Liver Transplant and Combined Liver-Kidney Transplant - CAM 70306

Description:
Liver transplantation is currently the treatment of last resort for patients with end-stage liver disease. Liver transplantation may be performed with a 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 the Organ Procurement and Transplantation Network and the United Network of Organ Sharing. The severity of illness is determined by the Model for End-stage Liver Disease and Pediatric End-stage Liver Disease scores..

Additional Information
In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers while this policy was under review in 2012. 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. Liver transplant is an accepted treatment of end-stage liver disease that provides a survival benefit in appropriately selected patients and may be considered medically necessary for the indications listed in the Policy section and inpatients otherwise meeting United Network of Organ Sharing criteria. Liver transplantation is investigational in patients in whom the procedure is expected to be futile due to comorbid disease or in whom post-transplantation care is expected to worsen comorbid conditions significantly. Based on survival data, transplantation in patients with hilar cholangiocarcinoma who meet strict eligibility criteria may be considered medically necessary; transplantation for neuroendocrine tumors metastatic to the liver is considered investigational. Clinical vetting supported retransplantation following primary graft nonfunction, hepatic artery thrombosis, ischemic biliary injury after donation after cardiac death, chronic rejection, or certain recurrent non-neoplastic diseases resulting in end-stage liver failure in a primary transplant. As a result, retransplantation after initially failed liver transplant may be considered medically necessary in these situations.

Background
Solid organ transplantation offers a treatment option for patients with different types of end stage organ failure that can be lifesaving or provide significant improvements to a patient’s quality of life.¹ Many advances have been made in the last several decades to reduce perioperative complications. Available data supports improvement in long-term survival as well as improved quality of life particularly for liver, kidney, pancreas, heart, and lung transplants. Allograft rejection remains a key early and late complication risk for any organ transplantation. Transplant recipients require life-long immunosuppression to prevent rejection. 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.

Liver transplantation
Liver transplantation is 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. Certain populations are prioritized as Status 1A (e.g., acute liver failure with a life expectancy of fewer than 7 days without a liver transplant) or Status 1B (pediatric patients with chronic liver disease). Following Status 1, donor livers are prioritized to those with the highest scores on the Model for End-stage Liver Disease (MELD) and Pediatric End-stage Liver Disease (PELD) scales. 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 2 segments that can be used for 2 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.

Regulatory Status
Solid organ transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA).

The FDA 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. Solid organs used for transplantation are subject to these regulations.

Related Policies
70305 Small Bowel/Liver and Multivisceral Transplant

Policy:
A liver transplant using a cadaver or living donor may be considered MEDICALLY NECESSARY for carefully selected patients 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
α1-Antitrypsin deficiency
Hemochromatosis
Nonalcoholic steatohepatitis
Protoporphyria
Wilson's 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 creiteria)

E. Inborn errors of metabolism

F. Trauma and toxic reactions

G. Miscellaneous

Familial amyloid polyneuropathy

Liver transplantation may be considered MEDICALLY NECESSARY in patients with polycystic disease of the liver who have massive hepatomegaly causing obstruction or functional impairment.

Liver transplantation may be considered MEDICALLY NECESSARY in patients with unresectable hilar cholangiocarcinoma (see Policy Guidelines for patient selection criteria).

Liver transplantation may be considered MEDICALLY NECESSARY in pediatric patients with nonmetastatic hepatoblastoma.

Liver retransplantation may be considered MEDICALLY NECESSARY in patients with:

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.

Combined liver-kidney transplantation may be considered MEDICALLY NECESSARY in patients who qualify for liver transplantation and have advanced irreversible kidney disease.

Liver transplantation is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY in the following situations::

Patients with intrahepatic cholangiocarcinoma
Patients with neuroendocrine tumors metastatic to the liver

Liver transplantation is considered NOT MEDICALLY NECESSARY in the following patients:

Patients with hepatocellular carcinoma that has extended beyond the liver (see Policy Guidelines section for patient selection criteria)
Patients 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.)

Liver transplantation is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY in all other situations not described above.

Policy Guidelines:
Contraindications
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 diseases 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.

Liver-Specific Criteria
The Model for End-stage Liver Disease (MELD) and Pediatric End-stage Liver Disease (PELD) scores range from 6 (less ill) to 40 (gravely ill). The MELD and PELD scores will change during a patient's tenure on the waiting list.

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.

Patients with familial amyloid polyneuropathy do not experience liver disease per se, but develop polyneuropathy and cardiac amyloidosis due to the production of a variant transthyretin molecule by the liver. MELD and PELD exception criteria and scores may apply to these cases. Candidacy for liver transplant is an individual consideration based on the morbidity of the polyneuropathy. Many patients may not be candidates for liver transplant alone due to coexisting cardiac disease.

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.

Living Donor Criteria
Donor morbidity and mortality are prime concerns in donors undergoing right lobe, left lobe, or left lateral segment donor partial hepatectomy as part of living donor liver transplantation. Partial hepatectomy is a technically demanding surgery, the success of which may be related to the availability of an experienced surgical team. The American Society of Transplant Surgeons proposed the following guidelines for living donors (American Society of Transplant Surgeons: Ethics Committee. American Society of Transplant Surgeons' position paper on adult-to-adult living donor liver transplantation. Liver Transplant. 2000;6(6):815-817. PMID 11084076):

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.

Combined liver-kidney transplant would be reported with the codes in this policy along with the codes in the evidence review on kidney transplant (70301).

Benefit Application
BlueCard/National Account Issues
Liver transplants should be considered for coverage under the transplant benefit.

What is covered under the scope of the human organ transplant (HOT) benefit needs to be considered. Typically, the following are covered under the HOT benefit:

Hospitalization of the recipient for medically recognized transplants from a donor to a transplant recipient
Pre-hospital workup and hospitalization of a living donor undergoing a partial hepatectomy should be considered as part of the recipient transplant costs
Evaluation tests requiring hospitalization to determine the suitability of both potential and actual donors, when such tests cannot be safely and effectively performed on an outpatient basis
Hospital room, board and general nursing in semi-private rooms
Special care units, such as coronary and intensive care
Hospital ancillary services
Physicians’ services for surgery, technical assistance, administration of anesthetics, medical care
Acquisition, preparation, transportation and storage of organ
Diagnostic services
Drugs that require a prescription by federal law

Expenses incurred in the evaluation and procurement of organs and tissues are benefits when billed by the hospital. Included in these expenses may be specific charges for participation with registries for organ procurement, operating rooms, supplies, use of hospital equipment and transportation of the tissue or organ to be evaluated.

Administration of products with a specific transplant benefit needs to be defined as to:

When the benefit begins (at the time of admission for the transplant or once the patient is determined eligible for a transplant, which may include tests or office visits prior to transplant).
When the benefit ends (at the time of discharge from the hospital or at the end of required follow-up, including the immunosuppressive drugs administered on an outpatient basis).

Coverage usually is not provided for:

HOT services, for which the cost is covered/funded by governmental, foundational or charitable grants.
Organs sold rather than donated to the recipient.
An artificial organ.

Rationale
This evidence review was created in December 1995 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 27, 2022.

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, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 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 (RCT) 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 Therapy 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 evidence review is: Does a liver transplant improve the net health outcome in individuals with hepatocellular disease?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with a hepatocellular disease, such as viral hepatitis or nonalcoholic steatohepatitis (NASH).

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 NASH do not abuse alcohol.

Interventions
The therapy being considered is a liver transplant.

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 post-surgery to 30 days post-transplantation; lifelong follow-up (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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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, who are not treated pretransplant, has been nearly universal, and 10% to 20% of patients will develop cirrhosis within 5 years.³

Historical data demonstrating inferior survival in transplant recipients with HCV is not applicable to the current treatment landscape with the availability of direct acting antiviral agents, which are associated with sustained virological response rates over 95%.⁴ Timing the receipt of direct acting antiviral agents either before or after transplantation is still controversial and the decision should be individualized based the presence of compensated/decompensated disease, Model for End-Stage Liver Disease (MELD) score, current quality of life, and the proportion of HCV-positive donors in the local and regional areas.

Nonalcoholic Steatohepatitis
Systematic Reviews
Liver transplantation is a treatment option for patients with 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 = .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 = .05) and sepsis (OR, 1.71; 95% CI, 1.17 to 2.50; p = .006) than non-NASH-related liver transplant patients.

Yong et al. (2021) presented an updated meta-analysis and systematic review analyzing 15 studies of 119,327 patients who received liver transplants.⁶ The pooled prevalence of NASH across studies was 20.2%. The pooled 1-, 5-, and 10-year all-cause mortality in NASH patients after liver transplant were 12.5%, 24.4%, and 37.9%, respectively. Overall survival was comparable between liver transplant recipients with NASH versus non-NASH (hazard ratio [HR], 0.91; 95% CI, 0.76 to 1.10; p = .34). There was no significant difference between patients with NASH or without NASH for all secondary outcomes, including infection rates, biliary complications, cardiovascular disease events, cardiac failure, cerebrovascular accident, and length of stay. Additionally, there were no significant differences in graft survival between patients who underwent liver transplantation for NASH versus non-NASH (n = 6 studies; HR, 0.95; 95% CI, 0.88 to 1.03; p = .20). Meta-regression demonstrated that a higher MELD score was associated with significantly worse overall survival in patients with NASH compared to patients without NASH after liver transplantation (95% CI, -0.0856 to -0.0181; p = .0026). There was no evidence of publication bias from the funnel plot conducted. This analysis is limited by large heterogeneity between studies, and a lack of information on donor quality to fully explore the association between higher MELD scores and early versus late mortality for NASH patients with liver transplantation.

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.⁷ In all, 63,061 patients underwent liver transplant from 2003 to 2014. Nonalcoholic steatohepatits 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 HCV (72.15%; 95% CI, 71.37 to 72.93; p < .001). Patients with NASH also demonstrated significantly higher posttransplant survival than patients with hepatitis C (HR, 0.75; 95% CI, 0.71 to 0.79; p < .001).

Section Summary: Liver Transplant for Hepatocellular Disease
The evidence on liver transplantation for a hepatocellular disease includes 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 Therapy Purpose
The purpose of a liver transplant for patients who have hepatocellular carcinoma (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 evidence review is: Does a liver transplant improve net health outcomes in individuals with HCC?

The following PICO was used to select literature to inform this review.

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

Interventions
The therapy being considered is a liver transplant.

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 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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Liver Transplantation Versus Liver Resection for Hepatocellular Carcinoma
Systematic Reviews
Schoenberg et al. (2017) published a systematic review and meta-analysis of 54 retrospective studies (N = 13,794) comparing liver resection (n = 7,990) with transplantation (n = 5,804) in patients with HCC.⁸ At 1-year follow-up, survival rates were higher in those receiving resection than in those receiving liver transplant (86.17% vs 80.58%; OR, 1.19; 95% CI, 0.99 to 1.43; p = .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 < .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 = .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 < .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 (N = 10,170 ) comparing liver transplantation with liver resection for HCC.⁹ Overall 1-year survival was similar between procedures (OR, 1.08; 95% CI, 0.81 to 1.43; p = .61). However, overall 3- (OR, 1.47; 95% CI, 1.18 to 1.84; p < .001) and 5-year survival (OR, 1.77; 95% CI, 1.45 to 2.16; p < .001) significantly favored liver transplantation over resection. 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 < .001). Recurrence rates were also 30% lower in liver transplantation than resection (OR, 0.20; 95% CI, 0.15 to 0.28; p < .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 4.¹⁰ 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 4 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.¹¹

Ioannou et al. (2008) analyzed UNOS data pre- and postadoption of the 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.¹² The subgroup of patients with larger (3 to 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.¹³ 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 1 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 2 validation cohorts.

Mazzafaro et al (1996) identified patient criteria associated with improved outcomes after liver transplantation for HCC with cirrhosis.¹⁴ 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 3 tumors 3 cm or less. Patients with extrahepatic spread or macrovascular invasion have a poor prognosis. The 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.¹⁵ 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.¹⁶ 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 and primary liver transplant for individuals with HCC.¹⁷ Twenty retrospective studies (10 of which were also included in Murali et al. [2017]) with a total of 9,879 patients were included in the analysis. One-year OS was better for salvage liver transplant (74.30%) than primary liver transplant (77.01%, OR, 0.86; 95% CI, 0.75 to 0.98; p = .03). Salvage liver transplant also had higher 3-year (55.69% and 59.07%, respectively; OR, 0.85; 95% CI, 0.76 to 0.96; p = .01) and 5-year OS (48.67% and 52.32%, respectively; OR, 0.85; 95% CI, 0.76 to 0.96; p = .009) than primary liver transplant. One-year (OR, 0.86; 95% CI, 0.75 to 0.99; p = .03), 3-year (OR, 0.56; 95% CI, 0.39 to 0.81; p = .002), and 5-year DFS (OR, 0.75; 95% CI, 0.66 to 0.86; p < .001) were worse for primary liver transplant (70.03%, 74.08%, and 47.09%, respectively) than for salvage liver transplant (67.69%, 57.02%, and 41.27%, respectively). There was no significant difference between the 2 groups for postoperative biliary complications (p = .19) or sepsis (p = .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 to those who received a liver transplant, stratified by liver disease stage, the extent of cancer, and whether salvage liver transplant was offered.¹⁸ Among the 48 studies selected, 9835 patients were analyzed. For all categories of locoregional therapy with curative intent 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 < .01). Intention-to-treat analysis showed no significant difference in 5-year OS (OR, 1.0; 95% CI, 0.6 to 1.7) between locoregional therapy with curative intent followed by salvage liver transplant when salvage liver transplant was offered after locoregional therapy with curative intent, though noninferiority could not be shown. Only 32.5% of patients with HCC after locoregional therapy with curative intent received salvage liver transplant because the rest were medically ineligible. Disease free survival was worse with locoregional therapy with curative intent and salvage liver transplant 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.¹⁹

Chan et al. (2014) systematically reviewed 16 nonrandomized studies (N = 319 patients) assessing salvage liver transplant after primary hepatic resection for HCC.²⁰ Reviewers found that OS and DFS outcomes with salvage liver transplant were similar to reported primary liver transplantation outcomes. Median OS rates for salvage liver transplant patients were 89%, 80%, and 62% at 1, 3, and 5 years, respectively. Disease free survival rates were 86%, 68%, and 67% at 1, 3, and 5 years, respectively. Salvage liver transplant studies had a median OS rate of 62% (range, 41% to 89%) compared with a range of 61% to 80% in the literature for primary liver transplantation. The median DFS rate for salvage liver transplant was 67% (range, 29% to 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 = 1,272 for primary transplant, n = 236 for salvage).²¹ Disease-free survival, 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 = .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 salvage liver transplant might be a viable option in these patients.

Section Summary: Liver Transplant for Hepatocellular Carcinoma
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 3 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 Extrahepatic Cholangiocarcinoma (Hilar or Perihilar)
Clinical Context and Therapy Purpose
The purpose of a liver transplant for patients who have extrahepatic cholangiocarcinoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with extra hepatic cholangiocarcinoma.

Interventions
The therapy being considered is a liver transplant.

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 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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Cambridge et al. (2021) reported on a systematic review and meta-analysis/meta-regression of 20 observational studies (N = 428) on orthotopic liver transplantation for unresectable perihilar cholangiocarcinoma.²² Pooled 1- (n = 265), 3- (n = 240), and 5-year (n = 309) survival rates were 76.9% (95% CI, 69.5 to 83.5 ), 55.3% (95% CI, 43.7 to 66.5 ), and 44.9% (95% CI, 31.4 to 58.8 ), respectively. In patients who received neoadjuvant chemoradiation, 1- (n = 109), 3- (n = 89), and 5-year (n = 210) pooled survival rates improved to 82.8% (95% CI, 73 to 90.8 ), 65.5% (95% CI, 48.7 to 80.5 ), and 65.1% (95% CI, 55.1 to 74.5 ), respectively.

Gu et al. (2012) reported on a systematic review and meta-analysis of 14 clinical trials on liver transplantation for cholangiocarcinoma.²³ 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.²⁴ 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.

Observational Studies
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).²⁵ 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 < .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).^26,27 Unresectable patients underwent neoadjuvant radiochemotherapy. The 1-year survival rate was 91%, and the 5-year survival rate was 76% (see Table 2).

Populations With Extrahepatic or Mixed Cholangiocarcinoma
Systematic Reviews
Data from the European Liver Transplant Registry was assessed in a review article by Pascher et al. (2003).²⁸ In 169 patients with extrahepatic cholangiocarcinoma, the probabilities for 1- and 5-year survival 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%.

Observational Studies
Studies on hepatic cholangiocarcinoma are described in Tables 1 and 2.

Friman et al. (2011) reported on 53 patients who received liver transplants for cholangiocarcinoma from 1984 to 2005, in Norway, Sweden, and Finland.²⁹ 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% versus 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 level of 100 or less.

Meyers et al. (2000) reported on data from 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%.³⁰ In a multicenter study, Robles et al. (2004) reported on 36 patients with hilar tumors and 23 with peripheral intrahepatic disease.³¹ One-year survival was 82% and 77%, while 5-year survival was 30% and 23% for those with hilar tumors compared with peripheral intrahepatic disease, respectively.

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

Study	Country	Participants	Treatment	Follow-Up, years
Darwish Murad et al. (2012)²⁵	U.S.	287	Liver transplant	5
Friman et al. (2011)²⁹	Norway, Sweden, Finland	53	Liver transplant	5
Heimbach et al. (2006)²⁶; Rea et al. (2005)²⁷	U.S.	65	Liver transplant	5
Robles et al. (2004)³¹	Spain	59	Liver transplant	5
Meyer et al. (2000)³⁰	U.S.	207	Liver transplant	5
Casavilla et al. (1997)³²	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)²⁵	Liver transplant	EH perihilar			53
Heimbach et al. (2006)²⁶; Rea et al. (2005)²⁷	Liver transplant	EH perihilar	91		76
Meyer et al. (2000)³⁰^,^a	Liver transplant	IH/EH	72		23
Robles et al. (2004)^31,^b	Liver transplant	EH hilar	82	53	30
		IH	77	65	23
Casavilla et al. (1997)³²	Liver transplant	IH	70	29	18
Friman et al. (2011)²⁹^,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.

Section Summary: Liver Transplant for Extrahepatic Cholangiocarcinoma
The evidence on liver transplantation in patients with extrahepatic (hilar or perihilar) cholangiocarcinoma includes registry studies and systematic reviews of observational studies. For patients with extrahepatic cholangiocarcinoma treated with a liver transplant and adjuvant chemotherapy, 5-year survival rates have been reported to be as high as 76%.

Liver Transplant for Intrahepatic Cholangiocarcinoma
Clinical Context and Therapy Purpose
The purpose of a liver transplant for patients who have intrahepatic cholangiocarcinoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with intrahepatic cholangiocarcinoma.

Interventions
The therapy being considered is a liver transplant.

Comparators
The following practice is currently being used to make decisions about managing intrahepatic 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 10 years or more given current survival data) is necessary due to ongoing immunosuppression and risk of graft failure.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis conducted by Ziogas et al. (2021) pooled available data to assess liver transplantation for intrahepatic cholangiocarcinoma.³³ They included 18 studies with 355 patients, including Casavilla et al. (1997) and Friman et al. (2011), noted below, and a registry study of 385 patients. The pooled 1-, 3-, and 5-year OS rates were 75% (95% CI, 64 to 84), 56% (95% CI, 46 to 67), and 42% (95% CI, 29 to 55), respectively. The pooled 1-, 3-, and 5-year recurrence-free survival rates were 70% (95% CI, 63 to 75), 49% (95% CI, 41 to 57), and 38% (95% CI, 27 to 50), respectively. Cirrhosis was positively associated with recurrence-free survival but incidental diagnosis was not. The pooled overall recurrence rate was 42% (95% CI, 33 to 53) over a mean follow-up of 40.6 + 37.7 months. Patients with very early (single < 2 cm) intrahepatic cholangiocarcinoma exhibited superior pooled 5-year recurrence-free survival (67%; 95% CI, 47 to 86) versus advanced intrahepatic cholangiocarcinoma (34%; 95% CI, 23 to 46). This study is limited by the retrospective nature of the articles included and the potential presence of publication bias regarding the pooled OS data.

Observational Studies
Hue et al. (2020) used registry data from the National Cancer Database to compare outcomes among patients with intrahepatic cholangiocarcinoma who received liver transplantation (n = 74) to those who received surgical resection of the liver (n = 1,879).³⁴ Median OS was not significantly different when comparing patients who received liver resection versus those who received a liver transplant, respectively, at 1- (82.6% vs 89.4%), 3- (50.2% vs 53%), or 5-years (33% vs 40.8%) posttransplant; the overall median survival was 36.1 months in both groups (p = .34). Length of stay and unplanned 30-day readmission rates were also similar between groups (p = .11 and.18, respectively). These differences all remained nonsignificant in a propensity score matched analysis (n = 57 patients in each group).

One additional observational study reported on survival rates for 54 patients with intrahepatic cholangiocarcinoma.³² Survival rates at 1-, 3-, and 5-years posttransplant were reported to be 70%, 29%, and 18%, respectively. In studies of mixed populations of patients with extrahepatic or intrahepatic cholangiocarcinoma (see Tables 1 and 2 above), a single study reported a 1-year survival rate of 72%.³⁰ Five-year survival rates ranged between 23% and 25% in 2 studies.^30,29

Section Summary: Liver Transplant for Intrahepatic Cholangiocarcinoma
The evidence on liver transplantation in patients with intrahepatic cholangiocarcinoma includes registry studies and a systematic review of observational studies. In a registry study comparing outcomes in patients with intrahepatic cholangiocarcinoma who received liver transplantation to those who received surgical resection of the liver, no differences were found in OS, length of stay, or unplanned 30-day readmission rates between groups. Additional studies reporting survival rates in patients with intrahepatic cholangiocarcinoma or in mixed populations of patients with extrahepatic and intrahepatic cholangiocarcinoma have reported 5-year survival rates of less than 30%.

Liver Transplant for Individuals with Metastatic Neuroendocrine Tumors
Clinical Context and Therapy Purpose
The purpose of a liver transplant for patients who have metastatic neuroendocrine tumors (NETs) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with metastatic NETs.

Interventions
The therapy being considered is a liver transplant.

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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Two systematic reviews of case series have assessed metastatic NETs. Neuroendocrine tumors 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 (N = 706 patients) on liver transplantation for NET liver metastases of any origin.³⁵ 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.³⁶, Data from 89 transplanted patients treated in 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 Neuroendocrine Tumors
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.

Liver Transplant for Pediatric Hepatoblastoma
Clinical Context and Therapy 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 evidence review is: Does liver transplant improve net health outcomes in children with pediatric hepatoblastoma?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is children with pediatric hepatoblastoma.

Interventions
The therapy being considered is a liver transplant.

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

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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.³⁷ 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.³⁸ 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 2007.³⁹ 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.⁴⁰ Tumor recurrence caused all 4 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 = .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 is a treatment option with reports of good outcomes and high rates of survival.⁴¹ The UNOS guidelines list nonmetastatic hepatoblastoma as a condition eligible for pediatric liver transplantation.⁴²

Liver Retransplant for a Failed Liver Transplant
Clinical Context and Therapy Purpose
The purpose of a liver retransplant 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 evidence review is: Does a liver retransplant improve net health outcomes in individuals with a failed liver transplant?

The following PICO was used to select literature to inform this review.

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

Interventions
The therapy being considered is a liver retransplant.

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

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Cohort Studies
Salimi et al. (2021) reported on a retrospective cohort using records from 1,030 patients who underwent liver transplantation at a liver transplantation center in Iran between the years 2000 and 2016; of these, 966 were initial transplants and 64 were retransplants.⁴³ The mortality rate was significantly higher among patients who underwent retransplantation (54.68%) compared to patients who underwent primary liver transplantation (21.32%; p < .001). Overall survival at 1-, 3-, and 5-years posttransplant was 82%, 80%, and 70%, respectively, for patients undergoing initial transplant and 59%, 43%, and 32%, respectively, for patients undergoing retransplant. Patients who underwent retransplantation also had significantly higher MELD scores (10.73 ± 25.89) compared to patients who underwent primary liver transplantation (5.65 ± 20.51; p = .004).

Bellido et al. (2012) reported on a retrospective cohort using registry data on 68 consecutive adults with liver retransplantations.⁴⁴ Survival estimates using Kaplan-Meier curves to compare 21 urgent with 47 elective retransplantations were calculated. Overall survival 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.⁴⁵ When compared with primary liver transplantation patients, retransplantation patients had significantly lower 6-year survival rates (80% vs 58%, respectively; p < .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.⁴⁶ 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 Therapy Purpose
The purpose of a combined liver-kidney transplantation 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 evidence review is: Does a combined liver-kidney transplantation improve net health outcomes in individuals with indications for liver and kidney transplant?

The following PICO was used to select literature to inform this review.

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

Interventions
The therapy being considered is a combined liver-kidney transplantation.

Comparators
The following tools and practices are currently being used to make decisions about managing combined liver-kidney transplantation: medical management or single organ transplant.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Adults
Systematic Reviews
Bouari et al. (2021) performed a systematic review and meta-analysis of 4 retrospective observational studies (N = 22,736) comparing survival and other outcomes among adult patients who received combined liver-kidney transplant to those with renal dysfunction who received liver transplant alone.⁴⁷ No significant difference in mortality was found between patients who received combined liver-kidney transplant and those who received liver transplant alone at 1 year (pooled risk ratio [RR], 1.03; 95% CI, 0.97 to 1.09; p = .31), 3 years (pooled RR, 1.06; 95% CI, 0.99 to 1.13; p = .11), or 5-years (pooled RR, 1.08; 95% CI, 0.98 to 1.19; p = .11) posttransplant. Pooled results from 2 studies showed that liver graft loss was not significantly different at 1 year, but was significantly increased at 3 years in patients who received liver transplant alone (RR, 1.15; 95% CI, 1.08 to 1.24; p < .0001). A single study reporting on liver graft survival at 5 years found no difference between groups.

Observational Studies
In a retrospective study, Lunsford et al. (2017) evaluated factors for renal failure in patients who underwent combined liver-kidney transplantation.⁴⁸ Of 145 patients who had combined liver-kidney transplantation, 30 (20.7%) had renal failure. Survival at 1 and 3 years in the combined liver-kidney transplant group with renal failure (18.2% and 13.5%) was significantly worse than in combined liver-kidney transplant patients without renal failure (92.6% and 83.7%; p < .001). Multivariate predictors of renal failure were pretransplant dialysis duration (OR, 2.43; p = .008), kidney cold ischemia of more than 883 minutes (OR, 3.43; p = .011), kidney donor risk index (OR, 1.96; p = .012), and recipient hyperlipidemia (OR, 3.50; p = .028).

Fong et al. (2012) evaluated data from the OPTN and UNOS database to compare outcomes of combined liver-kidney transplantation with liver transplantation alone for adults with cirrhosis and renal failure.⁴⁹ 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, 2,774 patients had both liver and renal failure and received a liver transplant alone and 1,501 patients underwent combined liver-kidney transplantation. Patients who received combined liver-kidney transplantation 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 combined liver-kidney transplantation compared with liver transplant alone. At 5 years posttransplant, 67.4% of patients had survived in the combined liver-kidney transplantation arm compared with 62.9% in the liver alone arm (p < .001). The liver allograft survival rate after 5 years was 65.3% in the combined liver-kidney transplantation arm and 58.9% in the liver transplantation alone (p < .001). After adjusting for confounding factors, liver transplant alone remained a significant risk factor for liver allograft loss (HR, 1.24; p = .002) and mortality compared with combined liver-kidney transplantation (HR, 1.16; p = .043).

In a series of 74 combined liver-kidney transplantation procedures performed at a single institution over a 23-year period, Ruiz et al. (2010) reported a 5-year survival rate of 62%.⁵⁰ However, in patients who had a second combined liver-kidney transplantation or liver retransplantation, survival was 30% at 3 months. This finding led to a recommendation not to perform combined liver-kidney transplantation 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 = .001 over follow-up), and kidney graft survival was only 56% at 5 years.

Children
Observational Studies
Calinescu et al. (2014) evaluated combined liver-kidney transplantation outcomes in children using data from the Scientific Registry of Transplant Recipients from OPTN.⁵¹ There were 152 primary combined liver-kidney transplants performed between 1987 and 2011. Liver graft survival was 72.6% at 10 years, and kidney graft survival was 66.9%. Patient survival at 10 years after combined liver-kidney transplantation was 78.9%. In comparison, patient survival following isolated liver transplantation during the same period was 77.4% (n = 10,084) and, for an isolated kidney transplant, 90% at 10 years (n = 14,800). Thus, combined liver-kidney transplantation resulted in survival outcomes that were no worse than liver transplant alone but were inferior to kidney transplant alone. Indications for combined liver-kidney transplantation 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 combined liver-kidney transplantation.⁵² Examination of the OPTN/UNOS database between 1995 and 2005 identified 111 combined liver-kidney transplants and 3,798 kidney-only transplants in children. The patients in the combined liver-kidney transplantation group were younger on average than those in the kidney-only group (9 years vs 12 years, p = .007) and more had inherited disease as the primary cause (42% vs 28%), respectively. More patients in the combined liver-kidney transplantation group lost their kidney graft within 6 months (20.1% vs 5.9%, p = .001); however, late kidney graft survival was significantly better at 5 years posttransplant compared with the kidney-only group (p < .01). The authors described 2 situations when combined liver-kidney transplantation 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: Combined Liver-Kidney Transplant
The evidence on combined liver-kidney transplantation includes a systematic review of retrospective observational studies in adult patients and several registry studies that have compared combined organ transplantation with liver or with kidney transplantation alone. In adults undergoing liver transplant with kidney failure, a systematic review did not find differences in 1-, 3-, or 5-year survival when comparing combined liver-kidney transplantation to liver transplantation alone. Individual registry studies showed that combined liver-kidney transplantation resulted in a modest improvement in patient survival compared with liver transplantation alone. Liver allograft survival was also higher in the patients who received combined liver-kidney transplantation compared with patients who received a liver transplant alone. Relatively few children have received combined liver-kidney transplantation. Patient survival has been reported to be worse with combined liver-kidney transplantation than with kidney transplantation alone but no worse than for liver transplant alone. For kidney grafts that survive the first 6 months, the organ survival rate may be better than for a kidney graft alone. Together, these results would suggest that combined liver-kidney transplantation 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 combined liver-kidney transplantation 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
Review of Evidence
Living Donor Versus Deceased Donor Liver Transplant Recipient Outcomes
Due to the scarcity of donor organs and the success of living donation, living donor (LD) liver transplantation (LT) 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.^53,54,55,56

In December 2000, the National Institutes of Health convened a workshop focusing on living donor liver transplantation. Shiffman et al. (2002) summarized this workshop.⁵⁷ 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 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 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.⁵⁷

Grant et al. (2013) reported on a systematic review and meta-analysis of 16 studies to compare recipient outcomes between LD LT and deceased donor liver transplants for HCC.⁵⁸ For DFS after LD LT, the combined HR was 1.59 (95% CI, 1.02 to 2.49) compared with deceased donor liver transplantation. For OS, the combined hazard ratio 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. Another systematic review and meta-analysis by Tang et al. (2020) compared outcomes between LD LT and deceased donor liver transplants from 39 studies (N = 38,563; mainly retrospective in nature) of patients with end-stage liver disease.⁵⁹ Perioperative mortality, hospital length of stay, retransplantation rates, and recurrence rates for HCV and HCC were similar between groups. Living donor LT were associated with significant improvements in 1- (OR, 1.32; 95% CI, 1.01 to 1.72; p = .04), 3- (OR, 1.39; 95% CI, 1.14 to 1.69; p = .0010), and 5-year (OR, 1.33; 95% CI, 1.04 to 1.70; p = .02) OS and vascular (OR, 2.00; 95% CI, 1.31 to 3.07; p = .001) and biliary (OR, 2.23; 95% CI, 1.59 to 3.13; p < .00001) complication rates compared to deceased donor liver transplants.

Human Immunodeficiency Virus-Positive Patients
Solid-organ transplant for patients who are Human Immunodeficiency Virus (HIV)-positive was historically controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. Candidates for liver transplantation with HIV 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.⁶⁰ 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 HCV and HIV (n = 89), patients with only HCV (n = 235), and all transplant patients age 65 or older.⁶¹ Patient and graft survival reductions were significantly associated with only 1 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 3 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.⁶²

The American Society of Transplantation (2019) published a guideline on solid organ transplantation in HIV-infected patients.63, For liver transplants, the following criteria for transplantation are suggested:

Cluster of differentiation 4 (CD4) count > 100 cells/mL with no history of acquired immunodeficiency syndrome (AIDS)-defining illnesses such as opportunistic infection or malignancy or CD4 count > 200 cells/mL for at least 3 months
Undetectable HIV viral load while receiving antiretroviral therapy or a detectable HIV viral load in patients with intolerance to antiretroviral therapy that can be suppressed posttransplant
Documented compliance with a stable antiretroviral therapy regimen
Absence of active opportunistic infection and malignancy
Absence of chronic wasting or severe malnutrition
Appropriate follow-up with providers experienced in HIV management and ready access to immunosuppressive medication therapeutic drug monitoring

The guideline authors note that patients with a previous history of progressive multifocal leukoencephalopathy, chronic interstitial cryptosporidiosis, primary central nervous system lymphoma, or visceral Kaposi's sarcoma were excluded from studies of solid organ transplantation in HIV-infected patients. Patients with HIV and concomitant controlled hepatitis B infection may be considered for transplant. Caution is recommended in hepatitis C-coinfected patients who have not been initiated on direct acting antiviral therapy.

Hepatitis Infection
Terrault et al. (2012) also reported on the group of patients with HCV.⁶¹ 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 registry studies and systematic reviews. 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 nonalcoholic steatohepatitis, 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 an improvement in the net health outcome.

For individuals who have primary hepatocellular carcinoma who receive a liver transplant, the evidence includes systematic reviews of observational studies. 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 an 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 and individual registry studies. 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, 5-year survival rates have been reported as high as 76%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have intrahepatic cholangiocarcinoma who receive a liver transplant, the evidence includes registry studies and a systematic review of observational studies. Relevant outcomes include OS, morbid events, and treatment-related morbidity and mortality. In a registry study comparing outcomes in patients with intrahepatic cholangiocarcinoma who received liver transplantation to those who received surgical resection of the liver, no differences were found in OS, length of stay, or unplanned 30-day readmission rates between groups. Additional studies reporting survival rates in patients with intrahepatic cholangiocarcinoma or in mixed populations of patients with extrahepatic and intrahepatic cholangiocarcinoma have reported 5-year survival rates of less than 30%. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have metastatic neuroendocrine tumors who receive a liver transplant, the evidence includes systematic reviews of case series. 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 that the technology results in an improvement in the net health outcome.

For individuals who have pediatric hepatoblastoma who receive a liver transplant, the evidence includes case series. 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 the United Network for Organ Sharing criteria for patients eligible for liver transplantation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a failed liver transplant who receive a liver retransplant, the evidence includes observational studies. 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 an improvement in the net health outcome.

For individuals with indications for liver and kidney transplant who receive a combined liver-kidney transplant, the evidence includes a systematic review of retrospective observational studies in adults and several individual registry studies. 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 combined liver-kidney transplant 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 combined liver-kidney transplant is no worse, and possibly better, for graft and patient survival. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2012 Input
In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers while this policy was under review in 2012. 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
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

International Consensus Conference
In 2010, an International Consensus Conference, including representation from the U.S., convened with the goal of reviewing current practice regarding liver transplantation in patients with hepatocellular carcinoma (HCC).64, The Conference ultimately came up with recommendations beginning from the assessment of candidates with HCC for liver transplantation and managing patients on waitlists, to the role of liver transplantation and post-transplant management. Some notable recommendations are described.

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 5 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 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 and American Society of Transplantation
In 2013, the American Association for the Study of Liver Diseases and the American Society of Transplantation issued joint guidelines on evaluating patients for a liver transplant.⁶⁵ 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 from 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.

The guidelines also included 1-A recommendations (strong recommendation with high-quality evidence) for a liver transplant that:

"Tobacco consumption should be prohibited in LT [liver transplant] candidates."
"Patients with HIV [Human Immunodeficiency Virus] 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."

Contraindications to liver transplant included:

"MELD [Model for End-Stage Liver Disease] score < 15
Severe cardiac or pulmonary disease
AIDS [acquired immunodeficiency syndrome]
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."

In 2014, the American Association for the Study of Liver Diseases, the American Society of Transplantation, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition issued joint guidelines on the evaluation of the pediatric patients for liver transplant.⁶⁶ The guidelines stated that "disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult patients, justifying independent pediatric guidelines." The indications listed for liver transplantation included biliary atresia, Alagille syndrome, pediatric acute liver failure, hepatic tumors, HCC, hemangioendothelioma, cystic fibrosis-associated liver disease, urea cycle disorders, immune-mediated liver disease, along with other metabolic or genetic disorders.

In 2019, the American Association for the Study of Liver Diseases guideline on alcohol-associated liver disease provided recommendations on the timing of referral and selection of candidates for liver transplant.⁶⁷ The guidance notes that the patient's history of addiction to alcohol is a primary driver in selecting appropriate candidates for liver transplantation. Clinical characteristics that should trigger an evaluation and consideration for liver transplant include decompensated alcohol-associated cirrhosis, Child-Pugh-Turcotte class C cirrhosis, or a MELD-Na score ≥ 21. Additionally, the guideline notes that candidate selection "should not be based solely on a fixed interval of abstinence" and instead a formal psychological evaluation can help stratify patients into higher- or lesser-risk strata for relapse.

National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines on hepatobiliary cancers (v.1.2022 ) 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.¹⁶ 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 patients with unresectable disease who are not a transplant candidate should receive locoregional therapy with ablation, arterially directed therapies, or external beam radiation therapy (preferred) or may receive systemic therapy, best supportive care, or be enrolled in a clinical trial. These are level 2A recommendations based on lower-level evidence and uniform consensus.

The NCCN guidelines on neuroendocrine tumors (v.1.2022 ) indicate that liver transplantation for neuroendocrine liver metastases is considered investigational despite "encouraging" 5-year survival rates.⁶⁸

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review 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	160	Dec 2022
NCT02878473	Liver Transplantation for the Treatment of Early Stages of Intrahepatic Cholangiocarcinoma in Cirrhotics	30	Jan 2029

NCT: national clinical trial.

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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
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): 411-6. PMID 22805440
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): 807-11. PMID 20002463
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): 2861-8. PMID 25274400
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): 459-64. PMID 20070563
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
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): 921-7. PMID 11679994
Renz JF, Busuttil RW. Adult-to-adult living-donor liver transplantation: a critical analysis. Semin Liver Dis. 2000; 20(4): 411-24. PMID 11200412
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): 680-6. PMID 11510011
Shiffman ML, Brown RS, Olthoff KM, et al. Living donor liver transplantation: summary of a conference at The National Institutes of Health. Liver Transpl. Feb 2002; 8(2): 174-88. PMID 11862598
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): 140-7. PMID 23157398
Tang W, Qiu JG, Cai Y, et al. Increased Surgical Complications but Improved Overall Survival with Adult Living Donor Compared to Deceased Donor Liver Transplantation: A Systematic Review and Meta-Analysis. Biomed Res Int. 2020; 2020: 1320830. PMID 32908865
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): 777-86. PMID 21412058
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): 716-26. PMID 22328294
Organ Procurement and Transplantation Network (OPTN). Organ Procurement and Transplantation Network Policies. Updated June 28, 2022; https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed June 28, 2022.
Blumberg EA, Rogers CC. Solid organ transplantation in the HIV-infected patient: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. Sep 2019; 33(9): e13499. PMID 30773688
Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. Jan 2012; 13(1): e11-22. PMID 22047762
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 June 27, 2022.
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): 362-98. PMID 24782219
American Association for the Study of Liver Diseases. Diagnosis and Treatment of Alcohol Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.30866. Accessed June 27, 2022.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed June 27, 2022.
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 June 27, 2022.
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 June 28, 2022.

Coding Section

Codes	Number	Description
CPT	47133	Donor hepatectomy (including cold perservation); from cadaver donor
	47135	Liver allotransplantationl orthotopic; partial or whole, from cadaver or living donor, any age
	47136	Liver allotransplantationl heterotopic, partial or whole, from cadaver or living donor, any age
	47140-47142	Donor hepatectomy from living donor, code range
	47143-47145	Backbench standard preparation of cadaver liver graft, code range
	47146-47147	Backbench reconstruction of cadaver or living donor liver graft, code range
ICD-9 Procedure	00.91	Transplant from live related donor (used with code for transplant procedure)
	00.92	Transplant from live non-related donor (used with code for transplant procedure)
	00.93	Transplant from cadaver (used with code for transplant procedure)
	50.22	Partial hepatectomy
	50.4	Total hepatectomy
	50.51	Auxiliary liver transplant (leaving patient's own liver in situ)
	50.59	Other transplant of liver
ICD-9 Diagnosis	V59.6	Liver donor
	070.00-070.13	Viral hepatitis A code range
	070.20-070.33	Viral hepatitis B code range
	070.41	Acute hepatitis C with hepatic coma
	070.44	Chronic hepatitis C with hepatic coma
	070.51	Acute hepatitis C without mention of hepatic coma
	070.54	Chronic hepatitis C without mention of hepatic coma
	070.59	Other specified viral hepatitis withou mention of hepatic coma
	070.9	Unspecified viral hepatitis without mention of hepatic coma
	121.1	Biliary cirrhosis due to Clonorchiasis
	121.3	Biliary cirrhosis due to Fascioliasis
	155.0	Malignant neoplasm of liver (includes hepatoblastoma)
	270.0-270.9	Disorders of amio-acid transport and metabolism
	271.0-271.9	Disorders of carbohydrate transport and metabolism
	272.0-272.9	Disorders of lipoid metabolism
	275.09	Disorders of iron metabolism
	275.1	Disorders of copper metabolism
	277.1	Disorders of porphyrin metabolism
	277.30-277.39	Amyloidosis code range
	277.6	Other deficiencies of circulation enzymes
	277.9	Unspecified disorder of metabolism
	285.0	Sideroblastic anemia
	356.0	Hereditary peripheral neuropathy
	357.4	Polyneuropathy in other diseases classified elsewhere (Note: code is used in conjunction with 277.3 to indicate amyloid polyneuropathy)
	444.89	Arterial embolism and thrombosis, other artery (used for hepatic artery thrombosis)
	453.0	Budd-Chiari syndrome
	459.9	Unspecified circulatory system disorder
	571.6	Biliary cirhosis
	571.8	Other chronic nonalcoholic liver disease (includes non-alcoholic steatohepatitis cirrhosis)
	573.1	Hepatitis in viral diseases classified elsewhere (Note: underlying disease must be coded first with this code as secondary)
	573.2	Hepatitis in other infectious diseases classified elsewhere (Note: underlying disease must be coded first with this code as secondary)
	573.3	Hepatitis, unspecified
	576.1	Cholangitis
	576.2	Obstruction of bile duct
	576.8	Other specified disorders of biliary tract
	751.62	Congenital cystic disease of liver
	864.00-864.19	Injury to liver code range
	996.82	Complications of transplanted organ, liver (includes failure and rejection)
ICD-10-CM (effective 10/01/15)	B15.0-B15.9	Acute hepatitis A; code range
	B16.0-B16.9	Acute hepatitis B; code range
	B17.0-B17.9	Other acute viral hepatitis; code range
	B18.0-B18.9	Chronic viral hepatitis; code range
	B19.0-B19.9	Unspecified viral hepatitis; code range
	B25.1	Cytomegaloviral hepatitis
	B66.1	Clonorchiasis
	B66.5	Fasciolopsiasis
	C22.0-C22.9	Malignant neoplasm of liver and intrahepatic bile ducts; code range (includes hepatoblastoma)
	D81.810	Biotinidase deficiency
	D84.0-D84.9	Other immunodeficiencies; code range
	E72.00-E72.09	Disorders of amiono-acid metabolism; code range
	E74.00-E74.9	Other disorders of carbohydrate metabolism; code range
	E78.0-E78.9	Disorders of liprotein metabolism and other lipidemias; code range
	E80.0-E80.7	Disorders of porphyrin and bilirubin metabolism; code range
	E83.0-E83.09	Disorders of copper metabolism; code range
	E83.1-E83.19	Diorders of iron metabolism; code range
	E85.0-E85.9	Amyloidosis; code range
	E88.9	Metabolic disorder, unspecified
	G60.0-G60.9	Hereditary and idiopathic neuropathy; code range
	I74.8	Embolism and thrombosis of other arteries (includes hepatic artery thrombosis)
	I82.0	Budd-Chiari syndrome
	I99.99	Unspecified disorder of circulatory system
	K71.10-K71.9	Toxic liver disease
	K74.0-K74.69	Fibrosis and cirrhosis of liver; code range
	K75.81	nonalcoholic steatohepatitis (NASH)
	K77	Liver disorders in diseases classified elsewhere (code first underlying disease)
	K83.0-83.9	Other diseases of biliary track; code range
	Q44.6	Congenital Cystic disease of liver
	S36.12xA-S36.13xS	Injury of liver and gallbladder and bile duct; code range
	T86.41	Liver transplant rejection
	T86.42	Liver transplant failure
	Z52.6	Liver donor
ICD-10-PCS (effective 10/01/15)	0FB00ZZ, 0FB03ZZ, 0FB04ZZ	Surgical, excision, liver, code by approach (open, percutaneous or percutaneous endoscopic)
	0FB10ZZ, 0FB13ZZ, 0FB14ZZ, 0FB20ZZ, 0FB23ZZ, 0FB24ZZ,	Surgical, excision, lobe of liver, code by body part (right or left) and approach (open, percutaneous or percutaneous endoscopic)
	0FT00ZZ, 0FT04ZZ	Surgical, resection, liver, code by approach (open or percutaneous endoscopic)
	0FY00Z0, 0FY00Z1	Surgical, transplantation, liver, open, code by qualifier (allogeneic or syngeneic)
Type of Service	Surgery
Place of Service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Index
Hepatic Transplant
Liver Transplant
Transplant, Liver

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2013 Forward

12/06/2022	Annual review, no change to policy intent. Updating rationale and references
12/01/2021	Annual review, no change to policy intent. Updating description, rationale and references.
12/01/2020	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
12/02/2019	Annual review, no change to policy intent. Updating guidelines, rationale and references.
01/04/2019	Annual review, no change to policy intent. Updating rationale and references.
01/18/2018	Annual review, updating title to include liver-kidney transplantation, policy updated to include liver-kidney transplantation with medical necessity criteria, updating background, description, guidelines, rationale and references.
12/05/2016	Annual review, no change to policy intent.
11/19/2015	Annual review, no change to policy intent. Updating background, description, rationale and references.
12/03/2014	Annual review, no change to policy intent. Updated guidelines, policy verbiage, rationale and references. Added keywords and coding.
12/9/2013	Annual review. Updated rationale and references. Updated policy and guidelines. Added related policies.Policy verbiage added " hilar cholangiocarcinoma may be considered medically necessary. Intrahepatic cholangiocarcinoma was added as investigatonal. Add Benefit applications.

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Liver Transplant and Combined Liver-Kidney Transplant - CAM 70306