ORIGINAL ARTICLE. Liver Transplantation for the Treatment of Liver Metastases From Neuroendocrine Tumors

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1 ORIGINAL ARTICLE Liver Transplantation for the Treatment of Liver Metastases From Neuroendocrine Tumors An Analysis of the UNOS Database Roberto Gedaly, MD; Michael F. Daily, MD; Daniel Davenport, PhD; Patrick P. McHugh, MD; Alvaro Koch, MD; Paul Angulo, MD; Jonathan C. Hundley, MD Objective: To determine outcomes in patients undergoing liver transplantation (LT) for metastatic neuroendocrine tumors (NETs). Design: Retrospective analysis. Setting: University of Kentucky Medical Center. Patients: Patients undergoing LT performed for NET metastases from October 1, 1988, through January 31, 2008, were analyzed using the United Network for Organ Sharing database. Main Outcome Measure: Patient survival. Results: During the study period, LTs were performed. One hundred fifty LTs were performed for metastatic NETs. Among those 150 patients undergoing LT, 51 patients (34.0%) had carcinoid, 6 had insulinoma (4.0%), 3 had glucagonoma (2.0%), 11 had gastrinoma (7.3%), and 9 had vasoactive intestinal peptide secreting tumors (6.0%); an additional 70 (46.7%) had an unspecified NET. The mean (SE) age of the patients was 45.1 (12.5) years. The mean (SE) cold ischemic time was 8.9 (4.1) hours. One hundred forty-four patients were adults and 6 were children. Thirteen patients received another organ at the time of LT. During the same period, 4693 patients underwent transplantation for hepatocellular carcinoma. Overall, 1-, 3-, and 5-year survival rates for patients with NETs undergoing isolated LT were 81%, 65%, and 49%, respectively. No difference in survival was observed in patients with carcinoid vs noncarcinoid tumors (P=.84). No significant difference was observed in patient survival between those with metastatic NETs and those with hepatocellular carcinoma. Patients waiting for LT longer than 2 months had improved survival (P=.005). Conclusions: Patients with liver metastases from NETs who were undergoing LT had long-term survival similar to that of patients with hepatocellular carcinoma. Longer wait times were associated with better outcomes in our series. Waiting for disease to stabilize before considering patients with liver metastases from NETs for transplantation may be appropriate. Excellent results can be obtained in highly selected patients. Arch Surg. 2011;146(8): Author Affiliations: Transplant Center, University of Kentucky College of Medicine, Lexington. NEUROENDOCRINE TUmors (NETs) arise from the widespread neuroendocrine system 1 and include carcinoid tumors, pancreatic islet cell tumors (ie, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide secreting tumors, and somatostatinoma), paragangliomas, pheochromocytomas, and medullary thyroid carcinomas. These tumors can be placed into 2 broad categories. The first group has high-grade malignant neoplasms and a characteristic, small-cell, undifferentiated or anaplastic appearance by light microscopy. These conditions are characterized as poorly differentiated neuroendocrine carcinomas. The second group has variable but most often indolent biologic behavior and characteristic, well-differentiated histologic features that arise primarily in the gastrointestinal tract but also appear in the lungs, kidneys, and ovaries. 1 Gastrointestinal NETs are usually slow growing and are diagnosed at late stages. When metastases occur, the liver is by far the most commonly involved organ (ie, 40%-93% of the time), followed by the lung and bone. 1,2 Several different approaches have been used to treat patients with liver metastases from NETs, including surgery, transplantation, transarterial embolization or chemoembolization, radiofrequency ablation, chemotherapy, and somatostatin analogues. 3 Surgery remains the treatment of choice when the primary tumor has been resected and the metastatic dis- 953

2 Cumulative Survival Time, mo ease is confined to the liver. Even in patients with unilobar disease without evidence of extrahepatic disease, the recurrence rate is high. 1,4 Surgical resection is still an excellent form of palliation, especially in patients with symptoms. Nagorney et al 5 proposed that surgical resection in metastatic NETs is indicated if the primary tumor is resectable and if 90% of the metastases in the liver are resectable or are amenable for ablation. They have reported a 4-year survival rate of 75% with this approach. 5 Of interest, they showed no difference in survival between patients undergoing complete resection and those undergoing incomplete resection, defined as at least 90% of tumor excision. 5 Other reports have shown that resection of liver metastases from NETs may achieve 5-year survival rates in the range of 47% to 92%, with resolution of symptoms in more that 90% and very low operative mortality. 6,7 Sarmiento et al 4 from the same group reported a disease-free 5-year survival rate of only 16%, recognizing that tumor recurrence has been a major problem after liver resection. In the past few years, there has been increasing interest in determining the usefulness of liver transplantation (LT) for the treatment of liver metastases of NETs. The reported 5-year survival rate using LT to treat liver metastases from NETs ranges from 36% to as high as 80% Unfortunately, only a small number of studies have been published to date, limited by the small sample size, precluding meaningful conclusions. Therefore, the aim of our study was to determine the outcomes of a large number of patients undergoing LT for metastatic NETs. We used the United Network of Organ Sharing (UNOS) database, which includes all patients who underwent transplantation in the United States for metastatic NETs during a 20-year period. METHODS The UNOS database was analyzed for all patients undergoing transplantation in the United States from October 1, 1988, through January 31, Data from all patients undergoing LT for metastatic NETs were captured for analysis. Of LT procedures, 150 were performed for metastatic NETs. For patients identified as having metastatic NETs, data collected Type Carcinoid NET Noncarcinoid NET Carcinoid NET censored Noncarcinoid NET censored Figure 1. Patient survival after liver transplantation for carcinoid (n=51) vs noncarcinoid (n=99) neuroendocrine tumors (NETs) (Mantel-Cox log rank test, P=.84). included recipient age, sex, type of NET, serum creatinine level, total bilirubin level, international normalized ratio, coexisting liver disease, height and weight at the time of transplantation, blood type, presence of pretransplantation portal vein thrombosis, length of hospital stay, number of living vs deceased donors, incidence of multiorgan transplantations, incidence of acute cellular rejection at 6 months, tumor recurrence, and survival. Body mass index was calculated as weight in kilograms divided by height in meters squared. Donor characteristics, including age, cold ischemia time, and fatty infiltration, also were identified. Information from all patients with a diagnosis of hepatocellular carcinoma (HCC) was recorded to compare patient survival. Recurrence information was only available since October For that reason, we excluded patients who underwent LT before 1999 to calculate the recurrence rate (83 patients underwent LT after 1999 for liver metastases of NETs). Recurrence was defined by observation of tumor recurrence by imaging (eg, computed tomography or ultrasonography) or by histologic confirmation. We compared categorical variables by the 2 test and continuous variables by analysis of variance. Survival was determined by the Kaplan-Meier test. The log rank test was used to analyze the differences in survival by the Kaplan-Meier analysis. P.05 was considered significant. Statistical analysis was performed using SPSS software, version (SPSS Inc, Chicago, Illinois). RESULTS From October 1, 1988, through January 31, 2008, LTs were recorded in the UNOS database. Among these, 150 LTs were performed for metastatic NETs. Fifty-one patients (34.0%) had metastatic carcinoid, 6 (4.0%) had insulinoma, 3 (2.0%) had glucagonoma, 11 (7.3%) had gastrinoma, 9 (6.0%) had vasoactive intestinal peptide secreting tumors, and 70 (46.7%) underwent LT for unspecified NETs. The mean (SE) age of the patients was 45.1 (12.5) years, ranging from 11 to 69 years, and 84 patients (56.0%) were male. Seventy-nine patients (52.7%) had blood type A, 3 (2.0%) had type AB, 19 (12.7%) had type B, and 49 (32.7%) had type O. The mean (SE) cold ischemic time was 8.9 (4.1) hours, and the mean (SE) warm ischemic time was 46.1 (14.9) minutes. The mean (SE) donor age was 34.9 (17.5) years, ranging from 6 to 81 years. One hundred forty-four patients were adults and 6 were children. Seventy-five patients (50.0%) had had previous abdominal surgery. Three patients (2.0%) were diagnosed as having pretransplantation portal vein thrombosis. The mean (SE) total bilirubin level was 3.3 (8.9) mg/dl (to convert to micromoles per liter, multiply by ), the mean (SE) international normalized ratio was 1.17 (0.37), and the mean (SE) creatinine level was 1.3 (1.72) mg/dl (to convert to micromoles per liter, multiply by 88.4). The mean (SE) posttransplantation length of stay was 22.2 (23.6) days, ranging from 3 to 160 days. One patient had a positive serologic test result for hepatitis C virus. One hundred thirty-three patients (88.7%) underwent LT only. In 13 patients at least 1 other organ was transplanted, 4 patients underwent intestinal transplantation, 2 underwent kidney transplantation, and 15 underwent pancreas transplanta- 954

3 Table 1. Survival of Patients With NETs and HCC Treated With Liver Transplantation Survival, Mean (SE), % Tumor Type 1 Year 3 Years 5 Years Carcinoid NET graft (n=51) 71 (7) 51 (8) 44 (8) Noncarcinoid NET graft (n=99) 75 (4) 62 (5) 44 (6) Carcinoid NET patient survival (n=51) 76 (6) 55 (8) 47 (8) Noncarcinoid NET patient survival (n=99) 82 (4) 68 (5) 48 (7) Isolated OLT NET patient survival (n=133) 81 (4) 65 (5) 49 (6) NET patient survival (n=150) 80 (3) 64 (5) 48 (5) HCC patient survival (n=4693) 83 (1) 67 (1) 58 (1) Hepatitis C patient survival (n=18 875) 85 ( 1) 76 ( 1) 68 ( 1) Other liver disease patient survival (n=10 000) 85 ( 1) 78 ( 1) 73 ( 1) HCC patient survival for 1997 or earlier (before Milan) (n=775) a 71 (2) 52 (2) 43 (2) HCC patient survival after 1997 (after Milan) (n=3918) 86 (1) 71 (1) 62 (1) HCC patient survival for 2003 or earlier (before upgrade) (n=2062) b 79 (1) 64 (1) NA HCC patient survival after 2003 (after upgrade) (n=2631) 87 (1) 70 (1) NA Abbreviations: HCC, hepatocellular carcinoma; NA, not applicable; NETs, neuroendocrine tumors; OLT, orthotopic liver transplantation. a P=.57. b P.005. tion. One hundred forty patients (91.3%) underwent cadaveric LT; 3 of those were partial grafts. Ten patients (6.7%) underwent living donor LT. The incidence of acute cellular rejection within 6 months after transplantation was 12%. Tumor recurrence was seen in 26 of 83 patients who underwent LT after 1999, when information about tumor recurrence became available. Of these 26 patients, the median time to recurrence was 17 months (range, months). Regarding the site of recurrence, the UNOS database reported primary organ for 7 patients, adjacent organs for 9 patients, regional lymph nodes for 9 patients, and distant metastases for 10 patients. The median wait time was 67 days. During the same period, 4693 patients underwent transplantation for HCC. Cumulative Survival Time to Cancer Recurrence or Mortality, mo Survival function Censored PATIENT AND GRAFT SURVIVAL FOR NETs Overall, 1-, 3-, and 5-year survival rates were 81%, 65%, and 49%, respectively, in patients undergoing isolated LT for metastatic NETs, with a mean (SE) follow-up of 36.8 (43.2) months. When multivisceral transplant recipients were combined with those undergoing isolated LT, the overall 1-, 3-, and 5-year patient survival rates were almost identical, that is, 80%, 64%, and 48%, respectively. No significant difference in survival was observed in patients with carcinoid vs noncarcinoid tumors (P=.84) (Figure 1). Patients who received carcinoid subtype transplants had a mean (SE) survival of 40.5 (50.6) months and 1-, 3-, and 5-year patient and graft survival rates of 76%, 55%, and 47%, respectively, and 71%, 51%, and 44%, respectively. The 5-year survival rate was 49% in patients younger than 55 years compared with 37% in older recipients, but this finding was not statistically different (P=.16) (Table 1). Of the 83 patients from whom recurrence information is available, the disease-free survival rate was 77% at 1 year, 50% at 3 years, and 32% at 5 years. Figure 2 demonstrates the diseasefree survival curve in these patients. Figure 2. Cancer-free survival in 83 patients receiving liver transplants for neuroendocrine tumors. SURVIVAL AND WAIT TIME The median wait time for patients undergoing transplantation for metastatic NETs is 67 days. We calculated survival before and after 67 days and found that patients who underwent transplantation after that time had better outcomes compared with those with shorter wait times (63% vs 36% at 5 years, respectively; P=.005; Figure 3). Table 2 demonstrates survival by quartile of wait time. SURVIVAL OF NET PATIENTS AND THOSE WITH HCC Patients undergoing transplantation for HCC in the same period (n=4693) had 1-, 3-, and 5-year survival rates of 83%, 71%, and 62%, respectively. Survival in patients who underwent transplantation for HCC before 1997 was significantly shorter (P.001) (Table 1), as well as in HCC patients who underwent transplantation before 2003, when the Model for End-Stage Liver Disease (MELD) upgrade was implemented (P.001). Figure 4 illustrates 955

4 Cumulative Survival, % Wait > 67 days No Yes Not censored Censored Cumulative Survival, % Type NETs HCCs NETs censored HCCs censored Time, mo Time, mo Figure 3. Patient survival after liver transplantation for neuroendocrine tumors (NETs) by wait time longer than a median of 67 days. Dividing the patients into before 1998 and 1998 or after, hepatocellular carcinoma vs NETs is not significantly different (P=.57). Looking at NETs in patients older than 55 years and 55 years or younger, the mean (SE) 5-year survival rate was 50% (6%) vs 42% (11%) (log-rank P=.15). Table 2. Five-Year Survival Rates in Liver Transplantation Patients for Neuroendocrine Tumors by Quartile of Wait Time Wait Time, d No. of Patients 5-Year Survival, Mean (SE), % (9) (12) (11) (9) the survival curves of patients who underwent transplantation for metastatic NETs and those who underwent transplantation for HCC; no significant difference in survival was observed between these 2 groups (P=.20). Patient survival rates at 1 and 3 years in those with metastatic NETs were 80% and 64%, respectively, compared with 87% and 70%, respectively, in those with HCC. COMMENT Liver transplantation has been considered part of the treatment algorithm for patients with the metastatic form of NETs at several centers in Europe and the United States. Unfortunately, initial results with transplantation were disappointing, probably as a consequence of poor patient selection. Liver transplantation traditionally has been limited to individuals with limited tumor bulk, absence of disseminated disease, and biologically favorable features. The presence of noncarcinoid tumors or high-grade neuroendocrine carcinomas, nongastrointestinal carcinoids, or tumors not drained by the portal vein are considered to be associated with worse outcomes. 9,10 Several experts believe that only gastrointestinal tumors with portal drainage can be considered to have the liver as the first station and that other primary sites, such as the low rectum, esophagous, lung, adrenal glands, and thyroid, may Figure 4. Survival is comparable after liver transplantation for patients with hepatocellular carcinoma (HCC) (n=4693) vs patients with neuroendocrine tumors (NETs) (n=150) (Mantel-Cox log rank test, P=.23). have systemic disease by the time the liver shows metastases. Also, it has been reported that excision of the primary tumor at the time of LT is associated with worse outcomes. 8,11 The use of somatostatin analogues has been proposed in patients awaiting transplantation to control symptoms but also to induce apoptosis and to decrease expression of insulin-like growth factor 1 and vascular endothelial growth factor, helping to control tumor progression. These analogues also have been used after transplantation. 12 Transarterial chemoembolization and metaiodobenzylguanidine labeled with iodine 131 ( 131 I-MIBG) in patients with MIBG expression can be attempted to alleviate symptoms in the hope of maintaining disease stability before LT. In some patients, this approach can be associated with extensive tumor necrosis. 13,14 These measures seem reasonable by themselves or in combination, especially if the transplant team elects to wait and to observe disease stability. It is critical to determine tumor burden before surgery. The development and use of diagnostic techniques, such as pentetreotide labeled with indium 11, 131 I-MIBG, positron emission tomography with fluorodeoxyglucose 18 or fluorinated dihydroxyphenylalanine and, more recently, magnetic resonance imaging with liver-specific contrast, identify advanced lesions not suitable for surgical treatment, including LT. 15 This approach may improve outcomes by improving patient selection. Several authors have proposed criteria to select patients for transplantation. These criteria include carcinoid tumors, patient age younger than 55 years, less than 50% liver parenchyma involvement, stomach or intestinal origin with portal drainage from the primary cancer, and tumor removed in a previous surgery with stable disease for at least 6 months before transplantation, which are associated with improved outcomes. 1 Age previously has been proposed as part of the selection criteria in this group of patients. In this study, recipients older than 55 years had worse long-term outcomes compared with younger recipients, showing 5-year survival rates of 50% and 42%, respectively; 956

5 Table 3. Five-Year Survival Rates in Liver Transplantation Patients for Neuroendocrine Tumors by Age and Wait Time 5-Year Survival, Mean (SE), % (N=150) Wait Time, d Age 55 Years Age 55 Years (8) 17 (14) (8) 62 (14) however, this finding was not statistically significant. Although patients with carcinoid histologic characteristics were found to have slightly better long-term outcomes, survival was not statistically different compared with patients with other noncarcinoid NETs undergoing LT. Our series demonstrated that patients undergoing transplantation for metastatic NETs have similar 1-, 3-, and 5-year survival rates compared with patients undergoing transplantation for HCC (n=4693). Patients undergoing transplantation for HCC after 2003 received a MELD score upgrade exception and demonstrated better patient survival that those undergoing transplantation during the previous period. Our data showed that patients undergoing transplantation for HCC after 2003 had a 3-year survival rate of 70% compared with 64% for recipients undergoing transplantation for liver metastases from NETs. Tumor recurrence was 31% in patients with liver metastases from NETs, similar to rates reported previously. 9,10 This rate is higher when compared with rates in the range of 10% to 15% reported for patients undergoing transplantation for HCC Patients undergoing transplantation for HCC in recent series reporting these rates of recurrence use some type of selection criteria (eg, Milan or University of California, San Francisco) that has been shown to improve outcomes. We currently do not have a well-established system to select patients for transplantation in recipients with NET metastases to the liver. Once patients undergoing transplantation for more than 1 organ were excluded, the survival of isolated liver transplant recipients was slightly better, showing 1-, 3-, and 5-year survival rates of 81%, 65%, and 49%, respectively. Of interest, patients waiting more than 2 months after listing have significantly better outcomes. Patients waiting longer were associated with excellent 5-year survival rates in the range of 60% or better regardless of their age. Older patients with shorter wait times had worse outcomes (Table 3). The strength of our study comes not only from the large number of patients included in the database and the ability to compare a large number of individuals undergoing transplantation for metastatic NETs with patients undergoing transplantation for HCC but also from its clinically robust and uniform definitions of patient characteristics and events. However, our study has some limitations mostly related to the use of the UNOS database, which was not developed to study this specific patient population. For that reason, key variables were not captured, such as specific histologic data (eg, tumor size, location, number, percentage of liver parenchyma involved with tumor, and cell differentiation), characteristics and treatment of the primary tumor, the presence of an unspecified NET diagnosis in the UNOS database (which likely could represent nonfunctioning NETs because tumors such as insulinomas, glucagonomas, and vasoactive intestinal peptide secreting tumors are coded by their specific names), pretransplantation and posttransplantation treatments, and pretransplantation imaging used to determine the extent of the disease. In conclusion, our series demonstrates that patients with liver metastases from NETs have survival rates not significantly different from those undergoing transplantation for HCC, which is the most common transplantation indication for cancer. Longer wait time was associated with better outcomes in patients with metastatic NETs to the liver. This finding supports the recommendation of experts who have suggested that only patients with stable disease should undergo transplantation. Waiting for the disease to stabilize followed by a MELD score upgrade to prioritize these patients seems to be a reasonable approach. Although our data indicate that patients with carcinoid tumors have slightly better longterm outcomes compared with those with noncarcinoid tumors, overall survival was not found to be significantly different. Although surgical resection still should be considered the treatment of choice in patients with liver metastases from NETs, transplantation for unresectable disease is indicated in patients with stable disease without disseminated metastases. A national database should be developed to better understand predictors of outcomes in this patient population and to help produce and standardize selection criteria to obtain better outcomes. We believe it is time to carefully revise this indication. Accepted for Publication: June 30, Correspondence: Roberto Gedaly, MD, Transplant Center, University of Kentucky College of Medicine, 800 Rose St, Room C451, Lexington, KY (rgeda2@uky.edu). Author Contributions: Study concept and design: Gedaly, Davenport, McHugh, and Koch. Acquisition of data: Gedaly and McHugh. Analysis and interpretation of data: Gedaly, Daily, Davenport, Angulo, and Hundley. Drafting of the manuscript: Davenport and McHugh. Critical revision of the manuscript for important intellectual content: Gedaly, Daily, Koch, Angulo, and Hundley. Statistical analysis: Gedaly. Administrative, technical, and material support: Gedaly, Daily, Davenport, McHugh, Angulo, and Hundley. Study supervision: Gedaly and Davenport. Financial Disclosure: None reported. REFERENCES 1. Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol. 2007;47(4): Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg. 1995;169(1): Öberg K, Astrup L, Eriksson B, et al; Nordic NE Tumour Group. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms), part II specific NE tumour types. Acta Oncol. 2004;43(7):

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