Subscribe to RSS
DOI: 10.1055/s-0033-1351783
Hepatocellular Carcinoma: Resection versus Transplantation
Address for correspondence
Publication History
Publication Date:
13 August 2013 (online)
Abstract
Hepatic resection and transplantation remain the standard curative therapies for hepatocellular carcinoma. These treatments are limited to either patients with early-stage tumors in the case of transplantation or patients with preserved liver function in the case of resection. Currently, patients with early-stage tumors and advanced liver disease are best served by transplant evaluation; however, the best treatment strategy for patients with well-preserved liver function, absence of portal hypertension, and early-stage HCC is debated. Numerous retrospective studies have documented better disease-free survival with transplantation, although the benefit on overall survival is less clear. This effect is likely due to the availability of effective liver-directed therapies for recurrence postresection and the effect of immunosuppression on tumor progression following posttransplant recurrence. Survival studies based on intention-to-treat principle incorporating patients listed for transplantation, but did not undergo the procedure due to waitlist dropoff have also suggested that overall survival rates may not be different despite high recurrence rates following resection. Transplantation has been shown to offer a survival advantage beyond 5-years; however, improvements in adjuvant therapies may narrow this gap. Determining optimal therapy for an individual patient requires consideration of numerous factors including tumor stage, severity of liver disease, and comorbidities as well as geographic and logistical factors that may affect transplant availability.
#
Keywords
hepatocellular carcinoma - hepatic resection - liver transplantation - intention-to-treat - salvage transplantationHepatic transplantation and resection remain the cornerstone surgical therapies for hepatocellular carcinoma (HCC) and the therapeutic options with the greatest likelihood of cure. Relatively few patients, however, are candidates for transplantation due to advanced stage, and advanced chronic liver disease commonly limits suitability for resection.[1] In the Barcelona Clinic Liver Cancer (BCLC) treatment algorithm, which best incorporates tumor, liver, and patient characteristics, these potentially curative therapies are limited to patients with early stage (A) disease with palliative therapy for patients with intermediate (B) and advanced (C) stages disease.[2] Liver transplantation offers excellent outcomes with 5-year disease-free survival rates of ∼70% as it eliminates the tumor and associated diseased liver.[3] [4] [5] Transplantation, however, is restricted to those with relatively small, early-stage lesions, and donor organ availability further limits its broader applicability. Although improvements in HCC screening among cirrhotics and utilization of Model of Endstage Liver Disease (MELD) exemptions has improved transplantation rates and survival among patients with HCC, the majority of patients continue to present outside of the Milan criteria.[1] [6] [7] [8] [9] [10] [11] [12] Due to limitations in donor organ availability and very high costs as well as improvements in patient selection, operative and anesthetic techniques, and postoperative care, there has been renewed interested in resection for HCC.[13] [14] [15] [16] [17] The results of liver resection for HCC depend in large part on the functional capacity of the remnant liver, comorbid illness of the patient, tumor size/stage, and intraoperative factors such as blood loss. Transplantation and resection are often compared; however, significant differences in baseline characteristics of patients undergoing these procedures make interpretation of outcome data problematic.
Resection versus Transplantation
Liver transplantation remains the best theoretical option for HCC because it removes the tumor and underlying diseased liver. Clearly, in patients with advanced liver disease who are not candidates for resection, transplantation represents the only option with a significant chance of cure. Deceased donor organ shortages and poor outcomes in advanced cases, however, have limited transplant applicability to only early-stage disease[3] with < 30% of patients eligible for transplantation at presentation.[18] [19] Although transplantation in patients with stage III tumors (outside of Milan criteria) is offered at some institutions either through expanded criteria such as the University of California San Francisco (UCSF) criteria[20] [21] or utilizing downstaging strategies,[22] [23] these strategies have not been uniformly adopted.
Hepatocellular carcinoma in the absence of chronic liver disease accounts for ∼10 to 20% of cases.[24] [25] The fibrolamellar variant most commonly occurs in young Caucasian females often with lymph node metastasis and without elevations of alpha-fetoprotein.[26] Patients with fibrolamellar and sporadic HCC commonly present when tumors have grown large and symptomatic. When feasible, resection is the mainstay of therapy and is often well tolerated due to the ability of the healthy remnant liver to regenerate.[27] As expected, 5-year-survival rates for patients without chronic liver disease are as high as 50% despite the often advanced stage at presentation, highlighting the significant role that the presence or absence of underlying liver disease plays in both management and outcome.[16] [28]
Every patient with early-stage HCC cannot be offered transplantation; another form of extirpative therapy must be considered for select patients. Liver resection is immediately available, requires no waiting time, allows complete pathologic evaluation of the tumor, and does not, in theory, preclude future transplantation. Clearly, patients without chronic liver disease should undergo resection when technically feasible. Patients with end-stage liver disease, Child-Turcotte-Pugh (CTP) class B and C, should undergo transplantation if available, as should patients with relatively preserved hepatic function, but multifocal disease that is within Milan criteria. The difficulty lies in deciding which patients with chronic liver disease and small (< 5 cm) solitary tumors are best served by resection and which should proceed with transplant evaluation; this is the focus of this article.
Outcomes of Resection
Although rates of disease recurrence remain high, overall survival has improved over the past several decades, with 5-year patient-survival rates ranging from 25% to 55%, in large part likely due to improved therapy of intrahepatic recurrence.[14] [29] [30] [31] In well-selected patients, those with well-compensated liver disease and small (< 2 cm) solitary tumors without vascular invasion, resection can offer 5-year-survival rates as high as 81% in a recent report by Roayaie et al.[32] This is a very small proportion of the patients who present with HCC; however, these results are similar to those of liver transplantation for early-stage HCC.[3]
Tumor recurrence following resection remains common despite great advances in patient selection, and operative and anesthetic techniques, with 5-year-recurrence rates ranging from 60 to 100% in larger series.[14] [31] [32] [33] Recurrence most commonly occurs within the remnant liver, and clonality analysis of the recurrent tumor indicates that approximately one third result from multicentric occurrence rather than intrahepatic metastasis.[34] [35] Numerous factors influence the likelihood of intrahepatic recurrence, including the state of the native liver, tumor size, multicentricity, macro- or microvascular invasion, and in some series, the need for blood transfusion.[31] [36] [37] There is no standard therapy for intrahepatic recurrence following resection. When feasible, repeat resection should be considered although this approach is often not possible due to multicentric recurrence and/or progression of chronic liver disease.[38]
#
#
Transplantation
As liver transplantation was accepted as primary therapy for end-stage liver disease in the 1980s, interest in transplantation for primary hepatic malignancy increased. With improvements in operative technique and immunosuppression, routine survival extended beyond the first few months and the nonmalignant indications for transplantation expanded. During this decade, it would be shown that recurrence following transplantation for HCC was unacceptably high at 65 to 75% likely due in part to accelerated tumor growth associated with immunosuppression.[39] [40] Tumor recurrence was the rule. Several studies documented high recurrence rates and adjuvant therapy had little, if any, impact. In 1985, Iwatsuki et al published the initial experience of the Pittsburgh/Colorado group with transplantation for malignancy.[39] They found that no recurrence was noted in 12 patients with incidental tumors (median follow-up 16 months), while those with known malignancy had a 74% recurrence rate (median time to recurrence 8 months). Olthoff et al published the initial University of California Los Angeles (UCLA) experience of 16 patients who underwent transplantation for HCC.[41] Of the 12 patients that survived the first 3 months following transplantation, eight (67%) developed recurrence within 2 months to 2 years. These high recurrence rates and the ever-growing number of patients with nonmalignant indications for transplantation diminished interest in liver replacement for hepatic malignancy and a moratorium was placed on liver transplant for HCC outside of clinical trials in 1989.[42]
In 1996, Mazzaferro et al[3] published their landmark article that led to internationally renewed interest in liver transplantation for HCC and still forms the framework for transplant policy in North America and much of the world. This prospective cohort study included 48 cirrhotic patients who underwent transplantation for HCC with single tumors ≤5cm or up to three tumors, the largest of which is ≤3cm. The actuarial 4-year survival rate was 75% and was not different from the expected survival of patients with nonmalignant indications for transplantation. Based on this report and several studies validating these results, interest in transplantation as a therapeutic option for patients with early stage HCC was renewed.[43] [44] In an analysis of the Organ Procurement and Transplant Network (OPTN) dataset, Yoo et al examined 34,324 patients who underwent liver transplantation from 1987 to 2001 in the United States.[45] One- and 5-year patient survival rates were significantly worse in those transplanted for HCC when compared with those transplanted for non-HCC indications (1-year 77.0% vs. 86.7%, p < 0.001; 5-year 48.3% vs. 74.7%, p < 0.001). In fact, HCC was a strong predictor of worse survival at 1 and 5 years (hazard ratio [HR] 1.6 and 2.02, respectively). However, the authors did find a significant improvement in survival of patients with HCC over time without a concomitant increase in survival of the control, non-HCC group. Five-year survival rates of HCC patients increased from 25.3% in the 1987 to 1991 period, to 61.1% during 1996 to 2001. This study validated the supposition that improvement in survival of patients transplanted for HCC was due to better patient selection as selection criteria became more rigorous in the late 1990s.
Given the dramatically improved results of transplantation for early-stage HCC and the shortcomings and the CTP, time-based allocation system, many believed that HCC patients were distinctly disadvantaged in organ allocation. Although waiting time was the cornerstone of the tripartite CTP-based allocation system, time spent on the waitlist failed to correlate with risk of death while waiting for a deceased donor organ.[46] This led to efforts to improve deceased donor allocation and find a method to better predict waitlist dropout due to death or tumor progression. In 1998, the United States Health Resources and Services Administration of the Department of Health and Human Services issued the “Final Rule” calling for the development of a new allocation policy based on disease severity and likelihood of dying or becoming nontransplantable while awaiting liver transplantation.[47]
In February 2002, the Model for End Stage Liver Disease (MELD) was introduced as the system for deceased donor liver allocation in the United States. Three laboratory values (international normalized ration [INR], bilirubin, and creatinine) determine MELD score and this score determines waitlist ranking. Thus, severity of liver disease became the major determinant of organ allocation. Several studies have validated MELD as an accurate predictor of mortality in patients with end-stage liver disease.[48] [49] Soon after its implementation, additions to the waitlist decreased, the rate of transplantation increased, and linear relationship between MELD score and waitlist mortality was retrospectively demonstrated.[50] Although MELD clearly had a beneficial impact on organ allocation in patients with end-stage liver disease, the dilemma arose of how to allocate livers to patients with transplantable HCC and low MELD score before they progressed outside of Milan criteria. Initially, patients with HCC were arbitrarily assigned a score thought to allow for timely transplantation. The goal was to equate risk of progression beyond stage 2 disease (based on the American Liver Tumor Study Group modified TNM staging system) for HCC patients with risk of death on the waitlist for non-HCC transplant candidates over a similar period. Patients with stage 1 disease were assigned a MELD of 24, which estimates a 15% chance of progressing beyond Milan criteria in 3 months. Those with stage 2 disease were assigned 29 points approximating a 30% risk of progression within 3 months. Every 3 months thereafter, MELD points estimating a 10% increase in progression beyond stage 2 disease were added to the initial allocation score.
Soon after implementation of the new allocation scheme for HCC, the number of transplants for HCC increased from 7% the year preceding MELD to 22% in the year after, and 87% of patients with HCC were transplanted within 3 months of listing.[10] [51] Furthermore, the number of HCC patients who became nontransplantable or died was actually lower than the number of noncancer patients with a similar MELD score who died awaiting an organ.[52] As a result of these and other data, concern grew that HCC patients were given excess priority and the allocation model was changed in 2003 to give patients with stage 1 disease 20 points (or an 8% chance of dying or disease progression in 3 months) and stage 2 patients 24 points. This reduced the number of patients transplanted for HCC from 22% to 14%, although it did not significantly change the time on the waitlist or waitlist dropout in a study of the United Network for Organ Sharing (UNOS) database.[53] In an analysis of explant pathology reports, 31% of patients transplanted for stage 1 HCC were found to have no evidence of malignancy in the specimen compared with 9% of those with stage 2 disease.[52] This led to a cessation of MELD allocation priority to those with stage 1 tumors. Under current UNOS policy, patients receive an allocation priority MELD of 22, which is increased by an estimated 10% risk of dropout every 3 months.
Several studies have retrospectively validated improved survival of patients with HCC within Milan criteria undergoing liver transplantation. In the largest North American single-center experience, Duffy et al from UCLA presented the outcomes of 467 patients who underwent transplantation for HCC from 1984 to 2006.[54] Recurrence-free survival rates were significantly higher in patients within Milan criteria compared with those beyond (74% vs. 27%, respectively; p < 0.01). Notably, patients who underwent transplantation after the institution of MELD-based allocation had a 74% 5-year overall survival rate versus 47% of those transplanted prior to implementation of MELD (p = 0.001). In another report from a large American center, Onaca and Klintmalm demonstrate similar improvement in outcome following implementation of Milan criteria in selection for transplantation.[55] Five-year overall survival rates improved from 28.6% in 1987 to 1992 to 42.3% in 1992 to 1997, likely reflecting general improvements in liver transplantation. These results were inferior to those achieved in non-HCC patients. After 1997, 5-year survival rates improved to 76% for HCC patients, similar to the survival in nonmalignant indications. Tumor recurrence rates dropped from 52.9% (1987–1992) and 48.2% (1992–1997) to 11.4% (1997–2002). Again, it was demonstrated that MELD-based allocation reduced median wait time for patients with HCC.
Pretreatment Prior to Transplantation
Despite the improved prioritization for HCC under the MELD-based allocation system, there has been an increasing demand of a relatively fixed supply of deceased donor organs. This, in turn, has led to an increased dropout rate from the waitlist and worse overall survival of HCC patients awaiting transplantation.[56] Llovet et al documented a 25% dropout rate in the first 6-months awaiting liver transplantation.[14] In an analysis of the UNOS/Organ Procurement and Transplantation Network (OPTN) database, Pelletier et al demonstrated a 12% 1-year and 20% 3-year risk of dropping off the waitlist due to tumor progression or death.[57] The impact of pretransplant therapy in this study is unknown, but it does highlight the significant risk of waitlist drop-out and regional variation in transplant rates for HCC. In an effort to slow or halt disease progression while on the waitlist, many centers began to utilize ablative therapy such as trans-arterial chemoembolization (TACE), radiofrequency ablation (RFA), or percutaneous ethanol injection (PEI). Utilizing pretransplant chemoembolization, Maddala et al at the Mayo Clinic demonstrated 15% 6-month and 25% 1-year waitlist dropout rates.[58] Mazzaferro et al treated 60 tumors in 50 patients with pretransplant RFA.[59] After a median waiting time of 9.5 months, there were no patients dropped due to tumor progression and the 1- and 3-year overall survival rates were 95% and 83%, respectively.
Although pretransplant locoregional therapy such as TACE has a well-defined role as a “bridge” to transplant,[60] [61] [62] its role as neoadjuvant therapy to provide oncologic benefit after transplantation is less clear. In a retrospective analysis from two centers, Yao and colleagues demonstrated a beneficial effect of locoregional therapy in posttransplant recurrence-free survival for patients with T2 and T3 HCC.[63] In these patients, the 5-year recurrence-free survival rate was 93.8% for patients who received locoregional therapy versus 80.6% for those did not undergo pretransplant treatment (p = 0.049). The treatment benefit was most notable in those patients with T3 tumors suggesting that preoperative therapy may add a survival benefit to those who undergo transplantation, but may also allow for selection of patients whose tumors have “good biology.” Another report by Bharat retrospectively evaluated 100 patients with HCC who underwent transplantation with 46 receiving pretransplant locoregional therapy.[22] Those who underwent pretransplant therapy had better 5-year survival rates (82.4% vs. 51.8%; p = 0.01). When stratified by tumor stage, the treatment benefit was seen only in those with T2–T4 tumors. Patients with T1 tumors experienced excellent outcomes with or without neoadjuvant locoregional therapy. Interestingly, 16 patients were found to have 100% tumor necrosis on pathologic evaluation of the explanted liver. Eleven of these 16 had T2 or T3 disease and experienced better survival than those with T1 tumors as determined by pretransplant radiographic study.
#
Expanding the Milan Criteria
Several groups have challenged the restrictions imposed by Milan either through expanding the size criteria or by using liver-directed therapy in an attempt to “downstage” patients with advanced tumors to within criteria.[21] [54] [64] [65] [66] Most notable has been the group from UCSF who have proposed criteria of a single tumor ≤6.5cm or up to three tumors, the largest ≤4.5 cm and total tumor diameter ≤8 cm without gross vascular invasion.[21] These numbers were derived from explant tumor characteristics as the authors noted that explant pathology often revealed understaging by preoperative cross-sectional imaging; however, this did not necessarily result in inferior outcome. Of the 168 patients in the initial report, the 5-year recurrence-free survival rate was 90% for the 130 patients with a preoperative tumor stage within Milan versus 94% for the 30 patients that met the UCSF criteria but exceeded Milan (p = 0.58). These criteria were further evaluated in a series of 467 patients who underwent transplantation at UCLA.[54] Based on pretransplant imaging, 173 patients were within Milan criteria, 185 were beyond Milan but within UCSF criteria, and 109 were outside of UCSF criteria. The 5-year patient survival rate was 79% for those meeting Milan versus 64% for those beyond Milan but within UCSF (p = 0.061). Based on explant pathology the survival of those meeting Milan versus meeting only UCSF were 86% versus 81% at 5 years, respectively.
Inherent within the discussion of transplantation for tumors beyond Milan criteria is the idea of tumor downstaging with neoadjuvant locoregional therapy. Majno et al from the hospital Paul Brousse in Paris were the first to apply the concept of tumor downstaging to facilitate transplantation and the practice has been adopted by several centers.[67] A report from Washington University (St. Louis, MO) demonstrated the feasibility of tumor downstaging and the possibility of successful transplantation of advanced tumors using this strategy.[23] Of 202 patients with HCC evaluated for transplantation during the study period, 76 had stage III/IV disease and were otherwise transplant candidates. A median number of two TACE sessions were used and 18 patients (23.7%) achieved adequate downstaging to qualify for transplantation under Milan criteria. Seventeen (22.4%) patients went on to receive a deceased donor allograft at a median of 5.8 ± 3.5 months following their first TACE. The actuarial overall 5-year survival rate for patients with stage 2 disease who were chemoembolized and transplanted was 66% compared with 93.8% in patients with stage 3/4 disease who were downstaged and underwent transplantation (p = 0.03), suggesting that this strategy allows for selection of patients with good prognosis for long-term survival—“favorable biology” tumors. A similar result was seen by the UCSF group who utilized TACE for tumors exceeding Milan, but within UCSF criteria and a minimum observation period of 3 months following tumor therapy.[68] Tumor downstaging was achieved in 43 of 61 patients (70.5%) with treatment failure observed in 18 (29.5%). Of 35 patients who underwent liver transplantation, 13 had complete tumor necrosis, 17 met stage 2 criteria, and five patients were beyond stage 2. One and 4-year overall survival rates following transplantation were 96.2% and 92.1%, respectively. There was no tumor recurrence noted at a median follow-up of 25 months.
#
Comparative Outcomes of Resection and Transplantation
Although the roles of resection and transplantation in well-compensated cirrhotics with early-stage HCC are often debated and choice of therapy is influenced by nonclinical factors such as surgeon specialty and evaluation at a transplant center, patients who are eligible for either therapy represent a small portion of patients presenting with newly diagnosed hepatoma. Certainly, in most Western centers where HCV infection is the predominant etiology of chronic liver failure, patients presenting with early-stage HCC and well-compensated liver disease without portal hypertension are the exception rather than the rule. Despite this, debate continues regarding optimal surgical therapy for this small group of patients. Transplantation offers lower risk of recurrence, and excellent long-term disease-free survival due to complete removal of the cirrhotic liver. However, preneoplastic liver has inherent risks including disease progression while awaiting an organ and the need for chronic immunosuppression. Moreover, transplantation of potentially resectable HCC reduces the number of available allografts for patients with end-stage liver disease. Resection, in comparison, is immediately available, carries lower morbidity and early mortality in well-selected patients, and has no impact on the deceased donor organ pool. Recurrence following resection is common and candidate selection can be challenging. Despite the high risk of recurrence following resection, several studies have shown that the overall 5-year patient-survival rate is comparable to that of transplantation ([Fig. 1]).[14] [69] [70] [71] [72]
In addition to clinical variables including liver and tumor factors, nonclinical factors have been shown to play a role in the selection of therapy. In a survey of 336 liver surgeons, Nathan et al surveyed surgeons as to the best treatment modality in patients with HCC in various scenarios.[73] Fifty-four percent of respondents performed liver transplantation, 94% performed liver resection, and 49% performed both. Liver-transplant surgeons were more likely to choose liver transplantation for HCC than nonliver transplant surgeons (63% vs. 50%; p < 0.001). This result was maintained in a multivariable analysis; however, when clinical data was allowed to vary with surgeon specialty, the effect of surgeon specialty became insignificant, indicating that transplant and nontransplant surgeons weigh various clinical factors such as etiology of cirrhosis, estimated waitlist time, and type of resection differently. Interestingly, 60% of liver transplant surgeons indicated that they decide for or against liver transplantation first, then consider other therapeutic modalities, whereas 42% of nonliver transplant surgeons first considered transplantation. In a second analysis of the data, the authors investigated institutional and surgeon volume factors on therapeutic decision making.[74] In this analysis, prior receipt of liver-transplant training and formal training in surgical oncology did not affect preferences among surgeons who did not perform liver transplantation. Annual volume impacted choice of therapy with higher-volume surgeons favoring liver transplantation. Surgeons at institutions where liver transplant was performed were more likely to choose liver transplantation even if they did not personally perform transplantation.
Randomized controlled trials of transplantation and resection for early-stage HCC in patients with preserved liver function are infeasible due to the large number of patients required and differences in practice patterns. This has led to numerous retrospective analyses, however, retrospective comparison of transplantation and resection is complicated by numerous factors including waitlist dropout while awaiting transplantation, nonstandard selection criteria for hepatic resection, differences in tumor size/stage, severity of liver disease, and patient demographics. Perhaps the greatest barrier to analysis of these patients has been the capture of patients listed for transplantation that did not undergo the procedure due to disease progression, death, or other contraindication to transplantation; or patients who were initially resected and recurrence was treated with salvage transplantation. This has led to several analyses based on the intention-to-treat principal. In 1999, Llovet et al presented an intention-to-treat analysis of 164 patients evaluated for surgery at the Barcelona Liver Clinic.[14] Seventy-seven patients were resected and 87 transplanted. Of those resected, 74 were CTP A. The 1-, 3-, and 5-year intention-to-treat survival rates were 85%, 62%, and 51% for resection, and 84%, 69%, and 69% for transplantation. When patients with clinically relevant portal hypertension were excluded from analysis (n = 35), 5-year survival postresection rate increased to 74%, indicating that in well-selected patients, resection may carry an overall survival rate similar to that of transplantation in this group of patients. In another intention-to-treat analysis, Facciuto et al analyzed 179 patients with cirrhosis and HCC who underwent either resection or transplantation.[70] Patients with CTP C cirrhosis, incidental HCC, and macrovascular invasion were excluded, leaving 157 patients analyzed. Of these, 51 underwent resection and 106 were listed for transplantation of which 84 were transplanted. The mean waiting time for transplant was 7 months; 21 patients were removed from the waitlist due to tumor progression. Overall survival from time of listing or liver resection did not differ between the groups with 1- and 4-year overall survival rates of 88% and 61% for resection compared with 92% and 62% for transplantation (p = 0.54). As expected, survival rates were significantly lower in both treatment groups for patients with tumors beyond Milan criteria ([Fig. 2]).
Although overall 5-year survival for liver resection may not be different than that of transplantation, disease recurrence following resection is common. In an analysis of 217 patients treated with either resection or transplantation, Sapisochin et al found that 1-, 5-, and 10-year risk of recurrence rates were 19%, 67%, and 83% for resection compared with 4%, 18%, and 20% for transplantation.[75] This did not translate into a significant overall 1- and 4-year survival-rate difference (85% and 60% for resection and 82% and 62% for transplantation), likely indicating the effect of adjuvant locoregional therapies at extending survival following resection and near uniform fatality of recurrence following transplantation. There was, however, a significant difference in the 10-year survival rate with 33% of resected patients alive at 10 years compared with 49% of transplanted patients, indicating the effect of tumor recurrence and progression of liver disease on long-term survival. The primary difficulty in interpreting these studies is the inherent bias of retrospective studies regardless of intention to treat. In a meta-analysis of 10 retrospective studies comparing resection and transplantation, transplantation was found to have a survival advantage over resection (odds ratio [OR] = 0.581; 95% confidence interval [CI] 0.359–0.939; p = 0.027) ([Table 1]).[14] [72] [76] [77] [78] [79] [80] [81] [82] [83] [84] The studies included were heterogeneous and included patients with advanced liver disease and some were not based on intention to treat. Meta-analysis of three studies comparing transplantation and resection in patients with early HCC and well-compensated cirrhosis using an intention-to-treat analysis included 412 patients. A significant 5-year overall survival-rate advantage was demonstrated for patients undergoing transplantation (OR = 0.521; 95% CI 0.298–0.911; p = 0.022).[76]
|
Authors, year |
Country |
Departments[a] |
HR, n |
LT, n |
Tumour size |
Child-Pugh class |
ITT analysis |
OS after LT at years: |
OS after HR at years: |
Length of follow-up |
||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
1% |
3% |
5% |
1% |
3% |
5% |
|||||||||
|
Lee et al. (2010)[77] |
South Korea |
Surgery |
82 |
48 |
Within as well as outside the Milan Criteria[b] |
A, B |
No |
85 |
78 |
78 |
88 |
75 |
58 |
Mean: LT 49.1 months; HR 66.5 months |
|
Baccarani et al. (2008)[78] |
Italy |
Surgery and transplant |
38 |
48 |
Milan Criteria |
A, B, C |
Yes |
84 |
78 |
72 |
82 |
61 |
27 |
Median: LT 21 months (range: 1–85 months), HR 36 months (range: 10–84 months) |
|
Bellavance et al. (2008)[79] |
USA, Switzerland, Italy |
Surgery, transplant, surgical oncology |
245 |
134 |
Milan Criteria |
A |
No |
91 |
79 |
66 |
93 |
71 |
46 |
Median: overall 2.5 years: LT 3.3 years; HR 2.3 years |
|
Del Gaudio et al. (2008)[80] |
Italy |
Liver transplant |
80 |
293 |
Milan Criteria |
A, B, C |
Yes |
58 |
66 |
Mean: primary LT 36 months; salvage LT 26.2 months |
||||
|
Shah et al. (2007)[81] |
Canada |
Surgery |
121 |
140 |
Milan Criteria |
A, B |
Yes |
90 |
70 |
64 |
89 |
75 |
56 |
Median; 35 months |
|
Poon et al. (2007)[82] |
Hong Kong |
Surgery |
204 |
43 |
Milan Criteria |
A, B, C |
Yes |
44 |
60 |
Median; LT 49 months (range: 8–123 monthsj; HR 53 months (range: 8–124 months) |
||||
|
Margarit et al. (20O5)[72] |
Spain |
Liver transplant |
37 |
36 |
Milan Criteria |
A |
No |
78 |
65 |
92 |
70 |
Median: LT 44 months; HR 50 months |
||
|
Bigourdan et al. (2O03)[83] |
France |
Visceral transplant |
20 |
17 |
Milan Criteria |
A |
Yes |
87 |
71 |
67 |
36 |
Median: 55 months |
||
|
Llovet et al. (1999)[14] |
Spain |
Liver transplant |
77 |
37 |
Milan Criteria |
A |
Yes |
83 |
71 |
71 |
85 |
62 |
51 |
Median: LT 26 months; HR 32 months |
|
Weimann et al. (1999)[84] |
Germany |
Transplant |
32 |
31 |
Milan Criteria |
Not mentioned |
No |
87 |
72 |
63 |
78 |
41 |
35 |
Not mentioned |
a Countries of departmental affiliations indicated on the title page.
b Only data for patients with disease within the Milan Criteria were included in the meta-analysis.
LT, liver transplant; HR, hepatic resection; ITT, intention-to-treat; OS, overall survival.
Source: From Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB 2012;14:635–645. Copyright © International Hepato-Pancreato-Biliary Association with permission.
#
Resection with Salvage Transplantation
Several reports now document the use of “salvage transplantation” for intrahepatic recurrence or hepatic failure following resection.[36] [80] [85] This practice has not gained a tremendous foothold in the United States due to the MELD priority given to HCC; however, it has become a commonly debated topic as the number of patients waiting on transplantation is increasing as is the prevalence of HCC. The implications of this approach, especially for patients within the Milan criteria, is far reaching and is affected by numerous factors including waiting time and regional deceased-donor organ availability. The theoretical advantage of this approach is that a substantial portion of early-stage patients could be spared the inherent morbidity of liver transplantation and immunosuppression and an increase in the number of allografts available to patients with advanced liver disease. Salvage transplantation, however, is restricted to patients who develop recurrence with the Milan criteria and are otherwise candidates for transplantation and thus some candidates who may have been cured through transplantation may be converted to nontransplantable by a resection-first approach. Several series have utilized this approach in transplant candidates and demonstrated differing results. A study by Belghiti et al did not reveal inferior survival results, morbidity, or early mortality for those who underwent secondary liver transplantation after resection compared with patients who underwent primary liver transplantation.[86] A second study by Adam et al found that secondary liver transplantation after resection was associated with a much higher operative mortality, tumor recurrence, and lower 5-year posttransplant survival rates (41% vs. 61%; p = 0.03).[87] Ninety-eight patients who underwent resection were transplant eligible and tumor recurred in 69 (70%). Notably, only 17 patients (25%) of the 69 had transplantable tumor recurrence. The 5-year overall survival rate of those who underwent resection of transplant eligible tumors was significantly less than that of patients who underwent primary transplantation (50% vs. 61%; p = 0.05). A Markov model evaluating the harm and benefit of primary liver resection with salvage transplantation for HCC found that primary transplantation offered a greater life expectancy as long as 5-year posttransplant survival rates remained greater than 60%.[88] Based on an estimated 10% proportion of patients on the waiting list with HCC and a median time to transplant of 3 months, the harm caused to resected patients was higher than the benefit of having those livers reallocated to the waitlisted population.
An intention-to-treat analysis in the Bologna series demonstrated similar 5-year survival rates in the resection with salvage transplant group compared with patients listed for primary transplant. Similar analysis from Fuks et al in Paris found that 1- and 5-year survival rates were not different following primary transplantation versus resection with the possibility of salvage transplantation (1-year: 60% vs. 77%; 5-year: 56% vs. 40%).[69] The two groups were subject to selection bias inherent to retrospective studies with patients receiving primary transplantation having more advanced liver disease and those undergoing primary resection having more advanced tumors. Of the 138 patients undergoing resection, recurrence developed in 90 (65%) with 30 (33%) of these recurring beyond Milan. Twenty-one (35%) of the 60 patients recurring within Milan criteria were not eligible for transplantation for nontumor-related reasons and 39 (43.3%) of the 90 patients that recurred following resection were transplanted. Factors associated with recurrence beyond Milan included presence of cirrhosis, tumor diameter > 3 cm, vascular invasion, satellite nodules, and poor differentiation ([Table 2]). It is concluded that a resection-first strategy saved 22 allografts and precluded transplantation in these patients who were cured with resection. However, difficulty remains in predicting which patients, eligible for curative transplantation, will either develop advanced recurrence or become transplant ineligible for nontumor reasons—as occurred in 51 (45%) of the 112 patients resected for HCC in this study. Several studies have documented increase risk of recurrence with increased risk of recurrence beyond Milan criteria precluding salvage transplantation for tumors > 3 cm indicating that patients with these early-stage tumors may best be served by primary transplantation due to low rates of salvage transplantation in this group.[69] [70]
Abbreviations: AFP, α-fetoprotein: HCC, hepatocellular carcinoma; HR, hazard ratio; MC, Milan criteria; VHB, viral hepatitis B; VHC, viral hepatitis C; CI, confidence interval.
Source: From Fuks D, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 2012;55(1):132–140. Copyright © American Association for the Study of Liver Diseases with permission.
#
#
Conclusion
Hepatic resection and transplantation remain the cornerstone curative therapies for patients with HCC. In patients with early-stage tumors and advanced liver disease, transplantation is clearly the treatment of choice with 5-year survival rates of roughly 70%. Liver transplantation, however, is limited by organ shortage and the inherent risk of transplantation and immunosuppression. In patients without cirrhosis or cirrhotics with preserved liver function and absence of portal hypertension and tumors beyond the Milan criteria, resection remains the treatment of choice when feasible. Although recurrence following resection is common, several recent reports document 5-year overall survival rates following resection for very-early- and early-stage tumors similar to that of liver transplantation. Overall survival rates beyond 5 years, however, may be significantly worse for patients undergoing resection. The essential challenge is determining which therapeutic modality is best for patients with relatively early-stage tumors who could tolerate resection. Numerous factors must be considered including tumor size, multifocality, medical comorbidity, and geographic factors that affect waitlist time and organ availability.
#
#
-
References
- 1 Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol 2003; 38 (Suppl. 01) S136-S149
- 2 Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (3) 329-338
- 3 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 (11) 693-699
- 4 Tsoulfas G, Kawai T, Elias N , et al. Long-term experience with liver transplantation for hepatocellular carcinoma. J Gastroenterol 2011; 46 (2) 249-256
- 5 Island ER, Pomposelli J, Pomfret EA, Gordon FD, Lewis WD, Jenkins RL. Twenty-year experience with liver transplantation for hepatocellular carcinoma. Arch Surg 2005; 140 (4) 353-358
- 6 Trevisani F, Cantarini MC, Labate AM , et al; Italian Liver Cancer (ITALICA) group. Surveillance for hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects on cancer staging and patient survival. Am J Gastroenterol 2004; 99 (8) 1470-1476
- 7 Tong MJ, Blatt LM, Kao VW. Surveillance for hepatocellular carcinoma in patients with chronic viral hepatitis in the United States of America. J Gastroenterol Hepatol 2001; 16 (5) 553-559
- 8 Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130 (7) 417-422
- 9 Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31 (2) 330-335
- 10 Sharma P, Balan V, Hernandez JL , et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004; 10 (1) 36-41
- 11 Washburn K. Model for end stage liver disease and hepatocellular carcinoma: a moving target. Transplant Rev (Orlando) 2010; 24 (1) 11-17
- 12 Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35 (3) 519-524
- 13 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993; 218 (2) 145-151
- 14 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30 (6) 1434-1440
- 15 Poon RT, Fan ST, Lo CM , et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 2001; 234 (1) 63-70
- 16 Belghiti J, Regimbeau JM, Durand F , et al. Resection of hepatocellular carcinoma: a European experience on 328 cases. Hepatogastroenterology 2002; 49 (43) 41-46
- 17 Cha CH, Ruo L, Fong Y , et al. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003; 238 (3) 315-321 , discussion 321–323
- 18 Bilimoria MM, Lauwers GY, Doherty DA , et al; International Cooperative Study Group on Hepatocellular Carcinoma. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 2001; 136 (5) 528-535
- 19 Llovet JM, Fuster J, Bruix J. Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004; 10 (2) (Suppl. 01) S115-S120
- 20 Yao FY, Bass NM, Nikolai B , et al. Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 2002; 8 (10) 873-883
- 21 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 (6) 1394-1403
- 22 Bharat A, Brown DB, Crippin JS , et al. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg 2006; 203 (4) 411-420
- 23 Chapman WC, Majella Doyle MB, Stuart JE , et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg 2008; 248 (4) 617-625
- 24 Bralet MP, Régimbeau JM, Pineau P , et al. Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology 2000; 32 (2) 200-204
- 25 Grando-Lemaire V, Guettier C, Chevret S, Beaugrand M, Trinchet JC. Hepatocellular carcinoma without cirrhosis in the West: epidemiological factors and histopathology of the non-tumorous liver. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. J Hepatol 1999; 31 (3) 508-513
- 26 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004; 39 (3) 798-803
- 27 Poon RT, Fan ST, Wong J. Selection criteria for hepatic resection in patients with large hepatocellular carcinoma larger than 10 cm in diameter. J Am Coll Surg 2002; 194 (5) 592-602
- 28 Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB (Oxford) 2005; 7 (1) 42-49
- 29 Shimozawa N, Hanazaki K. Longterm prognosis after hepatic resection for small hepatocellular carcinoma. J Am Coll Surg 2004; 198 (3) 356-365
- 30 Vauthey JN, Klimstra D, Franceschi D , et al. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg 1995; 169 (1) 28-34 , discussion 34–35
- 31 Ercolani G, Grazi GL, Ravaioli M , et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237 (4) 536-543
- 32 Roayaie S, Obeidat K, Sposito C , et al. Resection of hepatocellular cancer </= 2 cm: results from two western centers. Hepatology 2013; 57 (4) 1426-1435
- 33 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 1999; 229 (2) 216-222
- 34 Li Q, Wang J, Juzi JT , et al. Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma. J Gastrointest Surg 2008; 12 (9) 1540-1547
- 35 Ng IO, Guan XY, Poon RT, Fan ST, Lee JM. Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis. J Pathol 2003; 199 (3) 345-353
- 36 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 (3) 373-382
- 37 Imamura H, Matsuyama Y, Tanaka E , et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38 (2) 200-207
- 38 Poon RT, Fan ST, O'Suilleabhain CB, Wong J. Aggressive management of patients with extrahepatic and intrahepatic recurrences of hepatocellular carcinoma by combined resection and locoregional therapy. J Am Coll Surg 2002; 195 (3) 311-318
- 39 Iwatsuki S, Gordon RD, Shaw Jr BW, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202 (4) 401-407
- 40 O'Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988; 207 (4) 373-379
- 41 Olthoff KM, Millis JM, Rosove MH, Goldstein LI, Ramming KP, Busuttil RW. Is liver transplantation justified for the treatment of hepatic malignancies?. Arch Surg 1990; 125 (10) 1261-1266 , discussion 1266–1268
- 42 Onaca N, Davis GL, Jennings LW, Goldstein RM, Klintmalm GB. Improved results of transplantation for hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2009; 15 (6) 574-580
- 43 Shetty K, Timmins K, Brensinger C , et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004; 10 (7) 911-918
- 44 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 (6) 1572-1577
- 45 Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003; 21 (23) 4329-4335
- 46 Freeman Jr RB, Edwards EB. Liver transplant waiting time does not correlate with waiting list mortality: implications for liver allocation policy. Liver Transpl 2000; 6 (5) 543-552
- 47 Organ Procurement and Transplantation Network. Organ Procurement and Transplantation Network. Health Resources and Services Administration, HHS. Final rule. Fed Regist 1999; 64 (202) 56650-56661
- 48 Wiesner RH, McDiarmid SV, Kamath PS , et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001; 7 (7) 567-580
- 49 Wiesner R, Edwards E, Freeman R , et al; United Network for Organ Sharing Liver Disease Severity Score Committee. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003; 124 (1) 91-96
- 50 Olthoff KM, Brown Jr RS, Delmonico FL , et al. Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA. Liver Transpl 2004; 10 (10) (Suppl. 02) A6-A22
- 51 Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R. United Network for Organ Sharing Organ Procurement and Transplantation Network Liver and Transplantation Committee. Results of the first year of the new liver allocation plan. Liver Transpl 2004; 10 (1) 7-15
- 52 Wiesner RH, Freeman RB, Mulligan DC. Liver transplantation for hepatocellular cancer: the impact of the MELD allocation policy. Gastroenterology 2004; 127 (5) (Suppl. 01) S261-S267
- 53 Sharma P, Harper AM, Hernandez JL , et al. Reduced priority MELD score for hepatocellular carcinoma does not adversely impact candidate survival awaiting liver transplantation. Am J Transplant 2006; 6 (8) 1957-1962
- 54 Duffy JP, Vardanian A, Benjamin E , et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007; 246 (3) 502-509 , discussion 509–511
- 55 Onaca N, Klintmalm GB. Liver transplantation for hepatocellular carcinoma: the Baylor experience. J Hepatobiliary Pancreat Sci 2010; 17 (5) 559-566
- 56 Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001; 33 (5) 1073-1079
- 57 Pelletier SJ, Fu S, Thyagarajan V , et al. An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data. Liver Transpl 2009; 15 (8) 859-868
- 58 Maddala YK, Stadheim L, Andrews JC , et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl 2004; 10 (3) 449-455
- 59 Mazzaferro V, Battiston C, Perrone S , et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004; 240 (5) 900-909
- 60 Llovet JM, Real MI, Montaña X , et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359 (9319) 1734-1739
- 61 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37 (2) 429-442
- 62 Lo CM, Ngan H, Tso WK , et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35 (5) 1164-1171
- 63 Yao FY, Kinkhabwala M, LaBerge JM , et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 2005; 5 (4 Pt 1) 795-804
- 64 Roayaie S, Frischer JS, Emre SH , et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 2002; 235 (4) 533-539
- 65 Kneteman NM, Oberholzer J, Al Saghier M , et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10 (10) 1301-1311
- 66 Onaca N, Davis GL, Goldstein RM, Jennings LW, Klintmalm GB. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2007; 13 (3) 391-399
- 67 Majno PE, Adam R, Bismuth H , et al. Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 1997; 226 (6) 688-701 , discussion 701–703
- 68 Yao FY, Kerlan Jr RK, Hirose R , et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008; 48 (3) 819-827
- 69 Fuks D, Dokmak S, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 2012; 55 (1) 132-140
- 70 Facciuto ME, Rochon C, Pandey M , et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria. HPB (Oxford) 2009; 11 (5) 398-404
- 71 Sogawa H, Shrager B, Jibara G, Tabrizian P, Roayaie S, Schwartz M. Resection or transplant-listing for solitary hepatitis C-associated hepatocellular carcinoma: an intention-to-treat analysis. HPB (Oxford) 2013; 15 (2) 134-141
- 72 Margarit C, Escartín A, Castells L, Vargas V, Allende E, Bilbao I. Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl 2005; 11 (10) 1242-1251
- 73 Nathan H, Bridges JF, Schulick RD , et al. Understanding surgical decision making in early hepatocellular carcinoma. J Clin Oncol 2011; 29 (6) 619-625
- 74 Nathan H, Segev DL, Bridges JF , et al. Influence of nonclinical factors on choice of therapy for early hepatocellular carcinoma. Ann Surg Oncol 2013; 20 (2) 448-456
- 75 Sapisochin G, Castells L, Dopazo C , et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg Oncol 2013; 20 (4) 1194-1202
- 76 Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 2012; 14 (9) 635-645
- 77 Lee KK, Kim DG, Moon IS, Lee MD, Park JH. Liver transplantation versus liver resection for the treatment of hepatocellular carcinoma. J Surg Oncol 2010; 101 (1) 47-53
- 78 Baccarani U, Isola M, Adani GL , et al. Superiority of transplantation versus resection for the treatment of small hepatocellular carcinoma. Transpl Int 2008; 21 (3) 247-254
- 79 Bellavance EC, Lumpkins KM, Mentha G , et al. Surgical management of early-stage hepatocellular carcinoma: resection or transplantation?. J Gastrointest Surg 2008; 12 (10) 1699-1708
- 80 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 (6) 1177-1185
- 81 Shah SA, Cleary SP, Tan JC , et al. An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Ann Surg Oncol 2007; 14 (9) 2608-2614
- 82 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival. Ann Surg 2007; 245 (1) 51-58
- 83 Bigourdan JM, Jaeck D, Meyer N , et al. Small hepatocellular carcinoma in Child A cirrhotic patients: hepatic resection versus transplantation. Liver Transpl 2003; 9 (5) 513-520
- 84 Weimann A, Schlitt HJ, Oldhafer KJ, Hoberg S, Tusch G, Raab R. Is liver transplantation superior to resection in early stage hepatocellular carcinoma?. Transplant Proc 1999; 31 (1-2) 500-501
- 85 Adam R, Azoulay D. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy?. Ann Surg 2005; 241 (4) 671-672
- 86 Belghiti J, Cortes A, Abdalla EK , et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003; 238 (6) 885-892 , discussion 892–893
- 87 Adam R, Azoulay D, Castaing D , et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?. Ann Surg 2003; 238 (4) 508-518 , discussion 518–519
- 88 Cucchetti A, Vitale A, Gaudio MD , et al. Harm and benefits of primary liver resection and salvage transplantation for hepatocellular carcinoma. Am J Transplant 2010; 10 (3) 619-627
Address for correspondence
-
References
- 1 Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol 2003; 38 (Suppl. 01) S136-S149
- 2 Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19 (3) 329-338
- 3 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 (11) 693-699
- 4 Tsoulfas G, Kawai T, Elias N , et al. Long-term experience with liver transplantation for hepatocellular carcinoma. J Gastroenterol 2011; 46 (2) 249-256
- 5 Island ER, Pomposelli J, Pomfret EA, Gordon FD, Lewis WD, Jenkins RL. Twenty-year experience with liver transplantation for hepatocellular carcinoma. Arch Surg 2005; 140 (4) 353-358
- 6 Trevisani F, Cantarini MC, Labate AM , et al; Italian Liver Cancer (ITALICA) group. Surveillance for hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects on cancer staging and patient survival. Am J Gastroenterol 2004; 99 (8) 1470-1476
- 7 Tong MJ, Blatt LM, Kao VW. Surveillance for hepatocellular carcinoma in patients with chronic viral hepatitis in the United States of America. J Gastroenterol Hepatol 2001; 16 (5) 553-559
- 8 Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130 (7) 417-422
- 9 Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31 (2) 330-335
- 10 Sharma P, Balan V, Hernandez JL , et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004; 10 (1) 36-41
- 11 Washburn K. Model for end stage liver disease and hepatocellular carcinoma: a moving target. Transplant Rev (Orlando) 2010; 24 (1) 11-17
- 12 Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35 (3) 519-524
- 13 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993; 218 (2) 145-151
- 14 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30 (6) 1434-1440
- 15 Poon RT, Fan ST, Lo CM , et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 2001; 234 (1) 63-70
- 16 Belghiti J, Regimbeau JM, Durand F , et al. Resection of hepatocellular carcinoma: a European experience on 328 cases. Hepatogastroenterology 2002; 49 (43) 41-46
- 17 Cha CH, Ruo L, Fong Y , et al. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003; 238 (3) 315-321 , discussion 321–323
- 18 Bilimoria MM, Lauwers GY, Doherty DA , et al; International Cooperative Study Group on Hepatocellular Carcinoma. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 2001; 136 (5) 528-535
- 19 Llovet JM, Fuster J, Bruix J. Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004; 10 (2) (Suppl. 01) S115-S120
- 20 Yao FY, Bass NM, Nikolai B , et al. Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 2002; 8 (10) 873-883
- 21 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 (6) 1394-1403
- 22 Bharat A, Brown DB, Crippin JS , et al. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg 2006; 203 (4) 411-420
- 23 Chapman WC, Majella Doyle MB, Stuart JE , et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg 2008; 248 (4) 617-625
- 24 Bralet MP, Régimbeau JM, Pineau P , et al. Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology 2000; 32 (2) 200-204
- 25 Grando-Lemaire V, Guettier C, Chevret S, Beaugrand M, Trinchet JC. Hepatocellular carcinoma without cirrhosis in the West: epidemiological factors and histopathology of the non-tumorous liver. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. J Hepatol 1999; 31 (3) 508-513
- 26 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004; 39 (3) 798-803
- 27 Poon RT, Fan ST, Wong J. Selection criteria for hepatic resection in patients with large hepatocellular carcinoma larger than 10 cm in diameter. J Am Coll Surg 2002; 194 (5) 592-602
- 28 Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB (Oxford) 2005; 7 (1) 42-49
- 29 Shimozawa N, Hanazaki K. Longterm prognosis after hepatic resection for small hepatocellular carcinoma. J Am Coll Surg 2004; 198 (3) 356-365
- 30 Vauthey JN, Klimstra D, Franceschi D , et al. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg 1995; 169 (1) 28-34 , discussion 34–35
- 31 Ercolani G, Grazi GL, Ravaioli M , et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237 (4) 536-543
- 32 Roayaie S, Obeidat K, Sposito C , et al. Resection of hepatocellular cancer </= 2 cm: results from two western centers. Hepatology 2013; 57 (4) 1426-1435
- 33 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 1999; 229 (2) 216-222
- 34 Li Q, Wang J, Juzi JT , et al. Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma. J Gastrointest Surg 2008; 12 (9) 1540-1547
- 35 Ng IO, Guan XY, Poon RT, Fan ST, Lee JM. Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis. J Pathol 2003; 199 (3) 345-353
- 36 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 (3) 373-382
- 37 Imamura H, Matsuyama Y, Tanaka E , et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38 (2) 200-207
- 38 Poon RT, Fan ST, O'Suilleabhain CB, Wong J. Aggressive management of patients with extrahepatic and intrahepatic recurrences of hepatocellular carcinoma by combined resection and locoregional therapy. J Am Coll Surg 2002; 195 (3) 311-318
- 39 Iwatsuki S, Gordon RD, Shaw Jr BW, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202 (4) 401-407
- 40 O'Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988; 207 (4) 373-379
- 41 Olthoff KM, Millis JM, Rosove MH, Goldstein LI, Ramming KP, Busuttil RW. Is liver transplantation justified for the treatment of hepatic malignancies?. Arch Surg 1990; 125 (10) 1261-1266 , discussion 1266–1268
- 42 Onaca N, Davis GL, Jennings LW, Goldstein RM, Klintmalm GB. Improved results of transplantation for hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2009; 15 (6) 574-580
- 43 Shetty K, Timmins K, Brensinger C , et al. Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome. Liver Transpl 2004; 10 (7) 911-918
- 44 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 (6) 1572-1577
- 45 Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003; 21 (23) 4329-4335
- 46 Freeman Jr RB, Edwards EB. Liver transplant waiting time does not correlate with waiting list mortality: implications for liver allocation policy. Liver Transpl 2000; 6 (5) 543-552
- 47 Organ Procurement and Transplantation Network. Organ Procurement and Transplantation Network. Health Resources and Services Administration, HHS. Final rule. Fed Regist 1999; 64 (202) 56650-56661
- 48 Wiesner RH, McDiarmid SV, Kamath PS , et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001; 7 (7) 567-580
- 49 Wiesner R, Edwards E, Freeman R , et al; United Network for Organ Sharing Liver Disease Severity Score Committee. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003; 124 (1) 91-96
- 50 Olthoff KM, Brown Jr RS, Delmonico FL , et al. Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA. Liver Transpl 2004; 10 (10) (Suppl. 02) A6-A22
- 51 Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R. United Network for Organ Sharing Organ Procurement and Transplantation Network Liver and Transplantation Committee. Results of the first year of the new liver allocation plan. Liver Transpl 2004; 10 (1) 7-15
- 52 Wiesner RH, Freeman RB, Mulligan DC. Liver transplantation for hepatocellular cancer: the impact of the MELD allocation policy. Gastroenterology 2004; 127 (5) (Suppl. 01) S261-S267
- 53 Sharma P, Harper AM, Hernandez JL , et al. Reduced priority MELD score for hepatocellular carcinoma does not adversely impact candidate survival awaiting liver transplantation. Am J Transplant 2006; 6 (8) 1957-1962
- 54 Duffy JP, Vardanian A, Benjamin E , et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007; 246 (3) 502-509 , discussion 509–511
- 55 Onaca N, Klintmalm GB. Liver transplantation for hepatocellular carcinoma: the Baylor experience. J Hepatobiliary Pancreat Sci 2010; 17 (5) 559-566
- 56 Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001; 33 (5) 1073-1079
- 57 Pelletier SJ, Fu S, Thyagarajan V , et al. An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data. Liver Transpl 2009; 15 (8) 859-868
- 58 Maddala YK, Stadheim L, Andrews JC , et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl 2004; 10 (3) 449-455
- 59 Mazzaferro V, Battiston C, Perrone S , et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004; 240 (5) 900-909
- 60 Llovet JM, Real MI, Montaña X , et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359 (9319) 1734-1739
- 61 Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37 (2) 429-442
- 62 Lo CM, Ngan H, Tso WK , et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35 (5) 1164-1171
- 63 Yao FY, Kinkhabwala M, LaBerge JM , et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 2005; 5 (4 Pt 1) 795-804
- 64 Roayaie S, Frischer JS, Emre SH , et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 2002; 235 (4) 533-539
- 65 Kneteman NM, Oberholzer J, Al Saghier M , et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10 (10) 1301-1311
- 66 Onaca N, Davis GL, Goldstein RM, Jennings LW, Klintmalm GB. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2007; 13 (3) 391-399
- 67 Majno PE, Adam R, Bismuth H , et al. Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 1997; 226 (6) 688-701 , discussion 701–703
- 68 Yao FY, Kerlan Jr RK, Hirose R , et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008; 48 (3) 819-827
- 69 Fuks D, Dokmak S, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 2012; 55 (1) 132-140
- 70 Facciuto ME, Rochon C, Pandey M , et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria. HPB (Oxford) 2009; 11 (5) 398-404
- 71 Sogawa H, Shrager B, Jibara G, Tabrizian P, Roayaie S, Schwartz M. Resection or transplant-listing for solitary hepatitis C-associated hepatocellular carcinoma: an intention-to-treat analysis. HPB (Oxford) 2013; 15 (2) 134-141
- 72 Margarit C, Escartín A, Castells L, Vargas V, Allende E, Bilbao I. Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl 2005; 11 (10) 1242-1251
- 73 Nathan H, Bridges JF, Schulick RD , et al. Understanding surgical decision making in early hepatocellular carcinoma. J Clin Oncol 2011; 29 (6) 619-625
- 74 Nathan H, Segev DL, Bridges JF , et al. Influence of nonclinical factors on choice of therapy for early hepatocellular carcinoma. Ann Surg Oncol 2013; 20 (2) 448-456
- 75 Sapisochin G, Castells L, Dopazo C , et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg Oncol 2013; 20 (4) 1194-1202
- 76 Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 2012; 14 (9) 635-645
- 77 Lee KK, Kim DG, Moon IS, Lee MD, Park JH. Liver transplantation versus liver resection for the treatment of hepatocellular carcinoma. J Surg Oncol 2010; 101 (1) 47-53
- 78 Baccarani U, Isola M, Adani GL , et al. Superiority of transplantation versus resection for the treatment of small hepatocellular carcinoma. Transpl Int 2008; 21 (3) 247-254
- 79 Bellavance EC, Lumpkins KM, Mentha G , et al. Surgical management of early-stage hepatocellular carcinoma: resection or transplantation?. J Gastrointest Surg 2008; 12 (10) 1699-1708
- 80 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 (6) 1177-1185
- 81 Shah SA, Cleary SP, Tan JC , et al. An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Ann Surg Oncol 2007; 14 (9) 2608-2614
- 82 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival. Ann Surg 2007; 245 (1) 51-58
- 83 Bigourdan JM, Jaeck D, Meyer N , et al. Small hepatocellular carcinoma in Child A cirrhotic patients: hepatic resection versus transplantation. Liver Transpl 2003; 9 (5) 513-520
- 84 Weimann A, Schlitt HJ, Oldhafer KJ, Hoberg S, Tusch G, Raab R. Is liver transplantation superior to resection in early stage hepatocellular carcinoma?. Transplant Proc 1999; 31 (1-2) 500-501
- 85 Adam R, Azoulay D. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy?. Ann Surg 2005; 241 (4) 671-672
- 86 Belghiti J, Cortes A, Abdalla EK , et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003; 238 (6) 885-892 , discussion 892–893
- 87 Adam R, Azoulay D, Castaing D , et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?. Ann Surg 2003; 238 (4) 508-518 , discussion 518–519
- 88 Cucchetti A, Vitale A, Gaudio MD , et al. Harm and benefits of primary liver resection and salvage transplantation for hepatocellular carcinoma. Am J Transplant 2010; 10 (3) 619-627