American Journal of Transplantation 2015; 15: 668–677 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.13011
List and Liver Transplant Survival According to Waiting Time in Patients With Hepatocellular Carcinoma P. R. Salvalaggio1,*, G. Felga1, D. A. Axelrod2, B. Della Guardia1, M. D. Almeida1 and M. B. Rezende1 Hospital Israelita Albert Einstein, Sa~o Paulo, Brazil Transplant Surgery, Dartmouth-Hitchcock, Medical Center, Lebanon, NH Corresponding author: Paolo R. Salvalaggio, [email protected] 1
Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with an estimated incidence of one million cases per year (1,2).
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The time that patients with hepatocellular carcinoma (HCC) can safely remain on the waiting list for liver transplantation (LT) is unknown. We investigated whether waiting time on the list impacts transplant survival of HCC candidates and transplant recipients. This is a single-center retrospective study of 283 adults with HCC. Patients were divided in groups according to waiting-list time. The main endpoint was survival. The median waiting time for LT was 4.9 months. The dropout rates at 3-, 6-, and 12-months were 6.4%, 12.4%, and 17.7%, respectively. Mortality on the list was 4.8%, but varied depending of the time on the list. Patients who waited less than 3-months had an inferior overall survival when compared to the other groups (p ¼ 0.027). Prolonged time on the list significantly reduced mortality in this analysis (p ¼ 0.02, HR ¼ 0.28). Model for End Stage Liver Disease (MELD) score at transplantation did also independently impact overall survival (p ¼ 0.03, HR ¼ 1.06). MELD was the only factor that independently impacted posttransplant survival (p ¼ 0.048, HR ¼ 1.05). We conclude that waiting time had no relation with posttransplant survival. It is beneficial to prolong the waiting list time for HCC candidates without having a negative impact in posttransplant survival. Abbreviations: AFP, alpha-fetoprotein; AJCC, American Joint Committee on Cancer; BMI, body mass index; CI, confidence interval; CIT, cold ischemia time; CT, computed tomography; CVA, cerebrovascular accident; DRI, donor risk index; HCC, hepatocellular carcinoma; HR, hazard ratio; LT, liver transplantation; MC, Milan criteria; MELD, model of end stage liver disease; MRI, magnetic resonance imaging; PY, patient-years; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing Received 24 December 2013, revised 10 September 2014 and accepted for publication 11 September 2014
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Liver transplantation (LT) has been utilized as a curative treatment for patients with HCC (3). In countries where the liver allograft allocation is based on the Model for EndStage Liver Disease (MELD) system, patients with HCC within the Milan criteria (MC) are awarded with exception points, which are adjusted over time to prevent dropout of the list (4–8). Recently, there have been critiques on the quantity of exception points granted to HCC patients when compared with non-HCC patients (9–12). To address this particular inequity of the MELD system, the United Network for Organ Sharing (UNOS) is now considering delaying the HCC MELD exception points. Preliminary data of the Liver and Intestine UNOS Committee have shown that a 6-month delay in receiving an HCC MELD exception would result in a nearly equal transplant rate for HCC and non-HCC recipients (13). However, the amount of time that HCC patients can safely remain waiting for LT is yet unknown and has also been a topic of controversy. Some experts have suggested the utilization of living donation to shorten waiting time. This ‘‘fast-tracking’’ approach would allow transplantation of tumors that would have been selected out with longer waiting list time (14). Other groups believe that an observation period is crucial to evaluate tumor biology while patients wait on the list. The ‘‘ablate-and-wait’’ strategy utilizes neoadjuvant therapy during this assessment period (15,16). Based on this premise, Chao et al found no direct impact of waiting time on LT outcomes (17). The state of Sa~o Paulo (in Brazil) has a population of 42 million habitants with more than 15 liver transplant centers. To have prompt access to LT, recipients must have a high score (MELD >30). Thus, candidates with HCC face a prolonged waiting time that averages consistently over 6months. We hypothesize that a prolonged waiting list time does not jeopardize overall and posttransplant survival among HCC patients that successful reach transplant. The
Time on the List and Survival in HCC Recipients
aim of this manuscript if to verify whether waiting time impacts transplants survival of HCC candidates and transplant recipients.
transplantation were censored from the analysis. The main endpoint was survival on the list. Dropout of the waiting list was considered as a secondary endpoint.
Patients and Methods
For posttransplant survival analysis, we divided the full cohort in quarters according to waiting list time. For practical reasons, we defined prolonged waiting-list time if patients stayed waiting on the list for more than 6 months.
Protocols and inclusion/exclusion criteria This study was performed according to the Good Clinical Practice recommendations, the Helsinki Declaration, and was approved by the Institutional Review Board. This is a single-center retrospective study of 283 adults (>18-years old) who had known HCC prior to listing and who underwent an adult deceased donor LT from July 16th, 2006 through October 31st, 2013. Data were censored on October 31st, 2013. Listing and LT were restricted to patients with HCC under the MC, including those who had HCC beyond MC and were successfully downstaged to MC with the utilization of neadjuvant therapy (n ¼ 29).
Screening, diagnosing, staging and listing patients with HCC Screening and diagnosis of HCC followed international recommendations (18–20). For patients with HCC, staging tests also included a chest computed tomography scanning (CT) and bone scan scintigraphy. Liver imaging tests followed guidelines with the utilization of CT scans of at least 8-detector rows and 2-mm slices. Magnetic resonance imaging (MRI) was performed in scanners of at least 1.5T (21,22). Patients with HCC and with clinically significant portal hypertension, multinodular disease, impaired liver function, and those who demanded extensive hepatic resections were deemed unresectable and included on the waiting list.
Data were obtained through the revision of electronic medical records of our institution and at the local Organ Procurement Organization. Data were available for more than 85% of patients on all variables collected. Included in the collection were date of listing, date of transplant, date and reason of removal of the list, date of HCC recurrence, date of last follow-up and death, diagnosis, laboratory MELD score at the time of listing and transplant and serial alpha-fetoprotein (AFP). Pretransplant radiology data included the number of lesions, size of each lesion, whether the lesions were within the MC, and use of and response to TACE. Demographic data included age, gender, body mass index (BMI), blood type, etiology of the underlying liver disease and MELD scores. On the liver explants we analyzed whether the nodules were within the MC, the histologic classification and the presence of microvascular invasion. For the purpose of this article, biological MELD score was considered the result of the calculation of the MELD formula without accounting for the exception points granted for HCC patients. MELD at transplantation was the score used to receive the liver allograft, either with the use of the exception points or the biological MELD, whichever was the highest. We also collected transplant and donor data for the calculation of the donor risk index (DRI) (26). To account for the racial variation of our population, we calculated the DRI by imputing race scores, as previously described (27).
Deceased donor liver allocation Treatment of HCC while waiting for LT At our center, superselective transarterial chemoembolization (TACE) is the treatment of choice for patients with HCC while on the waiting list for LT, while other modalities of locally ablative therapies are not routinely applied. A CT scan or, preferably, a MRI was performed within six weeks of the TACE procedure to determine the amount of necrosis induced by TACE, according to guidelines (22,23). TACE was repeated every 6–8 weeks until complete devascularization was achieved. Patients were followed by imaging every 3 months. Response to TACE was graded into four groups according to the modified response evaluation (mRECIST) criteria in solid tumors (16,24,25). The imaging study closest to the date of LT was used for the analysis of response to TACE.
Assessment of dropout on the waiting list Dropout from the waiting list was defined as a patient who was not transplanted and who died or was removed from the waiting list. Time to dropout was measured from the date of the initial HCC application for the exception MELD score to removal. Patients still waiting on the list were censored as of the date of the analysis. A dropout related to HCC disease was defined as tumor progression beyond MC, metastatic disease, and/or presence of macrovascular invasion by imaging.
Design, groups, endpoints, data collection, covariates and other definitions To study dropout and transplant rates an intention-to-treat analysis was performed including in the study cohort all candidates with HCC who entered the waiting list. Date of entry on the list set as time zero of the analysis. Patients who dropped out of the list and those who underwent
American Journal of Transplantation 2015; 15: 668–677
In Brazil, adult deceased donor organ allocation for LT follows the MELD system (6). Exception points to the MELD score are granted to HCC patients similarly to the UNOS policies. HCC patients enter the LT list with a MELD of 20. After 3-months the MELD rises to 24, and after other 3-months the MELD automatically reaches and it is capped at 29.
Posttransplant follow-up After discharge, patients were followed-up with one to four visits per month in the outpatient clinic for the first 6 months. Subsequently, LT recipients are followed lifelong by our team with three to four clinic visits per year. Screening for tumor recurrence was done by measurements of AFP as well as ultrasound every 3 months in the first 3 years after LT. A MRI of the abdomen and a CT scan of the chest were performed every year. Additional imaging was used if HCC recurrence was suspected. No adjuvant chemotherapy was administered to any patient. HCC recurrence was defined in liver, bone, or any other extra-hepatic site by imaging and/or percutaneous biopsy. Patients with known or suspected HCC recurrence had their immunosuppression minimized and were offered palliative medical, surgical, or radiation therapy for bulky or symptomatic metastases.
Statistical analysis The analysis was divided on: (a) the waiting list data, including dropout and transplantation rates, followed by: (b) posttransplant survival data. For the waiting list analysis we looked into the population as a single cohort (transplanted and not transplanted patients). We divided the entire
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Salvalaggio et al population according to time on the list and studied death on the list, dropout from the list, transplantation and posttransplant death as events of interest. The model incorporates transplantation as a time-dependent covariate (transplant cohort nested within the entire cohort). An intention-to-treat analysis was then performed rates as described above. The quantitative and categorical variables were expressed as median and interquartile range (25–75%), counts and percentages, respectively. The Mann–Whitney test was utilized to compare continuous variables without a normal distribution; otherwise, these variables were compared by t-tests. Categorical variables were compared with chi-square or Fisher tests. Survival curves were estimated using the Kaplan–Meier method and compared between groups by the log-rank test. Univariate analysis was utilized to identify factors that could impact the main and secondary endpoints. In recurrence-free survival analysis, both death and recurrence were counted as events. Relevant variables identified in the univariate analysis with a p < 0.2 then entered into an adjusted Cox proportional hazards model to isolate independent predictors of posttransplant survival and recurrence free-survival. A p < 0.05 was considered significant. All calculations were performed by SPSS version 11.0 for Windows (SPSS, Chicago, IL).
Results Demographics, transplant and HCC characteristics During the period of study, 283 patients initially met the inclusion criteria, were selected as potential candidates and were listed for LT. A total of 199 patients underwent LT, 52 patients were removed from the waiting list during the time
of the study and 32 of those candidates remained on the list at the end of the analysis. The median waiting time for LT for the entire cohort was 4.9 months (3.2 for first quartile–8.2 months for third quartile). The waiting time also remained stable according to blood type. Mean follow-up after LT of the entire cohort of study was 1.7 years (6 months–6.7 years). The demographic and radiological characteristics of the candidate and transplant recipients who entered the study were similar to most studies of HCC patients (Table 1). There was a preponderance of white, middle-aged males with hepatitis C virus with a low biological MELD score. These characteristics were equivalent for all groups of the study, for listed and transplanted patients. The median DRI was 1.5. Patients presented with one to two nodules, the largest being 29 mm. Most patients (85%) underwent TACE (1.5 Sessions) and were considered responders. The number of TACE sessions increased according to the time on the waiting list. The other pretransplant characteristics were equivalent within all groups of the study. Dropout from the waiting list During the study period 52 patients (16.1%) were removed from the waiting list. The dropout rates at 3-, 6-, and
Table 1: Demographics and tumor characteristics of all patients included in the study (n ¼ 283) Waiting list time Population (n ¼ 283) Male—n (%) Age (years)—Median (1st–3rd quartiles) Race—n (%) Asian Black White Blood Type—n (%) A AB B O Primary diagnosis—n (%) Others HBV HCV Alcohol Biological MELD—Median (1st–3rd quartiles) Number of nodules—Median (1st–3rd quartiles) Largest nodule (mm)—Median (1st–3rd quartiles) Total size (mm)—Median (1st–3rd quartiles) TACE—n (%) Responders—n (%) Sessions of TACE—Median (1st–3rd quartiles)
9 months (n ¼ 60)
234 58
82.7% 53–64
47 60
75.8% 53–65
93 58
88.6% 53–64
48 56
85.7% 51–62
46 59
76.7% 53–64
10 44 229
3.5% 15.5% 80.9%
2 11 47
3.3% 18.3% 78.3%
5 14 86
4.8% 13.3% 81.9%
3 11 44
5.2% 19% 75.9%
0 8 52
0% 13.3% 86.7%
126 9 38 110
44.5% 3.2% 13.4% 38.9%
23 3 19 17
37.1% 4.8% 30.6% 27.4%
47 5 14 39
44.8% 4.8% 13.3% 37.1%
30 1 1 24
53.6% 1.8% 1.8% 42.9%
26 0 4 30
43.3% 0% 6.7% 50%
32 21 195 35 12 1 29 40 248 161 2
11.3% 7.4% 68.9% 12.4% 10–15 1–2 24–40 29–54 87.9% 61% 1–2
7 5 45 5 12 1 28 45 50 26 1
11.3% 8.1% 72.6% 8.1% 9–17 1–2 24–41 29–53 83.3% 49.1% 1–2
16 10 67 12 12 1 30 42 94 64 2
15.2% 9.5% 63.8% 11.4% 10–14 1–2 24–40 29–54 90.4% 66.7% 1–2
3 4 41 8 12,5 1 29 39 53 36 2
5.4% 7.1% 73.2% 14.3% 9–15 1–2 24–40 29–54 91.4% 65.5% 1–3
6 2 42 10 12 1 27 35 51 35 2
10% 3.3% 70% 16.7% 10–15 1–2 22–35 26–53 85% 58.3% 1–3
HBV, hepatitis B virus; HCV, hepatitis C virus; MELD, Model for end stage liver disease; TACE, Transarterial chemoembolization.
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Time on the List and Survival in HCC Recipients
12-months were 6.4%, 12.4%, and 17.7%, respectively. Dropout rates remained stable during the interval of the study. Among the patients with HCC removed from the list, 40 (85.1%) were removed due to HCC progression beyond the MC. Patients who dropped out from the waiting list differed from successful transplant candidates on blood type (A and O more often dropped out) and response to TACE. Mortality on the list, transplant rate and posttransplant death Figure 1 depicts the pre and posttransplant mortality according to time on the list. The chance of receiving an allograft grows over time, reaching 90% of those who waited longer than 9-months on the list. Overall mortality on the list was 4.83% (13 deaths in 283 patients), but varied tremendously depending of the time on the list. Those who waited less than 6-months had a higher risk of death on the list than those who waited longer than 6-months Figure 2. Overall survival according to waiting time on the list is detailed in Figure 3. Patients who waited less than 3-months had an inferior survival when compared to the other groups (p ¼ 0.027). Factors influencing survival and the impact of waiting time on survival For all candidates included in the study, female sex, age of the recipient, multinodular disease, HCC within MC, times on the list and MELD at transplant were selected as potential risk factors for mortality in the univariate analysis. Prolonged time on the list significantly reduced mortality in this analysis (p ¼ 0.02, HR ¼ 0.28). Biological MELD at transplantation did also independently impact overall survival (p ¼ 0.03, HR ¼ 1.06, Table 2). AFP, tumor size, and response to TACE did not exert a major effect on survival (Figure 3).
Figure 2: Adjusted overall survival according to the waiting list (entire cohort, n ¼ 283).
Demographics of transplant recipients, stage, transplant characteristics, and pathology data The demographics of patient who underwent liver transplantation were not different than those who entered the list at the beginning of the study (Table 3). Most explants were under MC and without microvascular invasion. The majority of patients was classified on stage A of the Barcelona Cancer Liver Clinic (89.8%) and on stages I (50.3%) or II (45.9%) of the American Joint Committee on Cancer (AJCC) TNM Staging for Liver Tumors. Impact of other variables on posttransplant survival of patients with long waiting list time Female sex, age, HCC within MC and MELD at transplant were found to be significant risk factors on univariate analysis (p < 0.2). MELD was the only factor that independently impacted post-transplant survival (p ¼ 0.048, HR ¼ 1.05, Table 4) in the multivariate analysis.
Discussion
Figure 1: Cumulative incidence of pre and posttransplant according to time on the list (n ¼ 283). Time zero on the graphic was considered the date of inclusion of the patient the list.
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Under the current MELD allocation system, HCC patients have a higher transplant rate compared with non-HCC patients (10–13). A potential proposal to refine the liver allocation for HCC candidates in the United States would require a minimum waiting time prior to granting exception MELD points for these patients (13). However, the impact of a prolonged waiting list time on transplant outcomes is yet unknown. Herein, we assessed the impact of waiting list time on survival. To avoid potential biases from prior 671
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Figure 3: Unadjusted overall survival (entire cohort, n ¼ 283). MELD, Model for end stage liver disease; AFP, alpha-phetoprotein; TACE, Transarterial chemoembolization; HCC, hepatocellular carcinoma.
HCC studies, we used a group of patients who underwent deceased donor LT for HCC within the MC. Patients were diagnosed with HCC according to international standards, were mostly treated with effective TACE, followed a rigorous surveillance protocol and were transplanted under the MELD system in a very competitive region. The main finding of our study is the relationship of short waiting time with overall worse survival. Those who waited for a short time had a higher risk of death on the list than those who had long waiting, more likely related to acute changes of the severity of liver disease. We have also confirmed of the lack of a relationship between waiting time on the list for LT and posttransplant survival for patients with HCC. There is no linear relationship between waiting time on the list and posttransplant survival. Multivariate analysis did not isolate waiting time as a significant factor in predicting posttransplant survival, confirming the results 672
from the San Francisco group (17). We are now extending these findings to the subgroup of patients with a prolonged waiting time. These candidates are not disadvantaged in terms of posttransplant outcomes when compared with those HCC candidates who can be transplanted quickly. Indeed, prolonged time on the list significantly reduced overall mortality on the intention-to-treat analysis (p ¼ 0.02, HR ¼ 0.28). This can be explained not only by selection of patients with limit HCC progression and as well as preserved liver function. These factors reduce HCC related dropout from the list and allow time for appropriate selection of HCC candidates who will benefit from transplantation. Initial reports have shown that a short waiting-list time led to improved posttransplant outcomes in HCC recipients (28). Some transplant regions have waiting time for LT of patients with HCC approaching 1-year, which might American Journal of Transplantation 2015; 15: 668–677
Time on the List and Survival in HCC Recipients Table 2: Proportional hazards of patient survival for all patients included in the study (n ¼ 283)
Sex Female Male Age of the recipient (years) Waiting list time 9 months Blood type A AB B O Biologic MELD MELD at transplant DRI AFP Number of nodules 1 >1 Size of the largest nodule (mm) 1000), and these patients who were transplanted under the MC are still doing well and without signs of recurrence. However, in a short donor supply environment, one must accept that pretransplant AFP along with other radiological and clinical characteristics might be added to the decisionmaking process of determining transplant candidacy (11,34). 675
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MELD predicts mortality on the waiting list and defines the priority in deceased donor liver allocation. However, MELD is a poor predictor of posttransplant survival (32). Our findings corroborate the literature. For patients on the list, MELD determines overall survival and for those who are transplanted MELD does not impact posttransplant survival. We could not identify specific factors that determine overall or posttransplant survival on this study. Our study has several limitations. First, there are those limitations inherent to single-center retrospective studies. Second, there was also a limitation on the size of our population of study that was certainly less than ideal for a clean statistical analysis. It is possible that larger studies find an impact of waiting time on posttransplant survival (35). Third, due to the restricted inclusion criteria of this study, low tumor load and high utilization of neoadjuvant therapy, our results might not be generalizable due to the low recurrence rate of our population when compared to other recent studies (29,30,33,34). Future studies must test longer time for granting points for HCC recipients who have higher tumor load than our population and also test which recipients are under higher risk for dropout of the list with the adoption of this allocation policy. Fourth, waiting time on the list for liver transplantation varies immensely across the globe, and some centers might not find our current waiting time to be truly prolonged. If UNOS changes allocation for HCC candidates requiring an initial period of waiting prior to granting exception points, our findings must be retested in other centers. Finally, there is an inherent bias due to the tumor biology and self-selection of patients with HCC who wait for LT under the MELD system and drop out of the list. Tumor biology is extremely difficult to study, to control for, and to quantify. New technologies that advance our knowledge on this topic must be a priority for the LT community in the near future. We conclude that waiting list time had no relation with posttransplant survival, even in patients with prolonged waiting time. It is beneficial to prolong the waiting list time for HCC candidates without having a negative impact posttransplant survival and potential improving selection of patients with HCC most likely to benefit from liver transplantation.
Authors’ Contributions Dr. Salvalaggio: design, data collection, analysis, writing, review of the manuscript. Dr. Felga, Axelrod, Almeida, Della Guardia and Rezende: review of the data and manuscript.
Acknowledgments The liver transplantation unit of the Einstein Transplantation Program is supported by the Programa de Desenvolvimento Institucional do Sistema ¨ nico de Sau´de (PROADI-SUS) as a result of a partnership between the O Sociedade Israelita Brasileira Albert Einstein and the Ministe´rio da Sau´de.
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The authors thank to Elivane da Silva Victor, PhD, for assistance with the statistical analysis.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13011
List and Liver Transplant Survival According to Waiting Time in Patients With Hepatocellular Carcinoma P. R. Salvalaggio1,*, G. Felga1, D. A. Axelrod2, B. Della Guardia1, M. D. Almeida1 and M. B. Rezende1 Hospital Israelita Albert Einstein, Sa~o Paulo, Brazil Transplant Surgery, Dartmouth-Hitchcock, Medical Center, Lebanon, NH Corresponding author: Paolo R. Salvalaggio, [email protected] 1
Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with an estimated incidence of one million cases per year (1,2).
2
The time that patients with hepatocellular carcinoma (HCC) can safely remain on the waiting list for liver transplantation (LT) is unknown. We investigated whether waiting time on the list impacts transplant survival of HCC candidates and transplant recipients. This is a single-center retrospective study of 283 adults with HCC. Patients were divided in groups according to waiting-list time. The main endpoint was survival. The median waiting time for LT was 4.9 months. The dropout rates at 3-, 6-, and 12-months were 6.4%, 12.4%, and 17.7%, respectively. Mortality on the list was 4.8%, but varied depending of the time on the list. Patients who waited less than 3-months had an inferior overall survival when compared to the other groups (p ¼ 0.027). Prolonged time on the list significantly reduced mortality in this analysis (p ¼ 0.02, HR ¼ 0.28). Model for End Stage Liver Disease (MELD) score at transplantation did also independently impact overall survival (p ¼ 0.03, HR ¼ 1.06). MELD was the only factor that independently impacted posttransplant survival (p ¼ 0.048, HR ¼ 1.05). We conclude that waiting time had no relation with posttransplant survival. It is beneficial to prolong the waiting list time for HCC candidates without having a negative impact in posttransplant survival. Abbreviations: AFP, alpha-fetoprotein; AJCC, American Joint Committee on Cancer; BMI, body mass index; CI, confidence interval; CIT, cold ischemia time; CT, computed tomography; CVA, cerebrovascular accident; DRI, donor risk index; HCC, hepatocellular carcinoma; HR, hazard ratio; LT, liver transplantation; MC, Milan criteria; MELD, model of end stage liver disease; MRI, magnetic resonance imaging; PY, patient-years; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing Received 24 December 2013, revised 10 September 2014 and accepted for publication 11 September 2014
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Liver transplantation (LT) has been utilized as a curative treatment for patients with HCC (3). In countries where the liver allograft allocation is based on the Model for EndStage Liver Disease (MELD) system, patients with HCC within the Milan criteria (MC) are awarded with exception points, which are adjusted over time to prevent dropout of the list (4–8). Recently, there have been critiques on the quantity of exception points granted to HCC patients when compared with non-HCC patients (9–12). To address this particular inequity of the MELD system, the United Network for Organ Sharing (UNOS) is now considering delaying the HCC MELD exception points. Preliminary data of the Liver and Intestine UNOS Committee have shown that a 6-month delay in receiving an HCC MELD exception would result in a nearly equal transplant rate for HCC and non-HCC recipients (13). However, the amount of time that HCC patients can safely remain waiting for LT is yet unknown and has also been a topic of controversy. Some experts have suggested the utilization of living donation to shorten waiting time. This ‘‘fast-tracking’’ approach would allow transplantation of tumors that would have been selected out with longer waiting list time (14). Other groups believe that an observation period is crucial to evaluate tumor biology while patients wait on the list. The ‘‘ablate-and-wait’’ strategy utilizes neoadjuvant therapy during this assessment period (15,16). Based on this premise, Chao et al found no direct impact of waiting time on LT outcomes (17). The state of Sa~o Paulo (in Brazil) has a population of 42 million habitants with more than 15 liver transplant centers. To have prompt access to LT, recipients must have a high score (MELD >30). Thus, candidates with HCC face a prolonged waiting time that averages consistently over 6months. We hypothesize that a prolonged waiting list time does not jeopardize overall and posttransplant survival among HCC patients that successful reach transplant. The
Time on the List and Survival in HCC Recipients
aim of this manuscript if to verify whether waiting time impacts transplants survival of HCC candidates and transplant recipients.
transplantation were censored from the analysis. The main endpoint was survival on the list. Dropout of the waiting list was considered as a secondary endpoint.
Patients and Methods
For posttransplant survival analysis, we divided the full cohort in quarters according to waiting list time. For practical reasons, we defined prolonged waiting-list time if patients stayed waiting on the list for more than 6 months.
Protocols and inclusion/exclusion criteria This study was performed according to the Good Clinical Practice recommendations, the Helsinki Declaration, and was approved by the Institutional Review Board. This is a single-center retrospective study of 283 adults (>18-years old) who had known HCC prior to listing and who underwent an adult deceased donor LT from July 16th, 2006 through October 31st, 2013. Data were censored on October 31st, 2013. Listing and LT were restricted to patients with HCC under the MC, including those who had HCC beyond MC and were successfully downstaged to MC with the utilization of neadjuvant therapy (n ¼ 29).
Screening, diagnosing, staging and listing patients with HCC Screening and diagnosis of HCC followed international recommendations (18–20). For patients with HCC, staging tests also included a chest computed tomography scanning (CT) and bone scan scintigraphy. Liver imaging tests followed guidelines with the utilization of CT scans of at least 8-detector rows and 2-mm slices. Magnetic resonance imaging (MRI) was performed in scanners of at least 1.5T (21,22). Patients with HCC and with clinically significant portal hypertension, multinodular disease, impaired liver function, and those who demanded extensive hepatic resections were deemed unresectable and included on the waiting list.
Data were obtained through the revision of electronic medical records of our institution and at the local Organ Procurement Organization. Data were available for more than 85% of patients on all variables collected. Included in the collection were date of listing, date of transplant, date and reason of removal of the list, date of HCC recurrence, date of last follow-up and death, diagnosis, laboratory MELD score at the time of listing and transplant and serial alpha-fetoprotein (AFP). Pretransplant radiology data included the number of lesions, size of each lesion, whether the lesions were within the MC, and use of and response to TACE. Demographic data included age, gender, body mass index (BMI), blood type, etiology of the underlying liver disease and MELD scores. On the liver explants we analyzed whether the nodules were within the MC, the histologic classification and the presence of microvascular invasion. For the purpose of this article, biological MELD score was considered the result of the calculation of the MELD formula without accounting for the exception points granted for HCC patients. MELD at transplantation was the score used to receive the liver allograft, either with the use of the exception points or the biological MELD, whichever was the highest. We also collected transplant and donor data for the calculation of the donor risk index (DRI) (26). To account for the racial variation of our population, we calculated the DRI by imputing race scores, as previously described (27).
Deceased donor liver allocation Treatment of HCC while waiting for LT At our center, superselective transarterial chemoembolization (TACE) is the treatment of choice for patients with HCC while on the waiting list for LT, while other modalities of locally ablative therapies are not routinely applied. A CT scan or, preferably, a MRI was performed within six weeks of the TACE procedure to determine the amount of necrosis induced by TACE, according to guidelines (22,23). TACE was repeated every 6–8 weeks until complete devascularization was achieved. Patients were followed by imaging every 3 months. Response to TACE was graded into four groups according to the modified response evaluation (mRECIST) criteria in solid tumors (16,24,25). The imaging study closest to the date of LT was used for the analysis of response to TACE.
Assessment of dropout on the waiting list Dropout from the waiting list was defined as a patient who was not transplanted and who died or was removed from the waiting list. Time to dropout was measured from the date of the initial HCC application for the exception MELD score to removal. Patients still waiting on the list were censored as of the date of the analysis. A dropout related to HCC disease was defined as tumor progression beyond MC, metastatic disease, and/or presence of macrovascular invasion by imaging.
Design, groups, endpoints, data collection, covariates and other definitions To study dropout and transplant rates an intention-to-treat analysis was performed including in the study cohort all candidates with HCC who entered the waiting list. Date of entry on the list set as time zero of the analysis. Patients who dropped out of the list and those who underwent
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In Brazil, adult deceased donor organ allocation for LT follows the MELD system (6). Exception points to the MELD score are granted to HCC patients similarly to the UNOS policies. HCC patients enter the LT list with a MELD of 20. After 3-months the MELD rises to 24, and after other 3-months the MELD automatically reaches and it is capped at 29.
Posttransplant follow-up After discharge, patients were followed-up with one to four visits per month in the outpatient clinic for the first 6 months. Subsequently, LT recipients are followed lifelong by our team with three to four clinic visits per year. Screening for tumor recurrence was done by measurements of AFP as well as ultrasound every 3 months in the first 3 years after LT. A MRI of the abdomen and a CT scan of the chest were performed every year. Additional imaging was used if HCC recurrence was suspected. No adjuvant chemotherapy was administered to any patient. HCC recurrence was defined in liver, bone, or any other extra-hepatic site by imaging and/or percutaneous biopsy. Patients with known or suspected HCC recurrence had their immunosuppression minimized and were offered palliative medical, surgical, or radiation therapy for bulky or symptomatic metastases.
Statistical analysis The analysis was divided on: (a) the waiting list data, including dropout and transplantation rates, followed by: (b) posttransplant survival data. For the waiting list analysis we looked into the population as a single cohort (transplanted and not transplanted patients). We divided the entire
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Salvalaggio et al population according to time on the list and studied death on the list, dropout from the list, transplantation and posttransplant death as events of interest. The model incorporates transplantation as a time-dependent covariate (transplant cohort nested within the entire cohort). An intention-to-treat analysis was then performed rates as described above. The quantitative and categorical variables were expressed as median and interquartile range (25–75%), counts and percentages, respectively. The Mann–Whitney test was utilized to compare continuous variables without a normal distribution; otherwise, these variables were compared by t-tests. Categorical variables were compared with chi-square or Fisher tests. Survival curves were estimated using the Kaplan–Meier method and compared between groups by the log-rank test. Univariate analysis was utilized to identify factors that could impact the main and secondary endpoints. In recurrence-free survival analysis, both death and recurrence were counted as events. Relevant variables identified in the univariate analysis with a p < 0.2 then entered into an adjusted Cox proportional hazards model to isolate independent predictors of posttransplant survival and recurrence free-survival. A p < 0.05 was considered significant. All calculations were performed by SPSS version 11.0 for Windows (SPSS, Chicago, IL).
Results Demographics, transplant and HCC characteristics During the period of study, 283 patients initially met the inclusion criteria, were selected as potential candidates and were listed for LT. A total of 199 patients underwent LT, 52 patients were removed from the waiting list during the time
of the study and 32 of those candidates remained on the list at the end of the analysis. The median waiting time for LT for the entire cohort was 4.9 months (3.2 for first quartile–8.2 months for third quartile). The waiting time also remained stable according to blood type. Mean follow-up after LT of the entire cohort of study was 1.7 years (6 months–6.7 years). The demographic and radiological characteristics of the candidate and transplant recipients who entered the study were similar to most studies of HCC patients (Table 1). There was a preponderance of white, middle-aged males with hepatitis C virus with a low biological MELD score. These characteristics were equivalent for all groups of the study, for listed and transplanted patients. The median DRI was 1.5. Patients presented with one to two nodules, the largest being 29 mm. Most patients (85%) underwent TACE (1.5 Sessions) and were considered responders. The number of TACE sessions increased according to the time on the waiting list. The other pretransplant characteristics were equivalent within all groups of the study. Dropout from the waiting list During the study period 52 patients (16.1%) were removed from the waiting list. The dropout rates at 3-, 6-, and
Table 1: Demographics and tumor characteristics of all patients included in the study (n ¼ 283) Waiting list time Population (n ¼ 283) Male—n (%) Age (years)—Median (1st–3rd quartiles) Race—n (%) Asian Black White Blood Type—n (%) A AB B O Primary diagnosis—n (%) Others HBV HCV Alcohol Biological MELD—Median (1st–3rd quartiles) Number of nodules—Median (1st–3rd quartiles) Largest nodule (mm)—Median (1st–3rd quartiles) Total size (mm)—Median (1st–3rd quartiles) TACE—n (%) Responders—n (%) Sessions of TACE—Median (1st–3rd quartiles)
9 months (n ¼ 60)
234 58
82.7% 53–64
47 60
75.8% 53–65
93 58
88.6% 53–64
48 56
85.7% 51–62
46 59
76.7% 53–64
10 44 229
3.5% 15.5% 80.9%
2 11 47
3.3% 18.3% 78.3%
5 14 86
4.8% 13.3% 81.9%
3 11 44
5.2% 19% 75.9%
0 8 52
0% 13.3% 86.7%
126 9 38 110
44.5% 3.2% 13.4% 38.9%
23 3 19 17
37.1% 4.8% 30.6% 27.4%
47 5 14 39
44.8% 4.8% 13.3% 37.1%
30 1 1 24
53.6% 1.8% 1.8% 42.9%
26 0 4 30
43.3% 0% 6.7% 50%
32 21 195 35 12 1 29 40 248 161 2
11.3% 7.4% 68.9% 12.4% 10–15 1–2 24–40 29–54 87.9% 61% 1–2
7 5 45 5 12 1 28 45 50 26 1
11.3% 8.1% 72.6% 8.1% 9–17 1–2 24–41 29–53 83.3% 49.1% 1–2
16 10 67 12 12 1 30 42 94 64 2
15.2% 9.5% 63.8% 11.4% 10–14 1–2 24–40 29–54 90.4% 66.7% 1–2
3 4 41 8 12,5 1 29 39 53 36 2
5.4% 7.1% 73.2% 14.3% 9–15 1–2 24–40 29–54 91.4% 65.5% 1–3
6 2 42 10 12 1 27 35 51 35 2
10% 3.3% 70% 16.7% 10–15 1–2 22–35 26–53 85% 58.3% 1–3
HBV, hepatitis B virus; HCV, hepatitis C virus; MELD, Model for end stage liver disease; TACE, Transarterial chemoembolization.
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Time on the List and Survival in HCC Recipients
12-months were 6.4%, 12.4%, and 17.7%, respectively. Dropout rates remained stable during the interval of the study. Among the patients with HCC removed from the list, 40 (85.1%) were removed due to HCC progression beyond the MC. Patients who dropped out from the waiting list differed from successful transplant candidates on blood type (A and O more often dropped out) and response to TACE. Mortality on the list, transplant rate and posttransplant death Figure 1 depicts the pre and posttransplant mortality according to time on the list. The chance of receiving an allograft grows over time, reaching 90% of those who waited longer than 9-months on the list. Overall mortality on the list was 4.83% (13 deaths in 283 patients), but varied tremendously depending of the time on the list. Those who waited less than 6-months had a higher risk of death on the list than those who waited longer than 6-months Figure 2. Overall survival according to waiting time on the list is detailed in Figure 3. Patients who waited less than 3-months had an inferior survival when compared to the other groups (p ¼ 0.027). Factors influencing survival and the impact of waiting time on survival For all candidates included in the study, female sex, age of the recipient, multinodular disease, HCC within MC, times on the list and MELD at transplant were selected as potential risk factors for mortality in the univariate analysis. Prolonged time on the list significantly reduced mortality in this analysis (p ¼ 0.02, HR ¼ 0.28). Biological MELD at transplantation did also independently impact overall survival (p ¼ 0.03, HR ¼ 1.06, Table 2). AFP, tumor size, and response to TACE did not exert a major effect on survival (Figure 3).
Figure 2: Adjusted overall survival according to the waiting list (entire cohort, n ¼ 283).
Demographics of transplant recipients, stage, transplant characteristics, and pathology data The demographics of patient who underwent liver transplantation were not different than those who entered the list at the beginning of the study (Table 3). Most explants were under MC and without microvascular invasion. The majority of patients was classified on stage A of the Barcelona Cancer Liver Clinic (89.8%) and on stages I (50.3%) or II (45.9%) of the American Joint Committee on Cancer (AJCC) TNM Staging for Liver Tumors. Impact of other variables on posttransplant survival of patients with long waiting list time Female sex, age, HCC within MC and MELD at transplant were found to be significant risk factors on univariate analysis (p < 0.2). MELD was the only factor that independently impacted post-transplant survival (p ¼ 0.048, HR ¼ 1.05, Table 4) in the multivariate analysis.
Discussion
Figure 1: Cumulative incidence of pre and posttransplant according to time on the list (n ¼ 283). Time zero on the graphic was considered the date of inclusion of the patient the list.
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Under the current MELD allocation system, HCC patients have a higher transplant rate compared with non-HCC patients (10–13). A potential proposal to refine the liver allocation for HCC candidates in the United States would require a minimum waiting time prior to granting exception MELD points for these patients (13). However, the impact of a prolonged waiting list time on transplant outcomes is yet unknown. Herein, we assessed the impact of waiting list time on survival. To avoid potential biases from prior 671
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Figure 3: Unadjusted overall survival (entire cohort, n ¼ 283). MELD, Model for end stage liver disease; AFP, alpha-phetoprotein; TACE, Transarterial chemoembolization; HCC, hepatocellular carcinoma.
HCC studies, we used a group of patients who underwent deceased donor LT for HCC within the MC. Patients were diagnosed with HCC according to international standards, were mostly treated with effective TACE, followed a rigorous surveillance protocol and were transplanted under the MELD system in a very competitive region. The main finding of our study is the relationship of short waiting time with overall worse survival. Those who waited for a short time had a higher risk of death on the list than those who had long waiting, more likely related to acute changes of the severity of liver disease. We have also confirmed of the lack of a relationship between waiting time on the list for LT and posttransplant survival for patients with HCC. There is no linear relationship between waiting time on the list and posttransplant survival. Multivariate analysis did not isolate waiting time as a significant factor in predicting posttransplant survival, confirming the results 672
from the San Francisco group (17). We are now extending these findings to the subgroup of patients with a prolonged waiting time. These candidates are not disadvantaged in terms of posttransplant outcomes when compared with those HCC candidates who can be transplanted quickly. Indeed, prolonged time on the list significantly reduced overall mortality on the intention-to-treat analysis (p ¼ 0.02, HR ¼ 0.28). This can be explained not only by selection of patients with limit HCC progression and as well as preserved liver function. These factors reduce HCC related dropout from the list and allow time for appropriate selection of HCC candidates who will benefit from transplantation. Initial reports have shown that a short waiting-list time led to improved posttransplant outcomes in HCC recipients (28). Some transplant regions have waiting time for LT of patients with HCC approaching 1-year, which might American Journal of Transplantation 2015; 15: 668–677
Time on the List and Survival in HCC Recipients Table 2: Proportional hazards of patient survival for all patients included in the study (n ¼ 283)
Sex Female Male Age of the recipient (years) Waiting list time 9 months Blood type A AB B O Biologic MELD MELD at transplant DRI AFP Number of nodules 1 >1 Size of the largest nodule (mm) 1000), and these patients who were transplanted under the MC are still doing well and without signs of recurrence. However, in a short donor supply environment, one must accept that pretransplant AFP along with other radiological and clinical characteristics might be added to the decisionmaking process of determining transplant candidacy (11,34). 675
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MELD predicts mortality on the waiting list and defines the priority in deceased donor liver allocation. However, MELD is a poor predictor of posttransplant survival (32). Our findings corroborate the literature. For patients on the list, MELD determines overall survival and for those who are transplanted MELD does not impact posttransplant survival. We could not identify specific factors that determine overall or posttransplant survival on this study. Our study has several limitations. First, there are those limitations inherent to single-center retrospective studies. Second, there was also a limitation on the size of our population of study that was certainly less than ideal for a clean statistical analysis. It is possible that larger studies find an impact of waiting time on posttransplant survival (35). Third, due to the restricted inclusion criteria of this study, low tumor load and high utilization of neoadjuvant therapy, our results might not be generalizable due to the low recurrence rate of our population when compared to other recent studies (29,30,33,34). Future studies must test longer time for granting points for HCC recipients who have higher tumor load than our population and also test which recipients are under higher risk for dropout of the list with the adoption of this allocation policy. Fourth, waiting time on the list for liver transplantation varies immensely across the globe, and some centers might not find our current waiting time to be truly prolonged. If UNOS changes allocation for HCC candidates requiring an initial period of waiting prior to granting exception points, our findings must be retested in other centers. Finally, there is an inherent bias due to the tumor biology and self-selection of patients with HCC who wait for LT under the MELD system and drop out of the list. Tumor biology is extremely difficult to study, to control for, and to quantify. New technologies that advance our knowledge on this topic must be a priority for the LT community in the near future. We conclude that waiting list time had no relation with posttransplant survival, even in patients with prolonged waiting time. It is beneficial to prolong the waiting list time for HCC candidates without having a negative impact posttransplant survival and potential improving selection of patients with HCC most likely to benefit from liver transplantation.
Authors’ Contributions Dr. Salvalaggio: design, data collection, analysis, writing, review of the manuscript. Dr. Felga, Axelrod, Almeida, Della Guardia and Rezende: review of the data and manuscript.
Acknowledgments The liver transplantation unit of the Einstein Transplantation Program is supported by the Programa de Desenvolvimento Institucional do Sistema ¨ nico de Sau´de (PROADI-SUS) as a result of a partnership between the O Sociedade Israelita Brasileira Albert Einstein and the Ministe´rio da Sau´de.
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The authors thank to Elivane da Silva Victor, PhD, for assistance with the statistical analysis.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
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