Treatment Recurrence HCC After LT

8/2/2019 Treatment Recurrence HCC After LT

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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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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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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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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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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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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

Treatment Recurrence HCC After LT

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