Abstract
Objectives
There is controversy over whether hepatocellular carcinoma (HCC) should be primarily treated with living donor liver transplantation (LDLT) if liver resection (LR) can be effective. This retrospective study was conducted to compare survival outcomes in patients treated with either modality for solitary HCC measuring ≤8 cm in diameter.
Methods
Outcomes in patients with solitary HCC primarily treated by LDLT were analysed. Patients with solitary HCC of similar sizes with or without microvascular invasion primarily treated with LR were selected at a ratio of 6 : 1 for comparison.
Results
In-hospital mortality amounted to 0% and 1.3% in the LDLT (n = 50) and LR (n = 300) groups, respectively (P = 0.918). Complication rates were 34% and 20% in the LDLT and LR groups, respectively (P = 0.027). Rates of 1-, 3-, 5- and 10-year overall survival were 98%, 94%, 89% and 83%, respectively, in the LDLT group and 95%, 85%, 76% and 56%, respectively, in the LR group (P = 0.013). Rates of 1-, 3-, 5- and 10-year disease-free survival were 96%, 90%, 87% and 81%, respectively, in the LDLT group and 81%, 64%, 57% and 40%, respectively, in the LR group (P < 0.0001).
Conclusions
Living donor liver transplantation surpassed LR in survival outcomes, achieving a 10-year overall survival rate 1.5 times as high and a 10-year disease-free survival rate twice as high as those facilitated by LR. However, it entailed more complications, in addition to the inevitable risks to the donor.
Introduction
Liver resection (LR) and liver transplantation (LT) are accepted surgical treatments for hepatocellular carcinomas (HCCs) meeting standard criteria1,2 in patients with preserved liver function and decompensated liver function, respectively. Liver resection is readily available, but is associated with a high incidence of recurrence and may compromise subsequent LT.3 Liver transplantation is theoretically the best option because it cures both the tumour and the underlying liver disease. However, it is limited by the availability of liver grafts although theoretically living donor liver donation is an alternative source of grafts for transplantation.
Patients with solitary HCC generally achieve good survival after LR4,5 or LT.6 The present study was conducted to investigate the outcomes of LR and living donor LT (LDLT), respectively, in these patients.
Materials and methods
A retrospective analysis of data for all adult patients (aged ≥18 years) in whom solitary HCC was treated with LDLT as the primary treatment during the period from 1996 to 2010 at the University of Hong Kong was conducted. Tumour status was based on histopathological examination of resected specimens. A histopathological tumour diameter of 8 cm was used as the cut-off criterion because no HCC of >8 cm had been encountered in LDLTs performed at the study hospital. A group of adult patients in whom HCCs of similar sizes with or without microvascular invasion were treated with primary LR during the same period were selected on a ratio of 6 : 1 for comparison. This ratio was adopted because the highest possible power for analysis was 1 : 6 according to the number of patients in the LR group with HCCs of <5 cm in diameter and no microvascular invasion (Table 1). The LR patients were selected randomly using a computer run by a statistician. All data were collected prospectively by a single research assistant.
Table 1.
Distribution of patients grouped by tumour size and microvascular invasion before and after the matching of liver resection (LR) patients to living donor liver transplantation (LDLT) patients at a ratio of 6 : 1
| LR group, n | LDLT group, n | Total, n | |
|---|---|---|---|
| Before matching | |||
| <5 cm without microvascular invasion | 223 | 32 | 255 |
| <5 cm with microvascular invasion | 87 | 7 | 94 |
| 5–8 cm without microvascular invasion | 75 | 7 | 82 |
| 5–8 cm with microvascular invasion | 47 | 4 | 51 |
| Total | 432 | 50 | 482 |
| After matching | |||
| <5 cm without microvascular invasion | 192 | 32 | 224 |
| <5 cm with microvascular invasion | 42 | 7 | 51 |
| 5–8 cm without microvascular invasion | 42 | 7 | 49 |
| 5–8 cm with microvascular invasion | 24 | 4 | 28 |
| Total | 300 | 50 | 350 |
The strategies for the management of patients with known HCC and the selection of such patients for LDLT and LR have been described elsewhere.7,8 For LDLT, in general this institution's practice has followed the University of California San Francisco (UCSF) criteria, but patients with solitary HCC with a radiological size of slightly over 6.5 cm have been accepted provided that both the donor and recipient accepted the higher chance of recurrence. Tumours were evaluated using computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and thorax, in addition to a radionuclide bone scan performed at the initial diagnosis. Computed tomography was the first-line imaging modality, whereas MRI was performed in patients with a history of allergy or renal impairment or in whom the findings of CT were inconclusive. In recent years, dual-tracer (18F-fluorodeoxyglucose and 11C-acetate) positron emission tomography has been performed in selected patients to exclude extrahepatic metastasis. All living graft donors had a compatible ABO blood group, serology negative of hepatitis B surface antigen and hepatitis C antibody, and no evidence of any acute or chronic illness that would increase operation risk.
All patients were submitted to regular follow-up at the outpatient clinic by the surgical team and to regular surveillance for recurrence by serial α-fetoprotein level checks and helical contrast CT or MRI every 3 months in the first 2 years and every 6 months thereafter. Intrahepatic tumour recurrences were managed with re-resection, salvage transplantation, radiofrequency ablation or transarterial chemoembolization according to tumour status and liver function at the time of recurrence. Follow-up data for all patients were complete.
Operative procedures were defined using the Brisbane terminology. Major hepatectomy was defined as resection of four or more liver segments. Resection of fewer than four liver segments and non-anatomical resection were regarded as representing minor hepatectomy. Postoperative complications were evaluated according to the Clavien–Dindo system of classification. Hospital death was defined as death after surgery during the same hospitalization. Survival was defined as the period from the time of surgery to the time of death or time of data censoring. Recurrence was calculated from the time of surgery to the time of diagnosis of HCC recurrence and was censored at the time of the last follow-up visit or death if at that time there was no evidence of recurrence. The primary endpoint of the study was overall survival. The secondary endpoint was disease-free survival, which was defined as the absence of recurrence of HCC and death (excluding hospital deaths) after surgery. Deaths from all events were censored. Continuous variables were expressed as medians and ranges and compared using the Mann–Whitney U-test. Categorical variables were compared using Pearson's chi-squared test. Survival analysis was performed using the Kaplan–Meier method and compared between groups with the log-rank test. All analyses were performed using pasw Statistics for Windows Version 18.0 (SPSS, Inc., Chicago, IL, USA). P-values of <0.05 were considered to indicate statistical significance.
Results
A total of 720 adult patients with solitary HCC of ≤8 cm in diameter underwent surgery at the study hospital during the study period. Among them, 50 underwent LDLT and 432 underwent LR. For the purposes of comparison, 300 patients were selected from the 432 LR patients based on the matching of tumour size (<5 cm and 5–8 cm) and the presence or absence of microvascular invasion. Table 1 shows the distribution of patients grouped by tumour size and the presence or absence of microvascular invasion before and after matching.
Table 2 shows demographic and preoperative data for patients in the LR and LDLT groups. Patients in the LDLT group had significantly worse liver function. In the LR group, 112 (37%) patients underwent major hepatectomy and 188 (63%) underwent minor hepatectomy. The median resection margin was 1 cm (range: 0–4.5 cm). In the LDLT group, all patients except one received a right lobe graft. The median graft weight was 585 g (range: 415–930 g), the median graft : standard liver volume ratio was 47.1% (range: 31.7–79.2%), and the median graft : recipient weight ratio was 0.88 (range: 0.58–1.41). Table 3 shows intraoperative and postoperative data for patients in the two groups.
Table 2.
Demographic and preoperative data for the liver resection (LR) and living donor liver transplantation (LDLT) groups
| LR group | LDLT group | P-value | |
|---|---|---|---|
| (n = 300) | (n = 50) | ||
| Age, years, median (range) | 53 (19–65) | 54 (30–64) | 0.493 |
| Gender, male : female, n | 245 : 55 | 39 : 11 | 0.539 |
| Hepatitis B virus infection, n (%) | 276 (92%) | 42 (84%) | 0.121 |
| Hepatitis C virus infection, n (%) | 11 (4%) | 5 (10%) | 0.046 |
| Comorbidity, n (%) | 110 (37%) | 18 (36%) | 0.928 |
| Child–Pugh class, n (%) | <0.0001 | ||
| A | 291 (97%) | 18 (36%) | |
| B | 9 (3%) | 20 (40%) | |
| C | 0 | 12 (24%) | |
| Total bilirubin, umol/l, median (range) | 12.0 (2–58) | 33.5 (8–570) | <0.0001 |
| INR, median (range) | 1.0 (0.8–1.6) | 1.3 (1.0–3.6) | <0.0001 |
| Albumin, g/l, median (range) | 41 (23–50) | 33 (21–43) | <0.0001 |
| Aspartate transaminase, U/l, median (range) | 38 (13–393) | 62.5 (29–349) | <0.0001 |
| Prothrombin time, s, median (range) | 12.5 (9.5–18.2) | 16.1 (10.8–38.7) | <0.0001 |
| Platelet count, ×109/l, median (range) | 152.0 (27–421) | 59.5 (25–215) | <0.0001 |
| Urea, mmol/l, median (range) | 4.7 (2.3–13.6) | 4.6 (2.5–23.8) | 0.575 |
| Creatinine, umol/l, median (range) | 88 (35–839) | 80 (38–210) | 0.005 |
| ICG retention at 15 min, %, median (range) | 10.4 (1.2–78.0) | 35.3 (8.0–56.1) | <0.0001 |
| MELD score, median (range) | 7.72 (6–20) | 13.00 (6–43) | <0.0001 |
| Tumour size, cm, median (range) | 3.5 (0.7–8.0) | 2.5 (1.0–7.5) | 0.122 |
| α-fetoprotein, ng/ml, median (range) | 47.5 (2–32 843) | 42.5 (2–12 020) | 0.658 |
| Microvascular invasion, n (%) | 66 (22%) | 11 (22%) | >0.99 |
| Tumour cell differentiation, n (%) | 0.027 | ||
| Good | 96 (32%) | 22 (44%) | |
| Moderate | 160 (53%) | 23 (46%) | |
| Poor | 38 (13%) | 0 | |
| Not known | 2 (0.7%) | 5 (10%) | |
INR, international normalized ratio; ICG, indocyanine green; MELD, Model for End-stage Liver Disease.
Table 3.
Intraoperative and postoperative data for patients in the liver resection (LR) and living donor liver transplantation (LDLT) groups
| LR group | LDLT group | P-value | |
|---|---|---|---|
| (n = 300) | (n = 50) | ||
| Graft weight, g, median (range) | – | 585 (415–930) | – |
| Blood loss, l, median (range) | 0.60 (0.01–15.0) | 2.02 (0.25–15.5) | <0.0001 |
| Blood transfusion, n (%) | <0.0001 | ||
| No | 277 (93%) | 19 (38%) | |
| Yes | 23 (7%) | 31 (62%) | |
| Hospital death, n (%) | 4 (1%) | 0 | 0.918 |
| Hospital stay, days, median (range) | 8 (2–102) | 16 (7–38) | <0.0001 |
| Follow-up, months, median (range) | 71.8 (0.2–210.8) | 70.4 (5.9–178.5) | 0.751 |
| Postoperative complications, n (%) | 60 (20%) | 17 (34%) | 0.027 |
| Clavien–Dindo Grades I and II | 20 (7%) | 4 (8%) | |
| Clavien–Dindo Grade IIIa | 28 (9%) | 12 (24%) | |
| Clavien–Dindo Grade IIIb | 3 (1%) | 0 | |
| Clavien–Dindo Grade IV | 5 (2%) | 1 (2%) | |
| Clavien–Dindo Grade V | 4 (1%) | 0 | |
Recurrence
Table 4 displays the patterns of primary and recurrent disease and treatments for recurrence in the two groups. In the LR group, the median time to recurrence was 18.9 months (range: 1–126.7 months). In the LDLT group, the median time to recurrence was 26 months (range: 10–57 months). All patients with recurrence in this group, other than one who had extrahepatic recurrence, died from progression of disease.
Table 4.
Patterns of primary and recurrent disease and treatments for recurrence in the liver resection (LR) and living donor liver transplantation (LDLT) groups
| LR group | LDLT group | P-value | |
|---|---|---|---|
| (n = 146) | (n = 5) | ||
| Primary HCC, n (%) | |||
| Within Milan criteria | 123 (84%) | 5 | 0.741 |
| Beyond Milan criteria | 23 (16%) | 0 | |
| With microvascular invasion | 42 (29%) | 1 | >0.99 |
| Without microvascular invasion | 104 (71%) | 4 | |
| First recurrence of HCC, n (%) | |||
| Intrahepatic | 127 (87%) | 2 | 0.022 |
| Extrahepatic | 19 (13%) | 3 | |
| Within Milan criteria | 68 (47%) | 0 | 0.109 |
| Beyond Milan criteria | 78 (53%) | 5 | |
| Treatment of intrahepatic recurrence, n | (n = 127) | (n = 2) | |
| Re-resection | 33 | 0 | |
| Salvage transplantation | 4 | 0 | |
| Local ablative therapy | 23 | 0 | |
| Transarterial chemoembolization | 55 | 2 | |
| Others | 12 | 0 | |
HCC, hepatocellular carcinoma.
Survival
No hospital deaths occurred in the LDLT group, but four (1.3%) deaths occurred in the LR group. One patient died of ischaemic heart disease and three patients died of liver failure after the operation. Rates of 1-, 3-, 5- and 10-year overall survival were 95%, 85%, 76% and 56%, respectively, in the LR group, and 98%, 94%, 89% and 83%, respectively, in the LDLT group (P = 0.013) (Fig. 1). Rates of 1-, 3-, 5- and 10-year disease-free survival were 81%, 64%, 57% and 40%, respectively, in the LR group, and 96%, 90%, 87% and 81%, respectively, in the LDLT group (P < 0.0001) (Fig. 2). Within the LDLT group, patients with HCCs of <5 cm and patients with HCCs of 5–8 cm in diameter achieved comparable survival (P = 0.720) (Fig. 3). In patients with HCCs of ≤2 cm, HCCs of >2 cm but <5 cm, and HCCs of 5–8 cm, recipients of LDLT tended to have better overall survival than recipients of LR, but the difference did not reach statistical significance (P = 0.090, 0.205 and 0.161, respectively) (Figs 4–6).
Figure 1.
Overall survival in patients with solitary hepatocellular carcinomas of ≤8 cm in diameter submitted to liver resection (LR) or living donor liver transplantation (LDLT)
Figure 2.
Disease-free survival in patients with solitary hepatocellular carcinomas of ≤8 cm in diameter submitted to liver resection (LR) or living donor liver transplantation (LDLT)
Figure 3.
Overall survival in patients with solitary hepatocellular carcinomas of <5 cm or 5–8 cm in diameter submitted to living donor liver transplantation
Figure 4.
Overall survival in patients with solitary hepatocellular carcinomas of ≤2 cm in diameter submitted to liver resection (LR) or living donor liver transplantation (LDLT)
Figure 6.
Overall survival in patients with solitary hepatocellular carcinomas of 5–8 cm in diameter submitted to liver resection (LR) or living donor liver transplantation (LDLT)
Figure 5.
Overall survival in patients with solitary hepatocellular carcinomas of >2 cm but <5 cm in diameter submitted to liver resection (LR) or living donor liver transplantation (LDLT)
Discussion
In this study, both LDLT and LR performed to treat solitary HCC of ≤8 cm resulted in good longterm survival. Living donor LT is a technically more demanding operation, as evidenced by the higher complication rate, longer hospital stay and greater blood loss. However, rates of 1-, 3-, 5- and 10-year overall survival were 98%, 94%, 89% and 83%, respectively, in the LDLT group, and 95%, 85%, 76% and 56%, respectively, in the LR group (P = 0.013). Rates of 1-, 3-, 5- and 10-year disease-free survival were 96%, 90%, 87% and 81%, respectively, in the LDLT group, and 81%, 64%, 57% and 40%, respectively, in the LR group (P < 0.0001). The superiority of LDLT in terms of survival (overall as well as disease-free survival) became more conspicuous as time progressed. The 10-year disease-free survival rate achieved by LDLT was more than twice as good as that achieved by LR. The trend can also be observed in the three subgroups of patients with HCCs of ≤2 cm, HCCs of >2 cm but <5 cm, and HCCs of 5–8 cm, respectively, but without statistical significance, probably because the number of patients in each subgroup was small.
This study is one of the few items in the literature to demonstrate the role of LDLT in the management of solitary HCC. Living donor LT may be a plausible option, especially in young patients suffering from solitary HCC of ≤8 cm in size. The limited availability of liver grafts demands a system that selects the best recipient for a transplant rather than one that selects the best treatment for a patient. Decisions on voluntary liver donation represent a complicated psychological process for a potential donor that involves various social, cultural, interpersonal and family factors. Decisions on LDLT are not based on a comparison of the outcomes predicted for two patients, but on the balance between donor risks and recipient benefits.
The debate on the choice of primary transplantation versus primary resection is ongoing. A strategy of primary resection with salvage transplantation for intrahepatic recurrence has been proposed and may represent a reasonable approach for early HCC in patients with preserved liver function. Initial resection of HCC as a primary therapy allows for a good quality of life as patients do not need longterm immunosuppression. Moreover, it is less demanding than LT. Furthermore, grafts are saved for patients who have no treatment option other than transplantation.3,9,10 By contrast, LT is theoretically the best curative treatment for HCC. Firstly, it removes the tumour with the widest possible margin together with any intrahepatic metastasis. Secondly, it cures the underlying cirrhosis that is responsible for both hepatic decompensation and the development of a metachronous tumour after partial hepatectomy.
Several studies have compared the outcomes of various therapies performed for HCC with curative intent3,9–14 and have observed LR and LT to have similar overall outcomes. Rahbari et al.15 reviewed nine such studies and found that most of them did not identify any significant difference in patient survival. Nonetheless, when evaluated in an intention-to-treat analysis, the results of LT were much less satisfactory.16,17 This probably reflected the occurrence of dropouts from waiting lists as a result of tumour progression and death. In fact, the yield of LT seems directly related to the length of wait. Majno et al.,18 using a predictive decision model, suggested that LR would have a better outcome than LT if the wait exceeded 6 months, which is the case in most countries at present. It is important to note that most of these studies included cases of deceased donor LT (DDLT)9,11,12,18–21 or a combination of DDLTs and LDLTs.10,13 Adult LDLT is a relatively novel procedure with a short history and therefore its longterm outcome in the treatment of HCC is not yet well established.
Comparisons of DDLT and LDLT have been made in the context of treatment of HCC, and tendencies towards a higher rate of recurrence and a lower rate of survival after LDLT have been reported. A previous study conducted at the present centre reported cumulative 5-year recurrence rates of 29% in LDLT patients and 0% in DDLT patients who met the radiological Milan or UCSF criteria.22 The multicentre Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) reported similar findings of recurrence within 3 years of transplantation.23 Roayaie et al.24 reported a tendency for early recurrence after LDLT (mean time to recurrence: 8.7 months) compared with DDLT (mean time to recurrence: 19.6 months). Unlike in DDLT, patients seldom drop out of LDLT wait lists and thus tumours in recipients of LDLT might be more aggressive than those of DDLT recipients. Moreover, small-for-size graft injury and liver regeneration may enhance tumour growth and invasiveness.25,26
A study conducted in 2004 at the present centre reported a mean waiting time for DDLT in Hong Kong of 344 days and a dropout rate of 70%.8 A long waiting time and a high dropout rate provide justification for LDLT, with which the uncertainty about waiting time and the risk for dropping out can virtually be eliminated, and the overall applicability of LT has risen from 12% to >50%. In regions with a low rate of deceased donor organ donation and good LDLT results, there is a trend towards offering LDLTs to patients with HCC but preserved liver function.27,28 Hepatocellular carcinoma accounts for a third of the indications for LT in Asia, and 96% of LTs for HCC are LDLTs.29
Microscopic venous invasion has been shown to be the most important adverse prognostic factor in both LR and LT for HCC.30–34 Tumour size and tumour number are useful surrogate markers of the biological behaviour of HCCs and represent predictors of survival.6,31,35 Thus, in the present study, tumour size and microvascular invasion were used as parameters to match recipients of LR and LDLT in order to compare the outcomes of the two treatment modalities.
In the literature, survival after LR in transplantable patients with early HCC is comparable with that after LT, but the incidence of recurrence after LR is higher as a result of intrahepatic metastasis and metachronous hepatocarcinogenesis in cirrhotic liver remnants.12,36–38 Similarly, the LR group in the present study demonstrated comparable overall survival (76% versus 89%) but worse disease-free survival (57% versus 87%) at 5 years. The worse 5-year disease-free survival translates, at least partly, into the difference in 10-year survival between the two groups. This shows that longer-term outcome is important in this type of comparative study.
Salvage LT is one of the measures for treating recurrent HCC after LR. In an intention-to-treat analysis by Cherqui et al.,39 close monitoring with imaging after LR allowed 61% of patients with recurrence to undergo salvage LT. However, primary resection denies the chance of LT to initially transplantable patients who become unsuitable for salvage LT because their recurrent disease exceeds the criteria for transplantation. In the present study, 31% of cases of first recurrence in the LR group were beyond the Milan criteria. In addition to the failure to fulfil particular criteria, there are other reasons that prevent the performance of LT for recurrence, such as advanced age, acquired comorbidity and patient refusal.40 Salvage LDLT for HCC that recurs after curative treatment is associated with a high risk for re-recurrence even if the recurrent HCC is within standard criteria, and salvage LDLT itself has been identified as an independent poor prognostic factor that affects recurrence-free survival after LDLT for HCC.41
As LR can achieve a 10-year disease-free survival rate of 40%, as seen in the present study, LDLT may be considered as representing an over-treatment when donor risk is considered. It may arguably be unethical to subject a healthy person to risk when there is an alternative option of resection with acceptable longterm survival. It is also important to note that outcomes in patients who have recurrence of HCC after LT are worse than those in patients who have recurrence after LR, as demonstrated in a previous study conducted at this centre.5
Limitations and controversies
This research is derived from a single-centre study with a relatively small number of LDLT recipients, and did not take account of some transplant-related complications that can compromise longterm survival, such as graft rejection, opportunistic infection, and other malignancies resulting from immunosuppression.
Furthermore, it does not represent an intention-to-treat analysis, and the determination of tumour number and status was not based on preoperative radiological imaging, but on histopathological examination of the excised livers and resected specimens. Hence there are two possible sources of limitation. Firstly, it is possible that the study excluded patients who were believed to have solitary HCC before transplantation but were found to have multiple tumours in their excised livers. The study's inclusion of only patients with solitary HCC partly explains the excellent outcomes in both groups of patients. The adoption of histopathological criteria rather than radiological criteria avoided any heterogeneity in disease stage in both groups in the analysis.
Secondly, it is possible that HCCs may have been undetected in the remnant livers of LR recipients. If this were so, then the LR group in fact consisted of patients with different numbers of tumours, meaning that the two groups of patients were incomparable in terms of disease stage. Nonetheless, the ‘unfair’ effect of this possible incomparability was minimal given that only six (2%) of the 300 LR recipients were found to have intrahepatic HCC on postoperative imaging within 3 months of resection [four patients (1.3%) with solitary tumours and two patients (0.7%) with multifocal tumours] and, among these, four patients (1.3%) failed to survive a whole decade after resection. The remaining two patients underwent subsequent resection of their solitary tumours and survived for >10 years after the first resection. It is apparent that the survival outcome in the LR group has hardly been unfavourably affected.
Conclusions
This study shares with the surgical community an experience gained over 15 years at the only liver transplant centre in Hong Kong, which demonstrates that both LR and LDLT achieved good longterm survival in patients with solitary HCC of ≤8 cm, but that LDLT surpassed LR by demonstrating a 10-year overall survival rate 1.5 times as high and a 10-year disease-free survival rate twice as high. The study was not intended to promote LT in patients who are beyond the Milan or UCSF criteria, as only 11 patients in the LDLT group had HCCs of ≥5 cm. Neither does the study intend to discourage LR and encourage LDLT in treating the disease because the fact that LDLT is associated with a higher rate of complications and, most importantly, with risk to a healthy person's health and life cannot be discounted. Good practice should ensure that any decisions on treatment for HCC are made on a case-by-case basis.
Conflicts of interest
None declared.
References
- 1.Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699. doi: 10.1056/NEJM199603143341104. [DOI] [PubMed] [Google Scholar]
- 2.Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumour size limits does not adversely impact survival. Hepatology. 2001;33:1394–1403. doi: 10.1053/jhep.2001.24563. [DOI] [PubMed] [Google Scholar]
- 3.Adam R, Azoulay D, Castaing D, Eshkenazy R, Pascal G, Hashizume K, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis – a reasonable strategy? Ann Surg. 2003;238:508–518. doi: 10.1097/01.sla.0000090449.87109.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Yang LY, Fang F, Ou DP, Wu W, Zeng ZJ, Wu F. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg. 2009;249:118–123. doi: 10.1097/SLA.0b013e3181904988. [DOI] [PubMed] [Google Scholar]
- 5.Fan ST, Poon RT, Yeung C, Lam CM, Lo CM, Yuen WK, et al. Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria. Br J Surg. 2011;98:1292–1300. doi: 10.1002/bjs.7583. [DOI] [PubMed] [Google Scholar]
- 6.Mazzoferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35–43. doi: 10.1016/S1470-2045(08)70284-5. [DOI] [PubMed] [Google Scholar]
- 7.Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg. 1999;229:322–330. doi: 10.1097/00000658-199903000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lo CM, Fan ST, Liu CL, Chan SC, Wong J. The role and limitation of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl. 2004;10:440–447. doi: 10.1002/lt.20097. [DOI] [PubMed] [Google Scholar]
- 9.Beighiti J, Cortes A, Abdalla EK, Regimbeau JM, Prakash K, Durand F, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg. 2003;238:885–892. doi: 10.1097/01.sla.0000098621.74851.65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Shah SA, Cleary SP, Tan JC, Wei AC, Gallinger S, Grant DR, et al. An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Ann Surg Oncol. 2007;14:2608–2614. doi: 10.1245/s10434-007-9443-3. [DOI] [PubMed] [Google Scholar]
- 11.Bigourdan JM, Jaeck D, Meyer N, Meyer C, Oussoultzoglou E, Bachellier P, et al. Small hepatocellular carcinoma in Child A cirrhotic patients: hepatic resection versus transplantation. Liver Transpl. 2003;9:513–520. doi: 10.1053/jlts.2003.50070. [DOI] [PubMed] [Google Scholar]
- 12.Figueras J, Jaurrieta E, Valls C, Ramos E, Serrano T, Rafecas A, 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. doi: 10.1016/s1072-7515(00)00251-9. [DOI] [PubMed] [Google Scholar]
- 13.Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Difference in tumour invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation – impact on longterm survival. Ann Surg. 2007;245:51–58. doi: 10.1097/01.sla.0000225255.01668.65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Margarit C, Escartin 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;11:1242–1251. doi: 10.1002/lt.20398. [DOI] [PubMed] [Google Scholar]
- 15.Rahbari NN, Mehrabi A, Mollberg NM, Muller SA, Koch M, Buchler MW, et al. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 2011;253:453–469. doi: 10.1097/SLA.0b013e31820d944f. [DOI] [PubMed] [Google Scholar]
- 16.Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30:1434–1440. doi: 10.1002/hep.510300629. [DOI] [PubMed] [Google Scholar]
- 17.Yao FY, Bass NM, Nikolai B, Davern TJ, Kerlan R, Wu V, 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;8:873–883. doi: 10.1053/jlts.2002.34923. [DOI] [PubMed] [Google Scholar]
- 18.Majno PE, Sarasin FP, Mentha G, Hadengue A. Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology. 2000;31:899–906. doi: 10.1053/he.2000.5763. [DOI] [PubMed] [Google Scholar]
- 19.Del Gaudio M, Ercolani G, Ravaioli M, Cescon M, Lauro A, Vivarelli 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. doi: 10.1111/j.1600-6143.2008.02229.x. [DOI] [PubMed] [Google Scholar]
- 20.Koniaris LG, Levi DM, Pedroso FE, Franceschi D, Tzakis AG, Santamaria-Barria JA, et al. Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma? Ann Surg. 2011;254:527–538. doi: 10.1097/SLA.0b013e31822ca66f. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Facciuto ME, Rochon C, Pandey M, Rodriguez-Davalos M, Samaniego S, Wolf DC, et al. Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith the Milan criteria. HPB. 2009;11:398–404. doi: 10.1111/j.1477-2574.2009.00073.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94:78–86. doi: 10.1002/bjs.5528. [DOI] [PubMed] [Google Scholar]
- 23.Fisher RA, Kulik LM, Freise CE, Lok AS, Shearon TH, Brown RS, et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant. 2007;7:1601–1608. doi: 10.1111/j.1600-6143.2007.01802.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gondolesi GE, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl. 2004;10:534–540. doi: 10.1002/lt.20128. [DOI] [PubMed] [Google Scholar]
- 25.Ninomiya M, Harada N, Shiotani S, Hiroshige S, Minagawa R, Soejima Y, et al. Hepatocyte growth factor and transforming growth factor beta 1 contribute to regeneration of small-for-size liver graft immediately after transplantation. Transpl Int. 2003;16:814–819. doi: 10.1007/s00147-003-0628-9. [DOI] [PubMed] [Google Scholar]
- 26.Man K, Ng KT, Lo CM, Ho JW, Sun BS, Sun CK, et al. Ischaemia–reperfusion of small liver remnant promotes liver tumour growth and metastases – activation of cell invasion and migration pathways. Liver Transpl. 2007;13:1669–1677. doi: 10.1002/lt.21193. [DOI] [PubMed] [Google Scholar]
- 27.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;101:47–53. doi: 10.1002/jso.21415. [DOI] [PubMed] [Google Scholar]
- 28.Moon DB, Lee SG, Hwang S. Liver transplantation for hepatocellular carcinoma: single nodule with Child–Pugh class A sized less than 3 cm. Dig Dis. 2007;25:320–328. doi: 10.1159/000106912. [DOI] [PubMed] [Google Scholar]
- 29.De Villa V, Lo CM. Liver transplantation for hepatocellular carcinoma in Asia. Oncologist. 2007;12:1321–1331. doi: 10.1634/theoncologist.12-11-1321. [DOI] [PubMed] [Google Scholar]
- 30.Benckert C, Jonas S, Thelen A, Spinelli A, Schumacher G, Heise M, et al. Liver transplantation for hepatocellular carcinoma in cirrhosis: prognostic parameters. Transplant Proc. 2005;37:1693–1694. doi: 10.1016/j.transproceed.2005.03.143. [DOI] [PubMed] [Google Scholar]
- 31.Pawlik TM, Delman KA, Vauthey JN, Nagorney DM, Ng IO, Ikai I, et al. Tumour size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl. 2005;11:1086–1092. doi: 10.1002/lt.20472. [DOI] [PubMed] [Google Scholar]
- 32.Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma – longterm results of treatment and prognostic factors. Ann Surg. 1999;229:216–222. doi: 10.1097/00000658-199902000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Shimoda M, Ghobrial RM, Carmody IC, Anselmo DM, Farmer DG, Yersiz H, et al. Predictors of survival after liver transplantation for hepatocellular carcinoma associated with hepatitis C. Liver Transpl. 2004;10:1478–1486. doi: 10.1002/lt.20303. [DOI] [PubMed] [Google Scholar]
- 34.Chan SC, Fan ST, Chok KS, Cheung TT, Chan AC, Fung JY, et al. Survival advantage of primary liver transplantation for hepatocellular carcinoma within the up-to-7 criteria with microvascular invasion. Hepatol Int. 2011 doi: 10.1007/s12072-011-9318-3. Epub 2011/10/21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Chu KK, Chan SC, Fan ST, Chok KS, Cheung TT, Sharr WW, et al. Radiological prognosticators of hepatocellular carcinoma treated by hepatectomy. Hepatobiliary Pancreat Dis Int. 2012;11:612–617. doi: 10.1016/s1499-3872(12)60232-x. [DOI] [PubMed] [Google Scholar]
- 36.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;218:145–151. doi: 10.1097/00000658-199308000-00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Michel J, Suc B, Montpeyroux F, Hachemanne S, Blanc P, Domergue J, et al. Liver resection or transplantation for hepatocellular carcinoma? Retrospective analysis of 215 patients with cirrhosis. J Hepatol. 1997;26:1274–1280. doi: 10.1016/s0168-8278(97)80462-x. [DOI] [PubMed] [Google Scholar]
- 38.Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology. 1998;28:436–442. doi: 10.1002/hep.510280222. [DOI] [PubMed] [Google Scholar]
- 39.Cherqui D, Laurent A, Mocellin N, Tayar C, Luciani A, Van Nhieu JT, et al. Liver resection for transplantable hepatocellular carcinoma: longterm survival and role of secondary liver transplantation. Ann Surg. 2009;250:738–746. doi: 10.1097/SLA.0b013e3181bd582b. [DOI] [PubMed] [Google Scholar]
- 40.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;55:132–140. doi: 10.1002/hep.24680. [DOI] [PubMed] [Google Scholar]
- 41.Ng KK, Lo CM, Chan SC, Chok KS, Cheung TT, Fan ST. Liver transplantation for hepatocellular carcinoma: the Hong Kong experience. J Hepatobiliary Pancreat Sci. 2010;17:548–554. doi: 10.1007/s00534-009-0165-8. [DOI] [PubMed] [Google Scholar]