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Contents lists available at SciVerse ScienceDirect

Digestive and Liver Disease

j our nal ho me page: www.elsev ier .com/ locate /d ld

iver, Pancreas and Biliary Tract

reatment of hepatocellular carcinoma in Child-Pugh B patients

abio Piscagliaa,∗, Eleonora Terzia, Alessandro Cucchettib, Chiara Trimarchia, Alessandro Granitoa,imona Leonia, Sara Marinelli a, Patrizia Pinia, Luigi Bolondia

Division of Internal Medicine, Department of Digestive Diseases and Internal Medicine, S. Orsola-Malpighi University Hospital, Bologna, ItalyDivision of Liver and Multiorgan Transplantation, S. Orsola-Malpighi University Hospital, Bologna, Italy

r t i c l e i n f o

rticle history:eceived 31 October 2012ccepted 4 March 2013vailable online xxx

eywords:epatocellular carcinomaiver functionransarterial chemoembolisationumour staging systems

a b s t r a c t

Background: The frequency with which patients in Child-Pugh B having hepatocellular carcinoma aretreated following the international guidelines according to the Barcelona Clinic Liver Cancer stages isunknown.Aims: To investigate treatment allocation for Child-Pugh B patients in different tumour stages, withparticular interest in the intermediate stage.Methods: Patients were retrospectively identified from a consecutively collected series. Treatment wascarried out primarily according to the guidelines.Results: Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7%respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In theintermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child-

Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediatepatients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P = 0.048). Survival of the intermediate stage patientsundergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8.Conclusions: Approximately half of the intermediate stage patients can undergo locoregional treatmentwith good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting

refin Publi

that this tumour stage be© 2013

. Introduction

Hepatocellular carcinoma (HCC) is a major worldwide healthroblem and occurs primarily in patients with underlying cirrho-is. Thus, two separate and potentially lethal diseases, cancer andirrhosis, usually coexist in patients with HCC. Both the tumour bur-en and the underlying liver dysfunction have a negative effect onrognosis and are determinant regarding treatment. Accordingly,hen selecting a treatment for HCC, it is mandatory to consider not

nly the tumour burden but also liver function, and, in fact, tumourtaging systems for HCC include both components (i.e. integratedtaging systems).

Cirrhotic liver function is most commonly categorised accord-ng to the Child-Pugh-Turcotte score (CPT) [1] which has a strongrognostic value for HCC patients [2] and is included in all inte-rated HCC staging systems [2–5]. The Barcelona Clinic Liver Cancer

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

BCLC) system [5] is the integrated HCC staging system most usedorldwide.

∗ Corresponding author. Tel.: +39 051 6362568/42; fax: +39 051 6362725.E-mail address: fabio.piscaglia@unibo.it (F. Piscaglia).

590-8658/$36.00 © 2013 Published by Elsevier Ltd on behalf of Editrice Gastroenterologttp://dx.doi.org/10.1016/j.dld.2013.03.002

ed.shed by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Patients with well-preserved liver function (CPT-A) are consid-ered suitable for virtually all treatment modalities, and are easilyand rigorously treated according to the BCLC stage [5], even in theintermediate (BCLC-B) stage. Patients with severely compromisedliver function (CPT-C) are instead considered terminal patients [5],suitable only for palliative care (if not transplantable) and, as such,are managed in nearly all instances following the guidelines. Con-cerning the CPT-B class, it corresponds to an intermediate, partiallycompromised situation, in between well preserved and termi-nal condition and accordingly these patients have a fragile liverfunction. The CPT classification includes different degrees of liverdysfunction with 16 different scores ranging from 5 (best function)to 15 (worst function), categorised into three classes: A–C. Specif-ically, class B includes CPT-B7, -B8 and -B9 which are, however,considered as only one single group by the BCLC staging system.Depending on the tumour burden and/or the performance status,CPT-B patients can fall into various BCLC stages [5]. However, theyare frequently not ideal candidates for the first line treatmentsrecommended in general for their respective stage (Table 1) [6].

ocellular carcinoma in Child-Pugh B patients. Dig Liver Dis (2013),

Since the year 2000, the treatment of HCC in cirrhotic patientsin our centre has followed the BCLC staging system [5–7], buteach treatment strategy has been individually tailored and care-fully administered after multidisciplinary discussion. Transarterial

ica Italiana S.r.l.

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Table 1Recommended treatments and contraindications for Child-Pugh B patients in each Barcelona Clinic Liver Cancer stage according to the AASLD guidelines [6].

BCLC-A4 BCLC-B BCLC-C BCLC-D

Recommended treatment modality Resection Best supportive care Clinical trials SymptomatictreatmentsTransplantation (TACE?)

RFA

Contraindications Resection is not indicated for multiplenodules, portal hypertension andelevated bilirubin (frequent in CPT-Bpatients).

TACE can induce irreversible liverfailure in patients with compromisedliver function (CPT-B patients) and isthus not recommended.

Few trialsaccept CPT-Bpatients.

Transplantation can be offered to onlya few patients.RFA is not indicated in cases of ascites

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(frequent in CPT-B patients).

ASLD, American Association for the Study of Liver Diseases; BCLC, Barcelona Cransarterial chemoembolization.

hemoembolization (TACE) is the recommended treatment foratients in the BCLC-B tumour stage but evidence of the beneficial

mpact of TACE in CPT-B patients is lacking; the risk of ischaemicnsult to the liver following TACE led the authors of the guide-ines to advise against this treatment in Child-Pugh B patients, evenhough this exclusion cannot be found in the flowchart summaris-ng the treatment algorithm according to the BCLC stage [6,7]. Inact, the flowchart combines prognostic staging and treatment allo-ation, and is not as detailed as the text with an underlying risk forisinterpretation. In fact, from a prognostic point of view, BCLC-B

atients are grouped together regardless of whether they are Child-ugh A or B (thus, the flowchart is complete and correct). However,hen considering treatment, the text of the guidelines specifies

hat Child-Pugh A and B should be kept separate, as is mentionedn page 1226 [6] despite the fact that this different allocation is noteported in the flowchart and no additional information is given inhe legend of the chart in Fig. 2 of that article [6].

A retrospective investigation of treatments and outcomes ofPT-B patients (in particular, for those in the BCLC-B stage) with

primary diagnosis of HCC was carried out.The primary aims were to understand how often the guide-

ines could be followed in CPT-B patients and to identify possibleredictors of survival within this specific population of patients.his was attempted by reporting the field-practice treatments ofPT-B patients in various BCLC stages (in particular, in the BCLC-Btage), assessing CPT-B patient survival in various BCLC stages (alsoccording to the CPT specific numeric score) and investigating theresence of predictors of survival for CPT-B patients in the BCLC-Btage and for patients treated with TACE within the BCLC-B stage.

The secondary aim was to identify the predictors of eligibility forurative treatment or TACE for CPT-B patients in the BCLC-B stage

. Materials and methods

.1. Study design and patient population

From March 2001 to December 2007, 286 consecutive patientsith a primary diagnosis of HCC associated with cirrhosis were

bserved, and all data were collected at the time of observation. Thenrolment was closed in December 2007. Patients were followedp from enrolment until death or closure of the study in December011. This cut off date for enrolment allowed to have the full sur-ival history of almost all patients and was also set for consistencyecause Sorafenib was not available until then. The diagnosis of HCCas made following the most recent European Association for the

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

tudy of the Liver (EASL) and American Association for the Study ofiver Diseases (AASLD) guidelines [6,7]. Only patients in Child-Pughlass B liver function [1] at the time of HCC treatment were retro-pectively included in the present study. Given the retrospective

iver Cancer; CPT, Child-Pugh-Turcotte; RFA, radiofrequency ablation; and TACE,

design of the study, the Institutional Review Board, which approvedthe protocol, waived the need to obtain written informed consentfrom the participants. The final study group included 86 consecu-tive patients with a primary diagnosis of HCC in Child-Pugh classB liver function. According to the Child-Pugh numeric score, 42(48.8%) were scored as B7, 28 (32.6%) as B8 and 16 (18.6%) as B9.

2.2. Staging systems and treatment options

In our routine clinical practice, treatment options for CPT-Bpatients followed the BCLC staging system but were individualisedaccording to tumour extent, severity of the parameters contribut-ing to the Child-Pugh stage (and therefore the Child-Pugh numericscore), the presence of comorbidities and their severity, technicalapplicability of the treatment and individual consent for specifictreatments. In fact, the AASLD guidelines state that a “carefulselection of candidates for each treatment option and the expertapplication of these treatments are required to achieve the bestoutcomes” [6] and that recommendations are flexible and shouldbe implemented in a specific clinical setting [6].

2.3. Statistical analysis

Analysis of the data was carried out using SPSS statistical anal-ysis software v16 (SPSS Inc., Chicago, IL, USA). For continuousvariables, such as age and biochemical data, descriptive statisticswere calculated and reported as medians and ranges. Compar-isons among groups were carried out using non-parametric tests(Mann–Whitney and Wilcoxon). Categorical variables, includingCPT classification, BCLC classification, treatment strategy, ascites,encephalopathy, HCC aetiology, macroscopic vascular invasion,extrahepatic spread and portal hypertension, were described usingfrequency distributions.

The �2 test was used to detect differences in the BCLC and CPTgroups according to treatment strategy.

All tests were considered significant at P < 0.05.Survival curves were computed according to the Kaplan–Meier

method and were compared using Log rank tests. Analysis of thedata was carried out using SPSS statistical analysis software (SPSSInc., Chicago, IL, USA, 1999).

3. Results

3.1. Characteristics of the study population

ocellular carcinoma in Child-Pugh B patients. Dig Liver Dis (2013),

Baseline demographic and clinical data, and tumour character-istics of the patient cohort are summarised in Table 2. The vastmajority of patients were male (77.9%) with a median age of 68years. The most frequent aetiology of cirrhosis was the hepatic C

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Table 2Clinical and demographic characteristics of the study population.

Variable Study population(no. = 86)

Gender: male 67 (77.9%)Age in years, median (range) 68 (40–87)Aetiology of cirrhosis

HCV 53 (61.6%)HBV 8 (9.3%)HBV + HCV 1 (1.2%)Alcohol 16 (18.6%)HBV + Alcohol 3 (3.5%)HCV + Alcohol 1 (1.2%)Cryptogenic/NASH 4 (4.6%)

Serum albumin, median (gr/dl) (range) 3.2 (2.1–4.9)Serum total bilirubin, median (mg/dl) (range) 1.68 (0.8–18.6)Serum creatinine, median (mg/dl) (range) 0.98 (0.29–2.00)PT %, median (range) 66 (21–94)Serum AFP, median (ng/ml) (range) 20.0 (1.0–40,000.0)Ascites

Absent 43 (50.0%)Mild 37 (43.0%)Moderate 6 (7.0%)

Encephalopathy (all mild) 9 (10.5%)Presence of varices 55 (64.0%)Child-Pugh class

B7 42 (48.8%)B8 28 (32.6%)B9 16 (18.6%)

Presence of infiltrative HCC 6 (7.0%)Number of nodules, median (range) 1 (1–4)Diameter of the largest HCC nodule, median

(cm) (range)3.2 (1–10)

Presence of neoplastic vascular invasion 13 (15.1%)BCLC class

A4 45 (52.3%)B 27 (31.4%)C 12 (14.0%)D 2 (2.3%)

Treatment of HCCRFA/PEI 30 (34.9%)TACE 19 (22.1%)Yttrium90 (radioembolisation) 1 (1.2%)Irinotecan (intrarterial infusion) 6 (6.9%)Liver transplantation 5 (5.8%)Hepatic resection 3 (3.5%)Radiotherapy 1 (1.2%)Oral capecitabine 1 (1.2%)Supportive care plus Synchrolevels

(zebrafish extracts)7 (8.1%)

Supportive care 13 (15.1%)

HCV, hepatitis C virus; HBV, hepatits B virus; NASH, non alcoholic steatohepati-tis; PT, prothrombin time; AFP, Alpha-fetoprotein; HCC, hepatocellular carcinoma;Be

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score) heavily impacted survival. The median survival of patients

CLC, Barcelona Clinic Liver Cancer; RFA, radiofrequency ablation; PEI, percutaneousthanol injection; and TACE, transarterial chemoembolization.

irus (HCV) (61.6%) followed by alcohol (18.6%) and the hepatic Birus (HBV) (9.3%).

Approximately half (52.3%) of all CPT-B patients were in classCLC-A4, 31.4% were in BCLC-B, 14.0% were in BCLC-C and 2.3%ere in BCLC-D (Table 2).

Patients with a greater degree of liver dysfunction (CPT-B9) wereore often in advanced or terminal BCLC (BCLC-C/D) stages (6/16,

7.5%) than those classified as -B7 or -B8 (5/42, 11.9% and 3/28,0.7%, respectively; P = 0.011) (Table 3).

.2. Treatment of patients in various BCLC stages

.2.1. Treatment of patients in the early tumour stage (BLCL-A4)Among patients in Child-Pugh B7 liver function, the guide-

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

ines were followed in 20/21 BCLC-A4 patients (95.2% of patientsere treated with curative treatment, including three patientsho underwent resection which was individually considered to

PRESSr Disease xxx (2013) xxx– xxx 3

be much more suitable than ablation; the remaining patients 4.8%underwent TACE) (Table 3).

On the contrary, only 16/24 (66.7%) of the BCLC-A4 patients witha greater degree of liver dysfunction received curative treatment(10/15 patients in CPT-B8 and 6/9 in -B9) (Table 3). The remainingpatients received either TACE, 3/15 patients (20.0%) and 2/9 (22.2%)in CPT-B8 and -B9, respectively or only received palliative care 2/15(13.3%) and 1/9 (11.1%) in CPT-B8 and -B9, respectively.

3.2.2. Treatment of patients in the intermediate tumour stage(BCLC-B)

In our study, 59.3% of Child-Pugh B patients in BCLC-B stageunderwent curative treatment or TACE whereas the others wereincluded in research trials (3.7%) or received palliative care (37.0%).In detail, the frequency of CPT-B patients in the BCLC-B stage whounderwent curative treatment or TACE was 68.8% in Child-Pugh B7,50% in B8 and 0% in B9 (not statistically significant because of thelimited number of patients). Among patients in Child-Pugh B7 liverfunction, 11/16 (68.8%) underwent TACE (9/11, 81.8%) or curativetreatment (2/11, 18.2%) (Table 3). One patient was included in theresearch trial with Irinotecan because his large tumour burden pre-cluded TACE due to the high risk of liver decompensation [8]; theremaining four patients (25.0%) who were CPT-B7 were not con-sidered eligible for any tumour treatment and were managed withpalliative care. Among the patients who were CPT-B8, 5/10 under-went TACE and 5/10 received palliative care. The patient in CPT-B9liver function was managed with palliative care.

3.2.3. Treatment of patients in advanced and terminal tumourstages (BCLC-C/D)

For patients with advanced or terminal HCC (BCLC-C/D), noeffective treatment exists to date as the efficacy of Sorafenib hasonly been demonstrated in Child-Pugh A patients in the two regis-tration trials carried out in Western Countries or in the Asia Pacificregion [9,10]. We therefore examined the number of patients whoat least had the option of enrolment in HCC research trials in agree-ment with the guidelines for BCLC-C patients. These numbers arestrictly dependent on the types of trials available in each centre andtherefore no generalisation is postulated.

Despite the small numbers, the large majority of CPT-B7 patients(4/5, 80.0%) were enrolled in treatment studies. The percentagedecreased to 33.3% (1/3) in -B8 patients and to 16.7% (1/6) in -B9patients (not statistically significant because of the limited numberof patients).

3.3. Survival

After a median follow-up of 21.5 months (range 1 month to 9.2years), 76/86 patients (88.4%) died and 2 were lost to follow-up.The median overall survival of the entire study population was 21.0months (95% CI, 12.8–29.2), and the one- and three-year survivalrates were 60.7 and 25.0%, respectively. The long-term survivorsconsisted of the five patients who had received liver transplants(one died after 34 months). After the exclusion of these patientsfrom the analysis, the median survival decreased to 20.0 months(95% CI, 10.3–29.7), and the one- and three-year survival rates to58.2 and 21.5%, respectively. The median survival times in relationto the clinical and tumour characteristics are reported in Table 4.The analyses of prognosis showed tumour characteristics and somevariables of liver function (namely the presence of ascites andthe protrombin rate which contribute to the numeric Child-Pugh

ocellular carcinoma in Child-Pugh B patients. Dig Liver Dis (2013),

decreased with progression of the BCLC stage (Tables 4 and 5),confirming in Child-Pugh B patients the already well-known rela-tionship between survival and the BCLC stage (P = 0.001).

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Table 3Distribution of Child-Pugh class, median survival and treatment in relationship to the Barcelona Clinic Liver Cancer classification. Patients who underwent liver transplantationwere included in the analysis. One patient, included in those treated by transarterial chemoembolization in Child-Pugh class B7 as intermediate, underwent radioembolizationwith Yttrium90. Surgical procedures included 5 patients who underwent transplantation and 3 patients who underwent surgical resection.

Variable BCLC class P

A4 (no. = 45) B (no. = 27) C or D (no. = 14)

Child-Pugh score 0.057B7 (no. = 42) 46.7% (21) 59.3% (16) 35.7% (5)B8 (no. = 28) 33.3% (15) 37.0% (10) 21.4% (3)B9 (no. = 16) 20.0% (9) 3.7% (1) 42.9% (6)

Child-Pugh score, median (range) 8 (7–9) 7 (7–9) 8 (7–9) 0.075Median patient Survival, months (95% C.I.) 32.0 (26.5–37.5) 8.0 (5.5–10.5) 4.0 (2.2–5.8) 0.001Potentially effective treatments 93.3% (42) 59.3% (16) 0.0% (0) 0.001Surgical procedures (no. = 8) 17.8% (8) 0.0% (0) –

Child-Pugh class B7 11.1% (5) 0.0% (0) –Child-Pugh class B8 4.5% (2) 0.0% (0) –Child-Pugh class B9 2.2% (1) 0.0% (0) –

Percutaneous procedures (no. =30) 62.2% (28) 7.4% (2) –Child-Pugh class B7 33.3% (15) 7.4% (2) –Child-Pugh class B8 17.8% (8) 0.0% (0) –Child-Pugh class B9 11.1% (5) 0.0% (0) –

TACE (no. = 20) 13.3% (6) 51.8% (14) –Child-Pugh class B7 2.2% (1) 33.3% (9) –Child-Pugh class B8 6.7% (3) 18.5% (5) –Child-Pugh class B9 4.4% (2) 0.0% (0) –

Other treatments 6.7% (3) 40.7% (11) 100.0% (14) 0.001Child-Pugh class B7 0.0% (0) 18.5% (5) 35.7% (5)Child-Pugh class B8 4.5% (2) 18.5% (5) 21.4% (3)Child-Pugh class B9 2.2% (1) 3.7% (1) 42.9% (6)

BCLC, Barcelona Clinic Liver Cancer and TACE, transarterial chemoembolization.

Table 4Survival analysis. Patients who underwent liver transplantation were excluded from the analysis. Continuous variables were dichotomised on the basis of the median valuereported in Table 1. Statistical significance tests are reported as boldface numbers.

Variable Median survival (95% CI) P

Gender: male vs. female 16.0 (7.1–24.9) 25.0 (8.1–41.9) 0.544Age <68 vs. ≥68 years 23.0 (14.2–31.8) 13.0 (1.4–24.6) 0.282Hepatitis serology: HCV vs. non HCV 20.0 (8.5–31.5) 19.0 (4.9–33.1) 0.415History of heavy alcohol intake yes vs. no 27.0 (17.4–36.6) 16.0 (7.3–24.7) 0.342Serum albumin <3.2 vs. ≥3.2 gr/dl 9.0 (4.7–13.3) 25.0 (19.5–30.5) 0.059Serum total bilirubin <1.7 vs. ≥1.7 mg/dl 22.0 (17.9–26.1) 13.0 (5.7–20.3) 0.471Serum creatinine <1.00 vs. ≥1.00 mg/dl 22.0 (14.4–29.6) 13.0 (6.7–19.3) 0.153PT <66 vs. ≥66% 29.0 (23.4–34.6) 12.0 (7.6–16.4) 0.011Serum AFP <20 vs. ≥20 ng/ml 24.0 (18.1–29.9) 13.0 (5.5–20.5) 0.155Ascites: absent vs. present 27.0 (19.3–34.7) 12.0 (7.1–16.9) 0.011Mild encephalopathy: absent vs. present 20.0 (12.5–27.5) 9.0 (6.2–11.8) 0.984Esophageal varices: absent vs. present 19.0 (5.0–33.0) 16.0 (6.9–25.1) 0.565CTP class: B7-8 vs. B9 22.0 (13.0–31.0) 5.0 (0–12.3) 0.010Infiltrative HCC: absent vs. present 22.0 (14.6–29.4) 3.0 (1.4–4.6) 0.001Number of nodules: single vs. multiple 29.0 (21.4–36.6) 10.0 (5.4–14.6) 0.001Diameter of the largest nodule ≤3.0 vs. >3.0 cm 25.0 (20.4–29.6) 10.0 (0.3–19.7) 0.033Neoplastic vascular invasion: absent vs. present 24.0 (19.0–29.0) 4.0 (2.9–5.1) 0.001

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BCLC stage A4 vs. B–C–D 29.0 (24.0

CV, hepatitis C virus; PT, prothrombin time; AFP, Alpha-fetoprotein; CPT, Child-Pu

The median survival of patients in each BCLC stage on the basisf the Child-Pugh numeric score was analysed (Table 5).

.4. Predictors of survival for patients in BCLC-B stage

Univariate analysis was carried out to assess the role of clinicalariables regarding better survival of CPT-B patients in the BCLC-Btage. The variables analysed included age lower or greater than8 years, prothrombin rate lower or greater than 66%, AFP lowerr greater than 20 ng/dL, gender, presence or absence of ascites,resence or absence of esophageal varices, single or multinodu-

ar HCC, diameter of the largest HCC lower or greater than 3 cm

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

nd bilirubin level (tested at two thresholds to divide patients intowo groups according to the classic CPT threshold of 2 mg/dl or tohe median level of our patients of 1.7 mg/dl), CPT numeric scoreB7 (yes/no) and potentially effective treatments (yes/no). A better

) 6.0 (4.0–8.0) 0.001

rcotte; HCC, hepatocellular carcinoma; and BCLC, Barcelona Clinic Liver Cancer.

outcome was found in CPT-B7 patients (Table 5) than in CPT-B8and -B9 patients (P = 0.048) and in patients undergoing effectivetreatment (P = 0.029). In particular, TACE was found to be associ-ated with longer survival than palliative care (P = 0.049); however,the two groups were not totally comparable in terms of diseaseseverity, especially regarding the presence of ascites (42.9% in TACEpatients treated vs. 80% in best supportive care (BSC)) and serumcreatinine (0.99 vs. 1.25 mg/dl) (Table S1). A statistically significantdifference was reached, however, only for creatinine (probably dueto the small number of patients).

Moreover, considering all patients in the BCLC-B stage treatedby TACE, the median survival rate was 9.0 months (95% CI, 0–26.6).

ocellular carcinoma in Child-Pugh B patients. Dig Liver Dis (2013),

Univariate analysis was carried out to assess the role of clinicalvariables regarding better survival of CPT-B patients in the BCLC-Bstage treated with TACE but unfortunately we were unable to iden-tify any clinical variables suggesting a better outcome. Nonetheless,

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Table 5Median survival in Child-Pugh B patients subgrouped according to individual Child-Pugh numeric score and tumour stage. Patients who underwent liver transplantationwere excluded from the analysis, and two patients were lost to follow-up. Statistical significance tests are reported as boldface numbers.

Median survival (95% CI) P

BCLC-A4 (no. = 40) BCLC-B (no. = 26) BCLC-C or D (no. = 13)

Child-Pugh B 29.0 (24.0–34.0) 8.0 (5.5–10.5) 4.0 (0.9–2.2) 0.001Child-Pugh numeric score

B7 (no. = 39) 33.0 (26.8–39.2) 9.0 (0.0–36.4) 6.0 (2.8–9.2) 0.002B8-B9 (no. = 40) 27.0 (2.8–21.5) 6.0 (2.4–1.5) 4.0 (0.4–3.2) 0.001

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CLC, Barcelona Clinic Liver Cancer.

t should be noted that survival was poor (≤8 months) in a largeajority of the CPT-B8 patients whereas, among the Child-Pugh

7 patients, a consistent number achieved survival longer than 20onths. Unfortunately, we were unable to identify any clinical vari-

bles suggesting a better outcome in patients in the CPT-B7 groupith respect to the CPT-B8 group (Table 6).

.5. Predictors of curative treatment or TACE for patients in theCLC-B stage

Univariate analysis was carried out to assess the role of clini-al variables regarding the eligibility of CPT-B patients for curativeherapy (percutaneous treatments) or TACE when in the BCLC-Btage. The variables analysed included age lower or greater than 68ears, prothrombin rate lower or greater than 66%, AFP lower orreater than 20 ng/dL, gender, presence or absence of ascites, pres-nce or absence of esophageal varices, single or multinodular HCC,iameter of the largest HCC lower or greater than 3 cm and bilirubin

evel (tested at two thresholds to divide patients into two groupsccording to the classic CPT threshold of 2 mg/dl or to the medianevel of our patients of 1.7 mg/dl). The only prognostic factor foreceiving curative treatment or TACE was age <68 years (P = 0.047).

. Discussion

The percentage of CPT-B patients in the different classes of theCLC differed on the basis of the severity of liver function impair-ent (namely Child-Pugh numeric scores -B7, -B8 and -B9) as

atients with worse liver function were more often associated with

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

n advanced BCLC stage (Table 3). This finding can most likely bettributed to the presence of vascular invasion in BCLC-C/D patientshich can increase portal hypertension and deteriorate liver func-

ion (and consequently the CPT numeric score).

able 6urvival and clinical characteristics of intermediate patients who underwent chemoembo

CPT Survival (months) Mediansurvival (95%CI)

B7 (no. = 9) 4.00

22.0 (0–60.0)

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22.00

27.00

37.00

47.00

76.00

B8 (no. = 5) Drop out

3.00

6.0 (1.1–10.9)6.00

8.00

25.00

PT, Child-Pugh-Turcotte and HCC, hepatocellular carcinoma.

0.025

The present study confirmed that field practice HCC treatment inpatients in the Child-Pugh B class closely adhered to the indicationsof the international guidelines [5,6] only in the early (BCLC-A4) andadvanced (BCLC-C/D) HCC stages.

Concerning CPT-B patients in the intermediate stage (BCLC-B),the assessment was more complicated since the guidelines [5,6,11]were discordant and without a specific recommendation for thetreatment of these patients. In our centre, only selected CPT-Bpatients in the BCLC-B stage usually undergo selective or super-selective TACE (which has limited impact on liver function [12]and better effectiveness). The choice is made after multidisciplinaryexamination and consideration of the tumour burden and clin-ical conditions. We do so [13] in agreement with the fact thatsome Child-Pugh B patients were present in a meta-analysis whichdemonstrated a survival benefit for TACE therapy in nonresectableHCC [14], representing up to 28% of the randomised patients inone study [15] and in agreement with the opinion of a group ofexperts, which included also some members from our centre [8].This approach was also recently endorsed by EASL which proposedTACE in Child-Pugh B7 patients in the BCLC-B stage [11]. The majorcontraindications for TACE treatment in our clinical practice werefrank jaundice, clinical encephalopathy, refractory ascites or hepa-torenal syndrome. In the present series of patients, approximatelyhalf of the BCLC-B patients in Child-Pugh B class (namely, 11/16in -B7 and 5/10 in -B8) underwent potentially effective treatment(almost always TACE) whereas the remaining patients were mainlyoffered only palliative care. This finding points out the problem ofestablishing the most appropriate treatment for CPT-B patients inthe BCLC-B stage since, in routine clinical practice, approximately

ocellular carcinoma in Child-Pugh B patients. Dig Liver Dis (2013),

half of the patients received effective treatment and half of patientsreceived only palliative care.

In order to establish the clinical variables predictive of the eli-gibility for curative treatment or TACE in this group of patients,

lization (including one patient who underwent radioembolization with Yttrium90).

Number of nodules(diameter of the largestHCC nodule in cm)

Age (years) Aetiology

1 (8.0) 75 HCV1 (7.0) 77 Alcohol>3 (2.0) 63 Alcohol1 (6.0) 77 Cryptogenic>3 (3.3) 76 HBV>3 (1.9) 75 HCV>3 (4.2) 59 Alcohol>3 (5.5) 67 HCV3 (3.4) 76 HCV

3 (5.0) 60 HCV>3 (2.1) 65 Alcohol1 (7.6) 65 HCV>3 (5.8) 60 HCV2 (4.5) 61 HCV

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ARTICLEDLD-2393; No. of Pages 7

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nivariate analysis was carried out. However, the only variablehich was statistically significant for the likelihood of receiv-

ng curative treatment or TACE was age <68 years. It should beoted that the sample size of patients was small and the analysisight be subject to potential statistical underpowering. However,

s reported in Table 3, there is a trend towards a higher rate of eli-ibility for receiving effective treatment in patients in CPT-B7 thann -B8 or -B9 suggesting that clinical variables may have a role inetermining eligibility for treatment.

As expected, the analysis of survival showed a progres-ive decrease in survival with progression of the BCLC stageTables 4 and 5). For instance, patients in the BCLC-B stage had

median survival of 8.0 months (95% CI, 5.5–10.5). In addition, theurvival subanalysis according to the CPT numeric score (Table 5)howed that CPT-B7 patients had a longer survival rate thanatients in CPT-B8 and -B9 (9.0 vs. 6.0 months, P = 0.048) despitehe fact that they were both in the same Child-Pugh class and wouldccordingly receive the same prognostic weight in all staging sys-ems [2–5]. That data confirmed the very important role not only ofhe tumour burden in HCC patients but also of the precise impair-

ent of liver function on survival. In fact, patients within BCLC-Btage have a different prognosis if in CPT-A or CPT-B stage liverunction but also if in CPT-B7 or -B8 or -B9.

These findings again stress the extensive variability of patientsithin the BCLC-B class who cannot be considered a homoge-eous group having a similar prognosis even within specific CPT-Blass liver function. Individual Child-Pugh B numeric scores mayontribute to refining prognosis, even though they do not seemufficient to subdivide patients in the Child-Pugh B class. This isot in disagreement with previous studies showing the role of liver

unction in patient prognosis and treatment allocation since thosetudies [2,5] considered only entire Child-Pugh classes and not theole of individual numeric scores.

Since this is a field practice and not a randomised study, it ismpossible to establish whether there was a detrimental effect ofACE in our BCLC-B patients (which was not in the study design).owever, the survival subanalysis, according to the Child-Pughumeric score of the BCLC-B patients undergoing TACE (Table 6),ends to suggest that, in CPT-B8 patients, the prognosis is so grimmedian survival of 6.0 months, range 1.1–10.9) that the likeli-ood of a benefit from TACE as an antitumour treatment is stronglyhallenged by the detrimental effects on liver function. However,n CPT-B7 patients, a consistent number achieved acceptable sur-ival after TACE (median survival of 22.0 months, range 0–60.0),omparable to those included in Llovet’s meta-analysis [15] whichas largely based on Child-Pugh A patients. That result seems to

e in agreement with the most recent published guidelines [11]hich recommend TACE in patients with well-compensated liver

unction, including CPT-B7 patients, and with a recent expert opin-on proposal for BCLC substaging, which also includes specific CPTcores [16]. It is worth noting that survival rates of BCLC-B patientsreated with TACE in our study, even CPT-B7 patients, had a skewedistribution (Table 6). This also suggested the great heterogeneityf this limited population (as found in the control arms of differentandomised trials [17]). Unfortunately, we were unable to iden-ify any clinical variables suggesting a better outcome (Table 6);his was probably a consequence of the limited number of patientshich makes the analysis more subject to potential statisticalnder-powering. Future research focusing on the identification ofhe most suitable patients for TACE within the CPT-B7 group areeeded.

Altogether, our current data are in keeping with those reported

Please cite this article in press as: Piscaglia F, et al. Treatment of hepathttp://dx.doi.org/10.1016/j.dld.2013.03.002

n the Japanese guidelines [18] which have had good results andhich recommend TACE for adequately and highly selected inter-ediate patients. Nonetheless, the problem of the BCLC-B patients

n Child-Pugh B was not included in the 2009 publication of the

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PRESSr Disease xxx (2013) xxx– xxx

Japan Society of Hepatology regarding the actual management ofHCC in Japan [19], further strengthening the opinion that this isa highly neglected problem in research trials as well in practiceguidelines and requires dedicated studies.

The main limits of the current study are represented by the rel-atively low number of patients and the retrospective observationaldesign (no prospective randomisation) which prevent the rigorousdefinition of variables capable of indicating or contraindicating spe-cific treatments, or the superiority of one treatment as comparedto another. In the absence of any randomised prospective studies inthis class of patients (CPT-B), the strengths of the study supportingthe conclusions are the consecutive series of cases (thanks to theworking methodology of our Centre) and the experienced multidis-ciplinary team management which optimises treatment allocation,as suggested by the guidelines.

In conclusion, the difficulty in making recommendations forChild-Pugh class B patients in the BCLC-B stage is understandablesince hardly any study on the treatment of HCC has specificallyfocused on this group; they are most often grouped together withChild-Pugh A patients. Since the latter usually constituted themajority of the study populations in randomised controlled trials[10,15,20], they usually dictated prognosis and treatment alloca-tion.

Our findings confirmed the need for specific separate researchregarding the segment of Child-Pugh B patients in the BCLC-Bstage.

Conflicts of interestFabio Piscaglia has received speaker and advisory board fees fromBayer and Luigi Bolondi has received speaker and advisory boardfees from Bayer and Bristol-Myers Squibb. Others have nothing todisclose.

Appendix A. Supplementary data

Supplementary material related to this article found, in theonline version, at http://dx.doi.org/10.1016/j.dld.2013.03.002.

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