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Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: Clinical patterns and outcome variables
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EJSO 36 (2010) 275e280
www.ejso.com
Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: Clinical patterns and outcome variables A. Kornberg a,*, B. Ku¨pper a, A. Tannapfel a, K. Katenkamp a,b, K. Thrum a, O. Habrecht a, J. Wilberg a a
Department of General, Visceral and Vascular Surgery Friedrich-Schiller-University, Erlanger Allee 101, D-07740 Jena, Germany b Institute of Pathology, Friedrich-Schiller-University, Jena, Germany Accepted 1 October 2009 Available online 25 October 2009
Abstract Background: The objective of this trial was to analyze the clinical patterns and outcome variables of recurrent hepatocellular carcinoma (HCC) in liver transplant patients. Patients and methods: Sixty patients after liver transplantation (LT) for HCC were analyzed. All of them received initially a calcineurininhibitor based immunosuppressive regimen. Recurrent HCC was treated by surgical intervention, if eligible, or adjuvant therapies. Furthermore, patients were converted to a Sirolimus (SRL)-based immunosuppressive regimen after tumor relapse. The impact of clinical and histopathological variables on post-recurrence survival was analyzed in uni- and multivariate analysis. Results: Sixteen liver recipients developed HCC recurrence between 4 and 58 months (median: 23 months) post-LT. Sites of first tumor recurrence were lung (n ¼ 5), liver (n ¼ 4), bone (n ¼ 4), cerebrum (n ¼ 1), adrenal gland (n ¼ 1) and peritoneum (n ¼ 1). Seven patients were amenable for surgical resection, while 9 patients were only suitable for adjuvant treatment (n ¼ 4) or general medical support (n ¼ 5). Median survival rate post-recurrence was 65 months (range: 12e136 months) in patients amenable for surgical therapy, and 5 months (range: 1e52 months) in patients unsuitable for surgical intervention (P ¼ 0.01). Multivariate analysis identified late (>24 months) posttransplant tumor relapse (P ¼ 0.039) and surgical therapy (P ¼ 0.014) as independent predictors of long-term survival after tumor relapse. Five patients are tumour-free alive for a median of 65 months after surgical resection of recurrent HCC and conversion to SRL. Conclusion: Liver transplant patients with HCC recurrence should be treated surgically, if eligible, since this is an independent predictor of long-term survival. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Liver transplantation; Hepatocellular carcinoma; Milan criteria; Tumor biology; Microvascular invasion
Introduction Hepatocellular carcinoma (HCC) in liver cirrhosis has become a major indication for liver transplantation.1 Due to poor outcome data in the early transplant era, specific selection criteria systems have been established.1,2 In 1996 Mazzafero et al. proposed the so-called Milan criteria (single nodule 5 cm, 2e3 tumor nodules all 3 cm, without macroscopic vascular invasion), based on stringent macromorphological variables.3 With the adoption of these * Corresponding author. Tel.: þ49 3641 9322677; fax: þ49 3641 9322692. E-mail address: [email protected] (A. Kornberg). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.10.001
novel selection criteria, 5-year recurrence-free survival rates up to 83% have been reported after liver transplantation (LT) for HCC, which is comparable to those for non-malignant indications.4e7 As of recent, there is increasing concern that organ allocation based on these stringent selection variables might exclude a significant number of patients who, although not meeting the Milan criteria, would nonetheless benefit from LT.8e12 Several transplant groups have demonstrated that, apart from number and size of tumor nodules, parameters of tumor biology, such as differentiation and microvascular tumor invasion (MVI) play an important role for predicting patient prognosis, and should be, therefore, incorporated in the pretransplant selection process.4,8e11
276
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However, since expanding the selection criteria may increase the risk of tumor relapse, its justification will very much depend on outcome of posttransplant HCC recurrence.13e19 Nevertheless, there is currently only little information about natural history, treatment options and prognosis of posttransplant HCC recurrence. The aim of this retrospective study was, therefore, to analyze the clinical patterns and outcome variables of recurrent HCC in a series of patients after LT at our transplant center.
tacrolimus (Tac) -based, augmented with mycophenolate mofetil (MMF) or azathioprine (AZA), and steroids. AntiT-lymphocyte-globulin (ATG) or an interleukin-2-receptor antibody was administered for induction therapy. According to our center protocol, MMF and AZA were discontinued 6 months post-LT. Steroids were completely withdrawn latest 6 months post-LT, with exception of patients suffering from autoimmune hepatitis. Liver allograft biopsy was performed in cases of deteriorating liver function. Anti-rejection therapy consisted of prednisone pulse treatment or conversion to another CNI, if necessary.
Patients and methods Treatment of HCC recurrence Inclusion criteria and tumor surveillance program Between 1994 and 2007, a total of 60 patients with HCC in liver cirrhosis underwent LT at our transplant center. LT was performed according to standardized technique, either with piggy back technique or by grafting the donor’s inferior vena cava.20 Diagnosis of HCC was established by a combination of imaging studies (ultrasound, computed [CT] or magnetic resonance tomography) and measurement of alpha-fetoprotein (AFP) levels, without routinely using pretransplant tumor biopsy. Since 1998, the Milan criteria were used for indicating LT in patients with unresectable HCC in liver cirrhosis at our center.3 Extrahepatic tumor spread, evidence of nodal metastases or macroscopic vascular tumor invasion excluded patients from LT. Since 1999, patients underwent transarterial chemoembolization (TACE) of the tumor as neoadjuvant bridging to transplant, if eligible.12 Tumor surveillance post-LT consisted of abdomen ultrasound and determination of AFP-levels every 3 months during the whole posttransplant follow-up period. In addition, CT scans of the chest and abdomen were performed every 6 months for the first posttransplant year, and minimum once yearly thereafter. Rising AFP-levels alone without radiographic evidence of new tumor masses were not indicating HCC recurrence. Histopathology Explanted livers were examined by assessing number and size of tumor nodules, tumor differentiation (grading) and vascular invasion. Tumor staging was determined by co-operation of the surgical and pathological staff based on clinical and pathological data according the 5th edition of the Tumor, Node, Metastasis/International Union Against Cancer criteria.21 In addition, based on explant histopathology, tumors were retrospectively classified according to Milan criteria as ‘‘Milan In’’ versus ‘‘Milan Out’’.
In all patients with tumor recurrence the options of curative surgical intervention were thoroughly assessed. All patients considered to be unsuitable for surgical treatment were referred to palliative care by radiotherapy (bone metastases), TACE (multiple hepatic metastases), administration of a tyrosine kinase inhibitor (Sorafenib, NexavarÒ) and/or general medical support. Furthermore, the calcineurin-inhibitor was replaced by Sirolimus (SLR, RapamuneÒ, Whyeth Germany) since January 2003 in all patients with history or presence of recurrent HCC, as this is currently presumed to have anti-tumor capabilities.22,23 Assessment of variables Variables analyzed included clinical (recipient age, sex, underlying liver disease, type of allograft used, TACE, highest preoperative AFP-level, location of recurrence, treatment of recurrence, time to tumor relapse, immunosuppression) and primary histopathological tumor characteristics. Statistical analysis Data are expressed as mean standard deviation or median and range, as feasible. Risk factors for tumor recurrence were analyzed using chi square test, with a P < 0.05 indicating statistical significance. Time to recurrence and survival post-recurrence were compared between subgroups using independent t-test. Survival rates were calculated using the KaplaneMeier method and compared using the log rank test. A P < 0.05 was indicating statistical significance. All variables found to have a significant impact on posttransplant recurrence-free survival and on survival from tumor relapse on univariate analysis were entered into a stepwise Cox proportional hazard model for multivariate analysis. Results
Immunosuppressive therapy Standard immunosuppressive therapy consisted of a quadruple induction regimen, cyclosporine A (CsA)- or
Patient and tumor characteristics for those who underwent LT and for those who developed posttransplant tumor relapse are summarized in Table 1. Forty-nine patients
A. Kornberg et al. / EJSO 36 (2010) 275e280 Table 1 Patient and Tumor (Explant) Characteristics (n ¼ 60).
Age recipient (mean SD; yr) Gender (F/M) Child (n) A B C None Underlying liver disease Hepatitis B/C Alcohol Autoimmun Other Transplant procedure (n) DDLT LDLT Split-LT TACE Yes No Immunosuppression (n) CsA Tac Number of tumor nodules (median, range) Diameter largest tumor nodule (median, range) Grading Well Moderate Poor Lymphatic vascular invasion (n) Microvascular venous invasion (n) Tumor stage (n) I II III IV Milan criteria (n) within beyond
All liver transplant patients with HCC (n ¼ 60)
Patients with recurrent HCC (n ¼ 16)
58,2 7,6 14/46
56,5 8,5 3/13
31 11 15 3
8 2 5 1
16 32 2 9
3 11 0 2
49 10 1
14 2 0
24 36
10 6
27 33 1
9 7 4,5
4
6,3
13 35 12 11
3 6 7 5
25
12
4 21 17 18
0 0 4 12
27 33
1 15
277
number of tumor nodules > 3 and Milan Out status (P < 0.05). In multivariate analysis, only poor tumor grade (Hazard Ratio [HR] ¼ 21.8; Confidence Interval [CI] 95% ¼ 4.9e95.3; P < 0.001) and microvascular invasion ([MVI]; HR ¼ 14.1; CI 95% ¼ 1.4e147.1; P ¼ 0.027) were identified as independent risk factors for reduced recurrence-free survival post-LT. Only 1 out of 27 Milan In patients developed HCC recurrence (3.7%), while 15 out of 33 Milan Out recipients (45.4%) suffered from tumor relapse (P < 0.001). Recurrence-free 5-year survival rate was significantly higher in Milan In patients (96.2%), when compared to Milan Out recipients (43.2%). However, there was only a trend of a better overall survival in Milan In patients (85.8%) than in Milan Out recipients (65.6%, Fig. 1). Clinical patterns and treatment of HCC recurrence Sites of first tumor recurrence were lung (n ¼ 5), liver (n ¼ 4), bone (n ¼ 4), cerebrum (n ¼ 1), adrenal gland (n ¼ 1) and peritoneum (n ¼ 1). Seven patients underwent surgical therapy. It consisted of liver allograft resection (n ¼ 2), lung resection (n ¼ 2), cerebral tumor extirpation (n ¼ 1), adrenalectomy (n ¼ 1) and resection of a chest wall metastasis after pretransplant tumor biopsy in another hospital (n ¼ 1). Two patients developed bone metastases after surgical resection of first tumor relapse. One patient underwent successful liver allograft resection after lung resection, and another patient developed repeat lung metastases after lung re-resection, which were successfully treated by conversion to Sirolimus. Three out of 7 patients amenable for surgical therapy demonstrated MVI at primary explant pathology, compared to 9 out of 9 patients unsuitable for surgery (P ¼ 0.009). Six out of 9 patients with CsA suffered from resectable tumor relapse, while only 1 out of 7 patients under a Tac developed resectable HCC recurrence (P ¼ 0.03). Out of 7 surgically treated patients, 2 ultimately died with tumor, and 5 are currently alive free of disease.
DDLT, deceased donor liver transplantation; LDLT, living-donor-liver transplantation; TACE, transarterial chemoebolization.
1,0
Risk factors for tumor recurrence
survival (%)
0,8
received a full-size cadaveric transplant, in one patient left split liver transplantation was performed, and 10 patients underwent living-donor-liver transplantation (LDLT).
0,6
0,4
Milan In (n=27) Milan Out (n=33)
0,2
A total of 16 patients (26.7%) developed HCC recurrence between 4 and 58 months (median: 23 months) post-LT. Univariate risk factors for impaired recurrencefree survival were AFP-level > 100 ng/ml, poor tumor differentiation, tumor stage III o. IV, microvascular tumor invasion, tumor size > 5 cm, total tumor diameter > 8.5 cm,
0,0 0
20
40
60
80
100
120
months post-LT Figure 1. Overall survival rate only tended to be superior in Milan In patients, when compared to Milan Out patients (log rank ¼ 0.087).
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Nine patients were not eligible for surgical therapy. They received radiotherapy of bone metastases (n ¼ 3), TACE of intrahepatic tumor recurrence (n ¼ 1), and therapy with Sorafenib (n ¼ 1). Five patients with multifocal tumor relapse were only suitable for general medical support. A total of 10 liver recipients were converted to an SRLbased immunosuppression, five of them after surgical resection of tumor relapse, and five of them as part of nonsurgical supportive treatment. There was no case of tumor re-recurrence after surgical treatment of primary tumor relapse in 5 patients converted to SRL, while 2 patients without SRL-therapy developed bone metastases after resection of primary HCC relapse. In univariate analysis, only the application of a Tacbased immunosuppression versus a CsA-based regimen was related with early posttransplant tumor recurrence (Tac: 15.6 9.8 months post-LT; CsA: 33.7 16.4 months post-LT). Survival from transplant Currrent posttransplant follow-up of the whole study cohort (n ¼ 60) ranges between 5 and 180 months (median: 46.5 months). Actuarial overall and recurrence-free 5-year survival rate posttransplantation is currently at 74.4% and 65.2%, respectively. Median survival from LT was 32.5 months for patients with HCC recurrence and 49.5 months for those without tumor relapse. Five-year survival rate was significantly lower for patients with HCC recurrence (41.7%) than for patients without posttransplant tumor relapse (89.3%, P ¼ 0.002). Only suitability for surgical intervention and the application of a CsA-based immunosuppression were significantly associated with an improved survival from LT in patients with recurrent HCC (P < 0.05). Survival from tumor recurrence Overall median survival from tumor relapse was 10.5 months (range: 1e136 months). None of primary tumor characteristics but early (24 months) posttransplant tumor recurrence (P ¼ 0.043), the application of a CsA- (versus Tac-) based immunosuppression (P ¼ 0.014) and eligibility for surgical therapy (P ¼ 0.006) had a beneficial impact on survival from tumor recurrence in univariate analysis, while SRL-therapy only tended to have a positive impact (P ¼ 0,08). Multivariate analysis demonstrated that late posttransplant tumor relapse and surgical treatment of tumor recurrence were independent predictors of survival postrecurrence (Table 2). Median survival after tumor relapse was 65 months (range: 12e136 months) in patients amenable for surgical therapy, and 5 months (range. 1e52 months) in patients non-suitable for surgical intervention (P ¼ 0.01). Five patients are currently tumor-free alive between 12 and 136 months (median: 65 months) after surgical
Table 2 Multivariate analysis of independent variables for survival from tumor relapse.
Late tumor relapse Surgical treatment
Hazard Ratio
95% CI
P-value
10,4 19,5
1127e96,945 1826e208,702
0.039 (>24 months) 0.014
intervention and conversion to SRL, while 2 patients with unchanged immunosuppression after resection of first HCC recurrence died from tumor re-relapse. Discussion Predictive value of the Milan criteria Results of our study clearly confirm the value of the Milan criteria for indicating the risk of HCC recurrence after LT. Tumor recurrence rate was 3.7% in Milan In patients but 45.4% in Milan Out recipients. Nevertheless, overall fiveyear survival rate was 65.6% in patients with HCC beyond the Milan criteria, which is by far better than other currently available treatment options. This important result of our study is powered by a high proportion of Milan Out recipients (55%) in our series, which is in contrast to many other transplant centers.3,4,8,9 There are several explanations for this high ratio of advanced HCC patients in our study cohort. First, several patients included in this trial have undergone LT before Milan criteria were implemented in our clinical practice. Second, tumor understaging by preoperative radiographic imaging is a well-known problem in this field.6,24 Final pretransplant radiographic screening underestimated pathological tumor stage in 23 patients of our series (38.3%). And third, comparable to other transplant groups with excellent survival results, we were following a policy of patient drop-out from the transplant list based on major events during pretransplant waiting time (macrovascular tumor invasion, lymph node metastases, tumor-related symptoms, extrahepatic tumor spread) rather than on the Milan criteria alone.10,25 Although originally implemented as listing criteria, they are now widely used for patient drop-out, as well.1,25 Using the same selection criteria for listing and delisting of a patient, however, might significantly increase the exclusion rate of patients with macromorphological borderline tumors. Many of them may, nevertheless, benefit from LT by achieving long-term survival.7e11 Our outcome results in patients with advanced HCC are even better than results of other well-experienced transplant centers.2,15e17 About 30% of our overall study population would have been excluded from curative LT, if Milan criteria were used strictly for decision making about patient drop-out from the transplant list. It seems to be worth mentioning in this context, that, although tumor recurrence rate was significantly higher in Milan Out patients than in Milan In recipients, overall survival rate only tended to be lower in patients with
A. Kornberg et al. / EJSO 36 (2010) 275e280
advanced HCC (Fig. 1). This interesting result of our trial clearly points out the importance of an appropriate treatment of tumor relapse for improving overall patient prognosis. Survival from tumor relapse Impact of surgery It is no surprising result of our trial that long-term survival in patients without HCC recurrence is significantly better than in patients developing tumor relapse.16,17,19 However, we are able to report about an overall posttransplant 5-year survival rate above 40% in our subgroup of patients with recurrent HCC. To the best of our knowledge, this is the most favorable outcome data of liver recipients with HCC relapse reported so far in the literature. Roayaie et al. demonstrated a 22% 5-year survival rate in 57 patients with recurrent HCC.16 Regalia and colleagues demonstrated a 23% overall survival rate at 4 years in 21 patients suffering from HCC relapse.17 Comparable to these two trials, eligibility for surgical resection of tumor relapse was the most important independent outcome variable in our study (Fig. 2, Table 2). At our transplant center, we were following a policy of very close and concise posttransplant patient surveillance, aiming at early detection and aggressive surgical intervention of recurrent tumor, if possible. Thereby, 9 surgical procedures were performed in 7 out of 16 patients with tumor relapse (43.7%). In contrast, the transplant groups from New York and Milan reported about resection rates of 31.6% and 33.3%, respectively, which may explain the superior outcome data in our series. Contrary to other trials,16,17,19 we did not identify primary tumor variables to correlate with earlier tumor recurrence or shorter survival time from tumor relapse, which might be due to the relatively small sample size. However, it seems to be noteworthy that 100% of patients with 1,0 surgical therapy (n=7) non-surgical therapy (n=9)
survival (%)
0,8
0,6
0,4
0,2
0,0 0
10
20
30
40
50
60
70
months post-recurrence Figure 2. Liver transplant patients with recurrent HCC amenable for surgical therapy had a significantly better long-term survival post-recurrence than patients with tumor relapse unsuitable for surgical intervention (log rank ¼ 0.006).
279
unresectable HCC relapse in our study demonstrated MVI at primary tumor pathology, compared to 43% of patients with resectable tumor recurrence. This observation suggests that liver transplant patients with presence of MVI at primary explant pathology should undergo a more intensified posttransplant surveillance program. This might, possibly, improve the surgical treatment options after early detection of tumor relapse.
Impact of immunosuppression There is considerable experimental evidence of a favoring impact of immunosuppression on tumor growth and relapse26 Although this topic is of special interest in the transplantation setting, there are only few clinical trials that have analyzed the relationship between pharmacological immunosuppression and HCC recurrence post-LT.27,28 To date, there is, however, no data about the impact of immunosuppression on outcome after HCC recurrence. Results of our trial suggest that patients receiving a Tacbased immunosuppressive regimen are on a higher risk for developing early tumor relapse, which is unsuitable for surgical therapy. Tac has meanwhile taken the place of CsA and is presently used as main immunosuppressant drug after LT. A recent Cochrane database analysis demonstrated that Tac is superior to CsA in improving survival and preventing acute rejection after LT.29 This immunological predominance of the drug may be unfavorable in the context of LT for HCC. However, an exact interpretation of our data is hampered by a small sample size, the heterogeneous immunosuppressive regimens used and the lack of drug exposure measurements. The rationale for us to switch to an SRL-based regimen after tumor relapse was to use its suggested antiproliferative and antineoplastic capabilities.22,23 Rapamycine is an effective mTOR inhibitor, thus providing effective immunosuppressive activities. Since the mTOR pathway is activated in several models of HCC, it may reduce cell growth and tumor vascularity.30 Clinical data are, as yet, only preliminary and are derived from retrospective studies.31,32There is currently no experience about the value of Sirolimus for treating posttransplant HCC recurrence. The conversion of Sirolimus, irrespective of other applied interventions, tended to improve survival in our trial (P ¼ 0,08). However, as 50% of the patients have undergone surgical therapy before conversion to SRL, the real antiproliferative capabilities of this drug cannot be determined by our data. But it seems to be worth mentioning that in the subgroup of surgically treated patients, none have yet developed tumor re-relapse after conversion to SRL, while 2 patients with unchanged medication suffered from another HCC relapse after surgical intervention. Apart from that, repeat lung metastases after lung re-resection completely disappeared after switch to SRL in one patient of our series.33 Therefore, further prospective controlled investigations in this field are imperative.
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Conclusion Results of our trial indicate that the Milan criteria are very useful for predicting risk of posttransplant recurrence in patients with HCC. Nevertheless, they may achieve an excellent 5-year survival rate above 60%. Patients with recurrent HCC amenable to surgical treatment should undergo resection, as this was identified as strongest independent predictor of long-term survival in our trial. In some of them, a curative situation (up to 136 months post-recurrence) may be achieved. There seems to be a positive effect of SRL for preserving a tumor-free status quo after surgical intervention. This, however, has yet to be further analyzed in a prospective approach. Conflict of interest The authors declare that they have no conflict of interest. References 1. Schwarz M. Liver transplantation for hepatocellular carcinoma. Gastroenterology 2004;127:268–76. 2. Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214: 221–8. 3. Mazzafero V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 4. Jonas S, Bechstein WO, Steinmu¨ller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33: 1080–6. 5. Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233:652–9. 6. Llovet JM, Bruix J, Fuster J, et al. Liver transplantation for small hepatocellular carcinoma: the tumor node metastasis classification does not have prognostic power. Hepatology 1998;27:1572–7. 7. 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;21:4329–35. 8. Cillo U, Vitale A, Bassanello M, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004;239:150–9. 9. Herrero JL, Sangro B, Quiroga J, et al. Liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7:631–6. 10. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519–24. 11. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 12. Lubienski A. Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 2005;80:113–9.
13. Roayaie S, Llovet JM. Liver transplantation for hepatocellular carcinoma: is expansion of criteria justified? Clin Liver Dis 2005;9:315–28. 14. Botha JF, Langnas AN. Liver transplantation for hepatocellular carcinoma: an update. J Natl Compr Canc Netw 2006;4:762–7. 15. Roayaie S, Frisher JS, Emre SH, et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5cm. Ann Surg 2002;235:533–9. 16. Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534–40. 17. Regalia E, Fassati LR, Valente U, et al. Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J Hepatobiliary Pancreat Surg 1998;5:29–34. 18. Schwartz M, Roayaie S, Llovet J. How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated? J Hepatol 2005;43:584–9. 19. Schlitt HJ, Neipp M, Weimann A, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324–31. 20. Hoffmann K, Weigand MA, Hillebrand N, Bu¨chler MW, Schmidt J, Schemmer P. Clin Transpl 2009;23:1–8. 21. Sobin LH, Wittekind C, editors. TNM classification of malignant tumors. 5th ed. New York: Wiley; 1997. 22. Trotter JF. Sirolimus in liver transplantation. Transpl Proc 2003;35: 193–200. 23. Luan FL, Hojo M, Maluccio M, Yamaji K, Suthanthiran M. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002;73:1565–72. 24. Shah SA, Tan JC, McGilvray ID, et al. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation 2006;81:1633–9. 25. Schwartz ME, D’Amico F, Vitale A, Emre S, Cillo U. Liver transplantation for hepatocellular carcinoma: are the Milan criteria still valid? Eur J Surg Oncol 2008;34:256–62. 26. Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991;68:2095–100. 27. Vivarelli M, Cuccetti A, La Barba G, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg 2008;248:857–62. 28. Vivarelli M, Cuccetti A, Piscaglia F, et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 2005;11: 497–503. 29. Haddad EM, McAllister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006;18:CD005161. 30. Wang Z, Zhou J, Fan J, et al. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2009;135:715–22. 31. Zimmermann MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008;14:633–8. 32. Toso C, Meeberg GA, Bigam DL, et al. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects. Transplantation 2007; 15:1162–8. 33. Elsharkawi M, Staib L, Henne-Bruns D, Mayer J. Complete remission of posttransplant lung metastases from hepatocellular carcinoma under therapy with sirolimus and mycophenolate mofetil. Transplantation 2005;79:855–7.
EJSO 36 (2010) 275e280
www.ejso.com
Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: Clinical patterns and outcome variables A. Kornberg a,*, B. Ku¨pper a, A. Tannapfel a, K. Katenkamp a,b, K. Thrum a, O. Habrecht a, J. Wilberg a a
Department of General, Visceral and Vascular Surgery Friedrich-Schiller-University, Erlanger Allee 101, D-07740 Jena, Germany b Institute of Pathology, Friedrich-Schiller-University, Jena, Germany Accepted 1 October 2009 Available online 25 October 2009
Abstract Background: The objective of this trial was to analyze the clinical patterns and outcome variables of recurrent hepatocellular carcinoma (HCC) in liver transplant patients. Patients and methods: Sixty patients after liver transplantation (LT) for HCC were analyzed. All of them received initially a calcineurininhibitor based immunosuppressive regimen. Recurrent HCC was treated by surgical intervention, if eligible, or adjuvant therapies. Furthermore, patients were converted to a Sirolimus (SRL)-based immunosuppressive regimen after tumor relapse. The impact of clinical and histopathological variables on post-recurrence survival was analyzed in uni- and multivariate analysis. Results: Sixteen liver recipients developed HCC recurrence between 4 and 58 months (median: 23 months) post-LT. Sites of first tumor recurrence were lung (n ¼ 5), liver (n ¼ 4), bone (n ¼ 4), cerebrum (n ¼ 1), adrenal gland (n ¼ 1) and peritoneum (n ¼ 1). Seven patients were amenable for surgical resection, while 9 patients were only suitable for adjuvant treatment (n ¼ 4) or general medical support (n ¼ 5). Median survival rate post-recurrence was 65 months (range: 12e136 months) in patients amenable for surgical therapy, and 5 months (range: 1e52 months) in patients unsuitable for surgical intervention (P ¼ 0.01). Multivariate analysis identified late (>24 months) posttransplant tumor relapse (P ¼ 0.039) and surgical therapy (P ¼ 0.014) as independent predictors of long-term survival after tumor relapse. Five patients are tumour-free alive for a median of 65 months after surgical resection of recurrent HCC and conversion to SRL. Conclusion: Liver transplant patients with HCC recurrence should be treated surgically, if eligible, since this is an independent predictor of long-term survival. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Liver transplantation; Hepatocellular carcinoma; Milan criteria; Tumor biology; Microvascular invasion
Introduction Hepatocellular carcinoma (HCC) in liver cirrhosis has become a major indication for liver transplantation.1 Due to poor outcome data in the early transplant era, specific selection criteria systems have been established.1,2 In 1996 Mazzafero et al. proposed the so-called Milan criteria (single nodule 5 cm, 2e3 tumor nodules all 3 cm, without macroscopic vascular invasion), based on stringent macromorphological variables.3 With the adoption of these * Corresponding author. Tel.: þ49 3641 9322677; fax: þ49 3641 9322692. E-mail address: [email protected] (A. Kornberg). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.10.001
novel selection criteria, 5-year recurrence-free survival rates up to 83% have been reported after liver transplantation (LT) for HCC, which is comparable to those for non-malignant indications.4e7 As of recent, there is increasing concern that organ allocation based on these stringent selection variables might exclude a significant number of patients who, although not meeting the Milan criteria, would nonetheless benefit from LT.8e12 Several transplant groups have demonstrated that, apart from number and size of tumor nodules, parameters of tumor biology, such as differentiation and microvascular tumor invasion (MVI) play an important role for predicting patient prognosis, and should be, therefore, incorporated in the pretransplant selection process.4,8e11
276
A. Kornberg et al. / EJSO 36 (2010) 275e280
However, since expanding the selection criteria may increase the risk of tumor relapse, its justification will very much depend on outcome of posttransplant HCC recurrence.13e19 Nevertheless, there is currently only little information about natural history, treatment options and prognosis of posttransplant HCC recurrence. The aim of this retrospective study was, therefore, to analyze the clinical patterns and outcome variables of recurrent HCC in a series of patients after LT at our transplant center.
tacrolimus (Tac) -based, augmented with mycophenolate mofetil (MMF) or azathioprine (AZA), and steroids. AntiT-lymphocyte-globulin (ATG) or an interleukin-2-receptor antibody was administered for induction therapy. According to our center protocol, MMF and AZA were discontinued 6 months post-LT. Steroids were completely withdrawn latest 6 months post-LT, with exception of patients suffering from autoimmune hepatitis. Liver allograft biopsy was performed in cases of deteriorating liver function. Anti-rejection therapy consisted of prednisone pulse treatment or conversion to another CNI, if necessary.
Patients and methods Treatment of HCC recurrence Inclusion criteria and tumor surveillance program Between 1994 and 2007, a total of 60 patients with HCC in liver cirrhosis underwent LT at our transplant center. LT was performed according to standardized technique, either with piggy back technique or by grafting the donor’s inferior vena cava.20 Diagnosis of HCC was established by a combination of imaging studies (ultrasound, computed [CT] or magnetic resonance tomography) and measurement of alpha-fetoprotein (AFP) levels, without routinely using pretransplant tumor biopsy. Since 1998, the Milan criteria were used for indicating LT in patients with unresectable HCC in liver cirrhosis at our center.3 Extrahepatic tumor spread, evidence of nodal metastases or macroscopic vascular tumor invasion excluded patients from LT. Since 1999, patients underwent transarterial chemoembolization (TACE) of the tumor as neoadjuvant bridging to transplant, if eligible.12 Tumor surveillance post-LT consisted of abdomen ultrasound and determination of AFP-levels every 3 months during the whole posttransplant follow-up period. In addition, CT scans of the chest and abdomen were performed every 6 months for the first posttransplant year, and minimum once yearly thereafter. Rising AFP-levels alone without radiographic evidence of new tumor masses were not indicating HCC recurrence. Histopathology Explanted livers were examined by assessing number and size of tumor nodules, tumor differentiation (grading) and vascular invasion. Tumor staging was determined by co-operation of the surgical and pathological staff based on clinical and pathological data according the 5th edition of the Tumor, Node, Metastasis/International Union Against Cancer criteria.21 In addition, based on explant histopathology, tumors were retrospectively classified according to Milan criteria as ‘‘Milan In’’ versus ‘‘Milan Out’’.
In all patients with tumor recurrence the options of curative surgical intervention were thoroughly assessed. All patients considered to be unsuitable for surgical treatment were referred to palliative care by radiotherapy (bone metastases), TACE (multiple hepatic metastases), administration of a tyrosine kinase inhibitor (Sorafenib, NexavarÒ) and/or general medical support. Furthermore, the calcineurin-inhibitor was replaced by Sirolimus (SLR, RapamuneÒ, Whyeth Germany) since January 2003 in all patients with history or presence of recurrent HCC, as this is currently presumed to have anti-tumor capabilities.22,23 Assessment of variables Variables analyzed included clinical (recipient age, sex, underlying liver disease, type of allograft used, TACE, highest preoperative AFP-level, location of recurrence, treatment of recurrence, time to tumor relapse, immunosuppression) and primary histopathological tumor characteristics. Statistical analysis Data are expressed as mean standard deviation or median and range, as feasible. Risk factors for tumor recurrence were analyzed using chi square test, with a P < 0.05 indicating statistical significance. Time to recurrence and survival post-recurrence were compared between subgroups using independent t-test. Survival rates were calculated using the KaplaneMeier method and compared using the log rank test. A P < 0.05 was indicating statistical significance. All variables found to have a significant impact on posttransplant recurrence-free survival and on survival from tumor relapse on univariate analysis were entered into a stepwise Cox proportional hazard model for multivariate analysis. Results
Immunosuppressive therapy Standard immunosuppressive therapy consisted of a quadruple induction regimen, cyclosporine A (CsA)- or
Patient and tumor characteristics for those who underwent LT and for those who developed posttransplant tumor relapse are summarized in Table 1. Forty-nine patients
A. Kornberg et al. / EJSO 36 (2010) 275e280 Table 1 Patient and Tumor (Explant) Characteristics (n ¼ 60).
Age recipient (mean SD; yr) Gender (F/M) Child (n) A B C None Underlying liver disease Hepatitis B/C Alcohol Autoimmun Other Transplant procedure (n) DDLT LDLT Split-LT TACE Yes No Immunosuppression (n) CsA Tac Number of tumor nodules (median, range) Diameter largest tumor nodule (median, range) Grading Well Moderate Poor Lymphatic vascular invasion (n) Microvascular venous invasion (n) Tumor stage (n) I II III IV Milan criteria (n) within beyond
All liver transplant patients with HCC (n ¼ 60)
Patients with recurrent HCC (n ¼ 16)
58,2 7,6 14/46
56,5 8,5 3/13
31 11 15 3
8 2 5 1
16 32 2 9
3 11 0 2
49 10 1
14 2 0
24 36
10 6
27 33 1
9 7 4,5
4
6,3
13 35 12 11
3 6 7 5
25
12
4 21 17 18
0 0 4 12
27 33
1 15
277
number of tumor nodules > 3 and Milan Out status (P < 0.05). In multivariate analysis, only poor tumor grade (Hazard Ratio [HR] ¼ 21.8; Confidence Interval [CI] 95% ¼ 4.9e95.3; P < 0.001) and microvascular invasion ([MVI]; HR ¼ 14.1; CI 95% ¼ 1.4e147.1; P ¼ 0.027) were identified as independent risk factors for reduced recurrence-free survival post-LT. Only 1 out of 27 Milan In patients developed HCC recurrence (3.7%), while 15 out of 33 Milan Out recipients (45.4%) suffered from tumor relapse (P < 0.001). Recurrence-free 5-year survival rate was significantly higher in Milan In patients (96.2%), when compared to Milan Out recipients (43.2%). However, there was only a trend of a better overall survival in Milan In patients (85.8%) than in Milan Out recipients (65.6%, Fig. 1). Clinical patterns and treatment of HCC recurrence Sites of first tumor recurrence were lung (n ¼ 5), liver (n ¼ 4), bone (n ¼ 4), cerebrum (n ¼ 1), adrenal gland (n ¼ 1) and peritoneum (n ¼ 1). Seven patients underwent surgical therapy. It consisted of liver allograft resection (n ¼ 2), lung resection (n ¼ 2), cerebral tumor extirpation (n ¼ 1), adrenalectomy (n ¼ 1) and resection of a chest wall metastasis after pretransplant tumor biopsy in another hospital (n ¼ 1). Two patients developed bone metastases after surgical resection of first tumor relapse. One patient underwent successful liver allograft resection after lung resection, and another patient developed repeat lung metastases after lung re-resection, which were successfully treated by conversion to Sirolimus. Three out of 7 patients amenable for surgical therapy demonstrated MVI at primary explant pathology, compared to 9 out of 9 patients unsuitable for surgery (P ¼ 0.009). Six out of 9 patients with CsA suffered from resectable tumor relapse, while only 1 out of 7 patients under a Tac developed resectable HCC recurrence (P ¼ 0.03). Out of 7 surgically treated patients, 2 ultimately died with tumor, and 5 are currently alive free of disease.
DDLT, deceased donor liver transplantation; LDLT, living-donor-liver transplantation; TACE, transarterial chemoebolization.
1,0
Risk factors for tumor recurrence
survival (%)
0,8
received a full-size cadaveric transplant, in one patient left split liver transplantation was performed, and 10 patients underwent living-donor-liver transplantation (LDLT).
0,6
0,4
Milan In (n=27) Milan Out (n=33)
0,2
A total of 16 patients (26.7%) developed HCC recurrence between 4 and 58 months (median: 23 months) post-LT. Univariate risk factors for impaired recurrencefree survival were AFP-level > 100 ng/ml, poor tumor differentiation, tumor stage III o. IV, microvascular tumor invasion, tumor size > 5 cm, total tumor diameter > 8.5 cm,
0,0 0
20
40
60
80
100
120
months post-LT Figure 1. Overall survival rate only tended to be superior in Milan In patients, when compared to Milan Out patients (log rank ¼ 0.087).
278
A. Kornberg et al. / EJSO 36 (2010) 275e280
Nine patients were not eligible for surgical therapy. They received radiotherapy of bone metastases (n ¼ 3), TACE of intrahepatic tumor recurrence (n ¼ 1), and therapy with Sorafenib (n ¼ 1). Five patients with multifocal tumor relapse were only suitable for general medical support. A total of 10 liver recipients were converted to an SRLbased immunosuppression, five of them after surgical resection of tumor relapse, and five of them as part of nonsurgical supportive treatment. There was no case of tumor re-recurrence after surgical treatment of primary tumor relapse in 5 patients converted to SRL, while 2 patients without SRL-therapy developed bone metastases after resection of primary HCC relapse. In univariate analysis, only the application of a Tacbased immunosuppression versus a CsA-based regimen was related with early posttransplant tumor recurrence (Tac: 15.6 9.8 months post-LT; CsA: 33.7 16.4 months post-LT). Survival from transplant Currrent posttransplant follow-up of the whole study cohort (n ¼ 60) ranges between 5 and 180 months (median: 46.5 months). Actuarial overall and recurrence-free 5-year survival rate posttransplantation is currently at 74.4% and 65.2%, respectively. Median survival from LT was 32.5 months for patients with HCC recurrence and 49.5 months for those without tumor relapse. Five-year survival rate was significantly lower for patients with HCC recurrence (41.7%) than for patients without posttransplant tumor relapse (89.3%, P ¼ 0.002). Only suitability for surgical intervention and the application of a CsA-based immunosuppression were significantly associated with an improved survival from LT in patients with recurrent HCC (P < 0.05). Survival from tumor recurrence Overall median survival from tumor relapse was 10.5 months (range: 1e136 months). None of primary tumor characteristics but early (24 months) posttransplant tumor recurrence (P ¼ 0.043), the application of a CsA- (versus Tac-) based immunosuppression (P ¼ 0.014) and eligibility for surgical therapy (P ¼ 0.006) had a beneficial impact on survival from tumor recurrence in univariate analysis, while SRL-therapy only tended to have a positive impact (P ¼ 0,08). Multivariate analysis demonstrated that late posttransplant tumor relapse and surgical treatment of tumor recurrence were independent predictors of survival postrecurrence (Table 2). Median survival after tumor relapse was 65 months (range: 12e136 months) in patients amenable for surgical therapy, and 5 months (range. 1e52 months) in patients non-suitable for surgical intervention (P ¼ 0.01). Five patients are currently tumor-free alive between 12 and 136 months (median: 65 months) after surgical
Table 2 Multivariate analysis of independent variables for survival from tumor relapse.
Late tumor relapse Surgical treatment
Hazard Ratio
95% CI
P-value
10,4 19,5
1127e96,945 1826e208,702
0.039 (>24 months) 0.014
intervention and conversion to SRL, while 2 patients with unchanged immunosuppression after resection of first HCC recurrence died from tumor re-relapse. Discussion Predictive value of the Milan criteria Results of our study clearly confirm the value of the Milan criteria for indicating the risk of HCC recurrence after LT. Tumor recurrence rate was 3.7% in Milan In patients but 45.4% in Milan Out recipients. Nevertheless, overall fiveyear survival rate was 65.6% in patients with HCC beyond the Milan criteria, which is by far better than other currently available treatment options. This important result of our study is powered by a high proportion of Milan Out recipients (55%) in our series, which is in contrast to many other transplant centers.3,4,8,9 There are several explanations for this high ratio of advanced HCC patients in our study cohort. First, several patients included in this trial have undergone LT before Milan criteria were implemented in our clinical practice. Second, tumor understaging by preoperative radiographic imaging is a well-known problem in this field.6,24 Final pretransplant radiographic screening underestimated pathological tumor stage in 23 patients of our series (38.3%). And third, comparable to other transplant groups with excellent survival results, we were following a policy of patient drop-out from the transplant list based on major events during pretransplant waiting time (macrovascular tumor invasion, lymph node metastases, tumor-related symptoms, extrahepatic tumor spread) rather than on the Milan criteria alone.10,25 Although originally implemented as listing criteria, they are now widely used for patient drop-out, as well.1,25 Using the same selection criteria for listing and delisting of a patient, however, might significantly increase the exclusion rate of patients with macromorphological borderline tumors. Many of them may, nevertheless, benefit from LT by achieving long-term survival.7e11 Our outcome results in patients with advanced HCC are even better than results of other well-experienced transplant centers.2,15e17 About 30% of our overall study population would have been excluded from curative LT, if Milan criteria were used strictly for decision making about patient drop-out from the transplant list. It seems to be worth mentioning in this context, that, although tumor recurrence rate was significantly higher in Milan Out patients than in Milan In recipients, overall survival rate only tended to be lower in patients with
A. Kornberg et al. / EJSO 36 (2010) 275e280
advanced HCC (Fig. 1). This interesting result of our trial clearly points out the importance of an appropriate treatment of tumor relapse for improving overall patient prognosis. Survival from tumor relapse Impact of surgery It is no surprising result of our trial that long-term survival in patients without HCC recurrence is significantly better than in patients developing tumor relapse.16,17,19 However, we are able to report about an overall posttransplant 5-year survival rate above 40% in our subgroup of patients with recurrent HCC. To the best of our knowledge, this is the most favorable outcome data of liver recipients with HCC relapse reported so far in the literature. Roayaie et al. demonstrated a 22% 5-year survival rate in 57 patients with recurrent HCC.16 Regalia and colleagues demonstrated a 23% overall survival rate at 4 years in 21 patients suffering from HCC relapse.17 Comparable to these two trials, eligibility for surgical resection of tumor relapse was the most important independent outcome variable in our study (Fig. 2, Table 2). At our transplant center, we were following a policy of very close and concise posttransplant patient surveillance, aiming at early detection and aggressive surgical intervention of recurrent tumor, if possible. Thereby, 9 surgical procedures were performed in 7 out of 16 patients with tumor relapse (43.7%). In contrast, the transplant groups from New York and Milan reported about resection rates of 31.6% and 33.3%, respectively, which may explain the superior outcome data in our series. Contrary to other trials,16,17,19 we did not identify primary tumor variables to correlate with earlier tumor recurrence or shorter survival time from tumor relapse, which might be due to the relatively small sample size. However, it seems to be noteworthy that 100% of patients with 1,0 surgical therapy (n=7) non-surgical therapy (n=9)
survival (%)
0,8
0,6
0,4
0,2
0,0 0
10
20
30
40
50
60
70
months post-recurrence Figure 2. Liver transplant patients with recurrent HCC amenable for surgical therapy had a significantly better long-term survival post-recurrence than patients with tumor relapse unsuitable for surgical intervention (log rank ¼ 0.006).
279
unresectable HCC relapse in our study demonstrated MVI at primary tumor pathology, compared to 43% of patients with resectable tumor recurrence. This observation suggests that liver transplant patients with presence of MVI at primary explant pathology should undergo a more intensified posttransplant surveillance program. This might, possibly, improve the surgical treatment options after early detection of tumor relapse.
Impact of immunosuppression There is considerable experimental evidence of a favoring impact of immunosuppression on tumor growth and relapse26 Although this topic is of special interest in the transplantation setting, there are only few clinical trials that have analyzed the relationship between pharmacological immunosuppression and HCC recurrence post-LT.27,28 To date, there is, however, no data about the impact of immunosuppression on outcome after HCC recurrence. Results of our trial suggest that patients receiving a Tacbased immunosuppressive regimen are on a higher risk for developing early tumor relapse, which is unsuitable for surgical therapy. Tac has meanwhile taken the place of CsA and is presently used as main immunosuppressant drug after LT. A recent Cochrane database analysis demonstrated that Tac is superior to CsA in improving survival and preventing acute rejection after LT.29 This immunological predominance of the drug may be unfavorable in the context of LT for HCC. However, an exact interpretation of our data is hampered by a small sample size, the heterogeneous immunosuppressive regimens used and the lack of drug exposure measurements. The rationale for us to switch to an SRL-based regimen after tumor relapse was to use its suggested antiproliferative and antineoplastic capabilities.22,23 Rapamycine is an effective mTOR inhibitor, thus providing effective immunosuppressive activities. Since the mTOR pathway is activated in several models of HCC, it may reduce cell growth and tumor vascularity.30 Clinical data are, as yet, only preliminary and are derived from retrospective studies.31,32There is currently no experience about the value of Sirolimus for treating posttransplant HCC recurrence. The conversion of Sirolimus, irrespective of other applied interventions, tended to improve survival in our trial (P ¼ 0,08). However, as 50% of the patients have undergone surgical therapy before conversion to SRL, the real antiproliferative capabilities of this drug cannot be determined by our data. But it seems to be worth mentioning that in the subgroup of surgically treated patients, none have yet developed tumor re-relapse after conversion to SRL, while 2 patients with unchanged medication suffered from another HCC relapse after surgical intervention. Apart from that, repeat lung metastases after lung re-resection completely disappeared after switch to SRL in one patient of our series.33 Therefore, further prospective controlled investigations in this field are imperative.
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Conclusion Results of our trial indicate that the Milan criteria are very useful for predicting risk of posttransplant recurrence in patients with HCC. Nevertheless, they may achieve an excellent 5-year survival rate above 60%. Patients with recurrent HCC amenable to surgical treatment should undergo resection, as this was identified as strongest independent predictor of long-term survival in our trial. In some of them, a curative situation (up to 136 months post-recurrence) may be achieved. There seems to be a positive effect of SRL for preserving a tumor-free status quo after surgical intervention. This, however, has yet to be further analyzed in a prospective approach. Conflict of interest The authors declare that they have no conflict of interest. References 1. Schwarz M. Liver transplantation for hepatocellular carcinoma. Gastroenterology 2004;127:268–76. 2. Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214: 221–8. 3. Mazzafero V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 4. Jonas S, Bechstein WO, Steinmu¨ller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33: 1080–6. 5. Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233:652–9. 6. Llovet JM, Bruix J, Fuster J, et al. Liver transplantation for small hepatocellular carcinoma: the tumor node metastasis classification does not have prognostic power. Hepatology 1998;27:1572–7. 7. 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;21:4329–35. 8. Cillo U, Vitale A, Bassanello M, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004;239:150–9. 9. Herrero JL, Sangro B, Quiroga J, et al. Liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7:631–6. 10. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519–24. 11. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 12. Lubienski A. Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 2005;80:113–9.
13. Roayaie S, Llovet JM. Liver transplantation for hepatocellular carcinoma: is expansion of criteria justified? Clin Liver Dis 2005;9:315–28. 14. Botha JF, Langnas AN. Liver transplantation for hepatocellular carcinoma: an update. J Natl Compr Canc Netw 2006;4:762–7. 15. Roayaie S, Frisher JS, Emre SH, et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5cm. Ann Surg 2002;235:533–9. 16. Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534–40. 17. Regalia E, Fassati LR, Valente U, et al. Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J Hepatobiliary Pancreat Surg 1998;5:29–34. 18. Schwartz M, Roayaie S, Llovet J. How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated? J Hepatol 2005;43:584–9. 19. Schlitt HJ, Neipp M, Weimann A, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324–31. 20. Hoffmann K, Weigand MA, Hillebrand N, Bu¨chler MW, Schmidt J, Schemmer P. Clin Transpl 2009;23:1–8. 21. Sobin LH, Wittekind C, editors. TNM classification of malignant tumors. 5th ed. New York: Wiley; 1997. 22. Trotter JF. Sirolimus in liver transplantation. Transpl Proc 2003;35: 193–200. 23. Luan FL, Hojo M, Maluccio M, Yamaji K, Suthanthiran M. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002;73:1565–72. 24. Shah SA, Tan JC, McGilvray ID, et al. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation 2006;81:1633–9. 25. Schwartz ME, D’Amico F, Vitale A, Emre S, Cillo U. Liver transplantation for hepatocellular carcinoma: are the Milan criteria still valid? Eur J Surg Oncol 2008;34:256–62. 26. Yokoyama I, Carr B, Saitsu H, Iwatsuki S, Starzl TE. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 1991;68:2095–100. 27. Vivarelli M, Cuccetti A, La Barba G, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg 2008;248:857–62. 28. Vivarelli M, Cuccetti A, Piscaglia F, et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 2005;11: 497–503. 29. Haddad EM, McAllister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006;18:CD005161. 30. Wang Z, Zhou J, Fan J, et al. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2009;135:715–22. 31. Zimmermann MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008;14:633–8. 32. Toso C, Meeberg GA, Bigam DL, et al. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects. Transplantation 2007; 15:1162–8. 33. Elsharkawi M, Staib L, Henne-Bruns D, Mayer J. Complete remission of posttransplant lung metastases from hepatocellular carcinoma under therapy with sirolimus and mycophenolate mofetil. Transplantation 2005;79:855–7.