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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 transplantation for HCC versus patients wit
hout HCC.1
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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 recurrence; despite careful selection, howe
ver,
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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 recurrence 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 transplantation or was disseminated at the time of transplant
ation.
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Here we examine the treatment ofrecurrent HCC after transplantation, but we recognize at the outset that there is very
limited evidence on which recommendations can be based. Apart from the systemic treatment of recurrent HCC with sorafenib,the evidence currently addressing this issu
e comprises observational studies and expert opinion (levels C and D)
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ROLE OF LOCOREGIONAL
THERAPY
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Liver Recurrence
Isolated hepatic recurrence has been reported in15% to 20% of the patients in most series, and it
represents the pattern of recurrent HCC mostamenable to locoregional therapy. In the nontransplant setting, the selection of treatments for HCC confined to the liver is fairly well standardized,although local experience and preferences resultin some degree of variability; both the extent of the tumor and the condition of the underlying livermust be taken into account
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Liver Recurrence
There is essentially no literature that systematicallyanalyzes this issue in the posttransplant setting. There arekey differences between patients with posttransplant HCCrecurrence and patients with primary HCC, and these diffe
rences must be considered when we are trying to apply standard 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 noncirrhotic, at least in the first 2 years after transplantation; du
ring this time, the large majority of recurrences occur.
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Liver Recurrence
When surgery is being considered for recurrentHCC, the technical issues inherent to reoperative surgery on the liver and related portal structures must be weighed. Recurrent HCC in the liver is
by definition metastatic disease (except for thoseoccasional late recurrences observed in the setting of recurrent cirrhosis, which are usually due to hepatitis C); local treatments in this setting donot offer the hope of treating the primary site bef
ore the onset of tumor dissemination. On this basis, retransplantation for recurrent HCC is virtually never considered
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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 reviewed here.
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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 University 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 patients who did not experience HCC recurrence.
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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 impossible to
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determine the extent to which surgeryrather than favorable biology explains thedifference. There is indirect evidence for a
tumor biology explanation: vascular invasion was found during the original explant pathology examination in only 3 of 7 patients with surgically resectable recurrence but
in all 9 patients whose recurrence patternwas unsuitable for surgery in 1 study.8
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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 treatments for HCC recurrence is summarize
d in Table 2.
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Radiofrequency ablation, which is commonly used forboth primary and metastatic liver cancers, can be applied in the posttransplant setting for both liver and pulmonary recurrences. In general, resection is preferred for these pat
ients, but certain scenarios may make radiofrequency ablation more attractive (ie, large-volume ascites or hostile posttransplant adhesions that preclude safe surgical exploration and resection). In the New York City experience,2 half of the patients with isolated hepatic recurrences under
went liver resection, and each series reported a minority of patients treated in the same manner.
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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 afew medium-term survivors
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Chemoembolization
In a 2010 Korean study describing 28recurrences after living donor liver transplantation, transarterial chemoembolization (TACE) wasused initially for all isolated intrahepatic recurrences without any significant complications being reported.11 Despite early concerns about the safety and theoretical added risk of biliary ischemiain the transplanted liver parenchyma, each of the
other large groups has reported the use of TACEin isolated patients with unresectable recurrent HCC
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Fourteen patients who underwent lobaplatin-
based TACE for unresectable recurrent HCC aft
er transplantation were reported in early 2010; n
one of these patients developed major complications 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 both intrahepatic and extrahepatic recurrences.
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Retransplantation
A distinction must be made here between the vastmajority of posttransplant HCC recurrences, which result from the progression of tumors present at the time of transplantation, and those few cases of late recurrence,which r
epresent the de novo development of HCC (most commonly in the setting of recurrent hepatitis C and advancing fibrosis). De novo HCC conceptually fits into the established framework of transplantation for patients with primary HCC; patients with unresectable de novo HCC that is within the
Milan criteria are reasonable candidates for retransplantation
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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 12.7months 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 initial transplant (details about the timing of recurr
ence were not provided
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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 nearlyuniversal view that retransplantation is not
indicated for early HCC recurrence, just as
transplantation in general is contraindicated for patients with systemic malignancies.1
6
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Extrahepatic Recurrence
In contrast to primary HCC, most studies
of patients
with recurrent HCC after transplantation
have
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Extrahepatic Recurrence
reported aggressive attempts at locoregionaltherapy
of extrahepatic metastases. As with recurrencein the
liver, multiple reports concerning extrahepaticrecurrence
have shown better survival rates for surgically treated patients, and the same issue of case
selection has confounded attempts to relate surgery to
outcomes.
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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 hasbeen
reported
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Extrahepatic Recurrence
Five patients who underwent isolated lungresections for metastatic HCC after transplantation experienced survival similar to tha
t of patients who underwent isolated liver resections.17 A case of sequential, bilateral adrenal metastases treated with resection has been reported with long-term surviva
l.18 No reliable survival data are availablefor any of these approaches.
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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 independentof 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 metastatic bone tumors.
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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 Fiftyone patients with painful HCC bone metas
tases who were treated with radiotherapy
achieved effective palliation according to apain questionnaire.20
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ROLE OF SYSTEMIC
THERAPY
Immunosuppression Strategies as
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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
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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.
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It is unclear whether sirolimus should be
added to calcineurin inhibitors or should re
place them in this setting
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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; they 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 combination as its standard protocol for proven HCC recurr
ence since 2007.
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Sorafenib
Sorafenib is an oral, multipletyrosine
kinase inhibitor targeting molecular pathw
ays different than those targeted by mTOR
inhibitors. With the publication of the Sorafenib HCC Assessment Randomized Proto
col trial results in 2008, sorafenib became
the first and only drug licensed for treatingunresectable, advanced HCC.22
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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 toxicity in posttransplant patients versus pa
tients with primary HCC has emerged
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Sorafenib
A complete but temporary radiological responseof a multifocal HCC recurrence after treatment with sorafenib and sirolimus has been reported,23and an isolated complete radiological response o
f a lung metastasis after sorafenib therapy has been described as well.24 A 2010 retrospective series of 13 patients demonstrated no complete or partial responses, but disease stabilization wasobserved in approximately half of the studied pat
ients.25 The literature on the posttransplant useof sorafenib is summarized in Table 3.
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CONCLUSIONS
First, locoregional therapy has a well-
established role in the treatment of primary
intrahepatic HCC and a proven survival be
nefit; however, the case selection bias renders all existing studies inconclusive with r
espect to the survival benefit of locoregion
al therapy for posttransplant HCC recurrence
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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 interval 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 recurrence thought to represent de novo HCC, is rarel
y, if ever, appropriate.
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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 whether sirolimus or everolimus is preferabl
e and whether mTOR inhibitors should be
used in addition to (or instead of) calcineurin inhibitors.
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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 be used whenever a systemic treatment is
warranted
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