Dig Dis Sci (2014) 59:183–191 DOI 10.1007/s10620-013-2947-8
ORIGINAL ARTICLE
Primary Surgical Resection Versus Liver Transplantation for Transplant-Eligible Hepatocellular Carcinoma Patients Robert J. Wong • James Wantuck • Antonia Valenzuela • Aijaz Ahmed • Clark Bonham • Amy Gallo • Marc L. Melcher • Glen Lutchman • Waldo Concepcion • Carlos Esquivel • Gabriel Garcia • Tami Daugherty Mindie H. Nguyen
•
Received: 19 July 2013 / Accepted: 11 November 2013 / Published online: 27 November 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. Existing studies comparing outcomes after liver transplantation (LT) versus surgical resection among transplant-eligible patients are conflicting. Aim The purpose of this study was to compare long-term survival between consecutive transplant-eligible HCC patients treated with resection versus LT. Methods The present retrospective matched case cohort study compares long-term survival outcomes between consecutive transplant-eligible HCC patients treated with resection versus LT using intention-to-treat (ITT) and astreated models. Resection patients were matched to LT patients by age, sex, and etiology of HCC in a 1:2 ratio.
Results The study included 171 patients (57 resection and 114 LT). Resection patients had greater post-treatment tumor recurrence (43.9 vs. 12.9 %, p \ 0.001) compared to LT patients. In the as-treated model of the pre-model for end stage liver disease (MELD) era, LT patients had significantly better 5-year survival compared to resection patients (100 vs. 69.5 %, p = 0.04), but no difference was seen in the ITT model. In the multivariate Cox proportional hazards model, inclusive of age, sex, ethnicity, tumor stage, and MELD era (pre-MELD vs. post-MELD), treatment with resection was an independent predictor of poorer survival (HR 2.72; 95 % CI, 1.08–6.86). Conclusion Transplant-eligible HCC patients who received LT had significantly better survival than those
R. J. Wong A. Valenzuela A. Ahmed G. Lutchman G. Garcia T. Daugherty M. H. Nguyen (&) Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA e-mail: [email protected]
C. Bonham A. Gallo M. L. Melcher W. Concepcion C. Esquivel Department of Surgery, Stanford University Medical Center, 750 Welch Rd. #200, Stanford, CA 94304-5785, USA e-mail: [email protected]
A. Valenzuela e-mail: [email protected] A. Ahmed e-mail: [email protected] G. Lutchman e-mail: [email protected]
A. Gallo e-mail: [email protected] M. L. Melcher e-mail: [email protected] W. Concepcion e-mail: [email protected] C. Esquivel e-mail: [email protected]
G. Garcia e-mail: [email protected] T. Daugherty e-mail: [email protected] J. Wantuck Department of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA e-mail: [email protected]
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treated with resection, suggesting that patients who can successfully remain on LT listing and actually undergo LT have better outcomes. Keywords Liver cancer MELD score OLT Survival Recurrence
Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide [1, 2]. Despite improvements in screening and surveillance along with advances in the treatment options available, overall mortality remains poor [1–4]. According to recent populationbased data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry, overall 5-year survival of patients with HCC remains less than 20 % [2, 4]. This poor survival coupled with the continued rising incidence of HCC in many other regions in the world highlight the significant global health burden that HCC represents [2, 5]. While surgical resection and liver transplantation (LT) are both considered curative for HCC, the decision to pursue resection versus LT is often complex and involves incorporating various patient factors, tumor characteristics, availability of organs, and physician expertise to offer the optimal therapy. The role of surgical resection in the management of HCC is well-established for the treatment of small, localized tumors in patients with well-preserved hepatic function; and when surgically appropriate patients are selected, overall 5-year survival of 50–70 % has been reported [1, 6–14]. However, post-resection recurrence of HCC is not uncommon, and the surgical literature reports recurrence rates as high as 70 % at 5-years post-resection [11–16]. Among patients meeting established transplantation criteria (e.g. Milan criteria [17] or University of California, San Francisco (UCSF) criteria [18]), LT remains the most effective surgical option, with 5-year survival exceeding 70 % [1, 6, 7, 17–19]. Unfortunately, the benefits to this population of LT are severely limited as the increasing number of patients on the waitlist intensifies the competition for the limited availability of organs. Most evident among densely populated metropolitan regions, the scarce availability of livers to be transplanted results in patients waiting longer on the waitlist, during which the risk of HCC progression beyond transplant eligibility continues to increase [20, 21]. Cognizant of the limitations of both surgical resection and LT, it remains unclear whether one therapy is truly superior over the other. Some studies have demonstrated a survival advantage associated with LT while others have reported improved overall survival among patients treated with resection
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[13–16, 22–26]. These studies are limited by the lack of matched controls, a selection bias, and/or the lack of an intention-to-treat analysis, which is especially important to account for the mortality among transplant-waitlist patients whose disease progresses beyond transplant eligibility while waiting for a LT. Therefore, the present study compared long-term survival in transplant-eligible HCC patients undergoing surgical resection to those undergoing LT in a matched case cohort study utilizing intention-totreat (ITT) and as-treated models.
Experimental Procedures Study Design and Patient Population This retrospective matched case cohort study included consecutive HCC patients seen at Stanford University Medical Center from 1995 to 2012 who were identified via electronic query using ICD-9 codes and LT records. A total of 57 consecutive transplant-eligible HCC patients who underwent primary surgical resection during this time period were identified (cases). Transplant eligibility was determined according to accepted criteria at Stanford University Medical Center. HCC patients were first assessed for transplant eligibility based on Milan criteria [17], and if the tumor was outside of Milan criteria, patients were reassessed based on UCSF criteria [18]. The comparative control cohort included 114 transplant-eligible HCC patients who were listed for LT without any surgical resection treatment (controls). Controls were matched to cases by age (±5 years), sex, and etiology of HCC (hepatitis C virus [HCV] vs. non-HCV) in a 2:1 ratio. This study was approved by the Institutional Review Board of Stanford University, Stanford, CA. Demographic, clinical, laboratory, histopathological, and radiological data were reviewed and abstracted using a case report form. Detailed treatment history (resection, transplant listing, actual transplantation, other locoregional therapies received) and outcome (survival, tumor recurrence) data were evaluated. Long-term survival data were obtained by chart review and National Death Index query. Both initial HCC diagnosis and recurrent HCC were diagnosed via cytologic or pathologic diagnosis or noninvasive criteria according to the European Association for the Study of Liver Diseases (EASL) [6], which requires at least one of the following conditions: (1) presence of hypervascular lesion greater than 2 cm in two imaging studies (computed tomography [CT], magnetic resonance imaging [MRI], angiography), (2) presence of hypervascular lesion greater than 2 cm in one imaging study and alpha-fetoprotein (AFP) [ 200 ng/mL, (3) presence of enlarging hypervascular lesion or recurrent hypervascular
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lesions following chemoembolization, and (4) presence of AFP [ 1,000 ng/mL. Reasons for removing patients from the LT waitlist were categorized as death (died while waiting for LT), tumor progression (progression of disease beyond transplant eligibility), psychosocial issues (substance abuse, psychiatric disease, and lack of support), and comorbidities (development of comorbid diseases or advanced age that precluded LT). Study Outcomes The primary outcome of the present study was the overall long-term survival utilizing an ITT model. Secondary outcomes were survival by an as-treated model, comparing cases with controls who actually underwent LT, and rates of tumor recurrence in both the ITT and as-treated models. Among the group of HCC patients listed for liver transplantation, not every patient actually received a liver transplantation during the study period (e.g. died or dropped off waitlist or were still waiting on the list) but none were switched to surgical resection. To account for these events in our survival analysis, we included all patients who were initially listed for liver transplantation and referred to this as the ITT analysis. We subsequently performed an ‘‘as-treated’’ analysis that compared HCC patients that were treated with surgical resection versus HCC patients that actually underwent liver transplantation. For both survival and tumor recurrence outcomes, analyses included stratification based on year of diagnosis (pre-2003 and post-2003) to account for potential effect modification introduced by the implementation of model for end stage liver disease (MELD) scores in 2003 for the prioritization of LT patients on the waitlist (pre-MELD and postMELD). Statistical Analysis Clinical and demographic comparisons were evaluated using chi-square tests for categorical variables and Student’s t test for normally distributed continuous variables and nonparametric methods for those not normally distributed. Long-term survival and tumor recurrence rates were analyzed using Kaplan–Meier methods with log-rank testing for equality of functions. Forward stepwise multivariate Cox proportional hazards models were developed using variables that satisfied biological priori (i.e. age, sex) or those with p \ 0.1 in the univariate analyses. The final multivariate model included adjustments for age, sex (male vs. female), ethnicity (Asian vs. non-Asian), Barcelona clinic liver cancer stage (BCLC) (C/D vs. A/B), Childs Pugh Turcotte (CPT) score, number of tumors, and MELD era (post-MELD vs. pre-MELD). Statistical significance was met with a two-tailed p value \0.05. All statistical
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analyses were performed using the Stata statistical package (version 10, Stata Corporation, TX).
Results Demographic and Clinical Characteristics Clinical and demographic characteristics of HCC patients treated with resection versus LT are presented in Table 1. While cases and controls were matched by HCV status, among non-HCV etiologies, resection patients had higher rates of hepatitis B virus (HBV) infection (64.9 vs. 40.4 %, p \ 0.01), whereas alcoholic liver disease and cryptogenic/ non-alcoholic fatty liver disease were seen more commonly among the LT group. LT patients had lower median platelet levels (113,000 vs. 157,000/mL, p \ 0.001), higher mean total bilirubin (2.0 vs. 0.9 mg/dL, p \ 0.01), lower mean albumin (3.2 vs. 3.9 g/dL, p \ 0.001), higher median AST (64 vs. 43 U/L, p = 0.02) and higher median alkaline phosphatase levels (110 vs. 84 U/L, p \ 0.01) when compared to resection patients. LT patients also had higher mean medical MELD scores (11.2 vs. 8.9, p \ 0.01) and Child-Pugh-Turcotte (CPT) scores (6.8 vs. 5.6, p \ 0.001) compared to resection patients. While LT patients had higher median AFP levels than the resection group (52 vs. 25 ng/mL, p = 0.40), this difference was not statistically significant. Among the 37 HBV-related HCC patients treated with surgical resection, nine were not receiving antiviral therapy. Of the nine patients not receiving antiviral therapy, five had undetectable HBV DNA. The median HBV DNA level prior to surgery in the four HBV patients not on antiviral therapy with detectable DNA was 4,000 IU/mL (range 510–160,000 IU/mL). Among the 28 patients who were on antiviral therapy, ten had undetectable HBV DNA, and the median viral load among those patients with detectable viral load on antiviral therapy was 3,300 IU/mL (range 60–11,000,000 IU/mL). For HCV patients, 17 of the 20 who underwent surgical resection had received HCV therapy and but only six had sustained virologic response.
HCC Characteristics While all HCC patients in both the resection and LT groups met transplant eligibility, resection patients were more likely to have solitary tumors, whereas the majority of LT patients had either one or two tumors (Table 2). In addition, the resection group had earlier staged disease compared to the LT group based on BCLC staging with 100 % of the resection group versus 62.5 % of the LT group having BCLC A/B stage, p \ 0.001. While 37.5 % of the
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Table 1 Clinical characteristics of hepatocellular carcinoma patients treated with liver resection versus liver transplantation
Table 2 Tumor characteristics of hepatocellular carcinoma patients treated with liver resection versus liver transplantation
Characteristics
Liver resection (n = 57)
Liver transplantation (n = 114)
Characteristics
Age
60.5 ± 8.6
61.3 ± 13.3
BMI
25.3 ± 5.2
24.3 ± 4.3
0.27
1
96.5 %
Male
77.2 %
78.1 %
0.89
2
3.5 %
35.6 %
Asian
70.2 %
46.5 %
\0.001
3
0%
19.2 %
Cirrhosis
61.4 %
90.4 %
\0.001
2.7 ± 1.6
2.7 ± 1.1
31.6 %
33.3 %
0.82
A/B
100 %
62.5 %
C/D
p value
0.66
Etiology HCV Non-HCV
68.4 %
66.7 %
0.82
HBV
64.9 %
40.4 %
\0.01
Liver resection (n = 57)
Liver transplantation (n = 114)
\0.001
Number of tumors
Largest tumor size (cm, mean ± SD)
p value
45.2 %
0.87 \0.001
BCLC stage 0%
37.5 %
43.9 %
12.9 %
18 (2–69)
31 (12–105)
\0.001
Alcohol
3.5 %
17.5 %
0.01
Recurrence
Cryptogenic/fatty liver
0%
9.8 %
0.02
Time to recurrence (months, median, range)
Normally distributed variables are presented as mean ± standard deviation (SD) and non-normally distributed variables are presented as median (range)
Tobacco use
52.6 %
46.9 %
0.48
Alcohol history
40.4 %
48.2 %
0.34
Type 2 diabetes
17.5 %
28.1 %
0.13
Platelets (10 /mL)
157 (19–290)
113 (28–316)
\0.001
INR
1.1 ± 0.1
1.3 ± 0.2
\0.001
Creatinine (mg/dL)
0.93 ± 0.19
0.95 ± 0.23
Total bilirubin (mg/dL)
0.9 ± 0.4
2.0 ± 0.2
\0.01
Albumin (g/dL)
3.9 ± 0.5
3.2 ± 0.7
\0.001
AST (U/L)
43 (13–215)
64 (19–338)
ALT (U/L)
51 (15–297)
58 (13–330)
0.26
AP (U/L)
84 (37–212)
110 (29–638)
\0.001
AFP (ng/mL)
52 (1.5–5,371)
25 (1.3–42,800)
Laboratory MELD score
8.9 ± 2.4
11.2 ± 4.1
\0.01
CPT score
5.6 ± 1.7
6.8 ± 0.8
\0.001
3
0.58
0.02
0.40
Unless otherwise indicated, all normally distributed variables are presented as mean ± standard deviation (SD) and non-normally distributed variables are presented as median (range) BMI body mass index, INR international normalized ratio, AST aspartate aminotransferase, ALT alanine aminotransferase, AP alkaine phosphatase, AFP alpha fetoprotein, MELD model for end-stage liver disease, CPT Child Pugh Turcotte
LT group was BCLC C/D stage due to decompensated cirrhosis, transplant eligibility was met based on Milan criteria. Locoregional therapy with transarterial chemoembolization (TACE) was utilized in 21.1 % of the resection group and 65.8 % of the LT group. Significantly higher rates of post-treatment tumor recurrence were seen among the resection group (43.9 vs. 12.9 %, p \ 0.001), and median time to recurrence was also shorter among the resection group (18 vs. 31 months, p = 0.34), although this difference did not reach statistical significance.
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0.34
BCLC Barcelona clinic liver cancer
Liver Transplantation Outcomes Of the 114 HCC patients listed for LT, 55 (48.2 %) actually underwent transplantation during the study period. Among the 59 patients not receiving liver transplantation, 22 (37.3 %) remained on the waitlist at the end of the study period. The remaining 37 patients were removed from the waitlist secondary to death (8.5 %, n = 5), progression of disease (39.0 %, n = 23), psychosocial issues (3.4 %, n = 2), and development of comorbidities (11.9 %, n = 7). Long-Term Survival Overall survival among LT patients was significantly better than those treated with resection (log-rank test, p \ 0.04), but this survival advantage was limited to only the astreated model and LT patients in the post-MELD era (Fig. 1). No significant differences in overall survival were seen between LT patients and resection patients in the ITT model (p = 0.14) among both the pre-MELD and postMELD eras (Fig. 2). Direct comparisons of 3-year survival and 5-year survival between resection patients and LT patients among both the as-treated and ITT models are presented in Fig. 3. In the as-treated model, LT patients in the post-MELD era had significantly greater 3-year survival (100 vs. 82.9 %, p \ 0.01) and 5-year survival (100 vs. 69.5 %, p \ 0.01), but this survival advantage was not seen in the pre-MELD era (Fig. 3a). Among the ITT model, no significant differences were seen in the
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Fig. 1 Overall survival of hepatocellular carcinoma patients treated with liver resection versus actual liver transplantation in an as-treated model and by pre and post-MELD era
Fig. 3 Overall 3- and 5-year survival among hepatocellular carcinoma patients treated with resection or liver transplantation in as-treated (a) and intention-to-treat (b) models. Liver transplant patients were stratified by pre-MELD and post-MELD era
Fig. 2 Overall survival of hepatocellular carcinoma patients treated with liver resection versus liver transplantation in an intention-to-treat model and by pre and post-MELD era
post-MELD era, but there was a trend towards higher 3-year survival (82.9 vs. 68.2 %, p = 0.09) and 5-year survival (69.5 vs. 46.7 %, p = 0.09) in resection patients versus LT patients during the pre-MELD era (Fig. 3b). Sub-analysis of patients that actually received liver transplantation showed no significant difference in 5-year survival among those meeting Milan criteria (82.5 %, 95 % CI 62.8–92.3) and those outside of Milan criteria but within UCSF criteria (83.9 %, 95 % CI 70.3–91.6). Predictors of Long-Term Survival Multivariate Cox proportional hazards models were used to identify factors associated with poorer survival among both the ITT and as-treated models. In the ITT model, resection (vs. LT) was not associated with significantly different survival (HR 1.03, 95 % CI 0.43–2.44), whereas Asians (vs. non-Asians) were associated with better survival (HR
0.44, 95 % CI 0.23–0.84) (Table 3). Compared to patients with non-HCV etiology, there was a trend towards improved survival for patients with HCV etiology (HR 0.54, 95 % CI 0.27–1.07). No other significant associations were observed in the ITT model. In the as-treated model, resection (vs. LT) was associated with significantly poorer survival (HR 7.63, 95 % CI 1.79–32.47). There was also a trend towards poorer survival in males compared to females (HR 5.49, 95 % CI 0.69–43.48) and in patients with cirrhosis compared to those without (HR 3.18, 95 % CI 0.84–12.10), but these associations did not reach statistical significance.
Discussion The present study evaluated differences in long-term survival among transplant-eligible HCC patients who were treated with resection versus LT using ITT and as-treated models. HCC resection patients were more likely to be Asian, less likely to have cirrhosis, and more likely to have HBV infection. LT patients had higher MELD and CPT scores, greater proportion of multifocal tumors, and more advanced BCLC stage of disease. In terms of
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Table 3 Predictors for survival in patients with hepatocellular carcinoma undergoing liver resection or transplantation (LT), by intention-to-treat or as-treated model Variable
Univariate HR
Multivariate 95 % CI
p value
HR
95 % CI
p value
Intention-to-treat model Resection (vs. LT)
0.71
0.41–1.25
0.22
1.03
0.43–2.44
0.95
Male (vs. Female) Age
1.21 1.02
0.67–2.17 0.99–1.04
0.52 0.11
0.99 1.02
0.50–1.94 0.99–1.05
0.97 0.15
Asian (vs. non-Asian)
0.66
0.42–1.04
0.08
0.44
0.23–0.84
\0.02
HCV (vs. non-HCV)
1.04
0.65–1.70
0.85
0.54
0.27–1.07
0.08
BCLC C/D (vs. A/B)
1.50
0.77–2.95
0.26
1.61
0.62–4.18
0.33
Cirrhosis (vs. non-cirrhosis)
1.35
0.67–2.71
0.39
1.09
0.42–2.85
0.86
Post-MELD (vs. pre-MELD) era
0.67
0.42–1.08
0.10
1.03
0.56–1.90
0.93
CPT score
1.19
1.01–1.39
0.03
1.17
0.97–1.41
0.10
Number of tumors
1.35
0.99–1.84
0.06
1.00
0.66–1.52
0.99 \0.01
As-treated model Resection (vs. LT)
2.37
1.10–5.10
0.03
7.63
1.79–32.47
Male (vs. Female)
1.21
0.67–2.17
0.52
5.49
0.69–43.48
0.11
Age
1.02
0.99–1.04
0.11
0.97
0.93–1.01
0.16
Asian (vs. non-Asian)
0.66
0.42–1.04
0.08
0.68
0.21–2.21
0.52
HCV (vs. non-HCV)
1.04
0.65–1.70
0.85
0.44
0.13–1.53
0.20
BCLC C/D (vs. A/B) Cirrhosis (vs. non-cirrhosis)
1.50 1.35
0.77–2.95 0.67–2.71
0.26 0.39
0.88 3.18
0.14–5.47 0.84–12.10
0.90 0.09
Post-MELD (vs. pre-MELD) era
0.67
0.42–1.08
0.10
0.88
0.31–2.47
0.80
CPT score
1.19
1.01–1.39
0.03
1.26
0.84–1.88
0.27
Number of tumors
1.35
0.99–1.84
0.06
1.54
0.65–3.67
0.33
HR hazard ratio, CI confidence interval, HCV hepatitis C virus, BCLC Barcelona clinic liver cancer, MELD model for end stage liver disease
post-treatment HCC recurrence, higher rates occurred in resection patients. In the post-MELD era of the as-treated model, long-term survival was significantly better among LT patients versus resection patients, but no statistically significant survival difference was observed in the ITT model. Treatment with primary surgical resection was an independent predictor of poorer survival in the as-treated model, while Asian ethnicity demonstrated a trend towards predicting better outcomes in the ITT model. At present, there are no clear consensus guidelines that recommend whether surgical resection or LT should be the primary treatment modality among patients with transplant-eligible HCC. In the study by Figueras et al. [15], HCC patients who received LT had significantly higher 5-year disease-free survival (60 vs. 31 %, p = 0.027) compared to those treated with resection, but no difference was observed for overall 5-year survival (60 vs 51 %, p = 0.31). However, the LT and resection groups in this study were not completely comparable. Patients who received resection were limited to those with solitary HCC in which LT was contraindicated (e.g. advanced age, comorbidities), and thus the implications of the survival differences are not clear. In a similar study, Lee et al. [23]
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compared 78 HCC patients who received LT versus 130 HCC patients treated with resection and found no significant difference in overall 5-year survival (78.1 % for LT vs. 58.4 % for resection, p = 0.299). However, the vast majority of these patients had HBV-related HCC (86.5 %), and nearly 40 % of both resection and LT patient groups did not meet Milan criteria, precluding their generalizability to transplant-eligible HCC patients. As such, the decision to pursue resection versus LT in transplant-eligible HCC patients remains a dilemma that has not yet been resolved. The present study spanned a 17-year era during which time the implementation of the MELD score standardized the process for prioritizing patients on the transplant waitlist [27]. While no difference in long-term survival was observed in the ITT model, LT patients had significantly better survival compared to resection patients in the post-MELD era of the as-treated model (Figs. 1, 3), suggesting that patients who can successfully remain on the waitlist to receive LT ultimately fare better. These findings emphasize the importance of close follow-up and aggressive utilization of locoregional or systemic therapies to bridge HCC patients on the transplant waitlist
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Table 4 Median waiting time (days) to liver transplantation, by UNOS regions and blood types Region
Blood type O
Blood type A
Blood type B
Blood type AB
Region 5
2,256
1,142
685
371
Region 1
1,193
1,083
1,678
145
Region 2 Region 3
556 78
431 83
256 55
77 24
Region 4
495
561
355
97
Region 6
175
193
187
70
Region 7
309
232
210
200
Region 8
387
286
224
51
Region 9
1,165
914
328
136
Region 10
131
56
62
10
Region 11
639
466
343
76
Region 1: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island; Region 2: District of Columbia, Delaware, Maryland, New Jersey, Pennsylvania, West Virginia; Region 3: Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, Puerto Rico; Region 4: Oklahoma, Texas; Region 5:California, Nevada, Arizona, New Mexico, Utah; Region 6: Alaska, Hawaii, Idaho, Montana, Oregon, Washington; Region 7: Illinois, Minnesota, North Dakota, South Dakota, Wisconsin; Region 8: Colorado, Iowa, Kansas, Missouri, Nebraska, Wyoming; Region 9: New York, Vermont; Region 10: Indiana, Michigan, Ohio; Region 11: Kentucky, North Carolina, South Carolina, Tennessee, Virginia
towards actual transplantation. However, regional variations in the average MELD score transplanted is representative of variations in the average illness severity among each region’s waitlisted patients and directly affects median liver transplantation wait time (Table 4) [28, 29]. Our medical center shares in a densely populated transplant network region (region 5) and consequently has a higher MELD score at LT time, and ultimately a longer median wait time, predisposing patients to more waitlist morbidity and mortality, higher peri-operative complications, and poorer overall LT outcomes [30]. As demonstrated by data from the organ procurement and transplantation network (OPTN), LT median wait times in region 5 (our center) were 2,256, 1,142, 685, and 371 days for blood types O, A, B, and AB, respectively, and these were much higher than those seen in region 3 with corresponding median wait times of only 78, 83, 55, and 24 days [31]. As such, it is conceivable that the survival advantage of LT over resection may be more pronounced among centers with shorter LT wait times. Even among regions with intermediate wait times (e.g. region 9), LT may also result in a survival advantage given the significant differences in wait times compared to the region of the present study. However, an alternative argument could be made that regions with longer liver transplantation waitlist times may help improve
stratification of disease by better distinguishing HCC with more aggressive high risk disease from less aggressive, low risk HCC. Despite the risk of post-treatment recurrence of HCC, the idea of surgical resection in the management of small localized HCC is appealing in many ways. Surgical resection offers the potential for a cure with a single surgical procedure, avoids the complexities of post-transplant long-term immunosuppression, and allows the allocation of limited organs to transplant-eligible patients that have no other treatment alternatives. Furthermore, the decision to pursue primary surgical resection does not preclude the possibility of future transplantation for HCC recurrence, nor does it increase the operative risk [11, 16, 25, 32, 33]. The idea of primary surgical resection of HCC with the plan for subsequent LT for HCC recurrence or hepatic decompensation was termed salvage transplantation by Majno et al. [34]. Using a Markov-based analytic decision model (with assumptions of average transplant waitlist time of 12 months, HCC progression beyond transplant criteria while on waitlist of 4 % per year, post-resection HCC recurrence of 20 % per year, and post-resection HCC recurrence eligibility for salvage transplantation of 60 %), the average life expectancy was 8.8 years for primary LT and 7.6 years for resection-salvage transplantation, and there was a 29 % reduction in organ utilization associated with the resection-salvage model. Since that time, there have been multiple studies investigating the role of salvage transplantation for HCC recurrence after initial resection, and conflicting results highlight the need for additional welldesigned and well-powered studies [13–16, 25, 31–37]. Liu et al. [36] retrospectively analyzed 380 transplanteligible HCC patients, of whom 200 underwent primary surgical resection and 180 underwent primary LT. Among the resection group, there was a 43 % post-resection HCC recurrence, with 17 % of these recurrences no longer meeting transplant eligibility. However, there was no difference in overall survival between the primary LT group and the salvage transplantation group (5-year survival: 72 vs. 61 %, p = 0.54). In contrast, Fuks et al. [37] evaluated 329 transplant-eligible patients, of whom 191 were listed for primary LT and 138 were treated with primary surgical resection with the plan for salvage transplantation to manage HCC recurrence. While there was no statistically significant difference in overall 5-year survival (77 vs. 60 %, p = 0.12) and 5-year disease free survival (42 vs. 56 %, p = 0.30) between resection patients and LT patients, respectively, 33 % of post-resection HCC recurrences had disease beyond transplant-eligibility. Furthermore, 35 % of post-resection HCC recurrences who met transplant-eligibility were excluded from LT because of advanced age, acquired co-morbidities, or loss to follow up. Despite these findings, the potential role of resection
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followed by salvage transplantation for tumor recurrence may hold promise if researchers can develop prognostic markers to identify the cohort of patients that could achieve favorable outcomes similar to primary LT. The strengths of this study include the utilization of consecutive patients over a 17-year period at a single tertiary liver transplantation center. While the study is limited by factors typical of a retrospective observational analysis such as selection bias in the recruitment of resection and LT patients, strict and consistent inclusion criteria (transplant eligibility) were applied to both the resection and LT groups and included all consecutive eligible patients as opposed to convenience sampling. In addition, the primary predictor was resection versus LT, and the primary outcome was long-term survival, all of which are objective variables unlikely to harbor significant misclassification bias. Furthermore, survival data was confirmed by individual chart review and comprehensively assessed with National Death Index query. In conclusion, the present study demonstrates significantly better survival among transplant-eligible HCC patients who underwent LT versus resection in the postMELD era of the as-treated model. However, the survival advantage of LT over resection did not meet statistical significance in the ITT model. Transplant-eligible HCC patients who can remain on the waitlist to receive LT have better survival than those treated with primary surgical resection. The present study includes a population with a high MELD score at transplantation and a longer median transplantation wait time; and therefore, further studies are needed to determine whether the survival advantage of LT over resection is more pronounced at transplant network regions with shorter median wait times. Acknowledgments This project was supported in part by an institutional training grant from the National Institutes of Health (NIH) T32DK7056-37 (Wong). Conflict of interest
None.
References 1. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. 2. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, et al. SEER Cancer Statistics Review, 1975–2009, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/ csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012. 3. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 2008; 134:1752–1763. 4. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Cin Oncol. 2010;27:1485–1491.
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5. Mair RD, Valenzuela A, Ha NB, Ayoub WS, Daugherty T, Lutchman G, et al. Incidence of hepatocellular carcinoma among US patients with cirrhosis of viral or non-viral etiologies. Clin Gastroenterol Hepatol. 2012;10:1412–1417. 6. European Association for the Study of the Liver. European Organisation for Research and Treatment of Cancer. EASL– EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–943. 7. Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the study of the liver consensus recommendations on hepatocellular carcinoma. Hepatol Int. 2010;4:439–474. 8. Roayaie S, Obeidat K, Sposito C, Mariani L, Bhoori S, Pellegrinelli A, et al. Resection of hepatocellular cancer B 2 cm: results from two western centers. Hepatology 2013;57:1426– 1435. 9. Margarit C, Escartı´n A, Castells L, Vargas V, Allende E, Bilbao I. Resection for hepatocellular carcinoma is a good option in ChildTurcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl. 2005;11:1242–1251. 10. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology. 2008;134:1908–1916. 11. Cherqui D, Laurent A, Mocellin N, et al. Liver resection for transplantable hepatocellular carcinoma: long term survival and role of secondary liver transplantation. Ann Surg. 2009;250: 738–746. 12. Huang J, Yan L, Cheng Z, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252:903–912. 13. Belghiti J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver transplantation for HCC. Ann Surg Oncol. 2008;15:993–1000. 14. Del Gaudio M, Ercolani G, Ravaioli M, et al. Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. Am J Transplant. 2008;8:1177–1185. 15. Figueras J, Jaurrieta E, Valls C, et al. Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy. J Am Coll Surg. 2000; 190:580–587. 16. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235:373–382. 17. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699. 18. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–1403. 19. Llovet JM, Bruix J, Fuster J, et al. Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. Hepatology. 1998;27:1572– 1577. 20. Adler M, De Pauw F, Vereerstraeten P, et al. Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl. 2008;14:526–533. 21. Freeman RB, Edwards EB, Harper AM. Waiting list removal rates among patients with chronic and malignant liver diseases. Am J Transpl. 2006;6:1416–1421. 22. Sapisochin G, Castells L, Dopazo C, Bilbao I, Minguez B, Lazaro JL, et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcomes according to an intentionto-treat basis. Ann Surg Oncol. 2013;20:1194–1202.
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ORIGINAL ARTICLE
Primary Surgical Resection Versus Liver Transplantation for Transplant-Eligible Hepatocellular Carcinoma Patients Robert J. Wong • James Wantuck • Antonia Valenzuela • Aijaz Ahmed • Clark Bonham • Amy Gallo • Marc L. Melcher • Glen Lutchman • Waldo Concepcion • Carlos Esquivel • Gabriel Garcia • Tami Daugherty Mindie H. Nguyen
•
Received: 19 July 2013 / Accepted: 11 November 2013 / Published online: 27 November 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. Existing studies comparing outcomes after liver transplantation (LT) versus surgical resection among transplant-eligible patients are conflicting. Aim The purpose of this study was to compare long-term survival between consecutive transplant-eligible HCC patients treated with resection versus LT. Methods The present retrospective matched case cohort study compares long-term survival outcomes between consecutive transplant-eligible HCC patients treated with resection versus LT using intention-to-treat (ITT) and astreated models. Resection patients were matched to LT patients by age, sex, and etiology of HCC in a 1:2 ratio.
Results The study included 171 patients (57 resection and 114 LT). Resection patients had greater post-treatment tumor recurrence (43.9 vs. 12.9 %, p \ 0.001) compared to LT patients. In the as-treated model of the pre-model for end stage liver disease (MELD) era, LT patients had significantly better 5-year survival compared to resection patients (100 vs. 69.5 %, p = 0.04), but no difference was seen in the ITT model. In the multivariate Cox proportional hazards model, inclusive of age, sex, ethnicity, tumor stage, and MELD era (pre-MELD vs. post-MELD), treatment with resection was an independent predictor of poorer survival (HR 2.72; 95 % CI, 1.08–6.86). Conclusion Transplant-eligible HCC patients who received LT had significantly better survival than those
R. J. Wong A. Valenzuela A. Ahmed G. Lutchman G. Garcia T. Daugherty M. H. Nguyen (&) Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA e-mail: [email protected]
C. Bonham A. Gallo M. L. Melcher W. Concepcion C. Esquivel Department of Surgery, Stanford University Medical Center, 750 Welch Rd. #200, Stanford, CA 94304-5785, USA e-mail: [email protected]
A. Valenzuela e-mail: [email protected] A. Ahmed e-mail: [email protected] G. Lutchman e-mail: [email protected]
A. Gallo e-mail: [email protected] M. L. Melcher e-mail: [email protected] W. Concepcion e-mail: [email protected] C. Esquivel e-mail: [email protected]
G. Garcia e-mail: [email protected] T. Daugherty e-mail: [email protected] J. Wantuck Department of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA e-mail: [email protected]
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treated with resection, suggesting that patients who can successfully remain on LT listing and actually undergo LT have better outcomes. Keywords Liver cancer MELD score OLT Survival Recurrence
Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide [1, 2]. Despite improvements in screening and surveillance along with advances in the treatment options available, overall mortality remains poor [1–4]. According to recent populationbased data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry, overall 5-year survival of patients with HCC remains less than 20 % [2, 4]. This poor survival coupled with the continued rising incidence of HCC in many other regions in the world highlight the significant global health burden that HCC represents [2, 5]. While surgical resection and liver transplantation (LT) are both considered curative for HCC, the decision to pursue resection versus LT is often complex and involves incorporating various patient factors, tumor characteristics, availability of organs, and physician expertise to offer the optimal therapy. The role of surgical resection in the management of HCC is well-established for the treatment of small, localized tumors in patients with well-preserved hepatic function; and when surgically appropriate patients are selected, overall 5-year survival of 50–70 % has been reported [1, 6–14]. However, post-resection recurrence of HCC is not uncommon, and the surgical literature reports recurrence rates as high as 70 % at 5-years post-resection [11–16]. Among patients meeting established transplantation criteria (e.g. Milan criteria [17] or University of California, San Francisco (UCSF) criteria [18]), LT remains the most effective surgical option, with 5-year survival exceeding 70 % [1, 6, 7, 17–19]. Unfortunately, the benefits to this population of LT are severely limited as the increasing number of patients on the waitlist intensifies the competition for the limited availability of organs. Most evident among densely populated metropolitan regions, the scarce availability of livers to be transplanted results in patients waiting longer on the waitlist, during which the risk of HCC progression beyond transplant eligibility continues to increase [20, 21]. Cognizant of the limitations of both surgical resection and LT, it remains unclear whether one therapy is truly superior over the other. Some studies have demonstrated a survival advantage associated with LT while others have reported improved overall survival among patients treated with resection
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[13–16, 22–26]. These studies are limited by the lack of matched controls, a selection bias, and/or the lack of an intention-to-treat analysis, which is especially important to account for the mortality among transplant-waitlist patients whose disease progresses beyond transplant eligibility while waiting for a LT. Therefore, the present study compared long-term survival in transplant-eligible HCC patients undergoing surgical resection to those undergoing LT in a matched case cohort study utilizing intention-totreat (ITT) and as-treated models.
Experimental Procedures Study Design and Patient Population This retrospective matched case cohort study included consecutive HCC patients seen at Stanford University Medical Center from 1995 to 2012 who were identified via electronic query using ICD-9 codes and LT records. A total of 57 consecutive transplant-eligible HCC patients who underwent primary surgical resection during this time period were identified (cases). Transplant eligibility was determined according to accepted criteria at Stanford University Medical Center. HCC patients were first assessed for transplant eligibility based on Milan criteria [17], and if the tumor was outside of Milan criteria, patients were reassessed based on UCSF criteria [18]. The comparative control cohort included 114 transplant-eligible HCC patients who were listed for LT without any surgical resection treatment (controls). Controls were matched to cases by age (±5 years), sex, and etiology of HCC (hepatitis C virus [HCV] vs. non-HCV) in a 2:1 ratio. This study was approved by the Institutional Review Board of Stanford University, Stanford, CA. Demographic, clinical, laboratory, histopathological, and radiological data were reviewed and abstracted using a case report form. Detailed treatment history (resection, transplant listing, actual transplantation, other locoregional therapies received) and outcome (survival, tumor recurrence) data were evaluated. Long-term survival data were obtained by chart review and National Death Index query. Both initial HCC diagnosis and recurrent HCC were diagnosed via cytologic or pathologic diagnosis or noninvasive criteria according to the European Association for the Study of Liver Diseases (EASL) [6], which requires at least one of the following conditions: (1) presence of hypervascular lesion greater than 2 cm in two imaging studies (computed tomography [CT], magnetic resonance imaging [MRI], angiography), (2) presence of hypervascular lesion greater than 2 cm in one imaging study and alpha-fetoprotein (AFP) [ 200 ng/mL, (3) presence of enlarging hypervascular lesion or recurrent hypervascular
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lesions following chemoembolization, and (4) presence of AFP [ 1,000 ng/mL. Reasons for removing patients from the LT waitlist were categorized as death (died while waiting for LT), tumor progression (progression of disease beyond transplant eligibility), psychosocial issues (substance abuse, psychiatric disease, and lack of support), and comorbidities (development of comorbid diseases or advanced age that precluded LT). Study Outcomes The primary outcome of the present study was the overall long-term survival utilizing an ITT model. Secondary outcomes were survival by an as-treated model, comparing cases with controls who actually underwent LT, and rates of tumor recurrence in both the ITT and as-treated models. Among the group of HCC patients listed for liver transplantation, not every patient actually received a liver transplantation during the study period (e.g. died or dropped off waitlist or were still waiting on the list) but none were switched to surgical resection. To account for these events in our survival analysis, we included all patients who were initially listed for liver transplantation and referred to this as the ITT analysis. We subsequently performed an ‘‘as-treated’’ analysis that compared HCC patients that were treated with surgical resection versus HCC patients that actually underwent liver transplantation. For both survival and tumor recurrence outcomes, analyses included stratification based on year of diagnosis (pre-2003 and post-2003) to account for potential effect modification introduced by the implementation of model for end stage liver disease (MELD) scores in 2003 for the prioritization of LT patients on the waitlist (pre-MELD and postMELD). Statistical Analysis Clinical and demographic comparisons were evaluated using chi-square tests for categorical variables and Student’s t test for normally distributed continuous variables and nonparametric methods for those not normally distributed. Long-term survival and tumor recurrence rates were analyzed using Kaplan–Meier methods with log-rank testing for equality of functions. Forward stepwise multivariate Cox proportional hazards models were developed using variables that satisfied biological priori (i.e. age, sex) or those with p \ 0.1 in the univariate analyses. The final multivariate model included adjustments for age, sex (male vs. female), ethnicity (Asian vs. non-Asian), Barcelona clinic liver cancer stage (BCLC) (C/D vs. A/B), Childs Pugh Turcotte (CPT) score, number of tumors, and MELD era (post-MELD vs. pre-MELD). Statistical significance was met with a two-tailed p value \0.05. All statistical
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analyses were performed using the Stata statistical package (version 10, Stata Corporation, TX).
Results Demographic and Clinical Characteristics Clinical and demographic characteristics of HCC patients treated with resection versus LT are presented in Table 1. While cases and controls were matched by HCV status, among non-HCV etiologies, resection patients had higher rates of hepatitis B virus (HBV) infection (64.9 vs. 40.4 %, p \ 0.01), whereas alcoholic liver disease and cryptogenic/ non-alcoholic fatty liver disease were seen more commonly among the LT group. LT patients had lower median platelet levels (113,000 vs. 157,000/mL, p \ 0.001), higher mean total bilirubin (2.0 vs. 0.9 mg/dL, p \ 0.01), lower mean albumin (3.2 vs. 3.9 g/dL, p \ 0.001), higher median AST (64 vs. 43 U/L, p = 0.02) and higher median alkaline phosphatase levels (110 vs. 84 U/L, p \ 0.01) when compared to resection patients. LT patients also had higher mean medical MELD scores (11.2 vs. 8.9, p \ 0.01) and Child-Pugh-Turcotte (CPT) scores (6.8 vs. 5.6, p \ 0.001) compared to resection patients. While LT patients had higher median AFP levels than the resection group (52 vs. 25 ng/mL, p = 0.40), this difference was not statistically significant. Among the 37 HBV-related HCC patients treated with surgical resection, nine were not receiving antiviral therapy. Of the nine patients not receiving antiviral therapy, five had undetectable HBV DNA. The median HBV DNA level prior to surgery in the four HBV patients not on antiviral therapy with detectable DNA was 4,000 IU/mL (range 510–160,000 IU/mL). Among the 28 patients who were on antiviral therapy, ten had undetectable HBV DNA, and the median viral load among those patients with detectable viral load on antiviral therapy was 3,300 IU/mL (range 60–11,000,000 IU/mL). For HCV patients, 17 of the 20 who underwent surgical resection had received HCV therapy and but only six had sustained virologic response.
HCC Characteristics While all HCC patients in both the resection and LT groups met transplant eligibility, resection patients were more likely to have solitary tumors, whereas the majority of LT patients had either one or two tumors (Table 2). In addition, the resection group had earlier staged disease compared to the LT group based on BCLC staging with 100 % of the resection group versus 62.5 % of the LT group having BCLC A/B stage, p \ 0.001. While 37.5 % of the
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Table 1 Clinical characteristics of hepatocellular carcinoma patients treated with liver resection versus liver transplantation
Table 2 Tumor characteristics of hepatocellular carcinoma patients treated with liver resection versus liver transplantation
Characteristics
Liver resection (n = 57)
Liver transplantation (n = 114)
Characteristics
Age
60.5 ± 8.6
61.3 ± 13.3
BMI
25.3 ± 5.2
24.3 ± 4.3
0.27
1
96.5 %
Male
77.2 %
78.1 %
0.89
2
3.5 %
35.6 %
Asian
70.2 %
46.5 %
\0.001
3
0%
19.2 %
Cirrhosis
61.4 %
90.4 %
\0.001
2.7 ± 1.6
2.7 ± 1.1
31.6 %
33.3 %
0.82
A/B
100 %
62.5 %
C/D
p value
0.66
Etiology HCV Non-HCV
68.4 %
66.7 %
0.82
HBV
64.9 %
40.4 %
\0.01
Liver resection (n = 57)
Liver transplantation (n = 114)
\0.001
Number of tumors
Largest tumor size (cm, mean ± SD)
p value
45.2 %
0.87 \0.001
BCLC stage 0%
37.5 %
43.9 %
12.9 %
18 (2–69)
31 (12–105)
\0.001
Alcohol
3.5 %
17.5 %
0.01
Recurrence
Cryptogenic/fatty liver
0%
9.8 %
0.02
Time to recurrence (months, median, range)
Normally distributed variables are presented as mean ± standard deviation (SD) and non-normally distributed variables are presented as median (range)
Tobacco use
52.6 %
46.9 %
0.48
Alcohol history
40.4 %
48.2 %
0.34
Type 2 diabetes
17.5 %
28.1 %
0.13
Platelets (10 /mL)
157 (19–290)
113 (28–316)
\0.001
INR
1.1 ± 0.1
1.3 ± 0.2
\0.001
Creatinine (mg/dL)
0.93 ± 0.19
0.95 ± 0.23
Total bilirubin (mg/dL)
0.9 ± 0.4
2.0 ± 0.2
\0.01
Albumin (g/dL)
3.9 ± 0.5
3.2 ± 0.7
\0.001
AST (U/L)
43 (13–215)
64 (19–338)
ALT (U/L)
51 (15–297)
58 (13–330)
0.26
AP (U/L)
84 (37–212)
110 (29–638)
\0.001
AFP (ng/mL)
52 (1.5–5,371)
25 (1.3–42,800)
Laboratory MELD score
8.9 ± 2.4
11.2 ± 4.1
\0.01
CPT score
5.6 ± 1.7
6.8 ± 0.8
\0.001
3
0.58
0.02
0.40
Unless otherwise indicated, all normally distributed variables are presented as mean ± standard deviation (SD) and non-normally distributed variables are presented as median (range) BMI body mass index, INR international normalized ratio, AST aspartate aminotransferase, ALT alanine aminotransferase, AP alkaine phosphatase, AFP alpha fetoprotein, MELD model for end-stage liver disease, CPT Child Pugh Turcotte
LT group was BCLC C/D stage due to decompensated cirrhosis, transplant eligibility was met based on Milan criteria. Locoregional therapy with transarterial chemoembolization (TACE) was utilized in 21.1 % of the resection group and 65.8 % of the LT group. Significantly higher rates of post-treatment tumor recurrence were seen among the resection group (43.9 vs. 12.9 %, p \ 0.001), and median time to recurrence was also shorter among the resection group (18 vs. 31 months, p = 0.34), although this difference did not reach statistical significance.
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0.34
BCLC Barcelona clinic liver cancer
Liver Transplantation Outcomes Of the 114 HCC patients listed for LT, 55 (48.2 %) actually underwent transplantation during the study period. Among the 59 patients not receiving liver transplantation, 22 (37.3 %) remained on the waitlist at the end of the study period. The remaining 37 patients were removed from the waitlist secondary to death (8.5 %, n = 5), progression of disease (39.0 %, n = 23), psychosocial issues (3.4 %, n = 2), and development of comorbidities (11.9 %, n = 7). Long-Term Survival Overall survival among LT patients was significantly better than those treated with resection (log-rank test, p \ 0.04), but this survival advantage was limited to only the astreated model and LT patients in the post-MELD era (Fig. 1). No significant differences in overall survival were seen between LT patients and resection patients in the ITT model (p = 0.14) among both the pre-MELD and postMELD eras (Fig. 2). Direct comparisons of 3-year survival and 5-year survival between resection patients and LT patients among both the as-treated and ITT models are presented in Fig. 3. In the as-treated model, LT patients in the post-MELD era had significantly greater 3-year survival (100 vs. 82.9 %, p \ 0.01) and 5-year survival (100 vs. 69.5 %, p \ 0.01), but this survival advantage was not seen in the pre-MELD era (Fig. 3a). Among the ITT model, no significant differences were seen in the
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Fig. 1 Overall survival of hepatocellular carcinoma patients treated with liver resection versus actual liver transplantation in an as-treated model and by pre and post-MELD era
Fig. 3 Overall 3- and 5-year survival among hepatocellular carcinoma patients treated with resection or liver transplantation in as-treated (a) and intention-to-treat (b) models. Liver transplant patients were stratified by pre-MELD and post-MELD era
Fig. 2 Overall survival of hepatocellular carcinoma patients treated with liver resection versus liver transplantation in an intention-to-treat model and by pre and post-MELD era
post-MELD era, but there was a trend towards higher 3-year survival (82.9 vs. 68.2 %, p = 0.09) and 5-year survival (69.5 vs. 46.7 %, p = 0.09) in resection patients versus LT patients during the pre-MELD era (Fig. 3b). Sub-analysis of patients that actually received liver transplantation showed no significant difference in 5-year survival among those meeting Milan criteria (82.5 %, 95 % CI 62.8–92.3) and those outside of Milan criteria but within UCSF criteria (83.9 %, 95 % CI 70.3–91.6). Predictors of Long-Term Survival Multivariate Cox proportional hazards models were used to identify factors associated with poorer survival among both the ITT and as-treated models. In the ITT model, resection (vs. LT) was not associated with significantly different survival (HR 1.03, 95 % CI 0.43–2.44), whereas Asians (vs. non-Asians) were associated with better survival (HR
0.44, 95 % CI 0.23–0.84) (Table 3). Compared to patients with non-HCV etiology, there was a trend towards improved survival for patients with HCV etiology (HR 0.54, 95 % CI 0.27–1.07). No other significant associations were observed in the ITT model. In the as-treated model, resection (vs. LT) was associated with significantly poorer survival (HR 7.63, 95 % CI 1.79–32.47). There was also a trend towards poorer survival in males compared to females (HR 5.49, 95 % CI 0.69–43.48) and in patients with cirrhosis compared to those without (HR 3.18, 95 % CI 0.84–12.10), but these associations did not reach statistical significance.
Discussion The present study evaluated differences in long-term survival among transplant-eligible HCC patients who were treated with resection versus LT using ITT and as-treated models. HCC resection patients were more likely to be Asian, less likely to have cirrhosis, and more likely to have HBV infection. LT patients had higher MELD and CPT scores, greater proportion of multifocal tumors, and more advanced BCLC stage of disease. In terms of
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Table 3 Predictors for survival in patients with hepatocellular carcinoma undergoing liver resection or transplantation (LT), by intention-to-treat or as-treated model Variable
Univariate HR
Multivariate 95 % CI
p value
HR
95 % CI
p value
Intention-to-treat model Resection (vs. LT)
0.71
0.41–1.25
0.22
1.03
0.43–2.44
0.95
Male (vs. Female) Age
1.21 1.02
0.67–2.17 0.99–1.04
0.52 0.11
0.99 1.02
0.50–1.94 0.99–1.05
0.97 0.15
Asian (vs. non-Asian)
0.66
0.42–1.04
0.08
0.44
0.23–0.84
\0.02
HCV (vs. non-HCV)
1.04
0.65–1.70
0.85
0.54
0.27–1.07
0.08
BCLC C/D (vs. A/B)
1.50
0.77–2.95
0.26
1.61
0.62–4.18
0.33
Cirrhosis (vs. non-cirrhosis)
1.35
0.67–2.71
0.39
1.09
0.42–2.85
0.86
Post-MELD (vs. pre-MELD) era
0.67
0.42–1.08
0.10
1.03
0.56–1.90
0.93
CPT score
1.19
1.01–1.39
0.03
1.17
0.97–1.41
0.10
Number of tumors
1.35
0.99–1.84
0.06
1.00
0.66–1.52
0.99 \0.01
As-treated model Resection (vs. LT)
2.37
1.10–5.10
0.03
7.63
1.79–32.47
Male (vs. Female)
1.21
0.67–2.17
0.52
5.49
0.69–43.48
0.11
Age
1.02
0.99–1.04
0.11
0.97
0.93–1.01
0.16
Asian (vs. non-Asian)
0.66
0.42–1.04
0.08
0.68
0.21–2.21
0.52
HCV (vs. non-HCV)
1.04
0.65–1.70
0.85
0.44
0.13–1.53
0.20
BCLC C/D (vs. A/B) Cirrhosis (vs. non-cirrhosis)
1.50 1.35
0.77–2.95 0.67–2.71
0.26 0.39
0.88 3.18
0.14–5.47 0.84–12.10
0.90 0.09
Post-MELD (vs. pre-MELD) era
0.67
0.42–1.08
0.10
0.88
0.31–2.47
0.80
CPT score
1.19
1.01–1.39
0.03
1.26
0.84–1.88
0.27
Number of tumors
1.35
0.99–1.84
0.06
1.54
0.65–3.67
0.33
HR hazard ratio, CI confidence interval, HCV hepatitis C virus, BCLC Barcelona clinic liver cancer, MELD model for end stage liver disease
post-treatment HCC recurrence, higher rates occurred in resection patients. In the post-MELD era of the as-treated model, long-term survival was significantly better among LT patients versus resection patients, but no statistically significant survival difference was observed in the ITT model. Treatment with primary surgical resection was an independent predictor of poorer survival in the as-treated model, while Asian ethnicity demonstrated a trend towards predicting better outcomes in the ITT model. At present, there are no clear consensus guidelines that recommend whether surgical resection or LT should be the primary treatment modality among patients with transplant-eligible HCC. In the study by Figueras et al. [15], HCC patients who received LT had significantly higher 5-year disease-free survival (60 vs. 31 %, p = 0.027) compared to those treated with resection, but no difference was observed for overall 5-year survival (60 vs 51 %, p = 0.31). However, the LT and resection groups in this study were not completely comparable. Patients who received resection were limited to those with solitary HCC in which LT was contraindicated (e.g. advanced age, comorbidities), and thus the implications of the survival differences are not clear. In a similar study, Lee et al. [23]
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compared 78 HCC patients who received LT versus 130 HCC patients treated with resection and found no significant difference in overall 5-year survival (78.1 % for LT vs. 58.4 % for resection, p = 0.299). However, the vast majority of these patients had HBV-related HCC (86.5 %), and nearly 40 % of both resection and LT patient groups did not meet Milan criteria, precluding their generalizability to transplant-eligible HCC patients. As such, the decision to pursue resection versus LT in transplant-eligible HCC patients remains a dilemma that has not yet been resolved. The present study spanned a 17-year era during which time the implementation of the MELD score standardized the process for prioritizing patients on the transplant waitlist [27]. While no difference in long-term survival was observed in the ITT model, LT patients had significantly better survival compared to resection patients in the post-MELD era of the as-treated model (Figs. 1, 3), suggesting that patients who can successfully remain on the waitlist to receive LT ultimately fare better. These findings emphasize the importance of close follow-up and aggressive utilization of locoregional or systemic therapies to bridge HCC patients on the transplant waitlist
Dig Dis Sci (2014) 59:183–191
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Table 4 Median waiting time (days) to liver transplantation, by UNOS regions and blood types Region
Blood type O
Blood type A
Blood type B
Blood type AB
Region 5
2,256
1,142
685
371
Region 1
1,193
1,083
1,678
145
Region 2 Region 3
556 78
431 83
256 55
77 24
Region 4
495
561
355
97
Region 6
175
193
187
70
Region 7
309
232
210
200
Region 8
387
286
224
51
Region 9
1,165
914
328
136
Region 10
131
56
62
10
Region 11
639
466
343
76
Region 1: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island; Region 2: District of Columbia, Delaware, Maryland, New Jersey, Pennsylvania, West Virginia; Region 3: Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, Puerto Rico; Region 4: Oklahoma, Texas; Region 5:California, Nevada, Arizona, New Mexico, Utah; Region 6: Alaska, Hawaii, Idaho, Montana, Oregon, Washington; Region 7: Illinois, Minnesota, North Dakota, South Dakota, Wisconsin; Region 8: Colorado, Iowa, Kansas, Missouri, Nebraska, Wyoming; Region 9: New York, Vermont; Region 10: Indiana, Michigan, Ohio; Region 11: Kentucky, North Carolina, South Carolina, Tennessee, Virginia
towards actual transplantation. However, regional variations in the average MELD score transplanted is representative of variations in the average illness severity among each region’s waitlisted patients and directly affects median liver transplantation wait time (Table 4) [28, 29]. Our medical center shares in a densely populated transplant network region (region 5) and consequently has a higher MELD score at LT time, and ultimately a longer median wait time, predisposing patients to more waitlist morbidity and mortality, higher peri-operative complications, and poorer overall LT outcomes [30]. As demonstrated by data from the organ procurement and transplantation network (OPTN), LT median wait times in region 5 (our center) were 2,256, 1,142, 685, and 371 days for blood types O, A, B, and AB, respectively, and these were much higher than those seen in region 3 with corresponding median wait times of only 78, 83, 55, and 24 days [31]. As such, it is conceivable that the survival advantage of LT over resection may be more pronounced among centers with shorter LT wait times. Even among regions with intermediate wait times (e.g. region 9), LT may also result in a survival advantage given the significant differences in wait times compared to the region of the present study. However, an alternative argument could be made that regions with longer liver transplantation waitlist times may help improve
stratification of disease by better distinguishing HCC with more aggressive high risk disease from less aggressive, low risk HCC. Despite the risk of post-treatment recurrence of HCC, the idea of surgical resection in the management of small localized HCC is appealing in many ways. Surgical resection offers the potential for a cure with a single surgical procedure, avoids the complexities of post-transplant long-term immunosuppression, and allows the allocation of limited organs to transplant-eligible patients that have no other treatment alternatives. Furthermore, the decision to pursue primary surgical resection does not preclude the possibility of future transplantation for HCC recurrence, nor does it increase the operative risk [11, 16, 25, 32, 33]. The idea of primary surgical resection of HCC with the plan for subsequent LT for HCC recurrence or hepatic decompensation was termed salvage transplantation by Majno et al. [34]. Using a Markov-based analytic decision model (with assumptions of average transplant waitlist time of 12 months, HCC progression beyond transplant criteria while on waitlist of 4 % per year, post-resection HCC recurrence of 20 % per year, and post-resection HCC recurrence eligibility for salvage transplantation of 60 %), the average life expectancy was 8.8 years for primary LT and 7.6 years for resection-salvage transplantation, and there was a 29 % reduction in organ utilization associated with the resection-salvage model. Since that time, there have been multiple studies investigating the role of salvage transplantation for HCC recurrence after initial resection, and conflicting results highlight the need for additional welldesigned and well-powered studies [13–16, 25, 31–37]. Liu et al. [36] retrospectively analyzed 380 transplanteligible HCC patients, of whom 200 underwent primary surgical resection and 180 underwent primary LT. Among the resection group, there was a 43 % post-resection HCC recurrence, with 17 % of these recurrences no longer meeting transplant eligibility. However, there was no difference in overall survival between the primary LT group and the salvage transplantation group (5-year survival: 72 vs. 61 %, p = 0.54). In contrast, Fuks et al. [37] evaluated 329 transplant-eligible patients, of whom 191 were listed for primary LT and 138 were treated with primary surgical resection with the plan for salvage transplantation to manage HCC recurrence. While there was no statistically significant difference in overall 5-year survival (77 vs. 60 %, p = 0.12) and 5-year disease free survival (42 vs. 56 %, p = 0.30) between resection patients and LT patients, respectively, 33 % of post-resection HCC recurrences had disease beyond transplant-eligibility. Furthermore, 35 % of post-resection HCC recurrences who met transplant-eligibility were excluded from LT because of advanced age, acquired co-morbidities, or loss to follow up. Despite these findings, the potential role of resection
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Dig Dis Sci (2014) 59:183–191
followed by salvage transplantation for tumor recurrence may hold promise if researchers can develop prognostic markers to identify the cohort of patients that could achieve favorable outcomes similar to primary LT. The strengths of this study include the utilization of consecutive patients over a 17-year period at a single tertiary liver transplantation center. While the study is limited by factors typical of a retrospective observational analysis such as selection bias in the recruitment of resection and LT patients, strict and consistent inclusion criteria (transplant eligibility) were applied to both the resection and LT groups and included all consecutive eligible patients as opposed to convenience sampling. In addition, the primary predictor was resection versus LT, and the primary outcome was long-term survival, all of which are objective variables unlikely to harbor significant misclassification bias. Furthermore, survival data was confirmed by individual chart review and comprehensively assessed with National Death Index query. In conclusion, the present study demonstrates significantly better survival among transplant-eligible HCC patients who underwent LT versus resection in the postMELD era of the as-treated model. However, the survival advantage of LT over resection did not meet statistical significance in the ITT model. Transplant-eligible HCC patients who can remain on the waitlist to receive LT have better survival than those treated with primary surgical resection. The present study includes a population with a high MELD score at transplantation and a longer median transplantation wait time; and therefore, further studies are needed to determine whether the survival advantage of LT over resection is more pronounced at transplant network regions with shorter median wait times. Acknowledgments This project was supported in part by an institutional training grant from the National Institutes of Health (NIH) T32DK7056-37 (Wong). Conflict of interest
None.
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