In an ever-expanding patient population, liver transplantation provides the best hop e for long-term survival for many patients

s uffering from hepatocellular carcinoma (H CC) in the setting of cirrhosis. One study h as even demonstrated superior 1- and 3-y ear survival rates for patients undergoing t ransplantation for HCC versus patients wit hout HCC.1

 Because of the shortage of deceased organ donors, the donor risk in living donor transplantation, the high cost of liver trans plantation, and the poor outcomes of patie nts who develop recurrent HCC after trans plantation, restrictive criteria have been wi dely adopted to minimize the likelihood of r ecurrence; despite careful selection, howe ver,

 HCC recurrence remains the most important negative predictor of posttransplant survival and occurs in approximately 10% to 30% of patients. The literature describing the timing and sites of r ecurrence is summarized in Table 1. By definitio n, recurrent HCC following transplantation repres ents metastatic disease from the original tumor t hat either was not detectable before transplantati on or was disseminated at the time of transplant ation.

 Here we examine the treatment of recurrent HCC after transplantation, but w e recognize at the outset that there is very limited evidence on which recommendatio ns can be based. Apart from the systemic t reatment of recurrent HCC with sorafenib, the evidence currently addressing this issu e comprises observational studies and exp ert opinion (levels C and D)

ROLE OF LOCOREGIONAL THERAPY

Liver Recurrence
Isolated hepatic recurrence has been reported in 15% to 20% of the patients in most series, and it represents the pattern of recurrent HCC most amenable to locoregional therapy. In the nontran splant setting, the selection of treatments for HC C confined to the liver is fairly well standardized, although local experience and preferences result in some degree of variability; both the extent of t he tumor and the condition of the underlying liver must be taken into account

Liver Recurrence
There is essentially no literature that systematically analyzes this issue in the posttransplant setting. There are key differences between patients with posttransplant HCC recurrence and patients with primary HCC, and these diffe rences must be considered when we are trying to apply st andard treatment algorithms in the posttransplant setting. Unlike the large majority of livers harboring primary HCC, the liver in the patient with recurrent HCC is typically nonci rrhotic, at least in the first 2 years after transplantation; du ring this time, the large majority of recurrences occur.

Liver Recurrence
When surgery is being considered for recurrent HCC, the technical issues inherent to reoperativ e surgery on the liver and related portal structure s must be weighed. Recurrent HCC in the liver is by definition metastatic disease (except for those occasional late recurrences observed in the setti ng of recurrent cirrhosis, which are usually due t o hepatitis C); local treatments in this setting do not offer the hope of treating the primary site bef ore the onset of tumor dissemination. On this ba sis, retransplantation for recurrent HCC is virtuall y never considered

Liver Recurrence
These various issues notwithstanding, the various treatments available for primary H CC have all been applied in the posttransp lant setting, and the available literature is r eviewed here.

Resection/Radiofrequency Ablation
There is no controversy about the difference in the survival rates of patients whose recurrent HC C is surgically extirpated and patients who are tr eated nonsurgically. In fact, the Kyushu Universit y group in 2010 reported 17 patients with HCC r ecurrence limited to the liver after transplantation ; 9 of these patients were treated surgically and experienced survival approximating that of patie nts who did not experience HCC recurrence.

 All major series of HCC recurrence have substantiated the better survival of patient s treated with resection; there is, however, an obvious case selection bias, so it is imp ossible to

 determine the extent to which surgery rather than favorable biology explains the difference. There is indirect evidence for a tumor biology explanation: vascular invasi on was found during the original explant p athology examination in only 3 of 7 patient s with surgically resectable recurrence but in all 9 patients whose recurrence pattern was unsuitable for surgery in 1 study.8

 Liver resection after transplantation for a variety of indications, including recurrent H CC, has been shown to be safe.10 The lite rature concerning the results of surgical tre atments for HCC recurrence is summarize d in Table 2.

 Radiofrequency ablation, which is commonly used for both primary and metastatic liver cancers, can be applied i n the posttransplant setting for both liver and pulmonary r ecurrences. In general, resection is preferred for these pat ients, but certain scenarios may make radiofrequency abl ation more attractive (ie, large-volume ascites or hostile p osttransplant adhesions that preclude safe surgical explor ation and resection). In the New York City experience,2 h alf of the patients with isolated hepatic recurrences under went liver resection, and each series reported a minority o f patients treated in the same manner.

 When resection is intended, exploration also allows for the potential discovery and extirpation of small-volume peritoneal or n odal disease; most series have reported a few medium-term survivors

Chemoembolization
In a 2010 Korean study describing 28 recurrences after living donor liver transplantatio n, transarterial chemoembolization (TACE) was used initially for all isolated intrahepatic recurren ces without any significant complications being r eported.11 Despite early concerns about the saf ety and theoretical added risk of biliary ischemia in the transplanted liver parenchyma, each of the other large groups has reported the use of TACE in isolated patients with unresectable recurrent H CC

 Fourteen patients who underwent lobaplatinbased TACE for unresectable recurrent HCC aft er transplantation were reported in early 2010; n one of these patients developed major complicati ons related to the therapy, and more than half de monstrated a partial response.12 Other local the rapies with only short-term results that are not ye t in widespread use have been described for bot h intrahepatic and extrahepatic recurrences.

Retransplantation
A distinction must be made here between the vast majority of posttransplant HCC recurrences, which result f rom the progression of tumors present at the time of trans plantation, and those few cases of late recurrence,which r epresent the de novo development of HCC (most common ly in the setting of recurrent hepatitis C and advancing fibr osis). De novo HCC conceptually fits into the established f ramework of transplantation for patients with primary HCC ; patients with unresectable de novo HCC that is within the Milan criteria are reasonable candidates for retransplantati on

 There are a few Asian reports of retransplantation for the early recurrence of HCC . These reports include a single patient from Kor ea with multifocal recurrence in the liver at 12.7 months who underwent retransplantation after T ACE and was alive at 45 months11 and 5 patient s from China who underwent retransplantation fo r HCC recurrence more than 6 months after the i nitial transplant (details about the timing of recurr ence were not provided

 and 3 of the patients subsequently died of recurrence).15 Nevertheless, the fact that early recurrence is a reflection of systemic tumor dissemination has led to the nearly universal view that retransplantation is not indicated for early HCC recurrence, just as transplantation in general is contraindicate d for patients with systemic malignancies.1 6

Extrahepatic Recurrence
In contrast to primary HCC, most studies of patients with recurrent HCC after transplantation have

Extrahepatic Recurrence
reported aggressive attempts at locoregional therapy of extrahepatic metastases. As with recurrence in the liver, multiple reports concerning extrahepatic recurrence have shown better survival rates for surgically treated patients, and the same issue of case selection has confounded attempts to relate surgery to outcomes.

Extrahepatic Recurrence
The common theme of these reports is the selection of patients for surgical treatment who have good functional status, a single site of recurrence, and a long interval from transplantation to recurrence. The resection of metastases to the regional lymph nodes, lungs, and adrenal glands has been reported

Extrahepatic Recurrence
Five patients who underwent isolated lung resections for metastatic HCC after transpl antation experienced survival similar to tha t of patients who underwent isolated liver r esections.17 A case of sequential, bilatera l adrenal metastases treated with resectio n has been reported with long-term surviva l.18 No reliable survival data are available for any of these approaches.

Extrahepatic Recurrence
Bone metastases are a common presentation of metastatic HCC after transplantation. Roayaie et al.2 reported especially poor survival for patients with bone metastases, and this was independent of other metastatic diseases. These metastases are commonly quite symptomatic and are treated with external beam radiation. Zoledronic acid is a bisphosphonate used for myeloma and metastati c bone tumors.

Extrahepatic Recurrence
In a case series of 17 patients with bone metastases from HCC, significant reductio ns in pain scores were achieved, and the use of narcotics seemed to decline.19 Fifty one patients with painful HCC bone metas tases who were treated with radiotherapy achieved effective palliation according to a pain questionnaire.20

ROLE OF SYSTEMIC THERAPY

Immunosuppression Strategies as Salvage: Mammalian Target of Rap amycin (mTOR) Inhibitors

mTOR inhibitors have shown efficacy as antineoplastic agents for some solid tumors, including neuroendocrine tumors and renal carcinomas; angiogenesis inhibition is one of the purported mechanisms of action. Calcineurin inhibitors have been shown to promote hepatic regeneration and are believed by some to predispose patients to earlier and more aggressive tumor recurrence by a similar mechanism (but not because of immunosuppression per se

The dual effects of antiangiogenesis and immunosuppression that are afforded by sirolimus, therefore, make sirolimus an attractive therapeutic option for posttransplant immunosuppression in the setting of HCC. Although there is a good deal of literature concerning the preemptive use of sirolimus in patients undergoing transplantation for HCC, sirolimus as a treatment for HCC recurrence is reported in only 1 significant series.21 This study documented the safety of the drug, but no outcomes for the 7 patients with recurrent HCC were described.

 It is unclear whether sirolimus should be added to calcineurin inhibitors or should re place them in this setting

 Everolimus is an mTOR inhibitor marketed primarily as a cancer drug and used extensively f or metastatic renal carcinoma. In 2010, the Bilba o group reported 2 patients with recurrent HCC; t hey were managed solely with a combination of everolimus and sorafenib and were alive at 18.5 (without recurrence) and 10 months (with recurre nce)6; the Bilbao group has used this combinatio n as its standard protocol for proven HCC recurr ence since 2007.

Sorafenib
Sorafenib is an oral, multipletyrosine kinase inhibitor targeting molecular pathw ays different than those targeted by mTOR inhibitors. With the publication of the Soraf enib HCC Assessment Randomized Proto col trial results in 2008, sorafenib became the first and only drug licensed for treating unresectable, advanced HCC.22

Sorafenib
Several case and series reports of sorafenib use in posttransplant patients wit h HCC recurrence have been published. S o far, no evidence of increased sorafenib t oxicity in posttransplant patients versus pa tients with primary HCC has emerged

Sorafenib
A complete but temporary radiological response of a multifocal HCC recurrence after treatment wi th sorafenib and sirolimus has been reported,23 and an isolated complete radiological response o f a lung metastasis after sorafenib therapy has b een described as well.24 A 2010 retrospective s eries of 13 patients demonstrated no complete o r partial responses, but disease stabilization was observed in approximately half of the studied pat ients.25 The literature on the posttransplant use of sorafenib is summarized in Table 3.

CONCLUSIONS
First, locoregional therapy has a wellestablished role in the treatment of primary intrahepatic HCC and a proven survival be nefit; however, the case selection bias ren ders all existing studies inconclusive with r espect to the survival benefit of locoregion al therapy for posttransplant HCC recurren ce

 Nevertheless, it remains reasonable to pursue the locoregional treatment of isolated sites of HC C recurrence either within or outside the liver in patients whose disease is limited, for whom the i nterval between transplantation and recurrence i s long, and whose functional status is good as lo ng the treatment can be performed with little risk. Retransplantation, except in cases of late recurr ence thought to represent de novo HCC, is rarel y, if ever, appropriate.

 Second, although firm evidence is lacking, it is nevertheless reasonable to use an mTOR inhibitor for immunosuppression in patients with recurrent HCC. It is unclear w hether sirolimus or everolimus is preferabl e and whether mTOR inhibitors should be used in addition to (or instead of) calcineur in inhibitors.

 Third, sorafenib, the only drug with proven efficacy against HCC, appears to be safe in the posttransplant setting, even in conju nction with mTOR inhibitors, and should b e used whenever a systemic treatment is warranted