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ecurrence of Hepatocellular Carcinoma After Liver Transplantation

. Escartin, G. Sapisochin, I. Bilbao, R. Vilallonga, J. Bueno, L. Castells, C. Dopazo, E. Castro,. Caralt, and J. Balsells

ABSTRACT

Outcome after liver transplantation (OLT) clearly depends on recurrence of hepatocel-lular carcinoma (HCC). After recurrence, patient outcome will depend on the time andsite of appearance. The aim of this study was to analyze the therapeutic implications oftumor recurrence behavior. From October 1988 to December 2005, 685 patients receivedOLT, including 202 due to HCC (32%). We analyzed 28 recurrences (15.2%) among 184patients who survived at least 3 months (minimum follow-up 1 year). According to the timeof recurrence, we divided the patients into early recurrence (ER � 12 months; n � 9;32.1%) and late recurrence (LR � 12 months n � 19; 67.9%). Actuarial survivals at 1, 5, and10 years were 82%, 65%, and 50% and disease-free survival, 80%, 58%, and 46%, respectively.Risk factors for recurrence were: vascular invasion (P � .01), bad differentiation (P � .01), andprevious hepatectomy (P � .05). After OLT, ER presented at: 5.7 � 2.3 months (range 3–10)vs 33.5 � 24.3 months (range 12–103) for LR P � .001). Survival postrecurrence (SPR) wasshorter: 3.1 � 2.4 (range 1–8) months vs 16.4 � 14.2 (range 1–5) months (P � .001).Treatment was offered to one ER (11%) and to eight LR (47.1%; P � .05), achieving in thesecases longer SPR: 20.1 � 14 vs 6.9 � 9 months (P � .05).

The most common sites of recurrence were liver (n � 7), lung (n � 7), bone (n � 5),adrenal gland (n � 2), peritoneum (n � 2), lymph node (n � 2), skin (n � 2) or cerebral(n � 1). Early recurrences showed short survivals; no treatment could be offered to thesepatients. Liver recurrence appeared early. In contrast, most lung recurrences appearedlater with the possibility of treatment and longer SPR. Bone recurrence appeared later,usually associated with other locations. Treatment was paliative and prognosis was worse.Skin and lymph node recurrences can be treated curatively with prolonged survival. Inconclusion, HCC recurrence was difficult to treat curatively and was only prevented by

employing restricted criteria.

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IVER TRANSPLANTATION (OLT) for hepatocellu-lar carcinoma (HCC) should be undertaken with

dequate case selection, yielding long-term results similaro those in patients transplanted for benign diseases.1,2

owever, despite adequate selection of candidates, HCCecurrence is the leading cause of mortality. After recur-ence, patient outcomes depend on the time and site ofppearance. Despite various therapeutic options, the prog-osis is dismal.3–5 The aim of this study was to analyze theherapeutic implications of tumor recurrence behavior.

ATIENTS AND METHODS

rom October 1988 to December 2005, 685 patients received OLT.epatocellular carcinoma in a cirrhotic liver was diagnosed in 202

atients (32%). We analyzed 28 recurrences (15.2%) among 184 m

041-1345/07/$–see front matteroi:10.1016/j.transproceed.2007.06.042

308

atients who survived at least 3 months (minimum follow-upyear). According to the time of recurrence, we divided patients

nto early recurrence (ER � 12 months) versus late recurrenceLR � 12 months).

iagnosis and Preoperative Evaluation

CC, usually diagnosed by ultrasound, was confirmed by abdom-nal computerized tomography (CT). Tumor spread was evaluated

From the Liver Transplantation Unit, Hospital Vall d’Hebron,arcelona, Spain.Address reprint requests to Alfredo Escartin, MD, PhD, Unidad

e Trasplante Hepático, Hospital General Vall d’Hebron, P° Vall’Hebron 119-129, Barcelona 08035, Spain. E-mail: escartin@

ac.com

© 2007 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 39, 2308–2310 (2007)

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RECURRENCE OF HEPATOCELLULAR CARCINOMA 2309

y abdominal and chest CT, brain CT, and bone scintigraphy.bdominal nuclear magnetic resonance and selective hepatic

ngiograms were performed in selected cases. Transarterialhemoembolization (TACE) with lipiodol and adriamycin waserformed as a neoadjuvant anti tumor procedure. Our rate ofxclusion from the waiting list due to tumor growth was lowecause our waiting list is 67.8 � 56 days. Only patients withinhe Milan criteria were accepted for OLT.

osttransplant Management and Follow-Up

mmunosuppressive therapy after OLT consisted of cyclosporiner tacrolimus in combination with corticosteroids. Mycophenolateofetil was used in cases of rejection or toxicity from calcineurin

nhibitors. Corticosteroids were tapered to discontinuation at 3o 6 months after OLT. Tumor recurrence was screened byltrasound or CT and alpha-fetoprotein measurements every 3onths. No adjuvant chemotherapy was administered to any

atient after OLT.

urvival and Statistical Analysis

his retrospective study included data acquired prospectively thatre expressed as mean values (SD) with comparisons betweeneans performed by Student’s t test or the Mann-Whitney U test

or parametric and nonparametric analyses, respectively. Survivalstimates were determined using Kaplan-Meier analysis. All statis-ical analyses were performed using SPSS software (Chicago, IL).

� .05q was considered significant.

ESULTS

atients with HCC were of mean age of 59 � 7 yearsncluding 74% males. Indication for OLT was hepatitis Cirus (HCV) (74%), hepatitis B virus (6%), alcoholic cir-hosis (16%). OLT was indicated for tumor recurrence afterartial liver resection of HCC in 16 cases. Incidental HCCas found in 23 (12.5%) patients who were transplantedue to cirrhosis. Pathologic examination of the cirrhotic

iver revealed a tumor size over 5 cm in 10 cases (5.4%) andore than three nodules in 19 instances (10.3%). Macro-

copic vascular invasion was found in 11 patients (5.9%)ncluding 10 recurrences.

Actuarial survivals at 1, 5, and 10 years were 82%, 65%,nd 50%, and disease-free survivals, 80%, 58%, and 46%,espectively. Risk factors for HCC recurrence were vascularnvasion (P � .01), bad differentiation (P � .01), andrevious hepatectomy (P � .05).Recurrence appeared in 28 cases (15.8%) with 24 deaths

ue to this cause. Since we apply the Milan criteria tonclude patients on the waiting list, recurrence failed from6.4% to 11.5% when patients fulfil Milan criteria (P �

05). After recurrence, the median survival was 7 months.he ER rate was 4.9% and LR, 10.9%. However, there waswide time range between OLT and recurrence and of

urvivals postrecurrence.We observed 9 of 28 ER (32.1%) and 19 of 28 LR

67.9%). After OLT, early recurrences presented at 5.7 �.3 (range 3–10) months vs 33.5 � 24.3 (range 12–103)onths (P � .001), and survival postrecurrence (SPR) for

R was shorter: 3.1 � 2.4 (range 1–8) months vs 16.4 � O

4.2 (range 1–5) months (P � .001). The first site ofecurrence was most frequently systemic (n � 21, 75%)han hepatic (n � 7, 25%). Recurrence affected multiplergans in 11 patients (39.2%). Treatment was undertaken inhe last 10 years for one ER (11%) and eight LR (47.1%),� .05), achieving in these cases longer SPR: 20.1 � 14 vs

.9 � 9 months (P � .05).

iver Recurrence (n � 7)

ive patients recurred early, with SPR ranging between 0.8o 4.7 months; three had simultaneous lung or bone disease.nother patient recurred during the second year with an SPRf 3 months. The last patient recurred at 30 months and wasreated with TACE, achieving an SPR of 20 months.

ung Recurrence (n � 7)

wo patients recurred early, with SPR values of 4 and 6onths; both cases had simultaneous involvement of bone

nd pleura. Five patients recurred later, ranging from 25 to5 months with a mean SPR of 26 months. Three cases werereated with chemotherapy. In another case it was notossible due to cirrhosis from recurrent HCV.

one Recurrence (n � 5)

ll recurrences occurred beyond the first year (range 13–41onths). Two cases with simultaneous pulmonary involve-ent died 2 months later. Two patients were treated with

adiotherapy at SPR of 7 and 14 months. Another patient islive at 12 months after resection of the chest wall. In anotherve cases, bone metastasis appeared simultaneously or afternother site recurrence; the prognosis was bad.

ymph Node Recurrences (n � 2)

hese appeared late; both were treated with chemotherapy.ne died at 24 months and another is alive at 10 months.

kin Recurrences (n � 2)

hese appeared at 12 and 20 months in two patients. Botheceived treatment and are alive at 24 and 50 months afterurgery.

uprarrenal (n � 2), Peritoneal (n � 2), and Cerebraln � 1) Recurrences

ll three appeared at various times in advanced fashionnd without the possibility of treatment. The SPR wasery short.

ISCUSSION

utcomes after OLT clearly depend on HCC recurrence.voidance is not possible due to the lack of adjuvant

herapies.5 With adequate patient selection the recurrenceate is about 10%,2,3 preserving excellent survival after

LT. SPR is affected by the time from OLT to recurrence

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2310 ESCARTIN, SAPISOCHIN, BILBAO ET AL

nd the site of recurrence. Treatment was not alwaysossible, but in recent years management is more aggressive

n an attempt to improve survival. Early recurrence showshort survival postrecurrence; no treatment can be offeredo these patients. Liver recurrences appear early with ahort SPR. In contrast, most lung recurrences appearedater, with various treatment options and a longer SPR.one recurrences appeared later, usually associated withther sites. Despite treatment, the prognosis was worse.kin and lymph node recurrences could be treated in aurative fashion with prolonged survival.

In conclusion, HCC recurrence is difficult to treat in aurative way and can only be prevented by employing

estricted criteria for OLT.

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EFERENCES

1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantationor the treatment of small hepatocellular carcinomas in patientsith cirrhosis. N Engl J Med 334:693, 19962. Llovet J, Schwartz M, Mazzaferro V: Resection and liver

ransplantation for hepatocellular carcinoma. Semin Liver Dis5:181, 20053. Park JW, Lee KW, Kim SJ, et al: Outcome of patients with

ecurrent hepatocellular carcinoma in liver transplantation. Trans-lant Proc 38:2121, 20064. Schlitt HJ, Neipp M, Weimann A, et al: Recurrence patterns

f hepatocellular and fibrolamellar carcinoma after liver transplan-ation. J Clin Oncol 17:324, 1999

5. Schwartz M, Roayaie S, Llovet J: How should patients with

epatocellular carcinoma recurrence after liver transplantation bereated? J Hepatol 43:584, 2005