the role of hepatic resection in the treatment of ...hepatobiliary malignancies the role of hepatic...

HEPATOBILIARY MALIGNANCIES

The Role of Hepatic Resection in the Treatment ofHepatocellular Cancer

Sasan Roayaie,1 Ghalib Jibara,2 Parissa Tabrizian,3 Joong-Won Park,4 Jijin Yang,5 Lunan Yan,6

Myron Schwartz,3 Guohong Han,7 Francesco Izzo,8 Mishan Chen,9 Jean-Fr�ed�eric Blanc,10 Philip Johnson,11

Masatoshi Kudo,12 Lewis R. Roberts,13 and Morris Sherman14

Current guidelines recommend surgical resection as the primary treatment for a singlehepatocellular cancer (HCC) with Child’s A cirrhosis, normal serum bilirubin, and noclinically significant portal hypertension. We determined how frequently guidelines werefollowed and whether straying from them impacted survival. BRIDGE is a multiregionalcohort study including HCC patients diagnosed between January 1, 2005 and June 30,2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718ideal resection candidates who were resected; (B) 144 ideal resection candidates who werenot resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170nonideal resection candidates who were not resected. Median follow-up was 27 months.Log-rank and Cox’s regression analyses were conducted to determine differences betweengroups and variables associated with survival. Multivariate analysis of all ideal candidatesfor resection (A1B) revealed a higher risk of mortality with treatments other than resec-tion. For all resected patients (A1C), portal hypertension and bilirubin >1 mg/dL werenot associated with mortality. For all patients who were not ideal candidates for resection(C1D), resection was associated with better survival, compared to embolization and“other” treatments, but was inferior to ablation and transplantation. Conclusions: Themajority of patients undergoing resection would not be considered ideal candidates basedon current guidelines. Not resecting ideal candidates was associated with higher mortality.The study suggests that selection criteria for resection may be modestly expanded withoutcompromising outcomes, and that some nonideal candidates may still potentially benefitfrom resection over other treatment modalities. (HEPATOLOGY 2015;62:440-451)

See Editorial on Page 340

The current European Association for Study ofthe Liver (EASL) and American Association forthe Study of Liver Diseases (AASLD) guide-

lines recommend resection as the primary treatment

for hepatocellular carcinoma (HCC) in patients with asingle tumor, Child class A liver function with totalbilirubin �1mg/dL, no evidence of clinically signifi-cant portal hypertension (CSPH), and excellent per-formance status.1,2 The criteria also require patients tohave no evidence of extrahepatic disease or invasion ofportal or hepatic veins on imaging.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; BCLC, Barcelona Clinic Liver Cancer; CSPH, clinically significant portal hyper-tension; EASL, European Association for Study of the Liver; HCC, hepatocellular carcinoma; HVPG, hepatic vein portal gradient; PH, portal hypertension; RFA,radiofrequency ablation; WHO, World Health Organization.

From the 1North Shore-LIJ Health Systems, Lenox Hill Hospital, New York, NY; 2Brookdale’s Medical Center, Department of Urology, Brooklyn, NY; 3MountSinai Medical Center, New York, NY; 4Center for Liver Cancer, National Cancer Center, Goyang, Korea; 5Department of Interventional Radiology, ChanghaiHospital, Second Military Medical University, Shanghai, China; 6Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China;7Department of Hepatology and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University,Xi’an, China; 8Hepatobiliary Unit, National Cancer Institute of Naples, G. Pascale Foundation, Naples, Italy; 9Department of Hepatobiliary Surgery, Sun Yat-senUniversity Cancer Center, Guangzhou, China; 10Hepatology and Digestive Oncology Unit, Hopital Saint-Andr�e, Bordeaux, France; 11University of Liverpool, Liv-erpool, United Kingdom; 12Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan; 13Division of Gastroenterologyand Hepatology, Mayo Clinic College of Medicine, Rochester, MN; 14University of Toronto and University Health Network, Toronto, Ontario, Canada

Received February 16, 2014; accepted February 6, 2015.The BRIDGE database and data collection were funded by Bristol-Meyers Squibb. Centers were provided with funds for entry of data. The analysis of the data

reported here and the preparation of the manuscript were not funded by any source or company.

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http://onlinelibrary.wiley.com/doi/10.1002/hep.27831/full

These guidelines are essentially based on a study from1999 that drew its conclusions from 77 patients under-going hepatic resection for HCC.3 In addition, theguidelines are centered on the concept of who would be“ideal” candidates for resection, thus yielding the highestsurvival for surgery as a treatment modality. The guide-lines do not base their recommendations on what treat-ment modality yields the best outcome in a particularindividual. Thus, whereas a patient may not be an idealcandidate for resection, surgery may still yield better out-comes for that individual than the alternative treatmentmodality proposed by the current guidelines.

It is unclear what proportion of HCC patients areactually treated according to these guidelines in real-world practice. Two Italian studies looking at adher-ence to HCC guidelines have found that the majorityof patients with HCC are not treated according toAASLD/EASL guidelines.4,5 A multinational studylooking specifically at resection of HCC had a popula-tion comprised of 36% Barcelona Clinic Liver Cancer(BCLC) B and 14% BCLC C patients.6

In addition, multiple studies have tried to show thatexpanding the guidelines to include patients with mul-tiple tumors, portal hypertension (PH), or Child’s Bliver function will not have an adverse effect on out-come.7-14 All of these studies have included a relativelysmall number of patients and based their conclusionson a lack of significance in univariate log-rank or mul-tivariate Cox’s analyses.

BRIDGE is a multiregional, longitudinal cohortstudy of newly diagnosed cases of HCC. Centers werefree to use whatever treatment algorithm they saw fit.We used data from this study to answer the followingquestions regarding resection:

1. In what proportion of cases are the guidelines followed?2. Does straying from the guidelines result in lower

survival?3. What factors are associated with mortality after

resection and can inclusion criteria be expandedwithout increasing mortality?

4. How does resection compare to other treatmentmodalities in patients who do not meet criteria forresection based on current guidelines?

Patients and Methods

The global HCC BRIDGE study is a multiregionallongitudinal cohort trial including patients newly diag-nosed with HCC between January 1, 2005, and June30, 2011, who are receiving treatment for HCC atsites in the Asia-Pacific, European, and North Ameri-can regions. The study recruited patients from 42 sitesand followed them until death or the data cut-off dateof March 1, 2012. Centers were provided funds fordata entry by Bristol-Meyers Squibb. This analysis ofthe data and preparation of the manuscript receivedno funding from any source. The treatments employedwere at the discretion of the centers. Requests to par-ticipate in the study were sent to all centers.

During the initial data collection, centers wereaudited after enrolment of 15 patients and againafter 50 patients to ensure accurate data entry. Dur-ing the audit, source data were reviewed and com-pared to entries in the BRIDGE database. All stagingwas entirely based on imaging data from multiphasecontrast enhanced computer-assisted tomography scanor magnetic resonance imaging. Pathological datawere not used in this analysis. Study coordinatorswere educated and repeatedly reminded that WorldHealth Organization (WHO) performance status wasto be determined based on tumor-related symptoms.

Ablation included both alcohol ablation as well asradiofrequency ablation (RFA). Embolization includedtransarterial chemoembolization as well as bland embo-lization. “Other” therapies included locoregional treat-ments, such as hepatic artery chemoinfusion withoutembolization, yttrium-90 radioembolization, and exter-nal beam radiation, as well as systemic treatments,such as sorafenib, erlotinib, bevacizumab, andadriamycin.

All treatments for each patient were recorded. Forthe purposes of this analysis, patients with multipletypes of treatments were categorized as the treatmentmodality with the highest likelihood of cure as follows:

Transplantation ! Resection ! Ablation ! Embo-lization ! Other.

Patients were divided into four groups as follows:

Address reprint requests to: Sasan Roayaie, M.D., North Shore-LIJ Health Systems, Lenox Hill Hospital, 110 East 59th St, Suite 10B, New York, NY 10022.E-mail: [email protected]; fax: 11-212-434-4177.

Copyright VC 2015 by the American Association for the Study of Liver Diseases.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.27745Potential conflict of interest: Dr. Park is on the speakers’ bureau for and received grants from Bayer. He consults for Taiho. Dr. Sherman consults for

Bristol-Myers Squibb, Eli Lilly, and Bayer.

HEPATOLOGY, Vol. 62, No. 2, 2015 ROAYAIE ET AL. 441

A. Ideal candidates resected. These patients wererequired to have a single tumor of any size onimaging with no evidence of extrahepatic spreadand no evidence of invasion of the hepatic or por-tal vein branches. They also were required to haveno evidence of CSPH defined as either splenomeg-aly, varices, or ascites on imaging or platelet count<100,000/lL. In addition, patients were requiredto have a WHO performance status of 0. Finally,all patients were required to have Child’s A liverfunction with total bilirubin �1 mg/dL. Allpatients in this group underwent resection. Sepa-rate analyses were also run, defining PH as bothplatelet count <100,000/lL and the presence ofsplenomegaly, varices, or ascites on imaging.

B. Ideal candidates not resected. This group was com-prised of patients who met criteria for group A, butwere treated with a modality other than resection.

C. Nonideal candidates resected. This group was com-prised of patients who underwent resection, butdid not meet the criteria for group A.

D. Nonideal candidates not resected. This group con-sisted of patients who did not meet criteria forgroup A and were treated with a modality otherthan resection.

The primary endpoint studied was survival. Survivalwas calculated using Kaplan-Meier’s method, andgroups were compared using the log-rank test for uni-variate analyses. Multivariate analyses were conductedwith step-down Cox’s proportional hazard regressionmodels. Variables entered into the model includedones that have been repeatedly shown to correlate withsurvival in HCC patients, those found significant onunivariate analysis, as well as those that were signifi-cantly different among the groups included in themodel.

Three multivariate models were constructed:

1. All patients who were ideal candidates for resec-tion—groups A1B.

2. All patients who were resected—groups A1C.3. All patients who were not ideal candidates for

resection—groups C1D.

Results

Of the 42 centers enrolling patients, 20 agreed tosubmit data for inclusion in this study. Of the 10,135patients, 1,479 were missing essential data that wouldnot allow them to be properly categorized into any ofthe four groups and were excluded from the analysis.Figure 1A demonstrates the distribution of the

patients. The majority of the patients (5,886; 68%)were enrolled from Asian centers, followed by 1,472(17%) from North American centers, and 1,298(15%) from European centers.

Patient demographics and clinical data are summarizedin Table 1. Median follow-up of patients was 27 months.There were 3,605 deaths during follow-up. There were atotal of 82 perioperative deaths within 90 days of surgeryamong all of the resected patients (groups A1C). The90-day perioperative mortality rate was significantly loweramong ideal candidates (group A) than among nonidealcandidates (group C; 9 of 718 [1.2%] vs. 73 of 1,624[4.5%]; P< 0.001). However, the rate of morbidity caus-ing prolongation of hospital stay was similar for ideal(group A, 7%) and nonideal candidates (group C, 8%)undergoing resection (P 5 0.734).

In What Proportion of Cases Are the Guidelinesfor Resection Followed?

Figure 1B demonstrates that, overall, more than80% of patients who met criteria as ideal candidateswere treated with resection. However, only one third ofpatients undergoing resection met criteria as appropri-ate candidates. These proportions varied considerablyamong the three different regions contributing patients.

Fig. 1. Flowchart of patients included within the study (A). Adher-ence to AASLD/EASL criteria by region (B).

442 ROAYAIE ET AL. HEPATOLOGY, August 2015

Table 1. Patient Demographics, Liver Disease, Tumor Characteristics, and Treatments

Variable n (%)

A Ideal Candidates

Resected (n 5 718)

B Ideal Candidates

Not Resected (n 5 144)

C Nonideal Candidates

Resected (n 5 1,624)

D Nonideal Candidates

Not Resected (n 5 6,170)

Age, years, mean (SD) 55 (13.4) 62(12.9) 55 (13.0) 59(12.6)

Median (Q1-Q3) 55 (45-65) 63 (54-73) 55 (45-64) 59 (51-68)

Range 19-90 24-88 18-85 18-91

Gender (male, %) 603 (84) 120 (83) 1,327 (82) 4,970 (81)

Liver disease (%)

None 64 (9) 19 (13) 155 (10) 401 (6)

HBV 501 (70) 67 (47) 1,043 (64) 3,066 (50)

HCV 78 (11) 35 (24) 281 (17) 1,357 (22)

Alcohol 24 (3) 13 (9) 63 (4) 580 (9)

Other 22 (3) 9 (6) 37 (2) 756 (12)

Missing: 85 29 (4) 1 (1) 45 (3) 10 (0.1)

Comorbidities (%)

Cardiovascular 51 (7) 21 (15) 169 (10) 849 (14)

Missing: 349 13 (2) 0 44 (3) 292 (5)

Diabetes 110 (15) 29 (20) 230 (14) 1,375 (22)

Missing: 296 14 (2) 0 47 (3) 235 (4)

Hypertension 191 (27) 56 (39) 395 (24) 1,878 (30)

Missing: 190 9 (1) 0 36 (2) 145(2)

Pulmonary 29 (5) 10 (7) 196 (12) 683 (11)

Missing: 378 11 (1) 11(8) 48 (3) 308 (5)

Renal 29 (4) 8 (6) 84 (5) 367 (6)

Missing: 445 16 (2) 10 (7) 59 (4) 360 (6)

Tumor size, cm, mean (SD) 5.5 (3.4) 4.7 (3.4) 6.0 (3.6) 5.6 (4.1)

Median (Q1-Q3) 4.6 (3.0-7.2) 3.7 (2.2-6.0) 5.0 (3.2-8.0) 4.1 (2.4-8.0)

Range 1.0-22.0 1.0-20.0 0.9-20.0 0.7-28.0

Missing: 761 (%) 8 (1) 6 (4) 102 (6) 645 (10)

Single tumor <2 cm (%) 86 (12) 28 (19) 101 (6) 659 (11)

Missing: 761 8 (1) 6 (4) 102 (6) 645 (10)

Multiple tumors (%) 0 0 425 (26) 2,526 (41)

Missing: 392 0 0 50 (3) 342 (6)

Gross invasion (%) 0 0 191 (12) 587 (10)

Missing: 161 0 0 20 (2) 141 (3)

Extrahepatic (%) 0 0 215 (13) 995 (16)

Missing: 995 0 0 24 (2) 971 (16)

AFP, ng/mL, mean (SD) 5,503 (20,549) 3,916 (25,765) 12,009 (114,531) 12,142 (170,871)

Median (Q1-Q3) 36 (5-672) 10 (4.8-98) 64 (7-1,210) 64 (10.0-944.5)

Range 0.6-178,518 0.7-248,750 0.5-3,011,250 0.6-12,223,000

Missing: 849 (%) 46 (6) 17 (12) 121 (7) 665 (11)

AFP >400 ng/mL (%) 253 (35) 31 (21) 517 (32) 1,797 (29)

Bilirubin mg/dL, mean (SD) 0.67 (0.19) 0.69 (0.19) 1.04 (1.20) 1.34 (1.81)

Median (Q1-Q3) 0.68 (0.50-0.81) 0.70 (0.55-0.84) 0.85 (0.6-1.2) 0.99 (0.70-1.46)

Range 0.2-1.0 0.2-1.0 1.0-7.8 0.1-43.2

Missing: 340 (%) 0 0 29 (2) 311 (5)

Creatinine mg/dL, mean (SD) 0.95 (0.44) 0.96 (0.58) 0.90 (0.29) 1.12 (0.52)

Median (Q1-Q3) 0.90 (0.80-1.03) 0.87 (0.74-1.01) 0.89 (0.76-01.00) 1.00 (1.00-1.10)

Range 0.4—8.4 0.4-6.8 0.1-4.7 0.5-12.6

Missing: 611 (%) 0 8 (6) 55 (3) 548 (9)

INR, mean (SD) 1.03 (0.09) 1.05 (0.11) 1.07 (0.16) 1.15 (0.34)

Median (Q1-Q3) 1.02 (0.98-1.10) 1.00 (1.00-1.10) 1.05 (0.99-1.11) 1.10 (1.02-1.20)

Range 0.8-1.6 0.8-1.7 0.7-3.7 0.8-21.1

Missing: 710 (%) 0 0 58 (4) 652 (11)

Albumin g/dL, mean (SD) 4.2 (0.4) 4.0 (0.4) 4.0 (0.5) 3.8 (2.2)

Median (Q1-Q3) 4.2 (4.0-4.5) 4.1 (3.8-4.4) 4.1 (3.7-4.4) 3.8 (3.4-4.1)

Range 3.5-6.8 3.0-4.9 1.0-7.8 1.2-5.7

Missing: 490 (%) 0 0 87 (5) 403 (7)

Platelet 31,000/mL, mean (SD) 196 (66) 175 (61) 170 (93) 139 (85)

Median (Q1-Q3) 181 (147-230) 162 (121-214) 153 (103-215) 126 (82-189)

Range 101-656 100-380 11-850 4-507

Missing: 439 (%) 0 0 68 (4) 371 (6)

MELD, mean (SD) 7.5 (1.68) 7.7 (2.22) 8.2 (2.33) 9.7 (3.39)

Median (Q1-Q3) 7.5 (6.4-7.9) 7.4 (6.4-8.3) 7.5 (6.4-8.8) 8.8 (7.5-10.9)

Range 6-27 6-25 6-37 6-43


The most common area in which people strayedfrom the guidelines was by inclusion of patients with aperformance status >0, followed by resection ofpatients with PH (Table 1).

Does Straying From Guidelines Result in LowerSurvival?

Median survival was not reached for group A; the3- and 5-year survival rates were 74% and 65%.Group B also did not reach median survival and had3- and 5-year survivals of 55% and 55%. The mediansurvival for group C was 32.4 months, with 3- and 5-year survivals of 47% and 35% (Fig. 2A).

It is possible that some patients in group B werenot resected because of significant comorbidities. Tohelp address this issue, the 21 patients originallyincluded in group B who had cardiac comorbiditieswere reassigned to group D and survival was reex-amined; there was no appreciable change in outcomes(Fig. 2B).

Group C included patients with tumors at moreadvanced stages; thus, lead-time bias might explain thedecreased survival of this group. To help address this

issue, survival was compared among the three groupsincluding only the patients with BCLC stage Atumors. While the outcomes for groups A and Bremained unchanged, survival for group C improvedappreciably, but remained significantly lower thangroup A (Fig. 2C).

Multivariate analysis of all ideal candidates for resec-tion (groups A1B) revealed that treatments other thanresection were associated with a nearly 2-fold increasein risk of mortality (Table 2).

What Factors Are Associated With Mortality AfterResection and Can Inclusion Criteria BeExpanded Without Increasing Mortality?

Multivariate analysis of all patients undergoing resec-tion (groups A1C) confirmed that most factors typi-cally thought to be correlated with survival afterresection were indeed significantly associated with mor-tality (Table 2). However, in those undergoing resec-tion, PH alone, defined as the presence of eithervarices, splenomegaly, or platelet count <100,000/lL,but excluding those with ascites, was not associatedwith an appreciable decrease in survival either on uni-

TABLE 1. Continued

Variable n (%)

A Ideal Candidates

Resected (n 5 718)

B Ideal Candidates

Not Resected (n 5 144)

C Nonideal Candidates

Resected (n 5 1,624)

D Nonideal Candidates

Not Resected (n 5 6,170)

Missing: 934 (%) 0 8 (6) 89 (5) 837 (13)

Child’s Class (%)

A 718 (100) 144 (100) 1,388 (85) 4,219 (68)

B 0 0 113 (7) 981 (16)

C 0 0 2 (0.1) 95 (2)

Missing: 996 0 0 121 (8) 875 (14)

PH (%) 0 0 595 (37) 3,507 (57)

Missing: 231 0 0 0 231 (4)

Varices/splenomegaly 0 0 347 (21) 2,262 (37)

imaging (%) 0 0 68 261

Missing: 329

WHO performance status (%)

0 718 (100) 144 (100) 772 (48) 535 (9)

1-4 0 0 798 (49) 5,142 (83)

Missing: 549 0 0 56 (3) 493 (8)

BCLC stage (%)

A 718 (100) 144 (100) 448 (28) 317 (5)

B 0 0 110 (7) 40 (1)

C 0 0 969 (60) 5,213 (84)

D 0 0 41 (3) 173 (3)

Missing: 483 0 0 56 (4) 427 (7)

Treatments (%)

Resection 718 (100) 0 1,624 (100) 0

Ablation 0 68 (47) 0 1,917 (31)

Transplant 0 9 (6) 0 515 (8)

Embolization 0 61 (42) 0 3,569 (57)

Others 0 6 (4) 0 169 (3)

Abbreviations: SD, standard deviation; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; INR, international normalized ratio; MELD, Model for

End-Stage Liver Disease.


or multivariate analyses (Table 2; Fig. 3A). In patientswith Child’s A liver disease undergoing resection, plate-let count ranged from 11,000 to 817,000/lL, withonly 38 patients having a platelet count <50,000/lL.

Expansion of criteria to include more-severe liver dys-function (Fig. 3A), advanced tumor characteristics (Fig.3B), or compromised performance status (Fig. 3C) wasassociated with a significant detrimental effect on survival.

Resection of otherwise ideal candidates, but withtotal bilirubin over 1 mg/dL, did not have an appreci-able impact on survival. The range for total bilirubinin this group was 0.2-2.2 mg/dL, with only 8 patientshaving total bilirubin >2 mg/dL. Figure 4A showsthat, in patients who were otherwise ideal candidatesfor resection, a total bilirubin cutoff of 1 mg/dL hadno correlation with survival. However, if the criteriawere slightly expanded to also include patients withPH, then a total bilirubin cutoff of 1 mg/dL played amore discriminatory role (Fig. 4B). Thus, either PHalone or elevated total bilirubin alone had minimaleffects on survival, but the presence of both wasdetrimental.

A total of 3,103 patients were found to have PHwhen defined as the presence of both platelet count<100,000/lL as well as imaging findings of spleno-megaly, varices, or ascites (missing 5 439). Thepatient flow diagram and results of univariate analy-ses of survival when defining PH as both the pres-ence of imaging findings and platelet count<100,000/lL are displayed in Fig. 5. Likewise, theresults of the multivariate analysis of all resectedpatients (groups A1C) using this definition of PHare listed in Table 2. There was no meaningful dif-ference in outcomes when using the varying defini-tions of PH. Median survival after resection forpatients with PH who were otherwise ideal candi-dates was 48 months, irrespective of which definitionof PH was used.

How Does Resection Compare to Other TreatmentModalities in Patients Who Do Not Meet Criteriafor Resection Based on Current Guidelines?

Multivariate analysis of all patients who were notideal candidates for resection (groups C1D) revealedthat age >70 years along with the typical tumor char-acteristics and markers of liver function correlated sig-nificantly with mortality (Table 2). However, thepresence of multiple tumors was not significantly asso-ciated with survival in these patients. Multivariate anal-ysis of this same group of patients was conducted,substituting BCLC class for its individual components,Child’s class, gross vascular invasion, and performancestatus. BCLC stage was independently associated withoutcome, but the other results remained unchanged(Table 3).

In these patients, none of whom met criteria as idealcandidates for resection, surgery was associated withlower mortality, when compared to embolization and“other” treatments when controlling for variables thatsignificantly impact survival of HCC patients. However,

Fig. 2. Survival curves of patients stratified by whether they metAASLD/EASL criteria for resection and type of treatment used. Allpatients (A). Patients with cardiac comorbidities in group B removed(B). Including only BCLC A patients (C).


surgery fared worse than ablation and transplantation inthe same population on the multivariate analysis.

Discussion

The vast majority of patients with HCC who meetthe EASL/AASLD criteria for resection are treated withsurgery. However, it seems that the majority of patients,roughly two thirds, of those undergoing resection donot meet these criteria. It seems that the most commonareas where clinicians stray from the current recommen-

dations are by inclusion of patients with a performancestatus >0 and inclusion of patients with PH.

It would appear that the EASL/AASLD guidelinesfunction well in fulfilling the role for which they weredesigned, identifying those who will have the best out-comes after resection. In fact, median survival was notreached in ideal patients undergoing hepatic resection.In addition, it seems that straying from EASL/AASLDguidelines for resection, either by resecting nonidealcandidates or denying surgery to ideal ones, was associ-ated with a significant decrease in median survival.

Table 2. Multivariate Analyses of Survival

Hazard Ratio 95% Confidence Interval P Value

All ideal candidates for resection (groups A1 B), n 5 862

Age >70 years 1.068 0.655-1.740 0.792

Cardiac comorbidity 1.158 0.655-2.134 0.655

AFP >400 ng/mL 1.566 1.085-2.261 0.017

Treatment other than resection 2.068 1.349-3.170 <0.001

Tumor size >3 cm 3.041 1.781-5.193 <0.001

All resected patients (groups A1C), n 5 2,342: PH defined as presence of either imaging findings (splenomegaly, varices, and ascites) or platelet count

<100,000/lL

Age >70 years 0.984 0.755-1.281 0.902

PH 1.170 0.959-1.427 0.123

Multiple tumors 1.278 1.036-1.576 0.022

AFP >400 ng/mL 1.445 1.207-1.730 <0.001

WHO performance >0 1.503 1.375-1.644 <0.001

Extrahepatic tumor 1.513 1.167-1.961 0.002

Gross vascular Invasion 1.783 1.373-2.315 <0.001

Tumor size >3 cm 1.839 1.482-2.415 <0.001

Child’s B or C (only 2 patients Child’s C) 1.923 1.446-2.558 <0.001

All resected patients (groups A1C), n 5 2,342: PH defined as presence of both imaging findings (splenomegaly, varices, and ascites) and platelet count

<100,000/lL

Age >70 years 1.083 0.832-1.410 0.555

PH 1.237 0.973-1.571 0.082

Multiple tumors 1.346 1.095-1.654 0.005

AFP >400 ng/mL 1.435 1.198-1.719 <0.001

WHO performance >0 2.300 1.923-2.750 <0.001

Extrahepatic tumor 1.558 1.209-2.008 <0.001

Gross vascular Invasion 1.759 1.357-2.280 <0.001

Tumor size >3 cm 1.817 1.425-2.316 <0.001

Child’s B or C(only 2 patients Child’s C) 1.750 1.311-2.337 <0.001

All nonideal patients (groups C1D), n 5 7,794

Age >70 years 1.314 1.175-1.470 <0.001

Multiple tumors 1.0256 0.967-1.154 0.226

PH 1.109 1.013-1.215 0.026

Gross vascular invasion 1.353 1.198-1.528 <0.001

AFP >400 ng/mL 1.4216 1.292-1.551 <0.001

Extrahepatic tumor 1.563 1.408-1.735 <0.001

Child’ class (reference 5 A)

B 1.581 1.419-1.763 <0.001

C 1.855 1.299-2.648 <0.001

Tumor size >3 cm 1.728 1.543-1.963 <0.001

WHO performance >0 2.158 1.858-2.507 <0.001

Treatment (reference 5 resection)

Embolization 1.257 1.109-1.429 <0.001

Ablation 0.843 0.722-0.981 0.029

Transplant 0.189 0.133-0.271 <0.001

Other 1.782 1.334-2.383 <0.001

Abbreviation: AFP, alpha-fetoprotein.


Expansion of criteria along the lines of tumor char-acteristics, liver function, and performance status wasassociated with a significantly lower survival, evenwhen limiting analysis to BCLC stage A patients. Like-wise, subjecting patients who were ideal candidates for

resection to a treatment other than hepatectomy wasalso associated with a 2-fold increase in risk of death,even when taking into account the presence of cardiaccomorbidities.

Our analyses did reveal that there may be modestroom for expansion of criteria for resection withoutany appreciable compromise in survival. We foundthat patients with Child’s A liver disease and moderatePH had essentially the same survival after resection asthose without PH. It is very important to point outthat our definition of CSPH, platelet count<100,000/lL or presence of splenomegaly and/or vari-ces on imaging, is different than the one used byEASL/AASLD guidelines, with hepatic vein portal gra-dient (HVPG) �10 mmHg.2 However, data areemerging that there is, in fact, good correlationbetween HVPG and platelet count as well as withimaging findings of PH.15

Fig. 3. Survival for patients undergoing resection stratified by liverfunction (A), tumor characteristics (B), and WHO performance status(C). Abbreviation: HTN, hypertension.

Fig. 4. Survival for ideal candidates undergoing resection stratifiedby total bilirubin (Bili) cutoff at 1 mg/dL (A). Survival of Child’s Apatients with PH undergoing resection stratified by total bilirubin cutoffat 1 mg/dL (B). Abbreviation: HTN, hypertension.


Many, if not most, centers do not routinely performvenous pressure measurements and rely instead on theuniversally available surrogates of platelet count,splenomegaly, and varices to determine the presenceand degree of PH. In fact, of the 13 referral centersrepresented by the authors in this article, only oneroutinely measures HVPG before hepatectomy forHCC. Thus, it seems that the current EASL/AASLDrecommendations are based on a definition of PH thatis not used by a large proportion of centers treatingHCC. Perhaps future versions of EASL/AASLD guide-lines can incorporate these more widely used, noninva-sive methods for assessing PH.

Whereas it seems that many centers are alreadyoffering hepatectomy to such patients, formallyexpanding resection criteria to include those withmoderate PH, with a limit of platelet count above50,000/lL and without ascites, would increase thepool of ideal candidates by approximately 60%. It isdifficult to comment on expansion beyond this limitowing to such a small number of patients with plateletcount below this level in our cohort. These results

were consistent across two separate definitions of PH,one defining PH as the presence of either imagingfindings of PH or platelet count <100,000/lL whereas

Fig. 5. Figures based on a definition of PH that required both platelet count <100,000/lL and imaging findings of PH (varices, splenomeg-aly, or ascites). Flowchart of patients included within the study (A). Survival curves of patients stratified by whether they met AASLD/EASL criteriafor resection and type of treatment used. All patients (B). Including only BCLC A patients (C). Survival for patients undergoing resection stratifiedby liver function (D). Abbreviation: HTN, hypertension.

Table 3. Multivariate Analysis of Survival of All Patients ThatAre Not Ideal candidates for Surgery*

Hazard

Ratio

95% Confidence

Interval P Value

Age >70 years 1.2237 1.119-1.369 <0.001

Multiple tumors 1.034 0.954-1.119 0.416

PH 1.156 1.068-1.2751 <0.001

AFP >400 ng/mL 1.515 1.398-1.642 <0.001

Tumor size >3 cm 1.770 1.597-1.961 <0.001

BCLC stage (reference 5 A)

B 1.431 1.039-2.019 0.039

C 2.4319 1.905-2.823 <0.001

D 5.612 4.272-7.371 <0.001

Treatment (reference 5 resection)

Embolization 1.431 1.271-1.611 <0.001

Ablation 0.849 0.737-0.979 0.022

Transplant 0.195 0.141-0.272 <0.001

Other 1.784 1.358-2.344 <0.001

Groups C1D, n 5 7,794, with BCLC stage in place of Child’s class, gross vas-

cular invasion, extrahepatic disease, and performance status.

Abbreviation: AFP, alpha-fetoprotein.


the second definition required the presence of bothcriteria.

A recent meta-analysis by Berzigotti et al. alsolooked at the role of PH in the outcomes after resec-tion of HCC, but drew a very different conclusion.16

They found PH as significantly associated with mortal-ity after hepatic resection. The definition of PH usedin the study was slightly different than the ones usedhere. In addition, the Berzigotti et al. study was ameta-analysis spanning 17 years whereas the studyreported here is based on individual patient data overa much shorter, more contemporary period. Whereassome of the differences in the conclusions can beattributed to differences in definition and study design,it is clear that the role of PH in outcomes after resec-tion of HCC remains a topic of debate.

We also discovered that, in otherwise ideal candi-dates, a bilirubin cutoff of 1 mg/dL resulted in noappreciable difference in survival after resection. Again,formal expansion of criteria to include patients withmild elevation of bilirubin up to 2 mg/dL would allowfor approximately 25% more patients to undergoresection without any loss in long-term outcome.Again, our data do not allow us to comment onexpansion beyond this cutoff.

However, it seems that, in the context of PH, a bili-rubin cutoff of 1 mg/dL does have the ability to strat-ify patients in terms of survival after resection. Thus,whereas expansion along each variable by itself, in oth-erwise ideal resection candidates, did not worsen out-comes after surgery in our study, the combination ofthe two does seem to yield significantly lower survival.

Another point on which to caution readers isregarding the lack of data on the extent of resection.Thus, it is possible that patients with PH or elevatedbilirubin had more-limited resections than those with-out. We simply do not know. However, we must keepin mind that the current guidelines do not allow foreven limited resections in such patients. The data fromthe BRIDGE study clearly demonstrate that safe resec-tion with excellent outcomes is possible for patientswith moderate PH or for those with slightly elevatedbilirubin, but not both. Unfortunately, BRIDGE doesnot allow us to define the extent of a safe resection.Clearly, clinical judgment will be paramount in select-ing these patients for surgery.

A far more complex issue than which patients willachieve the best outcomes with resection is the ques-tion of which treatment modality would be best to usefor patients who are not considered ideal candidatesfor hepatic surgery. The current guidelines are basedon the principle of selecting candidates who will

achieve the best results with surgical resection, not onselecting the treatment that yields the best results in aparticular patient. Thus, whereas a patient may not bean ideal candidate for resection, surgery may still yieldthe best survival of all the available treatment strategies(Tables 2 and 3). Unfortunately, our data did notallow us to identify the characteristics of these patientsthat might benefit from surgery.

Our multivariate analysis of over 7,600 nonidealpatients (groups C1D) seemed to support the major-ity of the currently endorsed treatment algorithm.Those patients who are not ideal candidates for hepaticresection are better served by transplantation or abla-tion. In fact, transplantation was associated with a 5-fold decrease in mortality, compared to hepatectomy,in patients that did not meet AASLD/EASL criteriafor resection. Though it true that this was not exam-ined on an intention-to-treat basis, the inclusion ofdropouts is unlikely to completely eliminate such alarge hazard-ratio benefit. Nevertheless, our resultsshow that the applicability of transplant is quite lim-ited, given that transplantation accounted for only 7%of treatments in this group of patients.

The relative roles of resection and ablation as first-line treatments have been debated, even among HCCpatients who would meet AASLD/EASL criteria forsurgery. Three randomized trials have provided con-flicting results.17-19 Again, our study seems to suggestthat hepatic resection is the best choice in suchpatients, corroborating the findings of a large cohortstudy recently published from the Japanese nation-wide survey.20 However, our study also finds that noni-deal surgical candidates may be better served withablation, rather than resection, and that ablation seemsto be a much more widely applied treatment modality,compared to transplantation, for this group ofpatients.

A more unexpected finding was that resection ofsuch nonideal patients yielded better outcomes thanembolization and “other” treatments. These findingswill undoubtedly lead to significant debate, but areconsistent with some previously published studies sup-porting resection over embolization.21-23 More impor-tant, a recent randomized trial comparing resectionwith arterial embolization for patients with BCLC BHCC found a significant survival advantage with sur-gery.24 These findings will certainly bring into ques-tion the role of transarterial chemoembolization intreatment of patients with BCLC stage B tumors.

There are some obvious shortcomings of this studythat must be acknowledged. Perhaps the most limitingdeficiency is the short follow-up of 27 months. This


results in the survival data being reliable only toapproximately 36 months, after which less than 10%of the population remains at risk. As a result, conclu-sions regarding long-term survival are not possible.Nevertheless, the large number of patients allows us toreach robust conclusions regarding intermediate out-comes. Another limitation was the lack of a uniformtreatment algorithm used across the centers. However,this particular aspect of the study does allow us tocompare similar patients that were treated with differ-ent modalities at different institutions. Finally, therewas no uniform standard technique used for the vari-ous treatment modalities at the various centers. Forinstance, whereas one center may use drug-elutingbeads for embolization, another may still be using gel-atin foam and lipiodol. There is no easy way to sur-mount this particular limitation other than relying onthe very large sample size to overcome the heterogene-ity of technique within each of the various treatmentsused. As with any large database study, it is impossibleto determine exactly how certain treatment decisionswere made. Though we have attempted to correct forthis to the best of our abilities by running a separateanalysis excluding patients with cardiac comorbidities,it is certainly possible that patients were assigned to aparticular treatment for reasons not obvious fromreview of the data.

In summary, our analysis of over 8,500 patientsundergoing treatment for HCC yielded importantinsights into the role of hepatic resection. It appearsthat, though a relatively rare event, approximately20% of candidates who meet current EASL/AASLDcriteria for resection are denied surgery, and this courseof action is associated with a 2-fold increase in mortal-ity. A much more common practice is to offer surgeryto patients beyond the recommended criteria. In fact,the majority of patients in all regions undergoingresection did not meet AASLD/EASL criteria. Ourstudy suggests that the current AASLD/EASL criteriamight be expanded to include patients with eithermoderate PH or slightly elevated total bilirubin>1 mg/dL, but not both, without any appreciableincrease in mortality. However, expansion of criteriaalong other lines, such as tumor characteristics, liverfunction, and performance status, is associated withsignificantly lower survival. Finally, for patients whodo not meet AASLD/EASL criteria for surgery, resec-tion may still associated with longer survival, whencompared to embolization and “other” treatments,and shorter survival, in comparison to ablation andtransplantation, when controlling for other relevantfactors.

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