As experience with liver transplant has matured, patient selection criteria have broadened to include a wide variety of etiologies. The most controversial etiologies include viral hepatitis and primary hepatocellular cancer. In particular, the presence of hepatitis B virus (HBV) has been a controversial indication for liver transplantation because of the high potential for recurrence of the virus and subsequent recurrence of liver disease. However, registry data indicate a long-term survival rate (seven years) of 47% in HBV positive (HBV+) transplant recipients, which is lower than that seen in other primary liver diseases such as primary biliary cirrhosis (71%) or alcoholic liver disease (57%). Although these statistics raise questions about the most appropriate use of a scarce resource (donor livers), the long-term survival rate of 45% is significant in a group of patients who have no other treatment options. Similarly, the long-term outcome in patients with primary hepatocellular malignancies (19%) is poor compared to the overall survival of liver transplant recipients. Nevertheless, transplant represents the only curative approach for many of these patients who present with unresectable organ-confined disease. However, liver transplant cannot be considered curative in patients with locally extensive or metastatic liver cancer, or in patients with isolated liver metastases with extrahepatic primaries or in cholangiocarcinoma (CCA).
Due to the scarcity of donor organs and the success of living donation between parent and child, adult-to-adult living-donor liver transplantation has been investigated and is now performed at several transplant centers. Specifically, the living donor undergoes hepatectomy of the right lobe, which is then transplanted into the recipient. Since right hepatectomy involves the resection of 60%-70% of the total volume of the donor liver, the safety of the donor has been the major concern. For example, the surgical literature suggests that right hepatectomy of a diseased or injured liver is associated with mortality rates of about 5%. However, initial reports suggest that right hepatectomy in healthy donors has a lower morbidity and mortality. The Medical College of Virginia appears to have the most extensive experience and has reported the results of their first 40 adult-to adult living-donor liver transplantations, performed between June 1998 and October 1999. There were an equal number of related and unrelated donors. Minor complications occurred in seven donors. The outcomes among recipients were similar to those associated with cadaveric donor livers performed during the same period of time. However, in the initial series of 20 patients, four of the five deaths occurred in recipients who were classified as Status 2A (see Description section). In the subsequent 20 patients, recipients classified as Status 2A were not considered candidates for living-donor transplant. Other case series have reported similar success rates. Reports of several donor deaths re-emphasize the importance of careful patient selection based in part on a comprehensive consent process and an experienced surgical team. In December 2000, the National Institutes of Health convened a workshop focusing on living-donor liver transplantation. A summary of this workshop was published in 2002. According to this document, the risk of mortality to the donor undergoing right hepatectomy was estimated to be approximately 0.2%-0.5%. Based on survey results, the workshop reported that donor morbidity was common; 7% required re-exploration, 10% had to be re-hospitalized, and biliary tract complications occurred in 7%. 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 have a significant long-term and established relationship with the recipient. According to the workshop summary, “At the present time, nearly all centers strive to identify donors who are entirely healthy and at minimal risk during right hepatectomy. As a result, only approximately one third of persons originally interested in becoming a living liver donor complete the evaluation process and are accepted as candidates for this procedure.”
Criteria for a recipient of a living-related liver are also controversial, with some groups advocating that living-related donor livers be only used in those most critically ill; while others state 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.
In 2000, the American Society of Transplant Surgeons issued the following statement:
“Living donor transplantation in children has proven to be safe and effective for both donors and recipients and has helped to make death on the waiting list a less common event. Since its introduction in 1990, many of the technical and ethical issues have been addressed and the procedure is generally applied.
The development of left or right hepatectomy for adult-to-adult living-donor liver transplantation has been slower. Because of the ongoing shortage of cadaver livers suitable for transplantation, adult-to-adult living-donor liver transplantation has been undertaken at a number of centers. While early results appear encouraging, sufficient data are not available to ascertain donor morbidity and mortality rates. There is general consensus that the health and safety of the donor is and must remain central to living organ donation.”
A review of the literature based on the MEDLINE database for the period of 2002 through September 2006 did not identify any articles that would prompt reconsideration of the above policy. There is ongoing discussion of living-related adult-to-adult liver transplantation. Brown and colleagues reported on the results of a survey focusing on adult living-related recipients in the United States (U.S.). The following statistics were reported:
- The survey encompasses 449 adult-to-adult transplantations.
- Half of the responding programs already had performed at least one adult-to-adult living-donor liver transplantation, and 32 of the remaining 41 centers were planning to initiate such surgery.
- 14 centers had performed more than ten such transplantations, and these centers accounted for 80% of these transplants.
- A total of 45% of those evaluated for living donation subsequently donated a liver lobe; 99% were genetically or emotionally related to the recipient.
- Complications in the donor were more frequent in the centers that performed the fewest living-related donor transplantations.
- There was one death among the donors, but complications were relatively common, i.e., biliary complications in 6% and reoperation in 4.5%.
In 2002, the National Institutes of Health sponsored a conference on living-donor liver transplantation. This report offered the following observations:
- The incidence and type of complications encountered and mortality associated with living-donor liver transplant in both donors and recipients needs to be determined and compared with that for patients undergoing cadaveric transplantation.
- The question of whether all U.S. transplant programs should perform this operation or this complex procedure should be limited to only a few select centers needs to be addressed.
Human Immunodeficiency Virus Positive (HIV+) Patients
This subgroup of recipients has long been controversial, due to the long-term prognosis for human immunodeficiency virus (HIV) positivity, the impact of immunosuppression on HIV disease, and the interactions of immunosuppressive therapy with antiretroviral therapy in the setting of a transplanted liver. For example, most antiretroviral agents are metabolized through the liver and can cause varying degrees of hepatotoxicity. HIV candidates for liver transplantation are frequently co-infected with hepatitis B or C, and viral co-infection can further exacerbate drug-related hepatotoxicities. Although HIV+ transplant recipients may be a research interest of some transplant centers (i.e., the University of Pittsburgh, University of Miami, and the University of California at San Francisco), the minimal data regarding long-term outcome in these patients consist primarily of case reports and abstract presentations. Nevertheless, some liver transplant surgeons would argue that HIV positivity is no longer an absolute contraindication to liver transplant due to the advent of highly active antiretroviral therapy (HAART), which has markedly changed the natural history of the disease, and the increasing experience with liver transplant in HIV+ patients. Furthermore, UNOS states that asymptomatic HIV+ patients should not necessarily be excluded for candidacy for organ transplantation, stating “A potential candidate for organ transplantation whose test for HIV is positive but who is in an asymptomatic state should not necessarily be excluded from candidacy for organ transplantation, but should be advised that he or she may be at increased risk of morbidity and mortality because of immunosuppressive therapy. In 2001, the Clinical Practice Committee of the American Society of Transplantation proposed that the presence of AIDS could be considered a contraindication to kidney transplant unless the following criteria were present. These criteria may be extrapolated to other organs:
- CD4 count >200 cells/mm-3 for >6 months (CD4 is an antigenic marker on T cells);
- HIV-1 RNA undetectable (viral load, i.e., level of viral genetic material (RNA) present in blood plasma);
- On stable anti-retroviral therapy more than 3 months;
- No other complications from AIDS (e.g., opportunistic infection, including aspergillus, tuberculosis, coccidioses mycosis, resistant fungal infections, Kaposi’s sarcoma, or other neoplasm); and
- Meeting all other criteria for transplantation.
It is likely that each individual transplant center will have explicit patient selection criteria for HIV+ patients. In addition, there is an ongoing multi-institutional prospective study of liver and kidney transplantation in HIV+ recipients. The target enrollment is 150 kidney transplant recipients and 125 liver transplant recipients. The goals of the trial are described as follows:
“Primary aims of the study are to assess the impact of iatrogenic immunosuppression on patient survival and to assess the impact of HIV infection and antiretroviral treatment on graft survival, including in the setting of HBV or HCV [hepatitis C virus] coinfection and HIV-associated nephropathy. Secondary aims include assessment of the effect of immunosuppressant therapy on CD 4+ cell counts, HIV RNA levels, and opportunistic complications; exploration of the relationships among disease development, the host immune response and viral evolution with regard to HBV, HCV, CMV, herpes virus-8 and human papilloma virus (HPV); assessment of the impact of HIV infection on alloimmune response and graft rejection rates; and analysis of pharmacokinetic interactions between immunosuppressant drugs and hepatically metabolized antiretroviral agents.”
A literature search was conducted seeking evidence on two main issues: 1) whether selection criteria for hepatocellular carcinoma (HCC) should be expanded, and 2) whether cholangiocarcinoma (CCA) should be considered an acceptable indication for liver transplantation.
Hepatocellular Carcinoma (HCC)
Questions on patient selection criteria for HCC have focused mainly on the number and size of tumors. An editorial by Llovet noted that the Milan criteria are considered the gold standard and specify that patients may either have a solitary tumor with a maximum tumor diameter of 5 cm or less, or up to three tumors 3 cm or smaller. A 2001 paper from the University of California, San Francisco (UCSF), proposed expanded criteria, to include patients with a single tumor up to 6.5 cm in diameter, three or fewer tumors with maximum size 4.5 cm, and a total tumor size of 8 cm or less. It should be noted that either set of criteria can be applied preoperatively (with imaging) or with pathology of the explanted liver at the time of intended transplant. Preoperative staging often underestimates what is seen on surgical pathology. To apply pathologic criteria, a backup candidate must be available in case preoperative staging is inaccurate. Given donor organ scarcity, any expansion of liver transplant selection criteria has the potential to prolong waiting times for all candidates. 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 disease-free survival). Survival time can be estimated beginning when the patient is placed on the waiting list, using the intention-to-treat principal, or at the time of transplantation. Llovet stated that 1-year dropout rates for patients meeting Milan criteria are 15%–30% and 5-year survival rates not reported by intention-to-treat should be adjusted down by 10%–15%.
A very limited body of evidence is available for outcomes among patients exceeding Milan criteria but meeting UCSF criteria. The largest series was conducted in 14 centers in France, including an intention-to-treat total of 44 patients based on preoperative imaging at the time of listing, and a subset of 39 patients meeting pathologic UCSF criteria. The median waiting time was 4.5 months, shorter than the typical 6–12 months in North America. Dropouts composed 11.4%. Post-transplant overall patient 5-year survival, at 63.6%, was more favorable than the intention-to-treat probability (45.5%), but less favorable than among larger numbers of patients meeting Milan criteria. Similar findings were seen for disease-free survival and cumulative incidence of recurrence. Three centers in Massachusetts included 10 patients beyond pathologic Milan criteria but within UCSF criteria. Two-year survival post-transplant was 77.1%, with two patients dying and eight alive after a median of 32 months. A group of 74 patients meeting preoperative Milan criteria had a 2-year survival probability of about 73%, but it is inadvisable to compare different preoperative and pathologic staging criteria. From the series of patients that developed the expanded UCSF criteria, 14 satisfied those criteria on pathology but exceeded the Milan criteria. UCSF investigators do not provide survival duration data for this subgroup, but note that two patients died. A center in Essen, Germany, reported on four patients. Although the French series suggests that outcomes among patients exceeding Milan criteria and meeting UCSF criteria are worse than for patients meeting Milan criteria, it is unclear if the latter group still achieves acceptable results. A benchmark of 50% 5-year survival has been established in the liver transplant community, and the French study meets this by post-transplant pathologic staging results (63.6%) and falls short by preoperative intention-to-treat results (45.5%). Centers in the United States have published data for only 24 patients exceeding Milan criteria and meeting UCSF criteria; survival and recurrence data are very sparse. Overall, the evidence base is insufficient to permit conclusions about health outcomes after liver transplantation among patients exceeding Milan criteria and meeting expanded UCSF criteria.
The evolution of selection criteria continues to be a focus in the literature. In their 2008 review, Schwartz and colleagues argue that selection based exclusively on the Milan criteria risks prognostic inaccuracy due to the diagnostic limitations of imaging procedures and the surrogate nature of size and number of tumors. They predict that evolution of allocation policy will involve the following: 1) the development of a reliable prognostic staging system to help with allocation of therapeutic alternatives; 2) new molecular markers that might improve prognostic accuracy; 3) aggressive multimodality neoadjuvant therapy to downstage and limit tumor progression before transplant and possibly provide information about tumor biology based on response to therapy; and, 4) prioritization for transplantation should consider response to neoadjuvant therapy, time on waiting list, suitability of alternative donor sources. Two papers describe work on identifying predictors of survival and recurrence of disease. Ioannou and colleagues analyzed UNOS data pre- and post-adoption of the MELD allocation system finding a 6-fold increase in recipients with HCC, and that survival in the MELD era was similar to survival to patients without HCC. The subgroup of patients with larger (3-5 cm) tumors, serum alpha-fetoprotein level >455 mg/mL, or a MELD score >20, however, had poor transplantation survival. A predicting-cancer-recurrence scoring system was developed by Chan et al. based on a retrospective review and analysis of liver transplants at two centers to determine factors associated with recurrence of HCC. 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: size of one tumor >4.5 cm, macroinvasion, and bilobar tumor were positive predictors of recurrence, and the presence of only well-differentiated HCC was a negative predictor. Points were assigned to each factor in relation to its odds ratio. The accuracy of the method was confirmed in two validation cohorts.
Data are similarly sparse on outcomes after liver transplantation for CCA, or bile duct carcinoma. A MEDLINE search was conducted seeking data from patient series of 20 or more. The search identified evidence from two international registries, one multicenter report from Spain, and four individual centers, three of which are in the United States. Reports generally distinguish between intrahepatic and extrahepatic tumors, the latter including hilar or perihilar tumors. Recent efforts have focused on pretransplant downstaging of disease with neoadjuvant radiochemotherapy. Relevant outcomes include waiting time duration, dropout rates, survival time, and recurrence.
The European Liver Transplant Registry was cited by a review article. Among 186 patients with intrahepatic CCA, 1-year survival was 58% and 5-year survival was 29%. In 169 patients with extrahepatic CCA, the probabilities were 63% and 29%. The Cincinnati Transplant Registry reported on 207 patients with either intrahepatic or extrahepatic CCA, finding a 1-year survival of 72% and a 5-year rate of 23%. The multicenter Spanish report included 36 patients with hilar tumors and 23 with peripheral intrahepatic disease. One-year survival was 82% and 77%, while 5-year survival was 30% and 23%, in the two groups, respectively.
Among the individual centers, the Mayo Clinic in Minnesota has the most experience and most favorable results. Between 1993 and 2006, 65 patients underwent liver transplantation for unresectable perihilar CCA or had perihilar tumor due to primary sclerosing cholangitis (PSC). Patients with unresectable cancer underwent neoadjuvant radiochemotherapy. One-year survival was 91% and 5-year survival was 76%. The University of California, Los Angeles (UCLA)/Cedars-Sinai, reported on 25 cases of both intrahepatic and extrahepatic CCA. One-year survival was 71% and 3-year survival was 35%. The University of Pittsburgh found 1-year survival of 70% and 18% 5-year survival among 20 patients with intrahepatic CCA. A German study of 24 patients reported the poorest results.
Only two articles reported recurrence data using survival analysis techniques. In a series of 38 patients from the Mayo Clinic, cumulative recurrence was 0% at 1 year, 5% at 3 years, and 13% at 5 years. The series of 20 patients from the University of Pittsburgh experienced 67% 1-year tumor-free survival and a 31% 5-year rate. The multicenter Spanish series reported crude recurrence rates of 53% and 36% for extrahepatic and intrahepatic CCA, respectively. The German center at Hannover found a crude recurrence rate of 63%.
The Mayo Clinic remains the only center that has published outcome data for transplantation following neoadjuvant radiochemotherapy. In a 2008 review, Heimbach considers the published outcomes of the combined protocol in the context of recent data on outcomes for surgical resection, and concludes that outcomes of neoadjuvant chemoradiotherapy with subsequent liver transplantation for patients with early-stage hilar CCA that is unresectable, or arising in the setting of PSC, are comparable to transplantation for patients with HCC and other chronic liver diseases and superior to resection. The author describes intraoperative challenges attributable to the neoadjuvant therapy including severe inflammatory changes and dense fibrosis and suggests that key principles to be considered by centers considering use of the combined protocol include a multidisciplinary approach, pretransplant staging, inclusion of only patients without lymph node metastasis, replacement of irradiated vessels (when possible) and monitoring for postoperative vascular complications. Wu et al. describe an extensive surgical procedure combined with radiotherapy. They retrospectively review their experience with surveillance and early detection of CCA and en bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) in a small series of patients with early stage CCA complicating PSC. Surveillance involved endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, and cytological evaluation. Patients diagnosed with CCA were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple. CCA was detected in eight of the 42 patients followed up according to the surveillance protocol between 1988 and 2001, and six patients underwent OLT-Whipple. One died at 55 months after transplant of an unrelated cause without tumor recurrence, and five are without recurrence at 5.7–10.1 years.
In June, 2009, UNOS amended Policy 3.6 Allocation of Livers to state that candidates with cholangiocarcinoma may be eligible for a MELD/PELD exception when the following criteria are met:
- Centers must submit a written protocol for patient care to the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee before requesting a MELD score exception for a candidate with CCA. 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/UNOS Liver and Intestinal Organ Transplantation Committee.
- Candidates must satisfy diagnostic criteria for hilar CCA: malignant-appearing stricture on cholangiography and biopsy or cytology results demonstrating malignancy, carbohydrate antigen 19-9 100 U/mL, 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 (CT scan [computed tomography], ultrasound, MRI [magnetic resonance imaging]) demonstrate a mass, the mass should be 3 cm.
- Intra- and extra-hepatic metastases should be excluded by cross-sectional imaging studies of the chest and abdomen at the time of initial exception and every three 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.
Hepatitis C (HCV)
Mukherjee and Sorrell, reviewing controversies in liver transplantation for hepatitis C, indicate that the greatest opportunity for HCV eradication is pretransplant before hepatic decompensation. Challenges of treatment post-transplantation include immunosuppressive drugs, and abnormal hematologic, infectious, and liver function parameters. The authors list the following factors associated with poor outcomes in liver transplantation for recurrent HCV: high HCV-RNA level pretransplant, non-caucasian ethnicity, advanced donor age, T-cell depleting therapies, inappropriate treatment of Banff A1 ACR with steroid boluses, cytomegalovirus disease, and year of transplantation (worse with recent transplants). They cite the International Liver Transplantation Society Consensus on Retransplantation, which states that the following are associated with worse outcomes of retransplantation: total bilirubin level >10mg/dL, creatinine level >2 mg/dL, age >55 years, development of cirrhosis in the first post-transplant year, and donor age >40 years.
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