American Journal of Transplantation 2015; 15: 2704–2711 Wiley Periodicals Inc.
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13306
The Use of Donation After Cardiac Death Allografts Does Not Increase Recurrence of Hepatocellular Carcinoma K. P. Croome*, D. D. Lee, J. M. Burns, K. Musto, D. Paz, J. H. Nguyen, D. K. Perry, D. M. Harnois and C. B. Taner Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL Corresponding author: Kristopher P. Croome, [email protected]
Hepatocellular carcinoma (HCC) recurrence in patients undergoing liver transplantation (LT) with donation after brain death (DBD) and donation after cardiac death (DCD) allografts has not previously been investigated. Rates and patterns of HCC recurrences were investigated in patients undergoing DBD (N ¼ 1633) and DCD (N ¼ 243) LT between 2003 and 2012. LT for HCC was identified in 397 patients (340 DBD and 57 DCD). No difference in tumor number (p ¼ 0.26), tumor volume (p ¼ 0.34) and serum alphafetoprotein (AFP) (p ¼ 0.47) was seen between the groups. HCC recurrence was identified in 41 (12.1%) patients in the DBD group and 7 (12.3%) patients in the DCD group. There was no difference in recurrence-free survival (p ¼ 0.29) or cumulative incidence of HCC recurrence (p ¼ 0.91) between the groups. Liver allograft was the first site of recurrence in 22 (65%) patients in the DBD group and two (37%) patients in the DCD group (p ¼ 0.39). LT for HCC with DBD and DCD allografts demonstrate no difference in the rate of HCC recurrence. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database. Abbreviations: CI, confidence interval; CIT, cold ischemia time; CT, computed tomography; DCD, conation after cardiac death; DBD, donation after brain death; HCC, hepatocellular carcinoma; IRI, ischemia reperfusion injury; LT, liver transplant; MELD, model for endstage liver disease; SD, standard deviation; WIT, warm ischemia time Received 02 January 2015, revised 12 February 2015 and accepted for publication 08 March 2015
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Introduction The proportion of patients in the United States undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) has increased substantially over the last 10 years. Prior to 2002, transplantation for HCC accounted for only 5% of all LT performed; however, it increased to 22% of LT performed in 2012 (1). Under the current national system, patients with HCC receiving priority for LT have been consistently advantaged over nonHCC candidates resulting in longer wait times and higher waitlist mortality for nonHCC candidates (2,3). Donation after cardiac death (DCD) liver allografts have been pursued as one option to address the growing discordance between organ supply and demand by increasing the pool of available organs. Previous reports have demonstrated that proportionately DCD livers are used more frequently than donation after brain death (DBD) livers in patients with HCC (20.2% vs. 13%) (4,5). This is likely due to increasing tendency to use extended criteria organs in recipients with lower biological Model for End-Stage Liver Disease (MELD) scores because of the perception that these recipients are better able to tolerate an extended criteria organ (6). While DCD provide much needed liver allografts, the optimal use of these organs is yet to be fully elucidated (7). Previous studies examining data from the Scientific Registry of Transplant Recipients (SRTR) database have demonstrated inferior survival for recipients with HCC of DCD allografts in comparison to recipients of DBD allografts. Survival difference remained even after adjustments for the inherent inferiority observed in DCD allografts as well as other known risk factors (8). While it was postulated that the difference in survival could reflect an increased rate in the recurrence of HCC, the SRTR database does not contain specific data related to recurrence. In order to adequately address the question of HCC recurrence in DCD allografts, center-specific data from a highvolume program with detailed pathologic analysis and follow-up are needed. The present study aimed to compare the rate, timing and distribution of recurrences of HCC in patients undergoing transplantation with DBD and DCD allografts based on data from a center performing highvolume LT using DCD allografts.
No Difference in Recurrence of HCC in DCD and DBD
Materials and Methods This retrospective study was performed with approval of the Mayo Clinic Institutional Review Board. Data were acquired from patient medical records, outside medical records and from a prospectively maintained database on all patients who underwent LT. All patients undergoing LT with diagnosis of HCC between the dates of January 1, 2003 and December 31, 2012 were identified. Patients were divided into two groups depending on whether they received a DBD or DCD allograft. The primary outcome measure was HCC recurrence. Time to recurrence was calculated from the date of LT until the first identification of recurrent disease. Survival was calculated from the date of LT to death or last known follow-up. The techniques of DCD at our center have previously been described in detail (9,10). Potentially confounding donor and recipient factors examined included the following: all components of the donor risk index (DRI) (11), recipient age, MELD score, BMI, sex, liver disease etiology, ventilation at the time of LT and medical condition before LT. For DCD donors, donor warm ischemia time (DWIT) was defined as the time from withdrawal of both ventilator and cardiac support to the time of aortic cross clamping (9). Cold ischemia time (CIT) was defined as the time from infusion of cold preservation solution until portal reperfusion of the liver allograft in the recipient. Pretransplant HCC tumor characteristics (e.g. number, size and serum alphafetoprotein [AFP]) were taken from the closest available data to the time of LT. The total tumor volume (TTV) was calculated by the addition of the volumes of each HCC [(4/3)pr3], which were based on the maximum radiological radius of each tumor (12). Both time from original diagnosis of HCC and time from listing at our center until transplantation were recorded. Pretransplant treatments of HCC were recorded if they occurred at any time between HCC diagnosis and LT. Time from first transarterial chemoembolization (TACE) treatment or time from first radiofrequency ablation (RFA) treatment until transplantation were also recorded. Posttransplant HCC characteristics were based on pathologic analysis included size, number, grade, perineural invasion, perivascular invasion and nodal status. Downstaging was only considered successful if complete response of the lesion in question was seen on final explant pathology. All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX). Differences between groups were analyzed using the unpaired ttest for continuous variables and by the x2 test or continuity correction method for categorical variables. Wilcoxon rank-sum was used for variables that did not display a normal distribution. Survival curves for patient or recurrencefree survival were generated using the Kaplan–Meier method and compared by the log-rank test. All statistical tests were two-sided and differences were considered significant when p < 0.05. A competing risk analysis of cumulative incidence of recurrence of HCC was also performed. Using this method, the cumulative incidence function for an event of interest was calculated by appropriately accounting for the presence of competing risk events (in this scenario noncancer death) (13). Cumulative incidences of recurrence were compared using the log-rank test. A univariate Cox proportional hazard model predicting survival was performed. All variables were then used to perform a multivariate Cox proportional hazard model with backwards stepwise selection. A liberal retention criterion of p < 0.10 level of significance during the backward stepwise search was used (14).
Results Between January 1, 2003 and December 31, 2012, a total of 1876 LT were performed (243 DCD and 1633 DBD) at our American Journal of Transplantation 2015; 15: 2704–2711
program. Of these, 397 patients (21%) underwent LT for HCC. DBD donor allografts were used for 340 LT, while DCD donors were used for 57 LT. Donor characteristics for the two groups can be seen in Table 1. DBD donors had a slightly older mean age than DCD donors (46.3 17.4 vs. 38.1 17.4 years, p < 0.001), had a longer CIT (6.6 1.7 vs. 5.9 1.3 h, p ¼0.003) and were less likely to be Caucasian (66.2% vs. 80.7%, p ¼ 0.03). Recipients of DBD and DCD allografts were similar in age, biological MELD score at the time of LT, exception points, BMI and sex. A lower proportion of patients in the DBD group (57%) were hepatitis C–positive compared to patients in the DCD group (78%) (p ¼ 0.004). Recipient characteristics for the two groups are illustrated in Table 1. Pretransplant tumor characteristics of the two groups can be seen in Table 2. Based on pretransplant imaging, there were no significant differences in mean tumor number (p ¼ 0.26) or mean TTV (p ¼ 0.34) between the recipients of DBD and DCD allografts. Mean serum AFP level and the proportion of patients with serum AFP >400 ng/mL at listing were similar between the groups, p ¼ 0.47 and p ¼ 0.66, respectively. There was no difference in the proportion of patients initially within Milan criteria in the DBD (80%) and DCD (82.5%) groups, respectively (p ¼ 0.67). In the DBD group, 29 patients (8.5%) were initially beyond Milan criteria but within University of California, San Francisco (UCSF) criteria; of which 10 were successfully downstaged to within Milan criteria based on review of explant pathology. In the DCD group, five patients (8.8%) were initially beyond Milan criteria but within UCSF criteria, of which three were successfully downstaged to within Milan criteria. A total of 39 patients (11.5%) in the DBD group and five patients (8.8%) in the DCD group were beyond Milan and UCSF criteria initially, with 25 patients and four patients, respectively, being successfully downstaged to within Milan criteria based on final pathology. Time from initial diagnosis of HCC (211 vs. 230 days) and time from listing for transplant at our center until transplant (68 vs. 71 days) were not significantly different between the DBD and DCD groups. A similar proportion of patients in the DBD (74%) and DCD groups (81%) underwent pretransplant treatment of their HCC (p ¼ 0.31). TACE was performed in 65% of patients in each group, while RFA was performed in 10% of patients in the DBD group and 16% of patients in the DCD group (p ¼ 0.17). Time from first TACE treatment until transplant and time from first RFA treatment until transplant were not different between the DBD and DCD groups. Based on pathological analysis of the explanted native livers, posttransplant tumor characteristics can be seen in Table 3. Both mean tumor number (2.0 1.5 vs. 2.20 1.5, p ¼ 0.35) and TTV (34.6 90.4 vs. 23.6 31.6 cm, p ¼ 0.36) were similar between the DBD and DCD groups. Proportion 2705
Croome et al Table 1: Donor characteristics and recipient characteristics
Donor characteristics Age (years) Height (cm) Body mass index (kg/m2) Gender (male) Asystole to CC (minutes) Donor warm ischemia time (minutes) Cold ischemia time (hours) Rewarming anast. time (minutes) Race/ethnicity White Black Other Causes of death Anoxia Stroke Trauma Other Regional/national sharing Local Regional National DRI Recipient characteristics Age at transplant (years) Biologic MELD score HCC MELD exception points Body mass index (kg/m2) Gender (male) Liver disease etiology Hepatitis C virus serology positive ([ alcohol] HBV) HBV Alcohol NASH Primary biliary cirrhosis Hemochromatossis Primary sclerosing colangitis Alpha 1-antitrypsin deficiency Other
DBD (N ¼ 340)
DCD (N ¼ 57)
p-value
46.3 17.4 170.6 10.6 28.7 7.5 199 (58.5%) NA NA 6.6 1.7 33.0 0.6
38.1 13.6 173.3 10.0 27.3 7.8 42 (73.7%) 9.4 6.2 24.8 10.0 5.9 1.3 30.7 1.1
10 h was associated with higher HCC recurrence (27). In the present study, very few patients had CIT >10 h (3.5%). Relatively tight distribution of CIT for both DBD and DCD allografts in our experience does not allow us to speculate on effects of CIT in HCC recurrence. Ischemic risk factors specific to DCD allografts, WIT and time from asystole until cross clamp, did not show any correlation with HCC recurrence in the present study. We acknowledge that waitlist dynamics are variable from center to center and country to country. We are a large transplant referral center and as such receive a large number of patients that are referred to our center after initially being worked-up and even treated (TACE, etc.) at outside centers. In addition, we have a proportion of patients who travel from other parts of the country where they are already listed for transplantation at another center because we have shorter wait times in our geographic region. Nonetheless, we credit our aggressive use of DCD organs, at least in part, to the short wait times and a low waitlist drop-out rate of 7.2% at our center.
however, accuracy of explant and recurrence data would be paramount. It is unlikely that registry data will provide data with adequate granularity to address the question of HCC recurrence in this population. The limited number of patients may have resulted in a type 2 error for detecting differences in disease progression. In conclusion, the present study compares well-matched groups of recipients with HCC undergoing LT with DBD and DCD allografts and demonstrates no difference in the rate of HCC recurrence. The present study contains detailed explant pathology data and complete recurrence data that cannot be obtained from larger registry studies. The pattern of location of first HCC recurrence was also not significantly different between the groups. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database.
Authors’ Contributions Kris Croome, Justin M. Burns, Justin Nguyen, David D. Lee, Dana K. Perry, Denise Harnois and C. Burcin Taner participated in research design. Kris P. Croome and C. Burcin Taner participated in the writing of the paper. Kris P. Croome, David D. Lee, Diego Paz, Justin M. Burns, Denise M. Harnois and Kaitlyn Musto participated in the performance of the research. Kris Croome, David D. Lee and C. Burcin Taner participated in data analysis.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References
This study aimed to fill a void in our understanding of best use of DCD liver grafts. Limitations of the present study include its retrospective design as well as it representing data from a single center. Even though this is the largest reported single-center experience, the number of patients is relatively limited for adjustments for all the risk factors for HCC recurrence. While our LT program currently has the largest DCD experience, a multi-institutional study with detailed follow-up on HCC recurrence could be valuable;
1. Halazun KJ, Patzer RE, Rana AA, et al. Standing the test of time: Outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. Hepatology 2014; 60: 1957–1962. 2. Goldberg D, French B, Abt P, Feng S, Cameron AM. Increasing disparity in waitlist mortality rates with increased model for endstage liver disease scores for candidates with hepatocellular carcinoma versus candidates without hepatocellular carcinoma. Liver Transpl 2012; 18: 434–443. 3. Washburn K, Edwards E, Harper A, Freeman R. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant 2010; 10: 1643–1648. 4. Jay C, Ladner D, Wang E, et al. A comprehensive risk assessment of mortality following donation after cardiac death liver transplant—An analysis of the national registry. J Hepatol 2011; 55: 808–813.
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No Difference in Recurrence of HCC in DCD and DBD 5. Grewal HP, Willingham DL, Nguyen J, et al. Liver transplantation using controlled donation after cardiac death donors: An analysis of a large single-center experience. Liver Transpl 2009; 15: 1028–1035. 6. Schaubel DE, Sima CS, Goodrich NP, Feng S, Merion RM. The survival benefit of deceased donor liver transplantation as a function of candidate disease severity and donor quality. Am J Transplant 2008; 8: 419–425. 7. Croome KP, Marotta P, Wall WJ, et al. Should a lower quality organ go to the least sick patient? Model for End-Stage Liver Disease score and donor risk index as predictors of early allograft dysfunction. Transplant Proc 2012; 44: 1303–1306. 8. Croome KP, Wall W, Chandok N, Beck G, Marotta P, HernandezAlejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl 2013; 19: 1214–1223. 9. Taner CB, Bulatao IG, Perry DK, et al. Asystole to crossclamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. Transpl Int 2012; 25: 838–846. 10. Taner CB, Bulatao IG, Willingham DW, et al. Events in procurement as risk factors for development of ischeminc cholangiopathy in liver transplantation using donation after cardiac death donors. Liver Transpl 2012; 18: 101–112. 11. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006; 6: 783–790. 12. Toso C, Trotter J, Wei A, et al. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma. Liver Transpl 2008; 14: 1107–1115. 13. Fine J, Gray. R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509. 14. Croome KP, Farnell M, Que FG, Reid-Lombardo K, Nagorney D, Kendrick ML. Total laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: Oncologic advantages over open approaches? Ann Surg 2014; 260: 633–640. 15. Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death: The University of Wisconsin experience with liver transplantation. Ann Surg 2005; 242: 724–731. 16. Klein AS, Messersmith EE, Ratner LE, et al. Organ donation and utilization in the United States, 1999-2008. Am J Transplant 2010; 10: 973.
American Journal of Transplantation 2015; 15: 2704–2711
17. Bellingham JM, Santhanakrishnan C, Neidlinger N, et al. Donation after cardiac death: A 29-year experience. Surgery 2011; 150: 692– 702. 18. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010; 97: 744–753. 19. Saidi RF, Bradley J, Greer D, et al. Changing pattern of organ donation at a single center: Are potential brain dead donors being lost to donation after cardiac death? Am J Transplantation 2010; 10: 2536–2540. 20. Perry DK, Willingham DL, Sibulesky L, Bulatao IG, Nguyen JH, Taner CB. Should donation after cardiac death liver grafts be used for retransplantation? Ann Hepatol 2011; 10: 482– 485. 21. Taner CB, Bulatao IG, Arasi LC, et al. Liver transplantation in the critically ill: Donation after cardiac death compared to donation after brain death grafts. Ann Hepatol 2012; 11: 679– "685. 22. Wadei HM, Bulatao IG, Gonwa TA, et al. Inferior longterm outcomes of liver-kidney transplantation using donation after cardiac death donors: Single-center and organ procurement and transplantation network analyses. Liver Transpl 2014; 20: 728– 735. 23. van der Bilt JD, Kranenburg O, Nijkamp MW, et al. Ischemia/ reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology 2005; 42: 165–175. 24. Doi K, Horiuchi T, Uchinami M, et al. Hepatic ischemiareperfusion promotes liver metastasis of colon cancer. J Surg Res 2002; 105: 243–247. 25. Lee DD, Singh A, Burns JM, Perry DK, Nguyen JH, Taner CB. Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival. Liver Transpl 2014; 20: 1447–1453. 26. Croome KP, Wall W, Quan D, et al. Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts. Hepatobiliary Pancreat Dis Int 2012; 11: 372–376. 27. Nagai S, Yoshida A, Facciuto M, et al. Ischemia time impacts recurrence of hepatocellular carcinoma following liver transplantation. Hepatology 2015; 61: 895–904.
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13306
The Use of Donation After Cardiac Death Allografts Does Not Increase Recurrence of Hepatocellular Carcinoma K. P. Croome*, D. D. Lee, J. M. Burns, K. Musto, D. Paz, J. H. Nguyen, D. K. Perry, D. M. Harnois and C. B. Taner Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL Corresponding author: Kristopher P. Croome, [email protected]
Hepatocellular carcinoma (HCC) recurrence in patients undergoing liver transplantation (LT) with donation after brain death (DBD) and donation after cardiac death (DCD) allografts has not previously been investigated. Rates and patterns of HCC recurrences were investigated in patients undergoing DBD (N ¼ 1633) and DCD (N ¼ 243) LT between 2003 and 2012. LT for HCC was identified in 397 patients (340 DBD and 57 DCD). No difference in tumor number (p ¼ 0.26), tumor volume (p ¼ 0.34) and serum alphafetoprotein (AFP) (p ¼ 0.47) was seen between the groups. HCC recurrence was identified in 41 (12.1%) patients in the DBD group and 7 (12.3%) patients in the DCD group. There was no difference in recurrence-free survival (p ¼ 0.29) or cumulative incidence of HCC recurrence (p ¼ 0.91) between the groups. Liver allograft was the first site of recurrence in 22 (65%) patients in the DBD group and two (37%) patients in the DCD group (p ¼ 0.39). LT for HCC with DBD and DCD allografts demonstrate no difference in the rate of HCC recurrence. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database. Abbreviations: CI, confidence interval; CIT, cold ischemia time; CT, computed tomography; DCD, conation after cardiac death; DBD, donation after brain death; HCC, hepatocellular carcinoma; IRI, ischemia reperfusion injury; LT, liver transplant; MELD, model for endstage liver disease; SD, standard deviation; WIT, warm ischemia time Received 02 January 2015, revised 12 February 2015 and accepted for publication 08 March 2015
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Introduction The proportion of patients in the United States undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) has increased substantially over the last 10 years. Prior to 2002, transplantation for HCC accounted for only 5% of all LT performed; however, it increased to 22% of LT performed in 2012 (1). Under the current national system, patients with HCC receiving priority for LT have been consistently advantaged over nonHCC candidates resulting in longer wait times and higher waitlist mortality for nonHCC candidates (2,3). Donation after cardiac death (DCD) liver allografts have been pursued as one option to address the growing discordance between organ supply and demand by increasing the pool of available organs. Previous reports have demonstrated that proportionately DCD livers are used more frequently than donation after brain death (DBD) livers in patients with HCC (20.2% vs. 13%) (4,5). This is likely due to increasing tendency to use extended criteria organs in recipients with lower biological Model for End-Stage Liver Disease (MELD) scores because of the perception that these recipients are better able to tolerate an extended criteria organ (6). While DCD provide much needed liver allografts, the optimal use of these organs is yet to be fully elucidated (7). Previous studies examining data from the Scientific Registry of Transplant Recipients (SRTR) database have demonstrated inferior survival for recipients with HCC of DCD allografts in comparison to recipients of DBD allografts. Survival difference remained even after adjustments for the inherent inferiority observed in DCD allografts as well as other known risk factors (8). While it was postulated that the difference in survival could reflect an increased rate in the recurrence of HCC, the SRTR database does not contain specific data related to recurrence. In order to adequately address the question of HCC recurrence in DCD allografts, center-specific data from a highvolume program with detailed pathologic analysis and follow-up are needed. The present study aimed to compare the rate, timing and distribution of recurrences of HCC in patients undergoing transplantation with DBD and DCD allografts based on data from a center performing highvolume LT using DCD allografts.
No Difference in Recurrence of HCC in DCD and DBD
Materials and Methods This retrospective study was performed with approval of the Mayo Clinic Institutional Review Board. Data were acquired from patient medical records, outside medical records and from a prospectively maintained database on all patients who underwent LT. All patients undergoing LT with diagnosis of HCC between the dates of January 1, 2003 and December 31, 2012 were identified. Patients were divided into two groups depending on whether they received a DBD or DCD allograft. The primary outcome measure was HCC recurrence. Time to recurrence was calculated from the date of LT until the first identification of recurrent disease. Survival was calculated from the date of LT to death or last known follow-up. The techniques of DCD at our center have previously been described in detail (9,10). Potentially confounding donor and recipient factors examined included the following: all components of the donor risk index (DRI) (11), recipient age, MELD score, BMI, sex, liver disease etiology, ventilation at the time of LT and medical condition before LT. For DCD donors, donor warm ischemia time (DWIT) was defined as the time from withdrawal of both ventilator and cardiac support to the time of aortic cross clamping (9). Cold ischemia time (CIT) was defined as the time from infusion of cold preservation solution until portal reperfusion of the liver allograft in the recipient. Pretransplant HCC tumor characteristics (e.g. number, size and serum alphafetoprotein [AFP]) were taken from the closest available data to the time of LT. The total tumor volume (TTV) was calculated by the addition of the volumes of each HCC [(4/3)pr3], which were based on the maximum radiological radius of each tumor (12). Both time from original diagnosis of HCC and time from listing at our center until transplantation were recorded. Pretransplant treatments of HCC were recorded if they occurred at any time between HCC diagnosis and LT. Time from first transarterial chemoembolization (TACE) treatment or time from first radiofrequency ablation (RFA) treatment until transplantation were also recorded. Posttransplant HCC characteristics were based on pathologic analysis included size, number, grade, perineural invasion, perivascular invasion and nodal status. Downstaging was only considered successful if complete response of the lesion in question was seen on final explant pathology. All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX). Differences between groups were analyzed using the unpaired ttest for continuous variables and by the x2 test or continuity correction method for categorical variables. Wilcoxon rank-sum was used for variables that did not display a normal distribution. Survival curves for patient or recurrencefree survival were generated using the Kaplan–Meier method and compared by the log-rank test. All statistical tests were two-sided and differences were considered significant when p < 0.05. A competing risk analysis of cumulative incidence of recurrence of HCC was also performed. Using this method, the cumulative incidence function for an event of interest was calculated by appropriately accounting for the presence of competing risk events (in this scenario noncancer death) (13). Cumulative incidences of recurrence were compared using the log-rank test. A univariate Cox proportional hazard model predicting survival was performed. All variables were then used to perform a multivariate Cox proportional hazard model with backwards stepwise selection. A liberal retention criterion of p < 0.10 level of significance during the backward stepwise search was used (14).
Results Between January 1, 2003 and December 31, 2012, a total of 1876 LT were performed (243 DCD and 1633 DBD) at our American Journal of Transplantation 2015; 15: 2704–2711
program. Of these, 397 patients (21%) underwent LT for HCC. DBD donor allografts were used for 340 LT, while DCD donors were used for 57 LT. Donor characteristics for the two groups can be seen in Table 1. DBD donors had a slightly older mean age than DCD donors (46.3 17.4 vs. 38.1 17.4 years, p < 0.001), had a longer CIT (6.6 1.7 vs. 5.9 1.3 h, p ¼0.003) and were less likely to be Caucasian (66.2% vs. 80.7%, p ¼ 0.03). Recipients of DBD and DCD allografts were similar in age, biological MELD score at the time of LT, exception points, BMI and sex. A lower proportion of patients in the DBD group (57%) were hepatitis C–positive compared to patients in the DCD group (78%) (p ¼ 0.004). Recipient characteristics for the two groups are illustrated in Table 1. Pretransplant tumor characteristics of the two groups can be seen in Table 2. Based on pretransplant imaging, there were no significant differences in mean tumor number (p ¼ 0.26) or mean TTV (p ¼ 0.34) between the recipients of DBD and DCD allografts. Mean serum AFP level and the proportion of patients with serum AFP >400 ng/mL at listing were similar between the groups, p ¼ 0.47 and p ¼ 0.66, respectively. There was no difference in the proportion of patients initially within Milan criteria in the DBD (80%) and DCD (82.5%) groups, respectively (p ¼ 0.67). In the DBD group, 29 patients (8.5%) were initially beyond Milan criteria but within University of California, San Francisco (UCSF) criteria; of which 10 were successfully downstaged to within Milan criteria based on review of explant pathology. In the DCD group, five patients (8.8%) were initially beyond Milan criteria but within UCSF criteria, of which three were successfully downstaged to within Milan criteria. A total of 39 patients (11.5%) in the DBD group and five patients (8.8%) in the DCD group were beyond Milan and UCSF criteria initially, with 25 patients and four patients, respectively, being successfully downstaged to within Milan criteria based on final pathology. Time from initial diagnosis of HCC (211 vs. 230 days) and time from listing for transplant at our center until transplant (68 vs. 71 days) were not significantly different between the DBD and DCD groups. A similar proportion of patients in the DBD (74%) and DCD groups (81%) underwent pretransplant treatment of their HCC (p ¼ 0.31). TACE was performed in 65% of patients in each group, while RFA was performed in 10% of patients in the DBD group and 16% of patients in the DCD group (p ¼ 0.17). Time from first TACE treatment until transplant and time from first RFA treatment until transplant were not different between the DBD and DCD groups. Based on pathological analysis of the explanted native livers, posttransplant tumor characteristics can be seen in Table 3. Both mean tumor number (2.0 1.5 vs. 2.20 1.5, p ¼ 0.35) and TTV (34.6 90.4 vs. 23.6 31.6 cm, p ¼ 0.36) were similar between the DBD and DCD groups. Proportion 2705
Croome et al Table 1: Donor characteristics and recipient characteristics
Donor characteristics Age (years) Height (cm) Body mass index (kg/m2) Gender (male) Asystole to CC (minutes) Donor warm ischemia time (minutes) Cold ischemia time (hours) Rewarming anast. time (minutes) Race/ethnicity White Black Other Causes of death Anoxia Stroke Trauma Other Regional/national sharing Local Regional National DRI Recipient characteristics Age at transplant (years) Biologic MELD score HCC MELD exception points Body mass index (kg/m2) Gender (male) Liver disease etiology Hepatitis C virus serology positive ([ alcohol] HBV) HBV Alcohol NASH Primary biliary cirrhosis Hemochromatossis Primary sclerosing colangitis Alpha 1-antitrypsin deficiency Other
DBD (N ¼ 340)
DCD (N ¼ 57)
p-value
46.3 17.4 170.6 10.6 28.7 7.5 199 (58.5%) NA NA 6.6 1.7 33.0 0.6
38.1 13.6 173.3 10.0 27.3 7.8 42 (73.7%) 9.4 6.2 24.8 10.0 5.9 1.3 30.7 1.1
10 h was associated with higher HCC recurrence (27). In the present study, very few patients had CIT >10 h (3.5%). Relatively tight distribution of CIT for both DBD and DCD allografts in our experience does not allow us to speculate on effects of CIT in HCC recurrence. Ischemic risk factors specific to DCD allografts, WIT and time from asystole until cross clamp, did not show any correlation with HCC recurrence in the present study. We acknowledge that waitlist dynamics are variable from center to center and country to country. We are a large transplant referral center and as such receive a large number of patients that are referred to our center after initially being worked-up and even treated (TACE, etc.) at outside centers. In addition, we have a proportion of patients who travel from other parts of the country where they are already listed for transplantation at another center because we have shorter wait times in our geographic region. Nonetheless, we credit our aggressive use of DCD organs, at least in part, to the short wait times and a low waitlist drop-out rate of 7.2% at our center.
however, accuracy of explant and recurrence data would be paramount. It is unlikely that registry data will provide data with adequate granularity to address the question of HCC recurrence in this population. The limited number of patients may have resulted in a type 2 error for detecting differences in disease progression. In conclusion, the present study compares well-matched groups of recipients with HCC undergoing LT with DBD and DCD allografts and demonstrates no difference in the rate of HCC recurrence. The present study contains detailed explant pathology data and complete recurrence data that cannot be obtained from larger registry studies. The pattern of location of first HCC recurrence was also not significantly different between the groups. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database.
Authors’ Contributions Kris Croome, Justin M. Burns, Justin Nguyen, David D. Lee, Dana K. Perry, Denise Harnois and C. Burcin Taner participated in research design. Kris P. Croome and C. Burcin Taner participated in the writing of the paper. Kris P. Croome, David D. Lee, Diego Paz, Justin M. Burns, Denise M. Harnois and Kaitlyn Musto participated in the performance of the research. Kris Croome, David D. Lee and C. Burcin Taner participated in data analysis.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References
This study aimed to fill a void in our understanding of best use of DCD liver grafts. Limitations of the present study include its retrospective design as well as it representing data from a single center. Even though this is the largest reported single-center experience, the number of patients is relatively limited for adjustments for all the risk factors for HCC recurrence. While our LT program currently has the largest DCD experience, a multi-institutional study with detailed follow-up on HCC recurrence could be valuable;
1. Halazun KJ, Patzer RE, Rana AA, et al. Standing the test of time: Outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. Hepatology 2014; 60: 1957–1962. 2. Goldberg D, French B, Abt P, Feng S, Cameron AM. Increasing disparity in waitlist mortality rates with increased model for endstage liver disease scores for candidates with hepatocellular carcinoma versus candidates without hepatocellular carcinoma. Liver Transpl 2012; 18: 434–443. 3. Washburn K, Edwards E, Harper A, Freeman R. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant 2010; 10: 1643–1648. 4. Jay C, Ladner D, Wang E, et al. A comprehensive risk assessment of mortality following donation after cardiac death liver transplant—An analysis of the national registry. J Hepatol 2011; 55: 808–813.
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No Difference in Recurrence of HCC in DCD and DBD 5. Grewal HP, Willingham DL, Nguyen J, et al. Liver transplantation using controlled donation after cardiac death donors: An analysis of a large single-center experience. Liver Transpl 2009; 15: 1028–1035. 6. Schaubel DE, Sima CS, Goodrich NP, Feng S, Merion RM. The survival benefit of deceased donor liver transplantation as a function of candidate disease severity and donor quality. Am J Transplant 2008; 8: 419–425. 7. Croome KP, Marotta P, Wall WJ, et al. Should a lower quality organ go to the least sick patient? Model for End-Stage Liver Disease score and donor risk index as predictors of early allograft dysfunction. Transplant Proc 2012; 44: 1303–1306. 8. Croome KP, Wall W, Chandok N, Beck G, Marotta P, HernandezAlejandro R. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl 2013; 19: 1214–1223. 9. Taner CB, Bulatao IG, Perry DK, et al. Asystole to crossclamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. Transpl Int 2012; 25: 838–846. 10. Taner CB, Bulatao IG, Willingham DW, et al. Events in procurement as risk factors for development of ischeminc cholangiopathy in liver transplantation using donation after cardiac death donors. Liver Transpl 2012; 18: 101–112. 11. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006; 6: 783–790. 12. Toso C, Trotter J, Wei A, et al. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma. Liver Transpl 2008; 14: 1107–1115. 13. Fine J, Gray. R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509. 14. Croome KP, Farnell M, Que FG, Reid-Lombardo K, Nagorney D, Kendrick ML. Total laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: Oncologic advantages over open approaches? Ann Surg 2014; 260: 633–640. 15. Foley DP, Fernandez LA, Leverson G, et al. Donation after cardiac death: The University of Wisconsin experience with liver transplantation. Ann Surg 2005; 242: 724–731. 16. Klein AS, Messersmith EE, Ratner LE, et al. Organ donation and utilization in the United States, 1999-2008. Am J Transplant 2010; 10: 973.
American Journal of Transplantation 2015; 15: 2704–2711
17. Bellingham JM, Santhanakrishnan C, Neidlinger N, et al. Donation after cardiac death: A 29-year experience. Surgery 2011; 150: 692– 702. 18. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010; 97: 744–753. 19. Saidi RF, Bradley J, Greer D, et al. Changing pattern of organ donation at a single center: Are potential brain dead donors being lost to donation after cardiac death? Am J Transplantation 2010; 10: 2536–2540. 20. Perry DK, Willingham DL, Sibulesky L, Bulatao IG, Nguyen JH, Taner CB. Should donation after cardiac death liver grafts be used for retransplantation? Ann Hepatol 2011; 10: 482– 485. 21. Taner CB, Bulatao IG, Arasi LC, et al. Liver transplantation in the critically ill: Donation after cardiac death compared to donation after brain death grafts. Ann Hepatol 2012; 11: 679– "685. 22. Wadei HM, Bulatao IG, Gonwa TA, et al. Inferior longterm outcomes of liver-kidney transplantation using donation after cardiac death donors: Single-center and organ procurement and transplantation network analyses. Liver Transpl 2014; 20: 728– 735. 23. van der Bilt JD, Kranenburg O, Nijkamp MW, et al. Ischemia/ reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology 2005; 42: 165–175. 24. Doi K, Horiuchi T, Uchinami M, et al. Hepatic ischemiareperfusion promotes liver metastasis of colon cancer. J Surg Res 2002; 105: 243–247. 25. Lee DD, Singh A, Burns JM, Perry DK, Nguyen JH, Taner CB. Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival. Liver Transpl 2014; 20: 1447–1453. 26. Croome KP, Wall W, Quan D, et al. Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts. Hepatobiliary Pancreat Dis Int 2012; 11: 372–376. 27. Nagai S, Yoshida A, Facciuto M, et al. Ischemia time impacts recurrence of hepatocellular carcinoma following liver transplantation. Hepatology 2015; 61: 895–904.
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