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COMPLICATIONSRecurrent Disease

djuvant Chemotherapy for Prevention of Recurrence of Invasiveepatocellular Carcinoma After Orthotopic Liver Transplantation

. Bernal, J.L. Montero, M. Delgado, E. Fraga, G. Costán, P. Barrera, P. López-Vallejos, G. Solórzano,

. Rufián, J. Briceño, J. Padillo, P. López-Cillero, T. Marchal, J. Muntané, and M. de la Mata

ABSTRACT

Orthotopic liver transplantation (OLT) is the best treatment for nonresectable hepatocellularcarcinoma (HCC), but tumor recurrence reduces long-term and medium-term survival. Theeffectiveness of adjuvant chemotherapy to prevent tumor recurrence has not been fullyestablished.Methods. Three hundred eighty-seven consecutive patients, including 43 with HCCsuperimposed on liver cirrhosis, underwent OLT. Twelve patients with one or moreprognostic criteria for HCC recurrence were entered into a prospective prophylaxisprotocol with monthly cycles of cisplatin (60 mg/m2) and adriamycin (30 mg/m2), beginningthe fourth week post-OLT for a maximum of seven sessions.Results. The 5-year survival of the non-HCC patients was 65.7% and that of the HCCpatients was 60.46% (P � NS). Chemotherapy was reasonably well tolerated, but the 9patients with hepatitis C- or B-associated cirrhosis showed viral and histological recurrenceof the primary disease. A high proportion of patients (7 of 12) developed tumor recurrenceduring the first year after OLT. Six of these patients died, all but one due to HCC relapse.Five patients remain healthy and tumor free at 58 to 130 months. Post-OLT adjuvantchemotherapy does not avoid tumor recurrence and its fatal consequences but maycontribute to prolonged tumor-free survival among a significant proportion of patientswith high-risk HCC. However, the uncertain implications on viral recurrence and the lackof control groups do not allow post-OLT chemotherapy to be recommended outsidecontrolled clinical trials, which are clearly warranted.

From the Liver Transplant Unit, Reina Sofia University Hospi-al, Córdoba, Spain.

Address reprint requests to Dr Manuel de la Mata, Sección de

Menéndez Pidal s/n, 14004 Córdoba, Spain. E-mail: hepatoh2.hrs.sspa@juntadeandalucia.es

rasplante Hepático, Hospital Universitario Reina Sofía, Avda

2006 by Elsevier Inc. All rights reserved. 0041-1345/06/$–see front matter60 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2006.08.053

ransplantation Proceedings, 38, 2495–2498 (2006) 2495

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2496 BERNAL, MONTERO, DELGADO ET AL

EPATOCELLULAR CARCINOMA (HCC) is a se-vere complication in patients with liver cirrhosis. The

ncidence of this tumor is increasing all over the world; itas become a leading cause of death.1 Different treatmenttrategies have been developed, but only hepatic resectionnd orthotopic liver transplantation (OLT) may be consid-red to be curative therapies.2,3 However, less than 10% ofatients with cirrhosis and HCC can be resected, thisequires strictly normal liver function and, for many groups,bsence of portal hypertension.4 Therefore, OLT is increas-ngly accepted as the treatment of choice for HCC. How-ver, controversies regarding the best curative therapy forCC have been recently reviewed.5,6 OLT should be per-

ormed before vascular invasion and extrahepatic spread.he occurrence of intrahepatic or extrahepatic tumor re-urrence dramatically reduces the benefit of the procedure.herefore, an effort should be made to follow strict selec-

ion criteria, which achieve a 5-year survival of 70% and aecurrence rate below 15%.7–9 Adjuvant chemotherapy afterLT has been proposed to lower the risk of recurrence ofCC, but its efficacy has not been fully proven.10–13 We

esigned a prospective protocol to evaluate the efficacy ofystemic cytotoxic agents after OLT among patients withCC and a high risk of tumor recurrence.

ATIENTS AND METHODS

rom July 1989 to July 1999, 387 OLT procedures were performedn our institution. Forty-three patients (11%) had HCC associatedith liver cirrhosis. Patients with HCC were accepted as candidates

or OLT if they had one single nodule less than 5 cm in diameterr up to three nodules no greater than 3 cm each.14 After OLT,istological study of the liver explant revealed a poor prognosis forCC among 12 patients; (1) more than three nodules; (2) vascular

r lymphatic invasion; and (3) capsular rupture. These patientsTable 1) were eligible for treatment with systemic chemotherapyor prevention of cancer recurrence after obtaining informedonsent. The cytostatic agents were cisplatin (60 mg/m2 of bodyurface) and adriamycin (30 mg/m2 of body surface) once a monthtarting from the fourth week after OLT for up to 7 cycles, unlesshere was a severe adverse event.

Table 1. Demographic and Preoperative Clinical Features ofHigh-Risk HCC Patients

Patient Sex Age Cirrhosis HCC Child-Pugh Score

1 M 46 HBV 2 nodules A62 M 23 HCV 3 nodules B83 M 57 HCV 2 nodules A54 M 40 HBV � HDV 3 nodules A65 M 54 HCV 2 nodules B76 M 60 HCV � PCT 1 nodule A57 M 59 HCV � Alcohol 2 nodules A58 F 62 Alcohol Incidental B79 M 53 HCV 3 nodules A5

10 M 61 HBV 1 nodule A511 M 52 Alcohol 2 nodules A612 M 50 Alcohol 1 nodule B7

oHBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; PCT,

orphyria cutanea tarda; M, Male; F, Female.

ESULTSistological Findings After OLT

he explants were examined by a single pathologist. Cir-hosis was confirmed in all cases 10 macronodular and 2icronodular. In eight patients the pathological examina-

ion of the explanted livers revealed a high-risk group withreater than expected extension of the tumor. One patientad seven nodules, and five patients showed multipleodules diffusely distributed throughout the liver. The sizef the nodules ranged from 0.6 to 7 cm. Microscopicascular invasion was found in 10 patients, the capsule ofhe tumor was invaded in two (cases 3 and 10) and lymphessels, in another two patients (cases 4 and 9) (Table 2).

hemotherapy

ystemic chemotherapy with cisplatin and adriamycin wasdministered after OLT as well as granulocyte colonytimulating factor and antiemetic agents as necessary. Theumber of chemotherapy sessions ranged from one to sevenmean 4.6 sessions per patient). There were no differencesetween the mean number of cycles given to patients withr without tumor recurrence (4.6 vs 4.5). The most commondverse effects were leukopenia, thrombocytopenia, nau-ea, and vomiting. However, severe steatosis and renalailure also appeared in two patients.

urvival and Recurrence

he 5-year survival of the non-HCC versus HCC patientsndergoing OLT was 65.7% and 60.46%, respectively (P �S). None of the patients without poor prognostic criteriabserved in the explant developed tumor recurrence. Theurvival rate of the HCC patients undergoing OLT whoeveloped tumor recurrence was lower than that of thoseithout tumor recurrence (Fig 1). At the time of thisnalysis, the mean follow-up for the high risk HCC groupas 54.8 months (2.5–130); HCC had recurred in the graftr metastases had been found in seven patients (58.3%). Six

Table 2. Histopathological Findings of High-Risk HCC Patients

Patient Cirrhosis* Nodules† Size‡Vascular

InfiltrationLymphaticInfiltration

CapsularRupture

1 Macro 2 1.5–3.5 Yes No No2 Micro 7 0.5–2 No No No3 Micro 3 0.5–3 No No Yes4 Macro D 1.5–6.5 Yes Yes No5 Macro D 0.5–4 Yes No No6 Macro D 0.5–3 Yes No No7 Macro 2 2–3 Yes No No8 Macro D 0.5–2.5 Yes No No9 Macro 3 3–5 Yes Yes No

10 Macro 1 7 Yes No Yes11 Macro 3 2.3–5.5 Yes No No12 Macro D 1–4 Yes No No

*Type of cirrhosis: macronodular or micronodular.†Number of nodules: D: diffuse.‡Size (cm).

f these patients (1, 4, 5, 6, 10, 12) died between 78 and

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ADJUVANT CHEMOTHERAPY FOR RECURRENT CARCINOMA 2497

084 days after OLT (443 � 117.2 days). One patient islive with lung metastases, and five remain alive andumor-free between 58 and 130 months after OLT (mean0 months). The post-OLT interval for tumor recurrenceanged from 1 to 27 months (mean 10 months). All patientsith viral cirrhosis (HBV and HCV) developed biochemicalnd histological recurrence of the disease between 25 daysnd 19 months after chemotherapy (mean 5.6 months)Table 3).

ISCUSSION

lthough OLT is widely accepted as the best curativereatment for cirrhotic patients with HCC, their survival isiminished by tumor recurrence.7–9 It has been recognizedhat tumor growth rate is markedly increased under immu-osuppressive therapy.14 The factors in the explant thatnhance the risk of HCC recurrence after OLT includeore than three nodules, a nodule size greater than 3 cm,

ascular invasion, and nodal disease.7–9,11,12,15 However,ome authors have proposed expanding the current limits ofCC for OLT,16,17 although caution is warranted since the

ize and number of nodules has been associated with

Table 3. Recurrence Parameters and Survival of Patients WithHigh-Risk HCC After OLT

PatientViral

RecurrenceTumor

RecurrenceFollow-Up(months)

Time of Death(months after OLT)

1 Yes Yes — 72 Yes No 130 Alive3 Yes No 130 Alive4 Yes Yes — 365 Yes Yes — 176 Yes Yes — 37 Yes No 69 Alive8 No No 62 Alive9 Yes No 58 Alive

10 Yes Yes — 1211 No Yes 58 Alive

s12 No Yes — 15

ascular invasion.18 Our study shows that despite an im-rovement in accuracy, current imaging techniques cannotorrectly determine the exact tumor burden in cirrhoticivers.19,20 Indeed, in 10% to 50% of explanted livers theathologists will observe a previously undetected or under-stimated lesion often associated with vascular invasion.

In our study, the main factors involved in tumor recur-ence and patient survival were the size of the tumor (�3 cm)nd vascular invasion. A high proportion of patients (6 of 7)ith nodules greater than 3 cm developed HCC recurrence.he outcome in relation to vascular invasion followed a

imilar pattern. A high proportion of patients (7 of 10) withnfiltrated vessels in the explanted liver showed tumorecurrence.

A variety of studies have assessed the efficacy of differenthemotherapy protocols to prevent HCC recurrence. How-ver, the heterogeneity of the regimens, the small numberf patients treated, and the lack of control groups haverecluded clear conclusions.10–12 Furthermore, a systematiceview of adjuvant chemotherapy for HCC after resectionr OLT for HCC has failed to demonstrate a clear benefit.13

In our study, post-OLT chemotherapy did not preventumor recurrence in a high proportion of patients (7 of 12),ut a significant number (5) survived between 4 and0 years. Using current selection criteria, OLT offers pa-ients with HCC long-term survival and a recurrence rateelow 10%. However, among the subset of HCC patientsith invasive pathology in the explant, overall and tumor-

ree survival are largely reduced. These conditions shoulde identified and closely followed due to the high risk ofumor recurrence, which is the main cause of death. Inome patients, however, adjuvant chemotherapy post-OLTay favor long-term survival. Controlled studies assessing

ew anti-tumor regimens are clearly warranted.

EFERENCES

Fig 1. Survival of the series ofpatients with hepatocellular carci-noma (HCC), with or without tumorrecurrence, receiving orthotopicliver transplantation (OLT). Thesurvival of the patients undergo-ing OLT with tumor recurrencewas significantly lower than thesurvival observed in the patientswithout tumor recurrence (P �

.05).

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2498 BERNAL, MONTERO, DELGADO ET AL

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