohibited by UNOS guidelines, but such patients do not receive any priority on the waiting list. All patients with HCC awaiting transplantation are reassessed at 3-month intervals. Those whose tumors have progressed and are no longer stage T2 will lose the additional allocation points.

Additionally, nodules identified through imaging of cirrhotic livers are given a class 5 designation. Class 5B and 5T nodules are eligible for automatic priority. Class 5B criteria consist of a single nodule 2 cm or larger and up to 5 cm (T2 stage) that meets specified imaging criteria. Class 5T nodules have undergone subsequent locoregional treatment after being automatically approved on initial application or extension. A single class 5A nodule (>1 cm and <2 cm) corresponds to T1 HCC and does not qualify for automatic priority. However, combinations of class 5A nodules are eligible for automatic priority if they meet stage T2 criteria. Class 5X lesions are outside of stage T2 and ineligible for automatic exception points. Nodules less than 1 cm are considered indeterminate and are not considered for additional priority. Therefore, the UNOS allocation system provides strong incentives to use locoregional therapies to downsize tumors to T2 status and to prevent progression while on the waiting list.

Cholangiocarcinoma
According to the Organ Procurement and Transplantation Network (OPTN) policy on liver allocation, candidates with cholangiocarcinoma meeting the following criteria will be eligible for a MELD or PELD exception with a 10% mortality equivalent increase every 3 months:

· Centers must submit a written protocol for patient care to the OPTN and UNOS Liver and Intestinal Organ Transplantation Committee before requesting a MELD score exception for a candidate with cholangiocarcinoma. This protocol should include selection criteria, administration of neoadjuvant therapy before transplantation, and operative staging to exclude patients with regional hepatic lymph node metastases, intrahepatic metastases, and/or extrahepatic disease. The protocol should include data collection as deemed necessary by the OPTN and UNOS Liver and Intestinal Organ Transplantation Committee.
· Candidates must satisfy diagnostic criteria for hilar cholangiocarcinoma: malignant-appearing stricture on cholangiography and one of the following: carbohydrate antigen 19-9 100 U/mL, or and biopsy or cytology results demonstrating malignancy, or aneuploidy. The tumor should be considered unresectable on the basis of technical considerations or underlying liver disease (e.g., primary sclerosing cholangitis).
· If cross-sectional imaging studies (computed tomography scan, ultrasound, magnetic resonance imaging) demonstrate a mass, the mass should be 3 cm or less.
· Intra- and extrahepatic metastases should be excluded by cross-sectional imaging studies of the chest and abdomen at the time of initial exception and every 3 months before score increases.
· Regional hepatic lymph node involvement and peritoneal metastases should be assessed by operative staging after completion of neoadjuvant therapy and before liver transplantation. Endoscopic ultrasound-guided aspiration of regional hepatic lymph nodes may be advisable to exclude patients with obvious metastases before neoadjuvant therapy is initiated.
· Transperitoneal aspiration or biopsy of the primary tumor (either by endoscopic ultrasound, operative, or percutaneous approaches) should be avoided because of the high risk of tumor seeding associated with these procedures.

· They should be healthy individuals who are carefully evaluated and approved by a multidisciplinary team including hepatologists and surgeons to assure that they can tolerate the procedure
· They should undergo evaluation to ensure that they fully understand the procedure and associated risks
· They should be of legal age and have sufficient intellectual ability to understand the procedures and give informed consent
· They should be emotionally related to the recipients
· They must be excluded if the donor is felt or known to be coerced
· They need to have the ability and willingness to comply with long-term follow-up.

The patient is not a candidate for subtotal liver resection;
The patient’s tumor(s) is less than or equal to 5 cm in diameter;
There is no macrovascular involvement;
There is no identifiable extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal organs or bone; and,
The transplant is furnished in a facility that is approved by CMS as meeting institutional coverage criteria for liver transplants.

FIDE-SNP Coverage:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2009 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 10. 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Liver Transplant for Hepatocellular Disease

Clinical Context and Test Purpose

The purpose of a liver transplant for patients who have a hepatocellular disease (i.e., viral hepatitis or nonalcoholic steatohepatitis) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a liver transplant improve net health outcomes in individuals with a hepatocellular disease?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with a hepatocellular disease, such as viral hepatitis or nonalcoholic steatohepatitis.

Viral hepatitis is an infection that causes liver inflammation and damage. Hepatitis B, C, and D viruses can cause acute, chronic infections and lead to cirrhosis, liver failure, and liver cancer.

Nonalcoholic steatohepatitis is caused by a buildup of fat in the liver which leads to inflammation and damage. While many patients have no symptoms or problems, in some cases, the condition can worsen to cause liver scarring and cirrhosis. As noted by the name of the condition, patients with nonalcoholic steatohepatitis do not abuse alcohol

Interventions

The therapy being considered is a liver transplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practice is currently being used to make decisions about the end-stage hepatocellular disease: medical management.

Outcomes

The general outcomes of interest are overall survival (OS) and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Viral Hepatitis

The presence of hepatitis B virus and hepatitis C virus (HCV) have been controversial indications for liver transplantation because of the high potential for recurrence of the virus and subsequent recurrence of liver disease. However, in a review of registry data, Belle et al (1995) have indicated a long-term survival rate (7 years) of 47% in hepatitis B virus-positive transplant recipients, which is lower than that seen in other primary liver diseases such as primary biliary cirrhosis (71%) or alcoholic liver disease (57%).^2, Recurrence of HCV infection in transplant recipients has been nearly universal, and 10% to 20% of patients will develop cirrhosis within 5 years.^3,

Mukherjee and Sorrell (2008), reviewing controversies in liver transplantation for hepatitis C, indicated the greatest opportunity for HCV eradication is pretransplant before hepatic decompensation.^4, Challenges of treatment posttransplantation include immunosuppressive drugs and abnormal hematologic, infectious, and liver function parameters. The authors listed the following factors as associated with poor outcomes in liver transplantation for recurrent HCV: high HCV-RNA level pretransplant, non-Caucasian ethnicity, advanced donor age, T cell-depleting therapies, inappropriate treatment of Banff A1 acute cellular rejection with steroid boluses, cytomegalovirus disease, and year of transplantation (outcomes tend to be worse with recent transplants).

Nonalcoholic Steatohepatitis

Systematic Reviews

Liver transplantation is a treatment option for patients with nonalcoholic steatohepatitis (NASH) who progress to liver cirrhosis and failure. In a systematic review and meta-analysis, Wang et al (2014) evaluated 9 studies of 717 patients with NASH and 3520 without NASH comparing liver transplantation outcomes.^5, Patients with NASH had similar 1-, 3-, and 5-year survival outcomes after liver transplantation as patients without NASH. Patients with NASH also had lower graft failure risk than those without NASH (odds ratio[OR], 0.21; 95% confidence interval [CI], 0.05 to 0.89; p=0.03). However, NASH-related liver transplant patients had a greater risk of death related to cardiovascular disease (OR=1.65; 95% CI, 1.01 to 2.70; p=0.05) and sepsis (OR=1.71; 95% CI, 1.17 to 2.50; p=0.006) than non-NASH-related liver transplant patients.

Registry Studies

Cholankeril et al (2017) published a retrospective cohort analysis of records from 2003 to 2014 in the United Network Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) database to evaluate the frequency of NASH-related liver transplantation.^6, In all, 63061 patients underwent liver transplant from 2003 to 2014. NASH accounted for 17.38% of liver transplants in 2014. During the observation period, liver transplants secondary to NASH increased by 162.0%, a greater increase than either hepatitis C (33.0% increase) and alcoholic liver disease (55.0% increase). Five-year survival posttransplant in patients who had NASH (77.81%; 95% CI, 76.37% to 79.25%) was higher than patients who had hepatitis C (72.15%; 95% CI, 71.37 to 72.93; p<0.001). Patients with NASH also demonstrated significantly higher posttransplant survival than patients with hepatitis C (hazard ratio [HR], 0.75; 95% CI, 0.71 to 0.79; p<0.001).

Section Summary: Liver Transplant for Hepatocellular Disease

The evidence on liver transplantation for a hepatocellular disease includes case series, registry studies, and systematic reviews. Long-term survival rates in patients with viral hepatitis are significant in a group of patients who have no other treatment options. Also, survival can be improved by the eradication of the hepatitis virus before transplantation. For patients with NASH, a 2013 systematic review has indicated that OS rates are similar to other indications for liver transplantation

Liver transplant for Hepatocellular Carcinoma

Clinical Context and Test Purpose

The purpose of a liver transplant for patients who have HCC is to provide a treatment option that is an alternative to or an improvement on existing therapies. The criteria used to select HCC patients eligible for liver transplant include the Milan criteria, the University of California, San Francisco expanded criteria, and UNOS criteria.

The question addressed in this policy is: Does a liver transplant improve net health outcomes in individuals with HCC?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with HCC. See the detailed discussion in the Recipient Selection Criteria section below.

Interventions

The therapy being considered is a liver transplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practices are currently being used to make decisions about managing HCC: medical management, including chemotherapy, and medical procedures, including surgery.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Liver Transplantation vs Liver Resection for HCC

Schoenberg et al (2017) published a systematic review and meta-analysis of 54 retrospective studies (n=13794) comparing liver resection (n=7990) with transplantation (n=5804) in patients with HCC.^7, At 1-year follow-up, survival rates were higher in those receiving resection (86.17%) than in those receiving liver transplant (80.58%), (OR=1.19; 95% CI, 0.99 to 1.43; p=0.07). At 5-year follow-up, survival rates were better for those who received transplantation (61.26%) than for those receiving surgery (51.9%; OR=0.62; 95% CI, 0.50 to 0.76; p<0.001). When a subgroup of patients with early HCC (8 studies) was analyzed, 1-year follow-up showed comparable survival rates between surgically treated patients (92.14%), and transplanted patients (90.38%), (OR=0.97; 95% CI, 0.63 to 1.50; p=0.89). At 5 years, transplanted patients had a significantly higher survival rate (66.67%) than surgically treated patients (60.35%; OR=0.60; 95% CI, 0.45 to 0.78; p<0.001). Review limitations included a high level of heterogeneity between studies analyzed.

Zheng et al (2014) reported on a meta-analysis of 62 cohort studies (total n=10170 patients) comparing liver transplantation with liver resection for HCC.^8, Overall 1-year survival was similar between procedures (OR=1.08; 95% CI, 0.81 to 1.43; p=0.61). However, overall 3- and 5-year survival significantly favored liver transplantation (OR=1.47; 95% CI, 1.18 to 1.84; p<0.001) over resection (OR=1.77; 95% CI, 1.45 to 2.16; p<0.001). Disease-free survival (DFS) in liver transplant patients was 13%, 29%, and 39% higher than in liver resection patients at 1, 3, and 5 years, all respectively (p<0.001). Recurrence rates were also 30% lower in liver transplantation than resection (OR=0.20; 95% CI, 0.15 to 0.28; p<0.001).

Recipient Selection Criteria

Liver transplantation selection criteria for patients with HCC have focused mainly on the number and size of tumors. Guiteau et al (2010) reported on 445 patients who received transplants for HCC in a multicenter, prospective study in UNOS Region 4.^9,On preoperative imaging, 363 patients met Milan criteria, and 82 patients were under expanded Milan criteria; these expanded criteria consisted of 1 lesion less than 6 cm, 3 or fewer lesions, none greater than 5 cm and a total diameter less than 9 cm. Patient allograft survival and recurrence-free survival at 3 years did not differ significantly between patients meeting Milan criteria and patients not meeting the expanded criteria (71% vs 70.2% and 90.5% vs 86.9%, respectively). While preliminary results showed similar outcomes when using expanded Milan criteria, the authors noted their results were influenced by waiting times in region four and that outcomes might differ in other regions with different waiting times. Additionally, the authors noted that a report from a 2010 national consensus conference on liver allocation for patients with HCC did not recommend expanding Milan criteria nationally and encouraged regional agreement.^10,

Ioannou et al (2008) analyzed UNOS data pre- and postadoption of the Model for End-stage Liver Disease (MELD) allocation system finding a 6-fold increase in recipients with HCC and survival rates in the MELD era similar to survival rates in patients without HCC.^11, The subgroup of patients with larger (3-5 cm) tumors, serum a-fetoprotein level of 455 mg/mL or greater, or a MELD score of 20 or greater, however, had poor transplantation survival. A predictive cancer recurrence scoring system was developed by Chan et al (2008) based on a retrospective review and analysis of liver transplants at 2 centers.^12, Of 116 patients with findings of HCC in their explanted livers, 12 developed recurrent HCC. Four independent significant explant factors were identified by stepwise logistic regression: the size of one tumor greater than 4.5 cm, macroinvasion, and bilobar tumor were positive predictors of recurrence, while the presence of only well-differentiated HCC was a negative predictor. Points were assigned to each factor in relation to its odds. The accuracy of the method was confirmed in two validation cohorts.

Mazzafaroet al (1996) identified patient criteria associated with improved outcomes after liver transplantation for HCC with cirrhosis.^13,These selection criteria became known as the Milan criteria and specify patients may have either a solitary tumor with a maximum diameter of 5 cm or less or up to three tumors 3 cm or less. Patients with extrahepatic spread or macrovascular invasion have a poor prognosis. UNOS adopted the Milan criteria, combined with additional criteria (no evidence of extrahepatic spread or macrovascular invasion), as its liver transplantation criteria. Interest in expanding liver transplant selection criteria for HCC and other indications is ongoing. Important outcomes in assessing expanded criteria include waiting time duration, death, or deselection due to disease progression while waiting (dropout), survival time, and time to recurrence (or related outcomes such as DFS). Survival time can be estimated beginning when the patient is placed on the waiting list, using the intention-to-treat principle, or at the time of transplantation.

Newer algorithms for selecting transplant recipients, which reviewed more than the number and size of tumors, have been proposed as alternatives to Milan criteria.^14, However, these criteria are preliminary and need prospective evaluation.

Salvage Liver Transplantation

Liver transplantation is the criterion standard treatment for HCC meeting Milan criteria in decompensated livers as is the case in patients with Child-Pugh class B or C (moderate to severe cirrhosis). Liver resection is used for early HCC in livers classified as Child-Pugh class A.^15,In patients who have an HCC recurrence after primary liver resection, salvage liver transplantation has been considered a treatment alternative to repeat hepatic resection, chemotherapy, or other local therapies such as radiofrequency ablation, transarterial chemoembolization, percutaneous ethanol ablation, or cryoablation.

Several systematic reviews have evaluated the evidence on outcomes of salvage transplant compared with the primary transplant.

Yadav et al (2018) published a systematic review and meta-analysis comparing salvage liver transplant (SLT) and primary liver transplant (PLT) for individuals with HCC.^16, Twenty retrospective studies (10 of which were also included in Murali et al [2017]) with a total of 9879 patients were included in the analysis. One-year OS was better for SLT (74.30%) than PLT (77.01%, OR 0.86, 95% CI 0.75–0.98, p=0.03). SLT also had higher 3-year (55.69% and 59.07%, respectively; OR 0.85, 95% CI 0.76–0.96, p=0.01) and 5-year (48.67% and 52.32%, respectively; OR 0.85, 95% CI 0.76–0.96, p=0.009) OS than PLT. One-year (OR 0.86, 95% CI 0.75–0.99, p=0.03), 3-year (OR 0.56, 95% CI 0.39–0.81, p=0.002), and 5-year DFS (OR 0.75, 95% CI 0.66–0.86, p<0.001) were worse for PLT (70.03%, 74.08%, and 47.09%, respectively) than for SLT (67.69%, 57.02%, and 41.27%, respectively). There was no significant difference between the 2 groups for postoperative biliary complications (p=0.19) or sepsis (p=0.68). No limitations to the analysis were reported.

Murali et al (2017) conducted a systematic review and meta-analysis of studies comparing survival of patients treated who received locoregional therapy with curative intent (CLRT) with those who received a liver transplant, stratified by liver disease stage, the extent of cancer, and whether SLT was offered.^17, Among the 48 studies selected, 9835 patients were analyzed. For all categories of CLRT combined, 5-year OS and DFS were worse than for primary liver transplant (OR for OS=0.59; 95% CI, 0.48 to 0.71; p<0.01). Intention-to-treat analysis showed no significant difference in 5-year OS (OR=1.0; 95% CI, 0.6 to 1.7) between CLRT followed by SLT when SLT was offered after CLRT, though noninferiority could not be shown. Only 32.5% of patients with HCC after CLRT received SLT because the rest were medically ineligible. DFS was worse with CLRT and SLT than with liver transplant (OR=0.31; 95% CI, 0.2 to 0.6).

In a systematic review of liver transplantation for HCC, Maggs et al (2012) found 5-year OS rates ranged from 65% to 94.7% in reported studies.^18,

Chan et al (2014) systematically reviewed 16 nonrandomized studies (total n=319 patients) assessing SLT after primary hepatic resection for HCC.^19, Reviewers found that OS and DFS outcomes with SLT were similar to reported primary liver transplantation outcomes. Median OS rates for SLT patients were 89%, 80%, and 62% at 1, 3, and 5 years, respectively. DFS rates were 86%, 68%, and 67% at 1, 3, and 5 years, respectively. SLT studies had a median OS rate of 62% (range, 41%-89%) compared with a range of 61% to 80% in the literature for primary liver transplantation. The median DFS rate for SLT was 67% (range, 29%-100%) compared with a range of 58% to 89% for primary liver transplantation.

In a meta-analysis of 14 nonrandomized comparative studies by Zhu et al (2013), OS at 1, 3, and 5 years and DFS at 1 and 3 years did not differ significantly between groups (n=1272 for primary transplant, n=236 for salvage).^20, DFS, however, was significantly lower at 5 years with salvage liver transplantation than with primary transplantation (OR=0.62; 95% CI, 0.42 to 0.92; p=0.02). There were insufficient data to evaluate outcomes in patients exceeding Milan criteria; but, in patients meeting Milan criteria, survival outcomes did not differ significantly, suggesting SLT might be a viable option in these patients.

Section Summary: Liver Transplant for HCC

Use of standardized patient selection criteria, such as the Milan criteria (a solitary tumor with a maximum tumor diameter of £5 cm, or up to three tumors £3 cm and without extrahepatic spread or macrovascular invasion), has led to improved OS rates. A 2012 systematic review reported 5-year OS rates ranged from 65% to 94.7%. A liver transplant was also shown in a 2013 meta-analysis to result in higher survival rates than resection. Similar outcomes were identified in a 2017 meta-analysis, in which transplantation showed a significantly improved survival benefit, especially for patients with early HCC. In patients who present with unresectable organ-confined disease, transplant represents the only curative approach.

Note that expansion of patient selection criteria, bridging to transplant or downstaging of disease to qualify for liver transplantation, is frequently studied. Overall, the evidence base is insufficient to permit conclusions about health outcomes after liver transplantation among patients exceeding Milan criteria and meeting expanded University of California, San Francisco or other criteria.

Liver Transplant for Cholangiocarcinoma

Reports on outcomes after liver transplantation for cholangiocarcinoma or bile duct carcinoma distinguish between extrahepatic and intrahepatic tumors, the former including hilar or perihilar tumors. Recent efforts have focused on pretransplant downstaging of disease with neoadjuvant radiochemotherapy.

Clinical Context and Test Purpose

The purpose of a liver transplant for patients who have cholangiocarcinoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a liver transplant improve net health outcomes in individuals with cholangiocarcinoma?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with extra- or intrahepatic cholangiocarcinoma.

Interventions

The therapy being considered is a liver transplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practice is currently being used to make decisions about managing cholangiocarcinoma: medical management.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections).Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Extrahepatic Cholangiocarcinoma (Hilar or Perihilar)

Systematic Reviews

Gu et al (2012) reported on a systematic review and meta-analysis of 14 clinical trials on liver transplantation for cholangiocarcinoma.^21, Most studies reported on patients with extrahepatic or hilar cholangiocarcinoma. Overall 1-, 3-, and 5-year pooled survival rates from 605 study patients were 73% (95% CI, 65% to 80%), 42% (95% CI, 33% to 51%), and 39% (95% CI, 28% to 51%), respectively. When patients received adjuvant therapies preoperatively, 1-, 3-, and 5-year pooled survival rates improved to 83% (95% CI, 57% to 98%), 57% (95% CI, 18% to 92%), and 65% (95% CI, 40% to 87%), respectively.

In a review, Heimbach (2008) considered the published outcomes of the combined protocol in the context of data on outcomes for surgical resection.^22,Heimbach (2008) concluded that outcomes were comparable between transplantation for patients with HCC and other chronic liver diseases and neoadjuvant chemoradiotherapy with subsequent liver transplantation for patients with early-stage hilar cholangiocarcinoma, which is unresectable, or arose in the setting of primary sclerosing cholangitis. The reviewer further concluded that both methods were superior to resection.

Case Series

Darwish Murad et al (2012) reported on 287 patients from 12 transplant centers treated with neoadjuvant therapy for perihilar cholangiocarcinoma followed by liver transplantation (see Table 1).^23, Intention-to-treat survival (after a loss of 71 patients before liver transplantation) was 68% at 2 years and 53% at 5 years and recurrence-free survival rates posttransplant were 78% at 2 years and 65% at 5 years (see Table 2). Survival time was significantly shorter for patients who had a previous malignancy or did not meet UNOS criteria because they had a tumor size greater than 3 cm, metastatic disease, or transperitoneal tumor biopsy (p<0.001).

Heimbach et al (2006) reported on 65 patients who underwent liver transplantation for unresectable perihilar cholangiocarcinoma or for perihilar tumor due to primary sclerosing cholangitis between 1993 and 2006 (see Table 1).^24,25, Unresectable patients underwent neoadjuvant radiochemotherapy. The 1-year survival rate was 91%, and the 5-year survival rate was 76% (see Table 2).

Mixed Populations With Extrahepatic or Intrahepatic Cholangiocarcinoma

Systematic Reviews

Data from the European Liver Transplant Registry was assessed in a review article by Pascher et al (2003; see Table 1).^26, In 169 patients with extrahepatic cholangiocarcinoma, the probabilities were 63% and 29%, respectively. Among 186 patients with intrahepatic cholangiocarcinoma, the 1-year survival rate was 58%, and the 5-year survival rate was 29%.

Case Series

Friman et al (2011) reported on 53 patients who received liver transplants for cholangiocarcinoma from 1984 to 2005, in Norway, Sweden, and Finland (see Table 1).^27, The 5-year survival rate was 25% overall, 36% in patients with TNM stage 2 or less, and 10% in patients with TNM greater than stage 2. On further analysis using only data from those patients transplanted after 1995, the 5-year survival rate increased to 38% vs 0% for those transplanted before 1995 (see Table 2). Additionally, the 5-year survival rate increased to 58% in those patients transplanted after 1995 with TNM stage 2 or less and a CA 19-9 100 or less.

Meyers et al (2000) reported on data on 207 patients with intrahepatic or extrahepatic cholangiocarcinoma from the Cincinnati Transplant Registry, finding a 1-year survival of 72% and a 5-year rate of 23% (see Table 1).^28, In a multicenter study by Robles et al (2004) reported on 36 patients with hilar tumors and 23 with theperipheral intrahepatic disease.^29, One-year survival was 82% and 77%, while 5-year survival was 30% and 23% for those with hilar tumors compared with theperipheral intrahepatic disease, respectively.

Table 1. Summary of Key Case Series Characteristics for Extrahepatic or Intrahepatic Cholangiocarcinoma

Study	Country	Participants	Treatment	Follow-Up, y
Darwish Murad et al (2012)23,	U.S.	287	Liver transplant	5
Friman et al (2011)27,	Norway, Sweden, Finland	53	Liver transplant	5
Heimbach et al (2006)24,; Rea et al (2005)25,	U.S.	65	Liver transplant	5
Robles et al (2004)29,	Spain	59	Liver transplant	5
Meyer et al (2000)28,	U.S.	207	Liver transplant	5
Casavilla et al (1997)30,	U.S.	54	Liver transplant	6.8

Table 2. Summary of Key Case Series Results for Extrahepatic or Intrahepatic Cholangiocarcinoma

Study	Treatment	Group	Overall Survival, %
			Years
			1	3	5
Darwish Murad et al (2012)23,	Liver transplant	EH perihilar			53
Heimbach et al (2006)24,; Rea et al (2005)25,	Liver transplant	EH perihilar	91		76
Meyer et al (2000)28,,a	Liver transplant	IH/EH	72		23
Robles et al (2004)29,,b	Liver transplant	EH hilar	82	53	30
		IH	77	65	23
Casavilla et al (1997)30,	Liver transplant	IH	70	29	18
Friman et al (2011)27,,d	Liver transplant	IH/EH			25

EH: extrahepatic; IH: intrahepatic.

^aUnresectable cholangiohepatoma.

^b Hilar or peripheral cholangiohepatoma; unresectable, postoperative recurrent, or incidental.

^c Aggressive neoadjuvant radiochemotherapy.

^d Unresectable cholangiohepatoma.

The evidence on a liver transplant in patients with cholangiocarcinoma includes registry studies and systematic reviews of observational studies.

For patients with extrahepatic (hilar or perihilar) cholangiocarcinoma treated with a liver transplant and adjuvant chemotherapy, survival rates have been reported to be as high as 76%.

For patients with intrahepatic cholangiocarcinoma who received liver transplantation, the 5-year survival rate was less than 30%.

Liver Transplant for Individuals with Metastatic Neuroendocrine Tumors

Clinical Context and Test Purpose

The purpose of a liver transplant for patients who have metastatic NETs is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a liver transplant improve net health outcomes in individuals with metastatic NETs?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with metastatic NETs.

Interventions

The therapy being considered is a liver transplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practice is currently being used to make decisions about managing metastatic NETs: medical management. Treatment options to control or downstage the disease include chemotherapy and debulking procedures, including hepatic resection.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Systematic Reviews

Two systematic reviews of case series have assessed metastatic NETs. NETs are relatively rare neoplasms that are slow-growing but rarely cured when metastatic to the liver.

Fan et al (2015) reported on a systematic review of 46 studies (total n=706 patients) on liver transplantation for NET liver metastases of any origin.^31, Reported overall 5-year survival rates ranged from 0% to 100%, while 5-year DFS rates ranged from 0% to 80%. In studies with more than 100 patients, the 5-year OS rate and DFS rate averaged about 50% and 30%, respectively. Frequent and early NET recurrences after liver transplantation were reported in most studies.

Mathe et al (2011) conducted a systematic review of the literature on patient survival after liver transplant for pancreatic NETs.^32, Data from 89 transplanted patients treated at 20 clinical studies were reviewed. Sixty-nine patients had primary endocrine pancreatic tumors, 9 patients were carcinoids, and 11 patients were not further classified. Survival rates at 1, 3, and 5 years were 71%, 55%, and 44%, respectively. The mean calculated survival was 54.45 months, and the median calculated survival was 41 months (95% CI, 22 to 76 months).

Section Summary: Liver Transplant for Metastatic NETs

The evidence on liver transplant for NETs includes systematic reviews of NETs for metastases of any origin. In select patients with nonresectable, hormonally active liver metastases refractory to medical therapy, liver transplantation has been considered as an option to extend survival and minimize endocrine symptoms. While there may be centers that perform liver transplantation in select patients with NETs, the available studies were limited by their heterogeneous populations. Further studies are needed to define the appropriate selection criteria.

LiverTransplant for Pediatric Hepatoblastoma

Clinical Context and Test Purpose

The purpose of a liver transplant for children who have pediatric hepatoblastoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does liver transplant improve net health outcomes in children with pediatric hepatoblastoma?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are children with pediatric hepatoblastoma.

Interventions

The therapy being considered is a liver transplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practice is currently being used to make decisions about managing pediatric hepatoblastoma: medical management.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Case Series

Pediatric hepatoblastoma is a rare condition, and the available evidence consists of small case series. Most recently, Hamilton et al (2017) reported on 376 children with hepatoblastoma requiring liver transplantation; this was part of a larger cohort of 544 children receiving a liver transplant from 1987 to 2012, as recorded in the UNOS database.^33, The 5-year patient survival rate after liver transplant for hepatoblastoma was 73%, with a 5-year graft survival rate of 74%. The recurrent or metastatic disease was the most common (57%) cause of death for this population. Barrena et al (2011) reported on 15 children with hepatoblastoma requiring liver transplantation.^34, The OS rate after liver transplant was 93.3% at the 1-, 5-, and 10-year follow-up points. Malek et al (2010) reported on liver transplantation results for 27 patients with primary liver tumor identified from a retrospective review of patients treated between 1990 and 2007.^35, Tumor recurrence occurred in 1 patient after liver transplantation, and the OS rate was 93%. Browne et al (2008) reported on 14 hepatoblastoma patients treated with liver transplantation. The mean follow-up was 46 months, with OS in 10 (71%) of 14 patients.^36, Tumor recurrence caused all four deaths. In the 10 patients receiving primary liver transplantation, 9 survived while only 1 of 4 patients transplanted after primary resection survived (90% vs 25%, p=0.02).

Section Summary: Liver Transplant for Pediatric Hepatoblastoma

Hepatoblastoma is a rare malignant primary solid tumor of the liver that occurs in children. Treatment consists of chemotherapy and resection; however, tumors are often not discovered until they are unresectable. In cases of unresectable tumors, liver transplantation with pre- and/or postchemotherapy as a treatment option with reports of good outcomes and high rates of survival.^37, UNOS guidelines list nonmetastatic hepatoblastoma as a condition eligible for pediatric liver transplantation.^38,

Liver Retransplant for a Failed Liver Transplant

Clinical Context and Test Purpose

The purpose of a liver transplant for patients who have a failed liver transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a liver retransplant improve net health outcomes in individuals with a failed liver transplant?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with a failed liver transplant.

Interventions

The therapy being considered is a liver retransplant, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following practice is currently being used to make decisions about failed liver transplant: medical management.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to at 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Cohort Studies

Bellido et al (2012) reported on a retrospective cohort using registry data on 68 consecutive adults with liver retransplantations.^39, Survival estimates using Kaplan-Meier curves to compare 21 urgent with 47 elective retransplantations were calculated. OS rates were significantly better in patients undergoing urgent procedures (87%), which were mostly due to vascular complications, than elective procedures (76.5%), which were mostly related to chronic rejection. Remiszewski et al (2011) examined factors influencing survival outcomes in 43 liver retransplantation patients.^40, When compared with primary liver transplantation patients, retransplantation patients had significantly lower 6-year survival rates (80% vs 58%, respectively; p<0.001). The authors also reported low negative correlations between survival time and time from original transplantation until retransplantation and between survival time and patient age. Survival time and cold ischemia time showed a low positive correlation.

Hong et al (2011) reported on a prospective study of 466 adults to identify risk factors for survival after liver retransplantation.^41,Eight risk factors were identified as predictive of graft failure, including recipient age, MELD score greater than 27, more than 1 prior liver transplant, need for mechanical ventilation, serum albumin level of less than 2.5 g/dL, donor age older than 45 years, need for more than 30 units of packed red blood cells transfused intraoperatively, and time between prior transplantation and retransplantation of 15 to 180 days.

Section Summary: Liver Retransplant for a Failed Liver Transplant

Observational studies have evaluated the risk factors with a failed liver transplant for survival after liver retransplantation. Reported OS rates are lower after retransplantation than after initial liver transplantation but survival rates are acceptable in appropriately selected patients given the lack of treatment-related options.

Combined Liver-Kidney Transplantation

Clinical Context and Test Purpose

The purpose of a CLKT for patients who have indications for liver and kidney transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does a CLKT improve net health outcomes in individuals with indications for liver and kidney transplant?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with indications for liver and kidney transplant.

Interventions

The therapy being considered is a CLKT, which is provided in a hospital setting with specialized staff who are equipped to perform the surgical procedure and manage postsurgical intensive care.

Comparators

The following tools and practices are currently being used to make decisions about managing CLKT: medical management or single organ transplant.

Outcomes

The general outcomes of interest are OS and treatment-related adverse events (e.g., immunosuppression, graft failure, surgical complications, infections). Short-term follow-up ranges from immediate postsurgery to 30 days posttransplantation; lifelong follow-up (out to 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure. See the Potential Contraindications section for a detailed discussion.

Adults

In a retrospective study, Lunsford et al (2017) evaluated factors for renal failure in patients who underwent CLKT.^42, Of 145 patients who had CLKT, 30 (20.7%) had renal failure. Survival at 1 and 3 years in the CLKT group with renal failure (18.2% and 13.5%) was significantly worse than in CLKT patients without renal failure (92.6% and 83.7%, p<0.001). Multivariate predictors of renal failure were pretransplant dialysis duration (OR=2.43, p=0.008), kidney cold ischemia of more than 883 minutes (OR=3.43, p=0.011), kidney donor risk index (OR=1.96, p=0.012), and recipient hyperlipidemia (OR=3.50, p=0.028).

Fong et al (2012) evaluated data from the OPTN and UNOS database to compare outcomes of CLKT with liver transplantation alone for adults with cirrhosis and renal failure.^43, The analysis evaluated cirrhotic patients with serum creatinine levels of 2.5 mg/dL or higher or who had received dialysis at least twice during the week before liver transplantation. Between 2002 and 2008, 2774 patients had both liver and renal failure and received a liver transplant alone and 1501 patients underwent CLKT. Patients who received CLKT were more likely to be over 60 years of age, have minimal liver disease, and have been on dialysis. Patients in the combined transplant group were also not as sick, with fewer patients having a MELD score over 35 at listing, fewer being hospitalized before the transplant and fewer on life support. Liver and patient survival were higher in patients who received CLKT compared with liver transplant alone. At 5 years posttransplant, 67.4% of patients had survived in the CLKT arm compared with 62.9% in the liver alone arm (p<0.001). The liver allograft survival rate after 5 years was 65.3% in the CLKT arm and 58.9% in the liver transplantation alone (p<0.001). After adjusting for confounding factors, liver transplant alone remained a significant risk factor for liver allograft loss (HR=1.24; p=0.002) and mortality compared with CLKT transplantation (HR=1.16; p=0.043).

In a series of 74 CLKT procedures performed at a single institution over a 23-year period, Ruiz et al (2010) reported a 5-year survival rate of 62%.^44, However, in patients who had a second CLKT or liver retransplantation, survival was 30% at 3 months. This finding led to a recommendation not to perform CLKT in patients requiring liver retransplantation. There was no significant difference in survival between patients who were on hemodialysis pretransplantation and those who were not. However, survival in patients who required hemodialysis after transplantation was significantly worse (»30% at 5 years) than for patients who did not (»70%, p=0.001 over follow-up), and kidney graft survival was only 56% at 5 years.

Children

Calinescu et al (2014) evaluated CLKT outcomes in children using data from the Scientific Registry of Transplant Recipients from OPTN.^45, There were 152 primary CLKTs performed between 1987 and 2011. Liver graft survival was 72.6% at10years, and kidney graft survival was 66.9%. Patient survival at 10 years after CLKT was 78.9%. In comparison, patient survival following isolated liver transplantation during the same period was 77.4% (n=10084) and, for an isolated kidney transplant, 90% at 10 years (n=14800). Thus, CLKT resulted in survival outcomes that were no worse than liver transplant alone but were inferior to kidney transplant alone. Indications for CLKT were noted as primary hyperoxaluria and other liver-based metabolic abnormalities affecting the kidney, along with structural diseases affecting both the liver and kidney such as congenital hepatic fibrosis and polycystic kidney disease.

Some reports have suggested that liver transplantation may have a protective effect on kidney allografts. To test this hypothesis, de la Cerda et al (2010) evaluated kidney survival in children who had a kidney-only transplant or CLKT.^46, Examination of the OPTN/UNOS database between 1995 and 2005 identified 111 CLKTs and 3798 kidney-only transplants in children. The patients in the CLKT group were younger on average than those in the kidney-only group (9 years vs 12 years, p=0.007) and more had inherited disease as the primary cause (42% vs 28%), respectively. More patients in the CLKT group lost their kidney graft within 6 months (20.1% vs 5.9%, p=0.001); however, late kidney graft survival was significantly better at 5 years posttransplant compared with the kidney-only group (p<0.01). The authors described two situations when CLKT would be indicated in children: end-stage liver disease when the kidneys go into prolonged irreversible failure, and severe renal failure from an underlying disease that can be improved with a liver transplant.

Section Summary: CLKT

The evidence on CLKT includes mostly registry studies that have compared combined organ transplantation with liver or with kidney transplantation alone. In adults undergoing liver transplant with kidney failure, CLKT results in a modest improvement in patient survival compared with liver transplantation alone. Liver allograft survival was also higher in the patients who received CLKT compared with patients who received a liver transplant alone. Relatively few children have received CLKT. Patient survival has been reported to be worse with CLKT than with kidney transplantation alone but no worse than for liver transplant alone. For kidney grafts that survive the first six months, the organ survival rate may be better than for a kidney graft alone. Together, these results would suggest that CLKT is no worse, and possibly better, for graft and patient survival in adults and children who meet the requirements for liver transplantation and have concomitant renal failure. Indications for CLKT in children are rare and often congenital and include liver-based metabolic abnormalities affecting the kidney, along with structural diseases affecting both the liver and kidney.

Potential Contraindications (Applies to all previous indications)

Living Donor vs Deceased Donor Liver Transplant Recipient Outcomes

Due to the scarcity of donor organs and the success of living donation, living donor liver transplantation has become an accepted practice. The living donor undergoes hepatectomy of the right lobe, the left lobe, or the left lateral segment, which is then transplanted into the recipient. Because hepatectomy involves resection of up to 70% of the total volume of the donor liver, the safety of the donor has been a major concern. For example, the surgical literature suggests that right hepatectomy of the diseased or injured liver is associated with mortality rates of about 5%. However, reports have suggested that right hepatectomy in healthy donors has lower morbidity and mortality. Reports of several donor deaths have been reported.^47,48,49,50,

In December 2000, the National Institutes of Health convened a workshop focusing on living donor liver transplantation. Shiffman et al (2002) summarized this workshop.^51, According to their report, the risk of mortality to the donor undergoing right hepatectomy was estimated to be approximately 0.2% to 0.5%. The median complication rate reported by responding to transplant centers was 21%. Due to the potential morbidity and mortality experienced by the donor, the workshop also noted that donor consent for hepatectomy must be voluntary and free of coercion; therefore, it was preferable that the donor has a significant long-term and established a relationship with the recipient.

Criteria for a recipient of a living-related liver were also controversial, with some groups advocating that living-related donor livers be only used in those most critically ill, while others stated that the risk to the donor is unacceptable in critically ill recipients due to the increased risk of postoperative mortality of the recipient. According to this line of thought, living-related livers are best used in stable recipients who have a higher likelihood of achieving long-term survival.^51,

Grant et al (2013) reported on a systematic review and meta-analysis of 16 studies to compare recipient outcomes between living donor liver transplants and deceased donor liver transplants for HCC.^52, For DFS after living donor liver transplantation, the combined HR was 1.59 (95% CI, 1.02 to 2.49) compared with deceased donor liver transplantation. For OS, the combined HR was 0.97 (95% CI, 0.73 to 1.27). The studies included in the review were mostly retrospective and considered to be of low quality.

Human Immunodeficiency Virus-Positive Patients

Solid-organ transplant for patients who are HIV-positive was historically controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. HIV candidates for liver transplantation are frequently coinfected with hepatitis B or C, and viral coinfection can further exacerbate drug-related hepatotoxicities. Hepatitis is discussed below.

Cooper et al (2011) conducted a systematic review to evaluate liver transplantation in patients coinfected with HIV and hepatitis.^53, Reviewers included 15 cohort studies and 49 case series with individual patient data. The survival rate of patients was 84.4% (95% CI, 81.1% to 87.8%) at 12 months. Patients were 2.89 (95% CI, 1.41 to 5.91) times more likely to survive when HIV viral load at the time of transplantation was undetectable compared with those with detectable HIV viremia.

Terrault et al (2012) reported on a prospective, multicenter study to compare liver transplantation outcomes in 3 groups: patients with both hepatitis C virus (HCV) and HIV (n=89), patients with only HCV (n=235), and all transplant patients age 65 or older.^54, Patient and graft survival reductions were significantly associated with only one factor: HIV infection. At 3 years, in the HCV-only group, patient and graft survival rates were significantly better at 79% (95% CI, 72% to 84%) and 74% (95% CI, 66% to 79%), respectively, than the group with HIV and HCV coinfection at 60% (95% CI, 47% to 71%) and 53% (95% CI, 40% to 64%). While HIV infection reduced three-year survival rates after liver transplantation in patients coinfected with HCV, most patients still experienced long-term survival.

Current OPTN policy permits HIV-positive transplant candidates.^55,

The British HIV Association and the British Transplantation Society (2017) updated their guidelines on kidney transplantation in patients with HIV disease.^56, These criteria may be extrapolated to other organs:

• Adherent with treatment, particularly antiretroviral therapy
• Cluster of differentiation 4 count greater than 100 cells/mL (ideally >200 cells/mL) for at least 3 months
• Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months
• No opportunistic infections for at least six months
• No history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma.

Terrault et al (2012) also reported on the group of patients with HCV.^54, As reported above, HCV status was not significantly associated with reduced patient and graft survival.

Summary of Evidence

For individuals who have a hepatocellular disease who receive a liver transplant, the evidence includes case series, registry studies, and systematic reviews. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. Studies on liver transplantation for viral hepatitis have found that survival is lower than for other liver diseases. Although these statistics raise questions about the most appropriate use of a scarce resource (donor livers), the long-term survival rates are significant in a group of patients who have no other treatment options. Also, survival can be improved by the eradication of the hepatitis virus before transplantation. For patients with NASH, OS rates have been shown to be similar to other indications for liver transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have primary HCC who receive a liver transplant, the evidence includes systematic reviews of observational studies. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. In the past, long-term outcomes in patients with primary hepatocellular malignancies had been poor (19%) compared with the OS of liver transplant recipients. However, the recent use of standardized patient selection criteria (e.g., the Milan criteria diameter) has dramatically improved OS rates. In the appropriately selected patients, a liver transplant has been shown to result in higher survival rates than resection. In patients who present with unresectable organ-confined disease, transplant represents the only curative approach. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have extrahepatic cholangiocarcinoma who receive a liver transplant, the evidence includes systematic reviews of observational studies. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. For patients with extrahepatic (hilar or perihilar) cholangiocarcinoma who are treated with adjuvant chemotherapy, survival rates have been reported as high as 76%. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have intrahepatic cholangiocarcinoma who receive a liver transplant, the evidence includes registry studies. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. Five-year survival rates after liver transplantation in patients with cholangiocarcinoma are less than 30%. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have NETs who receive a liver transplant, the evidence includes systematic reviews of case series. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. In select patients with nonresectable, hormonally active liver metastases refractory to medical therapy, liver transplantation has been considered as an option to extend survival and minimize endocrine symptoms. While some centers may perform liver transplants on select patients with neuroendocrine tumors, the available studies are limited by their heterogeneous populations. Further studies are needed to determine the appropriate selection criteria. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have pediatric hepatoblastoma who receive a liver transplant, the evidence includes case series. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. The literature on liver transplantation for pediatric hepatoblastoma is limited but case series have demonstrated good outcomes and high rates of long-term survival. Additionally, nonmetastatic pediatric hepatoblastoma is among in United Network for Organ Sharing criteria for patients eligible for liver transplantation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a failed liver transplant who receive a liver retransplant, the evidence includes observational studies. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. Case series have demonstrated favorable outcomes with liver retransplantation in certain populations, such as when criteria for original liver transplantation are met for retransplantation. While some evidence has suggested outcomes after retransplantation may be less favorable than for initial transplantation in some patients, long-term survival benefits have been demonstrated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with indications for liver and kidney transplant who receive a CLKT, the evidence includes registry studies. The relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. Most of the evidence involves adults with cirrhosis and kidney failure. Indications for CLKT in children are rare and often congenital and include liver-based metabolic abnormalities affecting the kidney, along with structural diseases affecting both the liver and kidney. In both adults and children, comparisons with either liver or kidney transplantation alone would suggest that CLKT is no worse, and possibly better, for graft and patient survival. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from three physician specialty societies and five academic medical centers while this policy was under review. There was a consensus among reviewers that liver transplantation may be medically necessary for end-stage liver failure due to irreversibly damaged livers from various disease states such as those considered during the report update. There was also a consensus among reviewers that liver retransplantation is appropriate in patients with acute or chronic liver failure such as primary graft nonfunction, ischemic-type biliary injury after donation after cardiac death, hepatic artery thrombosis, chronic rejection or recurrent diseases such as primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis C resulting in end-stage liver failure. There was general support for the use of liver transplantation as a treatment for cholangiocarcinoma in patients who meet strict eligibility criteria. In general, there was no support for the use of liver transplantation for a neuroendocrine tumor metastatic to the liver.

Practice Guidelines and Position Statements

International Consensus Conference

The Milan criteria were recommended for use as the benchmark for patient selection, although it was suggested that the Milan criteria might be modestly expanded based on data from expansion studies that demonstrated outcomes are comparable with outcomes from studies using the Milan criteria. Candidates for liver transplantation should also have a predicted survival of five years or more. The consensus criteria indicate alpha-fetoprotein concentrations may be used with imaging to assist in determining patient prognosis.

Regarding liver retransplantation, the consensus criteria issued a weak recommendation for retransplantation after graft failure of a living donor transplant for hepatocellular carcinoma (HCC) in patients meeting regional criteria for a deceased donor liver transplant. A strong recommendation was issued against liver retransplantation with a deceased donor for graft failure for patients exceeding regional criteria. Also, the consensus criteria issued a strong recommendation that liver retransplantation for recurrent HCC would not be appropriate. However, a de novo case of HCC may be treated as a new tumor, and retransplantation may be considered even though data to support this is limited.

American Association for the Study of Liver Diseases et al

The American Association for the Study of Liver Diseases and the American Society of Transplantation (2013) issued joint guidelines on evaluating patients for a liver transplant.^57, These guidelines indicated liver transplantation for severe acute or advanced chronic liver disease after all effective medical treatments have been attempted. The formal evaluation should confirm the irreversible nature of the liver disease and lack of effective alternative medical therapy.

The guidelines also stated that liver transplant is indicated for the following conditions:

• Acute liver failure complications of cirrhosis
• Liver-based metabolic condition with systemic manifestations
  • α₁-Antitrypsin deficiency
  • Familial amyloidosis
  • Glycogen storage disease
  • Hemochromatosis
  • Primary oxaluria
  • Wilson disease
• Systemic complications of chronic liver disease.

• "Tobacco consumption should be prohibited in LT [liver transplant] candidates."
• "Patients with HIV infection are candidates for LT if immune function is adequate and the virus is expected to be undetectable by the time of LT."
• "LT candidates with HCV [hepatitis C virus] have the same indications for LT as for other etiologies of cirrhosis."

• "MELD [Model for End-stage Liver Disease] score < 15
• Severe cardiac or pulmonary disease
• AIDS
• Ongoing alcohol or illicit substance abuse
• Hepatocellular carcinoma with metastatic spread
• Uncontrolled sepsis
• Anatomic abnormality that precludes liver transplantation
• Intrahepatic cholangiocarcinoma\
• Extrahepatic malignancy
• Fulminant hepatic failure
• Hemangiosarcoma
• Persistent noncompliance
• Lack of adequate social support system."

National Comprehensive Cancer Network

The NCCN guidelines on hepatobiliary cancers (v.2.2019) recommend referral to a liver transplant center or bridge therapy for patients with HCC meeting United Network of Organ Sharing criteria of a single tumor measuring 2 to 5 cm, or 2 to 3 tumors 3 cm or less with no macrovascular involvement or extrahepatic disease.^59, Patients should be referred to the transplant center. Patients should be referred to the transplant center before the biopsy. In patients who are ineligible for transplant and in select patients with Child-Pugh class A or B liver function with tumors that are resectable, the NCCN indicates resection is the preferred treatment option; locoregional therapy may also be considered. Patients with unresectable HCC should be evaluated for liver transplantation; if the patient is a transplant candidate, then referral to a transplant center should be given or bridge therapy should be considered. The NCCN guidelines on hepatobiliary cancers also indicate that. These are level 2A recommendations based on lower-level evidence and uniform consensus.

The NCCN guidelines on neuroendocrine tumors (v.1.2019) indicate that liver transplantation for neuroendocrine liver metastases is considered investigational despite "encouraging" 5-year survival rates.^60,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03500315	HOPE in Action Prospective Multicenter, Clinical Trial of Deceased HIVD+ Kidney Transplants for HIV+ Recipients	360	Aug 2022
NCT02878473	Liver Transplantation for the Treatment of Early Stages of Intrahepatic Cholangiocarcinoma in Cirrhotics	30	Jan 2029

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Liver Transplant and Combined Liver-Kidney Transplant
Liver Transplant
Liver Transplantation
Transplant, Liver
Transplantation, Liver
Liver-Kidney Transplant
Combined Liver-Kidney Transplant

References:
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2. Belle SH, Beringer KC, Detre KM. An update on liver transplantation in the United States: recipient characteristics and outcome. Clin Transpl. Jan 1995:19-33. PMID 8794252.

3. Sheiner P, Rochon C. Recurrent hepatitis C after liver transplantation. Mt Sinai J Med. Mar-Apr 2012;79(2):190- 198. PMID 22499490.

4. Mukherjee S, Sorrell MF. Controversies in liver transplantation for hepatitis C. Gastroenterology. May 2008;134(6):1777-1788. PMID 18471554.

5. Wang X, Li J, Riaz DR, et al. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. Mar 2014;12(3):394-402.e391. PMID 24076414.

6. Cholankeril G, Wong RJ, Hu M, et al. Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes. Dig Dis Sci. Jul 25 2017;62(10):2915-2922. PMID 28744836.

7. Schoenberg MB, Bucher JN, Vater A, et al. Resection or transplant in early hpatocellular carcinoma. Dtsch Arztebl Int. 2017 114(31-32):519-526. PMID 28835324.

8. Zheng Z, Liang W, Milgrom DP, et al. Liver transplantation versus liver resection in the treatment of hepatocellular carcinoma: a meta-analysis of observational studies. Transplantation. Jan 27 2014;97(2):227-234. PMID 24142034.

9. Guiteau JJ, Cotton RT, Washburn WK, et al. An early regional experience with expansion of Milan Criteria for liver transplant recipients. Am J Transplant. Sep 2010;10(9):2092-2098. PMID 20883543.

10. Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. Mar 2010;16(3):262-278. PMID 20209641.

11. Ioannou GN, Perkins JD, Carithers RL, Jr. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology. May 2008;134(5):1342-1351. PMID 18471511.

12. Chan EY, Larson AM, Fix OK, et al. Identifying risk for recurrent hepatocellular carcinoma after liver transplantation: implications for surveillance studies and new adjuvant therapies. Liver Transpl. Jul 2008;14(7):956-965. PMID 18581511.

13. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. Mar 14 1996;334(11):693-699. PMID 8594428.

14. Firl DJ, Kimura S, McVey J, et al. Reframing the approach to patients with hepatocellular carcinoma: Longitudinal assessment with HALTHCC improves ablate and wait strategy. Hepatology. Mar 31 2018. PMID 29604231.

15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 2.2018. British Transplantation Society. Accessed July 30, 2018.

16. Yadav DK, Chen W, Bai X, et al. Salvage Liver Transplant versus Primary Liver Transplant for Patients with Hepatocellular Carcinoma. Ann Transplant. 2018 Aug 3;23:524-545. PMID: 30072683.

17. Murali AR, Patil S, Phillips KT, et al. Locoregional therapy with curative intent versus primary liver transplant for hepatocellular carcinoma: systematic review and meta-analysis. Transplantation. Jan 2017 101(8):e249-e257. PMID 28282359.

18. Maggs JR, Suddle AR, Aluvihare V, et al. Systematic review: the role of liver transplantation in the management of hepatocellular carcinoma. Aliment Pharmacol Ther. May 2012;35(10):1113-1134. PMID 22432733.

19. Chan DL, Alzahrani NA, Morris DL, et al. Systematic review of efficacy and outcomes of salvage liver transplantation after primary hepatic resection for hepatocellular carcinoma. J Gastroenterol Hepatol. Jan 2014;29(1):31-41. PMID 24117517.

20. Zhu Y, Dong J, Wang WL, et al. Short- and long-term outcomes after salvage liver transplantation versus primary liver transplantation for hepatocellular carcinoma: a meta-analysis. Transplant Proc. Nov 2013;45(9):3329-3342. PMID 24182812.

21. Gu J, Bai J, Shi X, et al. Efficacy and safety of liver transplantation in patients with cholangiocarcinoma: a systematic review and meta-analysis. Int J Cancer. May 1 2012;130(9):2155-2163. PMID 21387295.

22. Heimbach JK. Successful liver transplantation for hilar cholangiocarcinoma. Curr Opin Gastroenterol. May 2008;24(3):384-388. PMID 18408469.

23. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. Jul 2012;143(1):88-98.e83; quiz e14. PMID 22504095.

24. Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation. Dec 27 2006;82(12):1703-1707. PMID 17198263.

25. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. Sep 2005;242(3):451-458; discussion 458-461. PMID 16135931.

26. Pascher A, Jonas S, Neuhaus P. Intrahepatic cholangiocarcinoma: indication for transplantation. J Hepatobiliary Pancreat Surg. Nov 2003;10(4):282-287. PMID 14598146.

27. Friman S, Foss A, Isoniemi H, et al. Liver transplantation for cholangiocarcinoma: selection is essential for acceptable results. Scand J Gastroenterol. Mar 2011;46(3):370-375. PMID 21073376.

28. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. Apr 27 2000;69(8):1633-1637. PMID 10836374.

29. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg. Feb 2004;239(2):265-271. PMID 14745336.

30. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg. Nov 1997;185(5):429-436. PMID 9358085.

31. Fan ST, Le Treut YP, Mazzaferro V, et al. Liver transplantation for neuroendocrine tumour liver metastases. HPB (Oxford). Jan 2015;17(1):23-28. PMID 24992381.

32. Mathe Z, Tagkalos E, Paul A, et al. Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: a survival-based analysis. Transplantation. Mar 15 2011;91(5):575-582. PMID 21200365.

33. Hamilton EC, Balogh J, Nguyen DT, et al. Liver transplantation for primary hepatic malignancies of childhood: The UNOS experience. J Pediatr Surg. 2017 3468(17):30657-30657. PMID 29108844.

34. Barrena S, Hernandez F, Miguel M, et al. High-risk hepatoblastoma: results in a pediatric liver transplantation center. Eur J Pediatr Surg. Jan 2011;21(1):18-20. PMID 20938901.

35. Malek MM, Shah SR, Atri P, et al. Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. Surgery. Oct 2010;148(4):778-782; discussion 782-774. PMID 20728194.

36. Browne M, Sher D, Grant D, et al. Survival after liver transplantation for hepatoblastoma: a 2-center experience. J Pediatr Surg. Nov 2008;43(11):1973-1981. PMID 18970927.

37. Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer. May 2005;41(7):1031-1036. PMID 15862752.

38. Organ Procurement and Transplantation Network (OPTN). Policy 9: Allocation of Livers and Liver-Intestines. 2018; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_01. Accessed July 30, 2018.

39. Bellido CB, Martinez JM, Artacho GS, et al. Have we changed the liver retransplantation survival? Transplant Proc. Jul 2012;44(6):1526-1529. PMID 22841203.

40. Remiszewski P, Kalinowski P, Dudek K, et al. Influence of selected factors on survival after liver retransplantation. Transplant Proc. Oct 2011;43(8):3025-3028. PMID 21996216.

41. Hong JC, Kaldas FM, Kositamongkol P, et al. Predictive index for long-term survival after retransplantation of the liver in adult recipients: analysis of a 26-year experience in a single center. Ann Surg. Sep 2011;254(3):444-448; discussion 448-449. PMID 21817890.

42. Lunsford KE, Bodzin AS, Markovic D, et al. Avoiding futility in simultaneous liver-kidney transplantation: analysis of 331 consecutive patients listed for dual organ replacement. Ann Surg. May 2017;265(5):1016-1024. PMID 27232249.

43. Fong TL, Khemichian S, Shah T, et al. Combined liver-kidney transplantation is preferable to liver transplant alone for cirrhotic patients with renal failure. Transplantation. Aug 27 2012;94(4):411-416. PMID 22805440.

44. Ruiz R, Jennings LW, Kim P, et al. Indications for combined liver and kidney transplantation: propositions after a 23-yr experience. Clin Transplant. Nov-Dec 2010;24(6):807-811. PMID 20002463.

45. Calinescu AM, Wildhaber BE, Poncet A, et al. Outcomes of combined liver-kidney transplantation in children: analysis of the scientific registry of transplant recipients. Am J Transplant. Dec 2014;14(12):2861-2868. PMID 25274400.

46. de la Cerda F, Jimenez WA, Gjertson DW, et al. Renal graft outcome after combined liver and kidney transplantation in children: UCLA and UNOS experience. Pediatr Transplant. Jun 2010;14(4):459-464. PMID 20070563.

47. Marcos A, Ham JM, Fisher RA, et al. Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe. Liver Transpl. May 2000;6(3):296-301. PMID 10827229.

48. Malago M, Testa G, Marcos A, et al. Ethical considerations and rationale of adult-to-adult living donor liver transplantation. Liver Transpl. Oct 2001;7(10):921-927. PMID 11679994.

49. Renz JF, Busuttil RW. Adult-to-adult living-donor liver transplantation: a critical analysis. Semin Liver Dis. Feb 2000;20(4):411-424. PMID 11200412.

50. Bak T, Wachs M, Trotter J, et al. Adult-to-adult living donor liver transplantation using right-lobe grafts: results and lessons learned from a single-center experience. Liver Transpl. Aug 2001;7(8):680-686. PMID 11510011.

51. Shiffman ML, Brown RS, Jr., Olthoff KM, et al. Living donor liver transplantation: summary of a conference at The National Institutes of Health. Liver Transpl. Feb 2002;8(2):174-188. PMID 11862598.

52. Grant RC, Sandhu L, Dixon PR, et al. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant. Jan-Feb 2013;27(1):140-147. PMID 23157398.

53. Cooper C, Kanters S, Klein M, et al. Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with synthetic cohort. AIDS. Mar 27 2011;25(6):777-786. PMID 21412058.

54. Terrault NA, Roland ME, Schiano T, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. Jun 2012;18(6):716-726. PMID 22328294.

55. Organ Procurement and Transplantation Network (OPTN). Organ Procurement and Transplantation Network Policies. 2018; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed July 30, 2018.

56. Working Party of the British Transplantation Society. Kidney and Pancreas Transplantation in Patients with HIV. Second Edition (Revised). British Transplantation Society Guidelines. Macclesfield, UK: British Transplantation Society; 2017.

57. American Association for the Study of Liver Diseases, American Society of Transplantation. Liver transplantation, evaluation of the adult patient. 2013; https://www.aasld.org/publications/practice-guidelines-0. Accessed July 30, 2018.

58. Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. Jul 2014;60(1):362-398. PMID 24782219.

59. National Comprehensive Cancer Network. Hepatobiliary Cancers. Version 2.2019. https://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed 25 June 2019.

60. National Comprehensive Cancer Network. Neuroendocrine and Adrenal Tumors. Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed 25 June 2019.

61. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Adult Liver Transplantation (260.1). 2012; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCAId=259&NcaName=Liver+Transplantation+for+Malignancies&ExpandComments=n&Comment Period=0&NCDId=70&ncdver=3&id=186&bc=gABAAAAAEEAAAA%3D%3D&. Accessed July 27, 2018.

62. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Pediatric Liver Transplantation (260.2). 1991; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?MCDId=17&ExpandComments=n&McdName=Clinical+Pharmacology+Compendium+Revision+Re quest+-+CAG- 00392&mcdtypename=Compendia&MCDIndexType=6&NCDId=71&ncdver=1&bc=AgAEAAAAAgAA&. Accessed July 27, 2018.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

47133
47135
47140
47141
47142
47143
47144
47145
47146
47147

Combined liver-kidney transplant would be reported with the codes in this policy along with the codes in the kidney transplant policy (Policy #087 in the Surgery Section)