Hepatocellular Carcinoma 2009

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Hepatocellular Carcinoma:
Current Management
urgical Therapy for Hepatocellular Carcinomahe age-adjusted incidence of hepatocellular carcinoma (HCC) has

ripled in the United States over the past 2 decades, fueled by the dramaticncrease of hepatitis C during that same time period. Currently, there aren estimated 3 million people with chronic hepatitis C and 1.2 millionith chronic hepatitis B in the United States. These patients are estimated

o develop HCC at a rate of 0.5% to 5% per year.1 The incidence of HCCn the United States still lags behind many parts of the world whereepatitis B is endemic, such as China, Southeast Asia, and southernfrica. Worldwide, HCC is the third most common cause of cancer death

nd there are an estimated 1 million cases worldwide.2 The medianurvival in unresectable cases is less than 4 months and under a year forntreated patients with less advanced disease.3-7 Fortunately, the long-erm survival rates from HCC in the United States have doubled over theast 2 decades, and a part of this increase is likely due to advances inurgical therapy for HCC, particularly as cancers are being detectedarlier and therefore are still localized.8 Both surgical resection andransplantation are highly effective in the treatment of patients withocalized HCC. Typically these surgical modalities complement eachther, as patients with preserved liver function are candidates foresection and those with poor underlying liver function would be directedoward transplantation. However, their relative roles in the treatment ofCC have generated quite a bit of debate. Ultimately, as the multitude of

reatment modalities proliferate, HCC must be treated in a multidisci-linary fashion, involving hepatologists, oncologists, surgeons, radiolo-ists, and pathologists, to come up with the best treatment plan for anyndividual patient.

iagnosisThe diagnosis of HCC is typically made because of symptomatic
isease or through screening of at-risk patients. Screening of high-risk
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atients involves the measurement of tumor markers such as alpha-etoprotein (AFP), as well as periodic radiographic imaging modalitiesuch as ultrasound (US), computed tomography (CT), and magneticesonance imaging (MRI). Although the sensitivity and specificity oferum AFP are only approximately 50% and 80%, respectively, an AFPevel greater than 200 ng/dL is highly suspicious for HCC.9-12 Althoughhe cost effectiveness of intensive screening is debatable,13 severaluthors have reported that 30% to 60% of patients are found withesectable disease at the time of diagnosis, which is nearly double the ratencountered in an unscreened population. Furthermore, those patientsho undergo intensive screening appear to have an improved long-term

urvival.14-16 Because of the characteristic imaging findings of tumors onynamic, contrast-enhanced CT scans and MRIs, the diagnosis of HCC isften possible without the need for biopsy. The classic finding of earlyrterial phase enhancement and contrast washout on the delayed venousmaging is highly specific for HCC. A mass larger than 2 cm in a patientith an AFP level greater than 200 ng/dL is also considered diagnostic ofCC. In at-risk patients with a newly discovered mass without typical

rterial enhancement or elevated AFP, a biopsy is recommended.17

valuating Hepatic ReserveOnce a diagnosis of HCC has been made, the next most relevantetermination is the severity of underlying liver dysfunction, since morehan 80% of patients with HCC will have some degree of cirrhosis.18 Theost common way to stratify patients according to hepatic reserve is thehild-Pugh classification. A normal liver can tolerate a resection of up to0% of the parenchyma with regeneration occurring within weeks. Ineneral, a Child A patient can be considered for resection of up to 50%f the liver parenchyma, a Child B patient, 25%, and a Child Classification would be a contraindication to resection.19,20 Child classi-cation, in combination with clinical assessment, and biochemical blood

ests (liver function tests [LFT], coagulation profile, and platelet count)rovide the most simple, reliable, and reproducible method to identifyatients at risk for liver insufficiency.21,22 Other investigators havetilized the Model of End-Stage Liver Disease (MELD) score, developedo quantify liver insufficiency before transplantation, as an assessment ofiver reserve before resection as well, and have found it to be anndependent predictor of perioperative mortality and long-term sur-ival.23,24 However, Schroeder and colleagues found that the American
ociety of Anesthesiologists (ASA) class and Child class were superior to
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ELD score in predicting postsurgical mortality in patients with cirrhosisndergoing resection for HCC.25

Indocyanine green (ICG) is an anionic dye cleared by hepatocytes andxcreted in bile. The clearance of ICG from the bloodstream at 15 minutess used as a measure of hepatocyte function.26 In a normal liver, the valuehould be less than 10% retention, and a value above 15% to 20%etention is abnormal, demonstrating liver insufficiency. A value of 40%etention at 15 minutes demonstrates severe liver dysfunction, suggestinghat any type of resection would not be tolerated.27,28 Clinically relevantortal hypertension is also defined as a hepatic venous wedge pressurereater than 10 mm Hg, splenomegaly with a platelet count less than00,000, or esophageal varices. Other less commonly used tests includehe galactose elimination capacity and the technetium-99m-labeled asia-oglycoprotein receptor quantity.29,30 Unfortunately, none of these meth-ds of determining hepatic reserve is ideal, nor is there any test that isonsidered standard. None can accurately assess all of the numerousunctions of the liver completely, nor has any single test been demon-trated to be superior to another in evaluating hepatic reserve orredicting postoperative outcome.

tagingAs opposed to other malignancies, long-term survival in patients withCC depends on both pathologic stage of the disease as well as severityf underlying liver dysfunction, and therefore, an ideal staging systemould take into consideration both pathological and clinical factors.nfortunately, the exact interaction between tumor and liver disease on

ong-term patient outcome has never been well established, and there iso one standard staging system. Furthermore, variations between geog-aphy, etiology of disease, and genetic factors can make this standard-zation more difficult. By far, the most widely used staging system forCC is the American Joint Committee on Cancer (AJCC) TNM (tumor,ode, metastasis) staging system31 (Table 1). This classification systemategorizes patients based on tumor size, number, vascular invasion,egional node status, and distant metastases. It follows the TNM model ofther cancers, but requires tissue for adequate staging. The Okuda stagingystem, proposed by Okuda and colleagues in 19857 was the first stagingystem to include variables of liver function such as ascites, albumin, andilirubin levels in addition to tumor size. An alternative system wasreated in 1998 by the Cancer of the Liver Italian Program Investigators
CLIP), which incorporates Child stage, tumor morphology, AFP levels,

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nd the presence of portal vein thrombosis (PVT).32 The Japan Integratedtaging Score from the Cancer Study Group of Japan combines Childtaging with a modified TNM staging and incorporates measures ofunctional capacity as well.33 Some investigators have proposed using the

ELD score as a predictor of long-term outcome itself; however, it is aurely clinical scoring system that does not take tumor characteristics intoccount. Despite this, the MELD score has been demonstrated to predictoth immediate postoperative outcome as well as long-term survivalollowing hepatic resection.23,24,34,35 Other classifications include thehinese University Prognostic Index (CUPI), simplified Vauthey staging,nd the Barcelona Clinic Liver Cancer (BCLC) staging classification. TheCLC system uses tumor characteristics and clinical features and links

hese data to suggested treatment modalities and their associated lifexpectancies. The American Association for the Study of Liveriseases (AASLD) has adopted the BCLC algorithm as part of itsractice guidelines.36 The American Hepato-Pancreato-Biliary Asso-iation has recommended the use of CLIP for clinical staging and

ABLE 1. American Joint Committee on Cancer TNM staging system for hepatocellular cancer

Stages for hepatocellular carcinoma

TumorT: Primary tumorTx: Primary tumor cannot be assessedT0: No evidence of primary tumorT1: Solitary tumor without vascular invasionT2: Solitary tumor with vascular invasion or multiple tumors, none �5 cmT3: Multiple tumors �5 cm or tumor involving major branch or portal or hepatic veinT4: Tumor with direct invasion of adjacent organs

NodeN: Regional lymph nodesNx: Regional lymph nodes cannot be assessedN0: No regional lymph node metastasisN1: Regional lymph node metastasis

MetastasisM: Distant metastasisMx: Distant metastasis cannot be assessedM1: Distant metastasis

StagingStage I: T1N0M0Stage II: T2N0M0Stage IIIA: T3N0M0Stage IIIB: T4N0M0Stage IIIC: Any T, N1M0Stage IV: Any T, any N, M1

JCC for pathological staging.37


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urgical TreatmentThe primary goal of therapy for HCC is to improve long-term survival

n patients amenable to surgical therapy and possibly affecting cure,hether it is via resection or transplantation. Nonsurgical therapies such

s radiofrequency ablation (RFA), cryoablation, microwave coagulation,ercutaneous ethanol injection (PEI), and transarterial embolization haveraditionally been used for local tumor control, particularly as a bridge toransplantation as well as for palliation. These modalities will beiscussed further in the last section. More recently data have suggestedhat RFA can potentially be as effective as surgery, and potentiallyurative for small HCC. These data are provocative, but need to beonfirmed on a larger scale before RFA can be considered a substitute forurgical therapy for HCC. Until then, surgical resection and transplanta-ion can be considered the only potentially curative therapies in thereatment of HCC.

iver ResectionAdvances in surgical technique, anesthetic management, intraoperativeS, and intensive care unit (ICU) care have improved the ability toerform surgical resection for HCC. Despite these advances, only 15% to0% of patients with HCC are operative candidates, due to advancedisease, extrahepatic metastases, or inadequate liver reserve althoughhese numbers nearly double with intensive screening.38 For those whore candidates for surgical resection, operative mortality is typically lesshan 5% and the 5-year survival rate is 40% to 70% depending on thetage of disease (Table 2). Determining who qualifies as a resectionandidate can vary from surgeon to surgeon, as the modality of assess-ent of liver dysfunction varies, and there are institutional, regional, and

ndividual surgeon biases. For example, portal hypertension clearlyffects postoperative complications and long-term survival,51 and someroups, including the Barcelona group, have advocated that any clinicalvidence of portal hypertension be a contraindication to surgical resec-ion. Others have demonstrated that portal hypertension alone should note a contraindication to resection, with Ishizawa and colleagues demon-trating a 5-year survival rate as high as 68% in selected patients withortal hypertension.52,53 Although the type of resection in this populationf patient tends to be limited to less than 2 segments, with good surgicaludgment and reasonable hepatic reserve, portal hypertension alone mayot be a contraindication to resection, but rather represents additional data
hat influences the size and scope of resection possible.

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One of the ways to increase the safety of resection and expand the poolf patients eligible is portal vein embolization (PVE). PVE is a techniquesed to occlude the portal inflow to the portion of liver that is destined toe removed, inducing hypertrophy in the portion of liver that will be leftehind, known as the future liver remnant, over the period of 3 to 4eeks.54 Although typically a procedure performed by interventional

adiology using a percutaneous, transhepatic approach, the occlusion origation can also be performed open or laparoscopically at the time ofnother operation. In a cirrhotic liver, where only up to 40% of the liveran be resected, PVE increases the ability to resect the liver safely,educing the incidence of complications, and decreasing the length of stayompared with patients without PVE.55-57

Resection for Early HCC. The reported survival rate following resec-ion of HCC is approximately 40% to 70% in most series depending onhe stage of disease and the amount of liver dysfunction (Table 2). A

ABLE 2. Results of resection for hepatocellular carcinoma

Author NOperative

mortality (%) 1 yearSurvival3 years 5 years

kuda, 19857 153 30 30 15 12apan Liver Survey, 1994*39 468 — 76 55 45

3500 — 76 52 36ismuth, 1993, 199540,41 68 3 74 52 40

60 10 80 52 —ong, 199942 54 3.7 83 58 42

100 5 77 47 37razi, 200143

Before 1992 107 9.3 — 53 32After 1992 157 1.3 — 72 49

oon, 200244

Milan Criteria 135 4 90 76 70snaola, 200345

USA 169 5.3 31France 187 6.4 31Japan 230 3.5 41

ha, 200346

Milan Criteria 36 2.8 85 74 69Ouside Milan 144 5 70 44 31u, 200547 105 1 86 70 55uzzo, 200748 113 3 44

24 (10 years)atz, 200949 192 4.6 75 56 41

23 (10 years)athan, 2009 SEER50 788 39

Multi-institutional series.

ecent study by Katz and colleagues found the median overall survival


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OS) rate following resection was 40 months and the proportions ofatients alive at 5 and 10 years were 41% and 23%, respectively. Theedian disease-specific survival (DSS) and recurrence-free survival

RFS) were 54 and 22 months, respectively. After resection of HCC, 76%f patients developed tumor recurrence by 5 years and 83% were foundo have recurrent disease at 10 years.49 Nathan and colleagues reviewedhe Surveillance, Epidemiology and End Results (SEER) database anddentified 788 patients with HCC smaller than 5 cm who underwentesection.50 The authors found 5-year survival to be 39%, with tumor sizereater than 2 cm, multifocality, and vascular invasion predicting worseurvival; patients with all 3 factors still had a 5-year survival rate of 29%.n carefully selected patients with good prognostic factors such as noascular invasion by tumor, solitary lesions without intrahepatic metas-asis, tumor diameter smaller than 5 cm, and negative surgical margins,-year survival rates as high as 78% following resection have beeneported.58-60

Recurrence after Resection. Recurrence of HCC following resection islearly a common occurrence, with 50% to 80% of patients experiencingecurrence by 5 years after resection, and the majority within 2 years.46,61

he mechanism is typically not an inadequate resection, but rather deovo tumor formation in the cirrhotic liver, or intrahepatic metastases thatere too small to be detected/identified at the time of resection. Tumor

haracteristics associated with recurrence include tumor size, number,ascular invasion, cirrhosis, and elevated AFP.46,62,63 When HCC doesecur, it typically returns in the liver alone,63,64 with one large seriesemonstrating that 86% of recurrences were isolated to the liver only.onsequently, liver-directed therapies are often successful in recurrentisease. In particular, re-resection of HCC has been associated withong-term outcomes similar to primary resection of HCC, with 5-yearurvival rates reported up to 56%.65-70

Resection for Advanced HCC. With regard to patients with largeumors and preserved liver function, there are no other curative optionsvailable other than resection, as transplantation is contraindicated. Onef the criticisms of the BCLC algorithm for treatment of patients withCC is that there is no treatment designated for patients with tumorsreater than 5 cm in size with good hepatic reserve. Although patientsith larger tumors are more likely to have occult vascular invasion,

urvival following resection is similar to small tumors when vascularnvasion is not identified. The OS rate for patients with tumors greater
han 10 cm is still approximately 40% in several multi-institutional series,

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hich was not statistically different from survival in patients with tumorsmaller than 10 cm.71-74

Tumor multifocality is a prognostic factor often associated with lowerurvival, but does not exclude a good outcome in selected patients. Ineveral studies, resection of multifocal HCC is associated with 5-yearurvival rates of approximately 24%.75,76 Lymph node metastases havelso been associated with lower long-term survivals in patients withCC.77,78 Routine lymphadenectomy is not recommended as part of

tandard resection, and enlarged periportal lymph nodes are often notedn preoperative imaging due to underlying hepatitis.Minimally Invasive Resections. Minimally invasive approaches to bothenign and malignant liver diseases are reported with increasing fre-uency and, as experience has increased, there has been interest to applyaparoscopic resection for HCC. A laparoscopic resection is especiallyppealing in patients with HCC, since they often cannot tolerate a majoriver resection due to hepatic insufficiency and are at risk for complica-ions of ascites and ensuing wound complications associated with a largepen incision. No prospective series is reported in the literature; however,n the largest published series, 116 patients underwent laparoscopic liveresection for HCC with the vast majority having less than 2 segmentsesected.79 There were no perioperative deaths, and the postoperativeomplication rate was less than 6%, with a 5-year survival rate ofpproximately 60%. In another series, the outcomes of 23 consecutiveirrhotic patients undergoing laparoscopic resection for HCC wereompared with a historical group of 23 patients who underwent openesection and were matched for age, gender, tumor location and size, andeverity of cirrhosis.80 One patient in the laparoscopic group wasonverted to an open procedure because of inadequate exposure. Theean operative time was longer in the laparoscopic surgery group (148

s. 125 minutes), whereas the frequency of intraoperative blood transfu-ion (0% vs. 17%), mean hospital stay (8.3 vs. 12 days), and postoperativeomplication rate (13% vs. 48%) were better in the laparoscopic group.erioperative mortality and 2-year survival rates were comparable in bothroups. The initial success encountered with laparoscopic resections inCC is largely due to the highly selected population of patients whondergo smaller, nonanatomic resections. This allows for resection inatients with marginal hepatic reserve who otherwise would not beligible. Clearly, more prospective data are needed; however, the prelim-nary results are encouraging, and it appears that, in experienced hands,
aparoscopic resection is feasible and safe. It is should be emphasized that

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aparoscopic resections for HCC are technically demanding and should bendertaken only with proper training and in high volume centers.

ransplantationThe idea of transplantation for HCC was initially proposed because, in

heory, it completely removes the tumor and underlying diseased liver,hile alleviating portal hypertension in the process. Initial investigatorsad to balance the unknown effect that immunosuppression would haven tumor growth with issues regarding the proper utilization of a limitedesource such as a deceased donor liver. Success was measured not onlyn demonstrating long-term survival, but the survival had to match theesults of transplantation in non-cancer-bearing patients with liver failure.he early experience with liver transplantation for HCC did not meet thistandard, with 5-year survival rates following transplantation of only 18%nd recurrence rates of approximately 50% at 2 years.81 However,ismuth and associates first recognized that patients with early or

ncidentally found HCC after transplantation had nearly equivalenturvivals as their non-HCC counterparts.40 This eventually led to theandmark study by Mazzaferro and colleagues, who demonstrated thatransplantation in patients with a solitary HCC lesion smaller than 5 cmn diameter or 3 tumors 3 cm or smaller (Milan Criteria) led to an OS ratef 75% at 4 years.82 On adopting these criteria, several investigators haveonfirmed this long-term survival benefit of transplantation, with 5-year

ABLE 3. Results of transplantation for hepatocellular carcinoma

Author N Notes

Operativemortality

(%)Recurrence

rate (%)Survival3 years 5 years

watsuki, 199187 105 — 57 39 36ismuth, 199340 60 5 54 47 —azzaferro,

19968248 6 — — 74 (4 years)

lovet, 199951 87 Intention to treatanalysis

— 10 69 69

emming, 200184 112 13 10 63 57ao, 200185 64 4.7 11 — 73e Carlis, 200383 121 4.5 10 62oo, 200386 Review of UNOS

Database45

1987 to 1991 270 25.31992 to 1995 282 46.61996 to 2001 433 61.1

NOS, United Network for Organ Sharing.

urvival rates reported at approximately 60% to 70%51,83-86 (Table 3).


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he United Network for Organ Sharing (UNOS) has adopted the Milanriteria and allocates organs based on the MELD scoring system. TheNOS criteria further specify that patients eligible for liver transplanta-

ion should not be resection candidates. Once they qualify for transplan-ation based on radiologic or pathologic criteria for diagnosis of HCC,atients are awarded MELD exception points (22 MELD points), pro-ided that they have at least a solitary lesion that is greater than 2 cm inize. Based on the 20% to 50% dropout rate seen at 1 year due torogression of disease,21,51 the patients are awarded an additional pointvery 3 months that they remain on the list until they receive theirransplantation. According to the UNOS Web site, in 2008, 18.1% of alliver transplantations performed in the United States were for HCC.88

Expanding Transplantation Criteria. Yao and associates85 from theniversity of California at San Francisco (UCSF) suggested a moderate

xpansion of the Milan criteria to include solitary tumors smaller than 6.5m or 3 or fewer nodules with the largest lesion less than 4.5 cm and totalumor diameter less than 8 cm. Using these UCSF criteria, the 5-yearurvival rate remained high at 75% after liver transplantation. A majorriticism of the UCSF study is that the results were based on tumorxplant characteristics, not preoperative imaging measurements. There-ore, Duffy and colleagues89 recently demonstrated that patients meetingCSF criteria had similar 5-year posttransplant survivals as patientseeting Milan criteria both by preoperative imaging (UCSF 64%, Milan

9%) and explant pathology (UCSF 71% vs. Milan 86%). These authorsave used these data to suggest that current transplantation criteria shoulde expanded. However, the current UNOS policy of limiting MELDoints to those patients with tumors larger than 2 cm as a consciousttempt to minimize the rate of overallocation of organs to patients withCC.90 Although some investigators feel the Milan criteria may be too

estrictive, potentially denying deserving patients access to transplanta-ion, the concern for the erosion of RFS rates and the understaging ofatients by pretransplantation imaging have dampened enthusiasm forxpansion of tumor guidelines. Although a moderate expansion of theilan criteria does not appear to significantly alter the long-term survival,

here is a trend toward increased recurrence and decreased survival,89 andertainly any expansion of criteria will increase the proportion of patientsith HCC receiving orthotopic liver transplantation, which already makesp nearly 20% of all liver transplantations currently performed in thenited States.Salvage Transplantation. Salvage transplantation has been proposed as
possible option for patients with recurrent disease following resection

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or HCC. Although it remains an unproven strategy, salvage transplan-ation may represent a practical means of rationing available organs.91

ome investigators have proposed this strategy as a feasible and cost-ffective approach that may provide a means of allocating organs to onlyhose patients requiring transplantation.92-94 The true practicality oferforming salvage transplantation is still a matter of debate.95-99 Al-hough some see this approach as essentially using resection as a “bridge”o transplantation, approximately one half to one quarter of patients whondergo resection will not recur, avoiding the potential complications ofiver transplantation and immunosuppression as well as preventing thennecessary utilization of a liver graft.Living Donor Liver Transplantation for HCC. Advances in livingonor liver transplantation (LDLT) over the past decade have made thisviable option for patients who otherwise face long waiting times for

eceased donor liver grafts. Several retrospective reviews have demon-trated that LDLT for HCC has a similar survival to that of deceasedonor transplantation.100-102 However, some authors have documented aigher rate of recurrence compared with deceased donor transplantationecipients.103-105 The reason for this is unknown, but perhaps it is due tohe 20% to 50% dropout rate seen in patients on the wait list for deceasedonor transplantation, which may serve to screen out biologically moreggressive tumors that would have had a propensity to metastasize orecur. Despite the paucity of data regarding live donor transplantation forCC, some surgeons are already advocating the expansion of UNOS

riteria for live donor transplantation to allow transplantation for largerumors.106,107 Clearly, the question of utilizing live donor liver transplan-ation for HCC remains unresolved and requires further prospectivenalysis.

ransplantation versus Resection for HCCThe debate regarding the most appropriate surgical therapy for a patientith early stage localized HCC is largely a nonissue, since most patientsho undergo resection are beyond the criteria for transplantation, andost patients transplanted for HCC have liver dysfunction that would not

llow for safe resection. A small proportion of HCC patients haveocalized disease and good enough hepatic reserve to be eligible for bothransplantation and the best primary therapy for these patients remainsnclear. The question is partially answered by the UNOS criteria forransplantation, which states that patients who are resection candidates arexcluded from eligibility for transplantation; however, the determination
f whether a patient is a candidate for resection can also be a source of

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ebate as well, as discussed above. There are no randomized controlledrials (RCTs) comparing resection and liver transplantation for thoseatients who would be eligible for both: those with small, early stageisease with good hepatic reserve. Proponents of resection for this patientopulation point to the equivalent long-term survival between resectionnd transplantation while avoiding the utilization of a scarce resource andvoiding lifelong immunosuppression. Proponents of transplantationoint to the high rate of recurrence in stage-matched resection patientsndergoing resection. Transplantation is clearly associated with a muchower rate of recurrence (approximately 10%) and Schwartz notedecently that the disease-free survival following transplantation for HCCppears to level off at approximately 5 years, whereas following resec-ion, the disease-free survival continues to trend downward at 5 and even0 years.108 Sophisticated analyses of cost, quality of life, and length ofait list times have failed to resolve this debate satisfactorily, but local

urgical expertise and individual and institutional biases play as big a roles any in determining whether these selected patients will undergoesection versus transplantation.Based on 5-year survival rates reported in most retrospective series, the

urvival following resection could be interpreted as being inferior to thatf transplantation at 5 years for HCC (50% vs. 70%). However, thisifference is explained by the fact that patients in resection series haveore advanced disease than those in transplantation series, where patients

re restricted by the Milan criteria. Accordingly, those patients who areesected and meet the Milan criteria have comparable survival to patientsho are transplanted.59,94 Therefore, stage for stage, transplantation and

esection appear to have equivalent OS rates. Furthermore, most trans-lantation series measure survival from the time of transplantation, ratherhan from the time of being listed for transplantation. Depending on theength of time on the wait list, up to 50% of patients will progress beyondhe Milan criteria and become ineligible for transplantation.51 Schwartzroposed using a cutoff of 1 year average wait list time to determinehether surgery or transplantation should be the primary treatmentodality, suggesting that dropouts occurring in the 1 year period negated

ny tumor recurrence advantage that transplantation may have.108

To properly utilize a limited resource such as a deceased donor liver forhe treatment of HCC requires the balance of individual needs withocietal concerns. The greatest difficulty is determining how to fairlyistribute a limited number of organs to those patients who will benefithe most, particularly when other modalities such as resection and
blation are available and can provide similar results. Ultimately, the

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reatment options for patients with HCC must be selected on an individualatient basis determined in a multidisciplinary fashion by assessing tumorharacteristics, underlying hepatic function, the patient’s condition, andvailable resources.

ocoregional Therapy for HCCHCC is the sixth most common cancer worldwide and is rising in

ncidence in the United States.109,110 HCC claims 500,000 lives world-ide annually.111,112 The majority of patients do not survive past 6onths after diagnosis.7 Although surgical resection is the gold standard

or HCC, many patients are not surgical candidates due to cirrhosis withnadequate hepatic reserve, multiple lesions, extrahepatic disease, ana-omic constraints of tumor, or medical comorbidities.113 Therefore, otheriver-directed therapies are employed in the treatment of HCC, includinghermal ablative techniques (RFA and microwave), ethanol injection,irected radiotherapy (RT), transcatheter arterial chemo- or bland embo-ization, and hepatic arterial infusion chemotherapy (HAIC). Dependingn the extent of disease, these therapies can be employed alone or inombination.

blationAblative techniques improve the ability to treat patients with unresect-

ble primary hepatic tumors.114 Ablative techniques destroy tumor viaemperature changes associated with cell death while causing minimalamage to adjacent, normal liver.115 The most commonly used techniquesnclude RFA and microwave ablation (MWA). Recurrence decreases withargins of at least 0.5 to 1.0 cm.The choice of technique depends on equipment availability and sur-eon/radiologist preference. There are limited randomized prospectivetudies that demonstrate superior outcomes between modalities, so it isnclear which specific modality is best for a given application. Currently,he most commonly utilized modality in the United States is radiofre-uency, whereas MWA is used more in Europe and Asia.

blation, RFAMechanism. RFA is the most frequently used thermoablative tech-ique.115 It produces coagulative necrosis via an alternating high-requency electric current in the radiofrequency range (460-500 kHz),elivered through an electrode placed in the center of a lesion.115 Ionicovement within the tissue creates frictional heat as the ions try to follow

his alternating current, with local tissue temperatures exceeding


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00°C.115 This ionic agitation leads to tissue destruction via tissue boilingnd creation of water vapor. Once lethal temperatures (�60°C) areeached, protein denaturation, tissue coagulation, and vascular thrombosisesult in a zone of complete ablation (Fig 1). A zone of partial tissueestruction up to 8 mm in diameter can be seen surrounding the zone ofoagulation.114 Heat-based ablation modalities cause profound vascularhrombosis, making bleeding an unusual complication of RFA.114

RFA can be delivered 3 ways: percutaneously, laparoscopic, or openlaparotomy).114,115 The mode chosen is based on known advantages of

IG 1. HCC in cirrhotic patient pre- (A), immediately before (B), and 9 months after RFA (C). Pre-RFAFP was 43.2 and 9 months later was 11.3.

ach technique. Although percutaneous ablation avoids a laparotomy,


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atients require an anesthetic due to the pain associated with therocedure. With percutaneous RFA, there is no ability to assess thebdomen for extrahepatic disease, and there is no access to intraoperativeS, which can detect additional hepatic disease in 40% to 55% ofatients.114,116,117 Laparoscopic ablation is technically difficult in itsimited ability to image the liver in multiple planes, limiting accuraterobe placement. Because of these limitations, open ablation is often thereferred mode of delivery for patients able to tolerate it.114

Indications. For HCC, RFA is currently indicated for unresectableisease, as a bridge to liver transplant for HCC, and as a substitute forurgical resection in those with medical contraindications to surgery.115

FA is the favored modality for coagulopathic patients due to thentrinsic cautery effect decreasing bleeding complications.114 In addition,andomized studies have found short-term outcomes comparable toesection for small HCC.118

Limitations/Complications. The main limitation of RFA is attainingestruction of adequate tissue volume. Monitoring of the ablation zone isifficult due to the air that is released during heating, which limits thebility to visualize coagulated tissue in real time. Treating lesions in theerihilar area or near large vascular structures is also difficult due tohe heat-sink effect of the blood flow in these areas and proximity to theile duct. Complications occur in 8% to 35% of patients undergoing RFAnd include abscess formation and biliary injury.114,115

FA for Small, Resectable HCCA recent RCT for RFA versus resection has demonstrated similar

urvival outcomes. In a prospective, randomized study comparing RFAith hepatectomy for small HCC, Chen and colleagues randomized 180atients to receive either RFA (percutaneous) or resection.118 To bencluded, adult patients needed to have a solitary HCC smaller than 5 cmn diameter without metastases, no invasion into the major portal/hepaticeins, Pugh-Child Class A liver function, and no previous treatment forCC. Preoperative demographics were similar between groups for age,ender, tumor size, AFP, bilirubin, albumin, and ICG-R15. The onlyignificant difference was in preoperative ALT levels, which were highern the ablation group (P � 0.046). The mean follow-up for ablation was7.9 months versus 29.2 months for resection. Hopefully, after longerollow-up, the authors will analyze the data again to determine whetherhe conclusions remain the same.All 90 patients in each group, RFA or surgery, were included for

nalysis and in compliance with the intention-to-treat analysis. Of the 90


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atients randomized to ablation, 19 patients withdrew their consent andnderwent resection. There were 21 patients in the RFA group whoeeded additional ethanol injections or RFA due to incomplete tumorecrosis on follow-up CT, and 2 patients receiving additional transcath-ter arterial chemoembolization (TACE) for residual tumors despiteepeated RFA/PEI. There were 2 patients in the surgical group with liverissemination who were therefore treated with ethanol, but were includedn the analysis. The 1- and 4-year OS rates were 95.8% and 67.9%,espectively, and 93.3% and 64%, respectively, after resection (P � NS).here was no difference between groups in 1- and 4-year disease-freeurvival rates (90% and 48% for ablation vs. 86% and 51% for resection).here was also no difference in survival rates between groups by tumorize.Major complications occurred significantly more frequently after

esection (50 of 90) than ablation (3 of 71, P � 0.05). Complicationsn the resection group included liver failure (n � 2), moderate/severescites (n � 27), gastrointestinal (GI) bleeding (n � 2), and jaundice0 days after surgery (n � 19). In the ablation group 8 patientseveloped postablation fevers higher than 38.5°C and 3 patientseveloped mild burns to the sites of electrode pad placement, but noemorrhage, infection, or tract seeding occurred. All patients requirednalgesia after resection, in comparison to 16 patients in the ablationroup. Therefore, it appears that although the survival and recurrencendpoints were similar, 21 patients needed reintervention in the RFAroup. However, the tradeoff is the higher complication rate followingesection. Note also that this study had a relatively short follow-up,nd survival and recurrence endpoints will need to be verified withonger follow-up.

FA in Locally Advanced HCCHCC is well suited for locoregional therapy due to its propensity to stayithin the liver, and patients usually die of liver failure secondary to local

issue growth and liver decompensation instead of metastatic disease.119

Curley and colleagues evaluated 110 cirrhotics with unresectable HCCChild class A-C) treated with RFA.120 The local recurrence rate was.6% (median follow-up, 19 months). New lesions (liver tumors orxtrahepatic metastases) developed in 45% of patients. Twenty-fiveercent of patients (n � 28) died of recurrent HCC, and 26 patients withecurrence were alive at study termination. Sixty-five patients had noadiographic evidence of HCC recurrence. These results demonstrated
hat hepatic RFA can be effective in appropriately selected patients, with

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ecurrence rates comparable to published data evaluating other ablationodalities.

blation, MicrowaveBackground. MWA refers to all electromagnetic methods of inducing

umor destruction by using devices generating frequencies of a minimumf 900 MHz.115,121 Under image guidance with CT, MRI, or US, aicrowave antenna is placed intratumorally and an electromagnetic wave

s emitted from the microwave generator through the exposed, noninsu-ated portion of the antenna. This leads to agitation of water molecules inumoral tissue creating friction and heat, leading ultimately to coagulativeecrosis and cell death.115,121

Although MWA shares many advantages with RFA, MWA has someheoretical advantages. Both offer flexible treatment approaches, consis-ent necrotic areas, and excellent patient tolerability. With MWA,ransmission is not limited by tissue desiccation and charring as in RFA,hich relies on conduction of electricity. Intratumoral temperatures cane driven higher, leading to a larger ablation zone, less treatment time,nd more complete tumor killing.121 Like RFA, MWA can be performeduring laparoscopy, laparotomy, or percutaneously. US guidance is usedo apply MWA to single or multiple tumors, inducing necrosis within theumor and in a margin of normal hepatic parenchyma.115 Image findingsndicative of tumor necrosis include echogenic change on US, loss ofontrast enhancement on CT and, on T2 MRI, there is decreasedntensity.122

Indications. The indications for MWA include unresectable HCC, HCCn anatomically difficult locations, and HCC patients unsuitable forurgery.115,123

Complications. Complications are similar to those of RFA, includingile duct stenosis, intraperitoneal bleeding, liver abscess, colonic perfo-ation, tumor seeding along the antennae track, and skin burns.121 Sideffects include pain, postablative syndrome (fever/malaise), and asymp-omatic pleural effusions that are self-limiting.121,122

utcome for Unresectable HCCMWA. Liang and colleagues evaluated prognostic factors for survival in88 cirrhotic patients with HCC.123 Eligibility criteria included HCCmaller than 8 cm, less than 5 lesions with diameters less than 6 cm, ando extrahepatic disease. One-year and 5-year cumulative survival ratesere 93% and 51% (mean follow-up, 31 months). On multivariate

nalysis, patients with a single nodule and tumors smaller than 4 cm had


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ignificantly improved survival rates. As expected, smaller tumors andess advanced disease were associated with improved outcomes afterherapy.MWA versus RFA. In a Japanese randomized study in 2002, MWAas compared with RFA in cirrhotic patients with small HCC.124

here was no difference in patient or tumor characteristics between theroups, and 72 patients with 94 HCC lesions were randomly assignedo RFA or MWA with equivalent therapeutic effects, complicationates, and rates of residual foci observed between the two modali-ies.124 Unfortunately, there were no survival data obtained after aean follow-up period of 18 months, nor have there been follow-up

tudies published to date.Clearly limited by small sample size, the results of these studies

epresent the only prospective trials evaluating the efficacy of MWA.ased on the results from these studies, the choice of ablative

echnique should be based on institutional and user experience andreference.

EI for Unresectable HCCBackground. PEI was first reported by Sugiura in 1983.125-127 Given

he limited indications for surgical resection in patients with advancedirrhosis,126 PEI is an accepted treatment for patients with small,nresectable HCC.Mechanism. PEI is performed under US guidance, where 2 to 8 mL of5% ethanol is administered at a time. Ethanol penetrates tumor cellsromptly, inducing coagulative necrosis and thrombosis in the tumoricrocirculation through protein denaturation, platelet aggregation, and

ehydration of both parenchymal and surrounding endothelium.127 Tu-or tissue has a different consistency compared with the surrounding

arenchyma, allowing homogeneous distribution of ethanol within theumor nodule127 (Fig 2). PEI offers low cost and a favorable compli-ation profile, with the best results demonstrated in patients with smallCC.128,129

Indications. As first-line therapy, current indications include HCCesions smaller than 3 cm.130,131 PEI is also indicated for small HCCesions recurring at distant sites after previous treatment.126,129,132

Limitations. Complete tumor necrosis correlates inversely with tumorize; therefore, local recurrence increases when PEI is administered to
arger tumors (demonstrated in studies comparing RFA to PEI).127,133

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ntratumoral septa prevent homogeneous tumor distribution througharger tumors and multinodular tumors, leading to inadequate margins andecurrence at the peripheral aspect of the tumor.127 There are no definitive

IG 2. Before (A) and after (B) PEI in cirrhotic patient with HCC.

riteria for the quantity and interval of injections; however, the best


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esults occur when dispersion exceeds the maximal tumor diameter by 1o 2 cm to create a 1-cm ablation ring around the HCC nodule.127 Sincexcessive ethanol increases side effects and results in unnecessary liveramage,127 there is a delicate balance to be considered when PEI is aotential therapy for larger tumors or in patients with severe hepaticysfunction.OutcomePEI. Several studies have evaluated the effectiveness of PEI in HCC.he outcomes of patients who underwent PEI as first-line treatment forCC in Japan were evaluated in a recent observational study.126 Indica-

ions for PEI included HCC tumors smaller than 3 cm and a maximum oftumors. Overall 5- and 10-year survival rates were 60% and 21%,

espectively. The survival was best in Child A patients with a solitaryCC (�2 cm), with 5- and 10-year survival rates of 74% and 31%,

espectively. Results from a long-term follow-up of Korean patientsemonstrate similar survival rates, where OS rate at 5 years was 39%, and5% for patients with tumors smaller than 2 cm.132 Thus, long-termurvival is possible after PEI alone for small HCC and likely correlatesith tumor size.PEI versus resection. There are conflicting survival data when PEI is

ompared with resection for small HCC.134-136 A recent RCT comparedEI with resection of HCC smaller than 3 cm in diameter and less than 2

esions.129 All 38 patients in each group had hepatitis, with or withoutirrhosis (Child class A or B). Patients with cirrhosis were without ascitesr coagulopathy, and the majority had single tumors. There were 76atients randomized, with no statistical difference between groups inither survival or recurrence. The 5-year tumor-free survival rates were5% in the PEI group and 48% in the resection group. Although theample size was small, these results suggest that in highly selectedatients with small, accessible HCC due to hepatitis, PEI may result inutcome comparable to resection.PEI versus RFA. According to the AASLD practice guidelines, PEI

hould be the standard against which other nonsurgical therapies areompared.36,137 According to the AASLD guidelines, RFA offers betterocal disease control for HCC greater than 2 cm, but a question remainsegarding survival benefit.36,137 Thus, there have been several RCTsomparing PEI with RFA (Table 4). Recent meta-analyses evaluatinghese RCTs concluded that for small HCC, RFA significantly improved-year survival compared with PEI, which may be due to the ability ofFA to provide a better margin of tissue destruction around the

umor.137,138


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Complications. In a 20-year observational study, complications afterEI primarily include hyperthermia (�38°C, 44%), elevated serum LFTs47.7%), and pain (14.4%).126 Less common are seeding of HCC to theody wall (1.9%), pleural effusion (1.5%), biliary stricture (3.3%), portalein thrombosis (0.7%), and bleeding in the biliary tract (0.7%). Deathnd emergency complications were not encountered. These results sug-est that PEI can be used safely for the treatment of small HCC tumors,rovided the dispersion area exceeds 1 to 2 cm of the maximal diameterf the tumor.127

adiotherapy for Advanced HCCBackground. Exposure to radiation in excess of 40 Gy can lead to

adiation-induced liver disease (RILD), a clinical syndrome characterizedy ascites, anicteric hepatomegaly, and elevated liver enzymes weeks toonths following therapy, therefore limiting the role for whole liver

xternal beam irradiation for HCC.112,144 However, recent data suggesthat local liver RT can be effective in abrogating the progression of

ABLE 4. Randomized controlled trials comparing percutaneous ethanol injection (PEI) to radiofre-uency ablation (RFA) for hepatocellular carcinoma137-139

Author N Cohorts

Tumorsize(cm)

Results

Follow-up

Completenecrosisrate (%)

Survival(%)

Recurrence(%)

runello,2008140

139 ● PEI● RFA

�3 Median follow-upPEI: 25.3 monthsRFA: 26.1 months

1-year CRPEI (36)RFA (65)

3-yearPEI (59)RFA (63)

Distant, overfollow-up

PEI (50.7)RFA (45.7)

in,2005133

187 ● PEI● PAI● RFA

�3 Median follow-up35 months

PEI (88)PAI (92)RFA (96)

3-yearsPEI (51)PAI (53)RFA (74)

3-years,local

PEI (34)PAI (31)RFA (14)

hiina,2005141

232 ● PEI● RFA

�3 Median follow-upPEI: 3 yearsRFA: 3 years

PEI (100)RFA (100)


4-yearoverall

PEI (85)RFA (70)

in,2004142

157 ● PEI● RFA

�4 Mean follow-upPEI: 35 monthsRFA: 37 months

PEI (88)RFA (96)


3-year DSFPEI (17)RFA (37)

encioni,2003143

102 ● PEI● RFA

�5 Mean follow-upPEI: 22.4 monthsRF: 22.9 months

PEI (82)RFA (91)


2-year DFSPEI (62)RFA (96)

AI, percutaneous acetic acid injection; DFS, disease-free survival; CR, complete response.

CC.145,146 In addition, RT can be highly effective in palliating pain.


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Technique. Recent technological advances in image guidance andeduction of breathing artifact allow for delivery of radiation conformallyo focal liver cancer, lessening the toxicity associated with whole liveradiation.147 Whole liver fractionated radiation is limited to 30 Gy, butigher doses can be applied if functional liver tissue can be spared fromhe high radiation.148,149 Stereotactic body radiation therapy (SBRT)efers to delivering radiation in few fractions, and has been utilized foroth primary liver tumors as well as liver metastases.148,150-152 Theosage of RT to the tumor bed is important, since dose-responseelationships have been demonstrative of improved tumor response ratesith higher doses of localized RT.146,153 Therefore, studies have beenerformed in hopes of maximizing the amount of RT to localized areas ofiver to protect the surrounding parenchyma and to maximize therapeuticutcome.OutcomesLocalized RT for Unresectable HCC. In a recent report from Tse and

olleagues, the authors performed a phase I study of individualized SBRTor unresectable HCC and intrahepatic cholangiocarcinoma (IHC).154 Of1 patients in their study, 31 had unresectable HCC and 61% of thoseere AJCC TNM stage T3, N0. Patients underwent 6-fraction SBRT (24

o 54 Gy) during a 2-week period. The median survival was 11.6 monthsor HCC patients with large-vessel thrombosis versus 17.2 months forhose without thrombosis (median follow-up, 17.6 months; P � NS).In HCC patients, the response of large-vessel thrombosis was 6%

omplete response (CR), 19% partial response (PR), and 38% stableisease. Most sites of recurrence were extrahepatic.Park and colleagues evaluated the response to local RT for unresectableCC in a retrospective study.145 Fifty-nine patients were treated with

ocalized RT with a curative intent at doses of 30 to 55 Gy. Tumoresponses were evaluated by the change in maximum tumor size on serialT scans. The median age was 59 years, 78% were male, and no patientsad extrahepatic metastases. Maximal tumor diameters were 9.6 � 4.2m. Thirty-three patients had portal vein thromboses confirmed onmaging. Patients were followed with serial CT scans 4 to 8 weeks afterT, and then at 2- to 3-month intervals.Eleven percent of patients had CRs, 61% had PRs (decreased tumor size50%), stable disease (decrease �50%) in 25%, and 8% had progressive

isease. There was a relationship between radiation dose and tumoresponsiveness, with a 73% CR or PR rate for doses greater than 50 Gyvs. 46.7% with dose larger than 50 Gy, P � 0.0299). Tumor size also
ffected responsiveness, with tumors larger than 10 cm having 50%

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esponse, and tumors smaller than 10 cm with 78.8% responsiveness (P �.0109). The in-field failure was significantly correlated with RT doseP � 0.031), where 47% failed when the dose was less than 50 Gy, andnly 16% failed when the dose exceeded 50 Gy. The median follow-upas 12.9 months after RT and 23 months after diagnosis. At the end of the

tudy, 16 patients remained alive. The 2-year OS rate after diagnosis was7% (median survival of 18 months) and, after RT, 27% (median survival0 months). In-field progression-free survival (PFS) at 2 years was 61%,ith a median survival of 10 months.Toxicity/Complications. There were no RILD or dose-limiting toxicities

een in the Tse and colleagues study.154 Eight of the 31 HCC patientseveloped grade 3 elevated liver enzymes. There were 3 patients whoeveloped transient asymptomatic right-sided pleural effusions 3 monthsfter SBRT. One patient developed a tumor-duodenal fistula 15 monthsfter SBRT, and died 22 months after SBRT due to GI bleeding, believedo be related to disease persistence or progression, with a possibleontribution from the radiation treatment.154

In the study by Park and colleagues, 62.7% of patients had nausea oromiting that was transient and improved with medication.145 This studylso noted that the incidence of morbidity was affected by which lobe wasrradiated, where 55% of patients developed acute morbidity after RT tohe right lobe, versus 92% of patients with RT to the left lobe. Lateorbidities developed in 8 patients, where 3 suffered RILD, 2 gastritis,

nd 3 with gastroduodenal ulceration. There were no fatal complications,or grade 4 adverse effects.

adioactive ParticlesBackground. Given the risk of RILD with whole liver radiation and theeed for doses of more than 40 Gy to inflict lethal injury to malignantissue, minimally invasive intra-arterial devices delivering high does ofadiation internally to the tumor have emerged. This therapy utilizesadioactive yttrium-90 microspheres to deliver high tumoricidal doseshile limiting the development of RILD.112

Technique. Yttrium-90 intra-arterial RT, also known as radioemboli-ation, is a minimally invasive catheter-based therapy delivering internaladiation via the tumor-feeding arterial vessels. Since hepatic tumorserive their blood supply primarily from the hepatic artery and normaliver parenchyma is supplied by the portal system, treatment is relativelyelective.155 Embolic particles are loaded with radionuclide containinghe pure beta-emitter, yttrium-90, and lodge in malignant microvascula-
ure, delivering high doses of ionizing radiation to the tumor compartment

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hile maintaining low radiation exposure of the normal liver. Currently,here are 2 commercially available yttrium-90 microsphere devices:heraSphere (MDS Nordion; Ottawa, ON, Canada) (made of glass) andelective Internal Radiation (SIR) spheres (Sirtex Medical, Sydney,ustralia) (made of resin).112,155-157 TheraSpheres are used primarily forCC.Contraindications. Absolute contraindications include significant hepa-

opulmonary shunting demonstrated on a pretreatment 99mTc macro-ggregated albumin (MAA) scan (results in �30 Gy being delivered tohe lungs with a single infusion), and the inability to prevent depositionf microspheres to the GI tract with modern catheter techniques. Relativeontraindications include compromised pulmonary function, inadequateiver reserve and kidney function (creatinine �2.0 mg/dL), and a plateletount of �75 � 109/L4.Morbidity. The most common clinical toxicity is a mild postembolic

yndrome that includes fatigue, vague abdominal discomfort, pain, andever. Other nontarget radiation-induced toxicities include cholecystitis,astric ulceration, gastroduodenitis, pancreatitis, radiation pneumonitis,nd RILD.112

Outcomes (TheraSpheres). TheraSpheres are used for HCC, and in aecent prospective study patients were stratified according to method ofreatment, risk, Okuda classification, and Child class.156 Patients werereated by liver segment or defined by catheter placement and blood flowistribution. The treatment was defined as segmental when the cathetererfused less than two Couinaud liver segments. If all individualreatments were segmental, then patients were classified as being treatedegmentally. All nonsegmental treatments were classified as lobar. Theumber of treatments depended on tumor distribution, hepatic function,nd vascular flow dynamics. The patients were divided into groupsncluding segmentally treated, lobar treated/low-risk, and lobar treated/igh risk. All patients treated in a lobar fashion with diffuse disease,umor replacement of more than 70% of the liver, ascites, AST or ALTevels more than 5 times the upper limit of normal, or total serum bilirubinreater than 2 mg/dL, were deemed high risk. Forty-three patients wereollowed, and there was no difference among groups in terms of tumoresponse. Fifty-one percent of lesions demonstrated a more than 50%eduction in tumor size, and 79% of patients had a tumor response whenercent reduction and/or tumor necrosis were used as measures. Theedian OS was significantly different between groups (segmental, 47onths; low-risk lobar, 17 months; high-risk lobar, 11 months; P �

.0001). In non-high-risk patients, median survival was 21 months versus


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1 months in high-risk patients (P � 0.0001). Median survival alsoiffered according to Okuda Stage (stage I, 24 months; stage II, 13onths; P � 0.0001). There was improved survival in Child’s class A

atients with median survivals of 21 months versus 14 months in class/C patients (P � 0.006). Based on these results, despite similar tumor

esponse rates, patients with better underlying liver function and lessumor burden have improved survival after directed RT for HCC.Further prospective studies are needed to compare outcomes to other

tandard therapies, given that results following this treatment have notet been reported with long-term follow-up or in comparison to otherherapeutic options.

mbolizationBackground. As described above, given the dual blood supply144

arious catheter-based, locoregional therapies exploit the preferentiallood flow to hepatic tumors via the hepatic arterial system and sparinghe nontumorous liver supplied by the portal system.115 TACE delivershemotherapeutics followed by either embolization or various materialso decrease intratumoral blood flow.115 The reduced blood flow to theumor leads to tumor ischemia as well as increased local concentrations ofntitumor drug, therefore reducing systemic toxicity.115

Technique. Both TACE and bland embolization involve deliveringascular occlusive agents that occlude tumor inflow via a temporaryatheter placed in the hepatic artery.158 Chemotherapeutics may or mayot be administered before embolization, resulting in either TACE orland embolization, respectively. Embolization agents can be permanentpolyvinyl alcohol [Ivadon]) or temporary (microspheres, degradabletarch microspheres [DSM], collagen and gelatin sponge [Gelfoam]).158

Specific to TACE, there are variations in protocols, including thehemotherapeutic used, the use of lipiodol, and the type of material usedo decrease blood flow.115 Doxorubicin, cisplatin, and mitomycin are therugs used most often in the United States. Lipiodol is an iodinated ethylster of fatty acids of poppyseed oil that is retained by liver tumor.115,159

ost protocols utilize this agent as a drug carrier and a tumor-seekinggent115 because it has a microvascular occlusive effect, and isreferentially retained by hepatic tumor cells.158 Some form ofmbolization with the agents mentioned above usually follows thedministration of drug to reduce arterial blood flow and induce tumorschemia. However, it is important to maintain some flow to tumor to
epeat TACE treatments.115

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ranscatheter Arterial ChemoembolizationIndications/Limitations. TACE is used for unresectable HCC and asridging for transplantation.115,160,161 TACE also has palliative indica-ions and offers symptomatic relief from tumors with invasion intolisson’s capsule.158

Given the promising results in its palliative role, TACE has beenvaluated as a neoadjuvant therapy with the hope of reducing tumor size,nducing tumor necrosis, and preventing tumor dissemination duringesection.162 Results are inconclusive, but randomized trials demonstratehat preoperative TACE did not improve surgical outcomes and resultedn dropout from definitive surgery because of disease progression andiver failure.162-164 The data are also inconclusive regarding its adjuvantole after resection,165,166 but there are randomized data to suggest it maye beneficial.166,167

Extensive intrahepatic metastases involving both lobes of the liver areimitations to TACE, precluding treatment of all feeding vasculature athe expense of normally perfused tissue.158

Adverse Effects/Complications. The most common adverse effect isostembolization syndrome (right upper quadrant pain, nausea, vomiting,nd fever with elevated liver enzymes),115 which occurs transiently inpproximately 4% to 10% of patients. Recovery normally occurs withinto 10 days.115 Mechanical complications can occur, and include catheterislodgement, thrombosis, and occlusion, site infection, mesenteric isch-mia, and inadvertent infusion embolization of the hepatic artery.158 Rareut serious complications include tumor rupture, acute liver failure, liverbscess, and pulmonary lipiodol embolism.115,158

OutcomesTACE in Unresectable HCC. TACE was the most frequent treatment forCC as initial therapy as demonstrated by the Liver Cancer Study Groupf Japan.168 An 8-year prospective study was performed by Takayasu andolleagues, and consisted of 8510 patients with unresectable HCC treatedith TACE. The median survival was 34 months (mean follow-up, 19onths), and the 5-year survival rates, stratified by TNM stage (I, II, III,

nd IV), were 47%, 32%, 20%, and 10%, respectively (P � 0.001). Thisemonstrates that the lower the stage, the better the survival rate afterACE therapy.Randomized trials have also demonstrated improved survival in patientsith unresectable HCC undergoing TACE versus symptomatic treat-ent.160,161 In the study from Lo and colleagues, 80 patients with

nresectable HCC were randomly assigned to TACE versus symptomatic


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reatment.161 Survival was the main endpoint, with 1- and 2-year survivalates of 57% and 31% in the TACE group, respectively, versus 32% and1%, respectively, in controls (P � 0.002). For tumors smaller than 5 cm,urvival was 29.8 months in the TACE group and 11.5 months in theontrols (P � 0.003). Again, TACE proves to be more effective thanymptomatic control for unresectable HCC.TACE versus Transcatheter Arterial Embolization (Bland Emboliza-

ion/TAE). Studies comparing TACE with TAE have shown no differencen survival in HCC patients.160 In a randomized study by Llovetomparing TACE, TAE, and symptomatic treatment of unresectable HCC,12 patients received embolization with gelfoam, chemoembolization withelfoam and doxorubicin, and symptomatic treatment.160 The primaryndpoint was survival (mean follow-up, 22 months for embolization, 21onths for chemoembolization, and 15 months for control groups). The

-year survival was 50% for embolization, 63% for chemoembolization, and7% for control (P � 0.009 control vs. chemoembolization, P � NSmbolization vs. chemoembolization). TACE improved survival comparedith conservative therapy, but not bland embolization.160 Therefore, the

hoice of bland versus chemoembolization is institution-dependent, since noeal differences in long-term outcome have been demonstrated.Combination TACE � RFA. Since the rate of complete necrosis in RFAecreases as tumor size increases, combining RFA with therapies thatcclude arterial supply or other local ablative therapy has been proposednd studied to increase the area of coagulative necrosis.119 Since TACEs commonly used for the treatment of unresectable HCC, researchersypothesized that blood flow occlusion in the tumor can decrease heatispersion by the bloodstream, and increase the size of the necrotic arearoduced with ablation.119

A randomized trial evaluated TACE combined with RFA versus TACElone versus RFA alone in patients with large HCC (�3 cm).169 OS wasmproved in patients receiving combination TACE-RFA compared withither treatment alone. The median survival was 24 months followingACE, 22 months following RFA, and 37 months following combination

reatment (P � 0.001 for TACE vs. the combination; P � �0.001 forACE vs. RFA). When subgroup analysis was performed according to

esion size, combination treatment increased survival over TACE (P �.008) and RFA (P � 0.001) in patients with lesions between 3 and 5 cm.or lesions larger than 5 cm, survival was highest in the combinationroup (P � 0.001, TACE-RFA vs. RFA and TACE). Therefore, combi-ation TACE-RFA may have survival benefits over either therapy alone
n HCC larger than 3 cm.

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TACE � RT (Unresectable HCC). TACE has been a primary treatmentor patients with unresectable HCC.170 Recent advances in local RT haveed to studies demonstrating improved response rates when added toACE for unresectable HCC.171,172 Thus far, TACE is not globallyccepted as a treatment for unresectable HCC with PVT.173,174 There isear of liver failure attributable to ischemia after these procedures, withisk of necrosis of noncancerous hepatic parenchyma and deterioration ofepatic function.175 Although Yamada and colleagues demonstratedeasibility in combination therapy for patients with PVT when TACE istrictly administered to the intrahepatic tumor and RT to PVT,176 theajority of TACE � RT is directed at advanced HCC without PVT.Patients with histologically proven unresectable HCC were included inprospective study by Cheng and colleagues.170 Twenty-five patientsith a mean tumor size of 10.3 � 4.4 cm all underwent local RT (meanose, 46.9 � 5.9 Gy), followed by TACE 1 month later unlessontraindicated (main PVT, bilirubin �3 mg/dL, and intrahepatic arte-iovenous shunting). Patients were classified as Child’s class A or B.

edian follow-up was 23 months. Median survival was 19.2 months, and- and 2-year survival rates were 54% and 41%, respectively. T4 patientseceiving only RT had shorter survival at 2 years (21% vs. 64% in non-T4atients). The 2-year survival rate was 13% for RT alone, and 55% forT � TACE (P � 0.003). Although PVT had a nonsignificant impact on-year survival, all 5 patients with PVT developed regional progressionfter treatment, compared to 7 of 20 patients without PVT. These resultsre similar to a study from Seong and colleagues, in which 30 patientsith unresectable HCC were enrolled in a prospective trial of combinedACE and RT.177 The median survival and 1-year survival rate were 17onths and 67%, respectively. Cheng concluded that TACE � RT was

ssociated with better control of HCC than RT alone, but acknowledgedhe bias of better patient selection in the combination group.

epatic Arterial Infusion ChemotherapyBackground. The role of systemic chemotherapy is limited, given poor

esponse rates in advanced, unresectable HCC.178-180 Therefore, localizedherapies have been implemented to improve the outcomes associatedith unresectable HCC, including HAIC either as a single therapy or in

ombination with other localized therapies mentioned above.Multiple studies have evaluated HAIC via an implantable port system

nd have reported it to be a useful therapeutic modality for patients withdvanced HCC.181,182 The advantages of HAIC compared with systemic
hemotherapy include delivery of higher concentrations with less sys-

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emic toxicity, and different chemotherapeutic agents have been usedlone or in combination.183

Technique. The indwelling catheter can be inserted percutaneously orntraoperatively. Percutaneously, the catheter is placed via the femoral orrachial artery using angiography. The tip of the catheter is placed at theommon hepatic artery or the proper hepatic artery.184 The other end ofhe catheter is connected to the injection port, and, in the operativepproach, the device is implanted subcutaneously in the right lowerbdominal quadrant.183,184

Adverse Reactions. Most commonly nausea and loss of appetite occur in5% of patients,184 and are controllable by medications and/or suspendingAIC. These adverse reactions are secondary to the chemotherapeutics used,

nd also include leukopenia/thrombocytopenia (13%), renal damage (2%),eterioration in hepatic function (13%), and auditory disturbances (2%).184

Complications. There are also rare technical problems associated withhe catheter, including catheter obstruction (10%), catheter sepsis (4%),atheter dislocation (2%), and hepatic artery occlusion (2%).184

Outcome in Locally Advanced HCC. In a previous study by Ando andolleagues, 48 patients with HCC and PVT were treated with HAIC vian implantable port.184 Patients received 4 serial courses of chemother-py, each consisting of daily cisplatin and 5-fluorouracil (5-FU) for 5ays. Responders were defined as either undergoing CR or PR andonresponders as having stable disease or progressive disease. Eightercent and 40% of patients had a CR and PR, respectively. The 1- and-year survival rates were 45% and 11%, respectively. The medianurvival for the 23 responders was 31.6 months, and 5.4 months foronresponders. For the responders, the 1- and 5-year survival rates were00% and 40%, respectively.In an attempt to shorten the duration of treatment without compromising

he therapeutic effect, Park and colleagues performed a prospective studyvaluating outcomes after repetitive short-course HAIC with high-dose-FU and cisplatin over 3 days every 4 weeks in patients with advancedCC.183 Thirty-four of 41 patients had PVT. A median of 6 cycles were

dministered, with 9 patients (22%) achieving PR, and 14 with stableisease (34%). The OS was 12 months, and the time to disease progressionas 7 months. Therefore, short-course HAIC is a safe alternative for patients

nd can be administered with systemic chemotherapy.

AIC and Localized RT (for Locally Advanced HCC)In advanced HCC with PVT, patients have a grave prognosis with often

ess than 6 months’ survival.7,185 Although resection is the gold-standard


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reatment for suitable candidates, with 1-year survival reported at 72%,186

t has little role in advanced HCC given patients’ poor liver function,xtensive liver and/or metastatic disease, and portal vein involvement.CC has a high risk of PVT, which has been observed in 65% at

utopsy.184,187 Unfortunately, most patients with locally advanced HCCre unresectable and have limited treatment options due to PVT. Givenhese limitations, there remains a need for effective therapeutics. Withrior studies demonstrating improved outcome when chemotherapy isirected intrahepatically via HAIC, and localized RT potentially lesseninghe risk of RILD,188,189 investigators have utilized the combination ofhese 2 for patients with locally advanced HCC.In a recent study by Han and colleagues, 40 patients with unresect-

ble HCC and associated PVT (main trunk or first branch) participatedn a trial of localized CCRT (intra-arterial chemotherapy plus externaleam radiation therapy) after HAIC.188 The subjects had a median agef 50, were predominantly male (90%), hepatitis B-positive, and haddequate liver reserve with Child-Pugh scores up to 6, total bilirubiness than 2.0 mg/dL, and ICG R15 less than 20%. Forty-five Gray (Gy)ere delivered over 5 weeks to the target volume, and concurrent

ontinuous-infusion hepatic arterial 5-FU was given during the firstnd fifth weeks of RT through a percutaneous chemoport. One monthfter CCRT, HAIC with 5-FU and cisplatin were administered every 4eeks for 3 to 12 cycles according to tumor response. HAIC was

topped after 3 cycles if there was progressive disease. The primaryndpoint of this study was OS and PFS. Mean follow-up was 18.2onths, with 1-year and 3-year OS being 58% and 24%, respectively.he median survival was 13.1 months from the start of RT. Theedian time to PFS was 6 months. Patients were divided into 2 groups

ased on their initial response after CCRT, and survival was signifi-antly improved in responders versus nonresponders (medial survival,9.9 months vs. 11.4 months).In a phase II trial of high-dose conformal RT with concurrent HAICith floxuridine in patients with unresectable intrahepatic malignancies,atients were included if they had Eastern Cooperative Oncology GroupECOG) performance status (PS) less than 2 and had life expectancies ofore than 12 weeks. The median survival was 15.2 months for HCC

atients compared with 8 months in historical controls (P � 0.0001).189

he authors compared all subjects in the study demonstrating improvedurvival when localized RT � 75 Gy, which improved median survival
rom 14.9 to 23.9 months. For all tumor types, PFS was also improved

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ith higher doses of RT of more than 75 Gy (20.7 vs. 10.9 months).hese data suggest short-term survival benefits with a combination of

ocalized therapies.

ummarySince most patients are inoperable at diagnosis, other liver-directed

herapies are needed to treat patients with HCC. Currently, the mostommonly utilized techniques include ablation (RFA and microwave),mbolization, PEI, HAIC, and directed RT. These therapies can bedministered alone, but can also be effective when utilized in combinationr with other chemotherapeutic regimens. An algorithm to approach thenitial steps in managing localized HCC is presented in Fig 3. Becausehere are many subtleties in treatment approaches dependent on patient-pecific factors, as well as institutional-dependent resource differences,his is meant as a guide to treatment options rather than a definitivechema. Based on the limitations of the currently available options to treatocalized HCC, there remains a need for randomized studies to betterddress which modalities are superior for treating HCC according to the

IG 3. HCC Algorithm. Locoregional therapy for HCC is dependent on Child’s-Pugh classification,epatitis B/C positivity, and tumor size and location. *Consider transplant particularly in hepatitis Cr Child-Pugh B patients with hepatitis. †Consider ablation if tumor(s) �3 cm.

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ystemic and Emerging Therapies for HCCHCC is a rapidly fatal disease in many patients190 and systemic therapyith cytotoxic agents has historically been of marginal benefit. Theedian survival for patients with intermediate or advanced stage tumors,hich make up 50% to 60% at diagnosis, is just 6 to 16 months when

reated. An improved understanding of the mechanism of hepatocarcino-enesis provides us a unique opportunity to evaluate novel agents againsthis cancer. As more is learned about the heterogeneity of HCC fromenomic and proteomic studies, the appreciation of its multidimensionalature has expanded, along with the ever-increasing armamentarium ofherapeutic agents and targets. HCC is currently receiving a great deal ofttention in the past few years as the era of molecularly targeted therapyontinues. Agents against angiogenesis and hepatic growth factors arelready in clinical use or are in development.

ytotoxic ChemotherapyCytotoxic therapy has long been used locally and systemically for HCC.lthough local therapy has proven to be of benefit for OS, systemic

herapy historically has demonstrated limited therapeutic efficacy andears no gold-standard option.18 Results of a phase III randomizedlacebo-controlled trial with the multikinase inhibitor sorafenib showed aurvival benefit, giving the oncology community reason for optimismbout the future of systemic therapy.

s There a Role for Chemotherapy in HCC?It is important to understand where the role of chemotherapy fits into theyriad of treatment options, which includes transplant, resection, ablation

RFA, cryo, PEI), and TACE.191 The majority of HCC patients present atn intermediate or advanced stage, for which curative surgical measuresnd ablative techniques are contraindicated. It is in this setting thatystemic therapy takes on a potentially important role. In addition,ystemic therapy may hold promise as an adjuvant therapy, but needsurther evaluation to test efficacy, since the only promising therapy,orafenib, has been tested only in patients with metastatic disease.A major challenge in patient selection for past chemotherapeutic trials

s the heterogeneity of the disease. Unlike most other solid tumors,epatomas arise in the setting of underlying organ dysfunction, and 80%ccur in cirrhotic livers. It is well known that the degree of hepaticysfunction correlates with the predicted OS. Accordingly, the benefits ofystemic agents are balanced against the risks related to morbidity and
rug tolerance. Impaired renal function, ascites, and thrombocytopenia

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re just 3 examples of factors that can reduce tolerance to chemotherapy.ndeed, varying degrees of dysfunction portend different prognoses, andhen additional variables like geography, disease etiology/etiologies, andatient PS are taken into account, the reliability of statistical findings areess sound. Nevertheless, the inclusion of chemotherapeutic agents haseen an attractive option for clinical trials and patient care.Another major challenge has been that HCC has proven refractory to

hemotherapy. Resistance could be intrinsic or acquired after chemother-py. The length of exposure to chemotherapeutic drugs is crucial inetermining response; poor tumoral perfusion, and consequently drugelivery, contributes to intrinsic resistance.192 The background of hepaticbrosis, with its architectural distortion, may also account for thesendings.The drug resistance of HCC involves changes in the expression andetabolism of drug targets, and is caused by defects in effector mecha-

isms.193 An example of this is the altered expression of glutathioneransferase, topoisomerase II, and DNA repair involving modulation ofellular response to chemotherapy.Another target with altered expression is p-glycoprotein, the product of

he MDR1 gene. It has been shown to increase after drug exposure initro.194 Response to systemic chemotherapy was inversely related to theevel of p-glycoprotein expression in patients with inoperable tumors.nother gene related to hepatoma formation is p53, whose pathway plays

ts part in cellular response to chemotherapeutic agents.195 Proteins haveeen identified that confer resistance to p53-induced apoptosis bynhibition of NF�B activity.196

oxorubicin and Topoisomerase II InhibitorsPerhaps no chemotherapeutic agent for HCC has been studied more

requently than doxorubicin.197 It is an anthracycline with mechanism ofction involving intercalation and topisomerase II inhibition. In 1 study ofore than 475 subjects, a 16% response rate has been documented, withmedian survival time of 3 to 4 months.198 In a prospective randomized

rial by Lai and colleagues199 involving 106 patients who were random-zed to receive either doxorubicin versus no antitumor therapy indvanced HCC patients, it was reported that the median survival time inatients receiving doxorubicin was 10.6 months versus 7.5 weeks in theo-therapy arm (P � 0.036).A phase III trial that randomized HCC patients to doxorubicin as a

ingle agent versus control group demonstrated a response rate of
0.5%.200 The median survival in patients treated with doxorubicin

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as 6.83 months. Another phase III RCT compared the survival of 445atients with unresectable HCC treated with nolatrexed or doxorubi-in. In this trial, it was reported that the median OS was 22.3 weeksor nolatrexed and 32.3 weeks for doxorubicin (P � 0.0068).200

bjective response rate (CR plus PR) was 1.4% for nolatrexed and.0% for doxorubicin. The studies with doxorubicin suffer from aeterogeneous patient population and study design. The major sideffects observed with doxorubicin use in these studies have been GI orematological (diarrhea, vomiting, anemia, thrombocytopenia, andeutropenia) along with fatigue and elevated LFTs.198-200 Clearly, theoxicity profile and poor response rate have led to decreased enthusi-sm for its use.Doxorubicin has also been studied in combination with other

hemotherapeutic agents including gemcitabine,201 cisplatin,202 bleo-ycin,197 and 5-FU plus mitomycin-C203 with response rates ranging

rom 11.8% to 18.9%.Pegylated liposomal doxorubicin (PLD), due to its liposomal formula-

ion, is purported to have longer circulation time and specific accumula-ion in tumor tissue with beneficial effects of reduced toxicity. It has beentudied in the past as a single chemotherapeutic agent in HCC with mixedesults. A study by Halm and colleagues in 2000204 showed neitherbjective response nor stable disease,204 and a small phase II study bychmidinger and colleagues in 2001 involving 14 patients showed anbjective response in 14% with 36% disease stabilization over 6onths.205 A study most recently published by Lind and colleagues206

rom Sweden failed to detect a response rate greater than 20%, with theuthors concluding that PLD appears ineffective in advanced HCC. Theommon side effect profile included palmoplantar erythrodysesthesia,rade 3 fatigue, and grade 3 hematological toxicity (thrombocytopenia/eutropenia and anemia), which were relatively mild as compared withonventional doxorubicin.However, PLD, when used in conjunction with gemcitabine in a phase

I trial involving 35 patients, showed CR in 2 patients and a PR in 6atients, with an overall response rate of 24% (preliminary data) and aedian survival rate of 8.8%.207

Epirubicin, which is a 4= epimer of doxorubicin, was thought to have theossibility of a better therapeutic index than doxorubicin. Epirubicin as aingle agent in advanced HCC showed no tumor response and the authorsoncluded that it had no major impact on survival.208 Results of studies
esting mitoxantrone were also disappointing.209

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ther Chemotherapeutic AgentsThere have been a variety of other chemotherapeutic agents used as a

ingle agent against advanced HCC with disappointing results. Thesenclude 5-FU, cisplatin, etoposide, and fludarabine.210-213 Irinotecan,aclitaxel, gemcitabine, capecitabine, and irofulven, which are relativelyewer chemotherapeutic agents, have also been used as single agentgainst advanced HCC, but all have shown relatively low responseates.180,214-217

ombination Chemotherapy in HCCDue to the dismal activity of single agents in treating advanced HCC,any combination chemotherapy regimens have been tried, with some

rials showing better response rates compared with single agent therapy.owever, considering the heterogeneity of HCC and the diversity in theatient population studied, the results of these studies need to benterpreted with caution. Also, combination chemotherapy seems to bessociated with higher toxicity in various studies.One of the most notable regimens that has evoked much discussion is

he combination of cisplatin, doxorubicin, 5-FU, and interferon-� (PIAF)n advanced unresectable HCC. Leung and colleagues reported in 1999hat, among 50 patients treated with this regimen as part of a single-armpen-label phase II study, 13 patients (26%) had an objective response,ith 9 of the 50 patients undergoing surgical resection secondary to the

esponse.218 Of these 9 patients, 4 patients had no histological evidencef tumor cells, with a median survival of 8.9 months. A recent phase IIICT by Yeo and colleagues comparing doxorubicin to PIAF regimen wasublished in 2005.178 The trial involved 188 patients with unresectableCC with the patients randomized to each arm. The overall response rates

n the doxorubicin and PIAF groups were 10.5% (95% confidence intervalCI], 3.9-16.9) and 20.9% (95% CI, 12.5-29.2), respectively. The medianurvival durations of the doxorubicin and PIAF groups were 6.83 months95% CI, 4.80-9.56) and 8.67 months (95% CI, 6.36-12.00), respectivelyP � 0.83), which were not statistically significant. Neutropenia (82% vs.3%, grade 3/4), thrombocytopenia (57% vs. 24%), and hypokalemia (7%s. 0%) were statistically significantly more common in patients treatedith PIAF than in patients treated with doxorubicin. Therefore, combi-ation therapy with PIAF is not recommended due to the lack ofignificant benefit and increased toxicities compared with doxorubicin.Gemcitabine and oxaliplatin (GEMOX) have been recently investigated

n their activity against advanced HCC.219 In a phase II study220 of


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EMOX administered every 2 weeks involving 32 patients with cirrhosisith previously untreated advanced HCC, the objective response rate was8% (95% CI, 8-34) with 58% experiencing stable disease (this includedminor responses). Median progression-free and OS times were, respec-

ively, 6.3 months (95% CI, 4.3-10.1) and 11.5 months (95% CI,.5-14.3). The main side effects experienced were thrombocytopeniagrade 3/4 in 27%), neutropenia (24%), anemia (9%) and neuropathy,rade 3–oxaliplatin induced (9%). They also reported that treatment usinghis regimen was more effective in patients with nonalcoholic cirrhosishan alcoholic cirrhosis. The authors attributed this finding to theifferences in liver parenchymal damage caused by alcohol as opposed toiral hepatitis or steatohepatitis. A subsequent uncontrolled study byouafi and colleagues using GEMOX every 3 weeks219 involving 44atients showed PR in 1 patient alone with stable disease in 20% (8atients) for an average duration of 20.2 weeks. The authors concludedhat the particular dosing schedule used in this study was ineffective andhould therefore not be used in patients with advanced HCC.A study by Merlin and colleagues involving GEMOX administered

very 2 weeks involving 15 patients showed 27% PR rate with 13% stableisease rate.221 The median OS was 7.7 months. It is likely that theEMOX regimen has some antitumor activity, and the response rate isigher than the prior mentioned studies, but more patients are needed toonfirm this.Epirubicin and VP-16 (etoposide) were used in an Italian phase II

tudy222 reported by Bobio-Pallavicini and colleagues in the late 1990s.he study involved 36 patients with an objective response rate of 39%

95% CI, 23-55) with 31% exhibiting stable disease. The median OS timeas 10 months and in the objective responders, the survival time was 13.5onths. The main side effect reported was hematological toxicity.owever, there have been no phase III trials using this combination since

ubsequent studies showed poor response rates.Cisplatin, doxorubicin, and capecitabine were studied in a trial involv-

ng 29 patients in Korea with advanced HCC.223 The response rate was4% (95% CI, 9-40) with 6 patients having stable disease. The medianime to progression was 3.7 months. The main side effect was GIoxicities and approximately 17% patients had low-grade hand-foot skineaction. The authors reported that despite the acceptable response ratend side effect profile, there was no survival benefit.A Chinese phase II study evaluated the combination of oxaliplatin and-FU/leucovorin (FOLFOX 4 regimen) in patients with unresectable
CC.224 This study involving 22 patients showed a response rate of

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8.2% (including 1 CR and 3 PRs). The main side effects experiencedncluded neutropenia, thrombocytopenia, liver transaminase (TA) eleva-ions, and diarrhea. The authors’ conclusion was that since the responses encouraging, phase III trials are warranted.

ormonal Therapy in HCCTamoxifen, an antiestrogen, has been extensively studied in advancedCC as a potential therapy for HCC, since estrogen receptors are present

n approximately one third of these tumors. There has also been evidenceo suggest that estrogen can promote tumor growth in vivo and potentiatesepatocyte growth in vitro.225 However, various prospective randomizedrials and a systematic review of the benefits of tamoxifen in HCCatients have failed to show any advantage with tamoxifen use.226-229 Aandomized controlled phase III trial published in 2005 by Barbare andolleagues227 evaluated the role of tamoxifen in advanced HCC with aotal of 420 patients randomized to the control or therapy arm (20 mgamoxifen daily). The estimated median survival times were 4.8 and 4.0onths in the tamoxifen and control groups, respectively (P � 0.25). Itas concluded that tamoxifen did not improve the OS of patients with

dvanced HCC. It is also postulated that tamoxifen might function as aotential inhibitor of p-glycoprotein, which is the MDR1 gene product.herefore, tamoxifen has been combined with various chemotherapeuticgents to treat against advanced HCC and also failed to show aenefit.230-232

iotherapy in HCCOctreotide, a somatostatin analog, has also been used as experimental

herapy for advanced HCC due to the identification of somatostatineceptors in HCC.233 Prior studies have been reported with conflictingata about the benefit of this drug. A phase II study that evaluated the usef octreotide LAR in 17 patients with advanced HCC and a CLIP scorereater than 3 showed PR in 6% (1 patient), stable disease in 60%, and aedian OS of 10 months.234 Adverse reactions reported included symp-

omatic hypoglycemia (12%), small bowel obstruction/ileus (6%), throm-ocytopenia (6%), and abdominal bloating (6%). Due to the improvededian survival expected for this group of patients, updated data afterore patients are enrolled are anticipated.

eed for Novel Agents in HCCDespite the availability of a large number of clinical trials searching for

n optimal therapy against advanced HCC, there is no single or combi-


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ation hormonal therapy or chemotherapy that is effective againstdvanced HCC. The heterogeneity, the aggressive nature of the disease,nd the underlying hepatic dysfunction are some of the main reasons forhe failure of systemic chemotherapy regimens to improve survival. Partf the answer to solve this difficult clinical problem lies in the develop-ent of molecularly targeted therapies and trials involving such therapies

o assess their efficacy in HCC.

argeting Angiogenesis in HCCSorafenib. There is at present a deluge of studies in genomic androteomic medicine related to HCC, and scientists are finding more andore potential targets, cellular processes, and methods of categorizingCC. Translating this information into clinical trials is paramount for theiscovery of newer, targeted therapies. The SHARP Trial (SorafenibCC Assessment Randomized Protocol) was the first to show a survivalenefit using one of the newer, molecularly targeted therapies. It was ahase III, international, multicenter, double-blind study sponsored by therug manufacturers, involving patients with late stage HCC. The rationaleehind the study was that Raf kinase is overexpressed and activated inCC,235 and that the RAF/MEK/ERK signaling pathway is implicated in

iver tumorigenesis. Sorafenib, approved in advanced renal cell carci-oma, is the only approved inhibitor of Raf kinase and is also a knownnhibitor of RAF, vascular endothelial growth factor receptor (VEGFR),nd other kinases.236 The clinicians based the study on the findings of ahase II trial of sorafenib for patients with advanced HCC and Child class

and B liver function status,237 whereby the drug demonstratedntitumor activity and was well tolerated.The primary objective of the SHARP Trial was OS and time to

ymptomatic progression; the secondary objective was time to progres-ion and disease control rate (overall response rate � SD).5 Six hundredwo patients, nearly all of Child class A and four fifths in BCLC stage C,ere randomized into a study or placebo arm. Of the primary outcomes,

he median OS showed a marked advantage for sorafenib (46.3 weeks vs.4.4 weeks for placebo; hazard ratio [HR], 0.00,058; P � 0.0077). Theedian time to progression also favored sorafenib (5.5 months vs. 2.8onths for placebo; HR, 0.58; P � 0.000007) (Table 5). The study was

alted early when the international data monitoring committee deter-ined that the OS endpoint had been met.Adverse events (AE) were relatively few and, surprisingly, were more

ommon for placebo (54%) than for sorafenib (52%). In practice,
owever, some physicians believe the true incidence of AE with sorafenib

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s higher than reported in this study. The most common AE for patientsaking sorafenib were diarrhea, anorexia, nausea, and hand-foot skineaction. The diarrhea is often tolerable but can be debilitating and canequire discontinuation of the agent. One limitation to the study was theelection criteria: Child-Pugh class A disease patients, whose hepaticunction should, in theory, tolerate the hepatically excreted study drugetter than a liver with poorer function. The authors concluded thatorafenib is the first systemic therapy to prolong survival in HCC patients,nd has now become a reference standard for systemic therapy of HCCatients.Sorafenib activity is, in part, predicated on the highly vascular nature ofCC. Antiangiogenic targets are not new in the scope of chemotherapeutic

rials, and several other biologic agents have been studied. Bevacizumab is aecombinant, humanized monoclonal antibody that targets vascular endothe-ial growth factor (VEGF). In addition to its direct antiangiogenic effects, its also thought to enhance chemotherapy efficacy by decreasing the elevatednterstitial pressure in tumors. Sorafenib improves OS in patients with HCC,et the response rate is low (2%), with no CRs by Response Evaluationriteria in Solid Tumors. Therefore, even though patients may not have a

adiographic response, as long as they have stable disease and are toleratingherapy, they should continue treatment.A randomized phase II study of sorafenib and doxorubicin versusoxorubicin alone was reported by Abou-Alfa and colleagues.238 The

ABLE 5. Phase III sorafenib hepatocellular carcinoma assessment randomized protocol trial

VariableSorafenib(n � 299)

Placebo(n � 303) HR P

verall response, no. (%)R 0 0PR 7 (2.3) 2 (0.7)SD 211 (71) 204 (67)PD 54 (18) 73 (24)

rogression-free rate at 4months, %

62 42

TP, weeks 24 12.3 0.58 .000007S, weeks 46.3 34.4 0.69 .00058ime to symptom progression

(FSHI8-TSP).77

R, hazards ratio; CR, complete response; PR, partial response; SD, stable disease; PD,rogressive disease; TTP, time to tumor progression; OS, overall survival; FSHI8-TSP, theunctional Assessment in Cancer Hepatobiliary Symptom Index Time to Symptom Progressioncoring system.

ombination arm of sorafenib and doxorubicin showed a higher median


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ime to progression of 8.6 months and median OS of 13.7 months overoxorubicin (Table 6).Bevacizumab. Siegel and colleagues used bevacizumab as a single

gent in a phase II study.239 Two doses, 5 and 10 mg/kg administered IVvery 2 weeks, were tested in patients with no overt metastases or localascular invasion. Of the 46 subjects studied, only 6 had objectiveesponses, although 65% were progression free at 6 months (median PFSas 6.9 months). As with the previously described studies, this study

uffers from small sample size, a nonrandomized nature, and possibleatient selection bias. Malka and colleagues also evaluated a bevacizumab-nly single-arm trial, and report a 12.5% response rate; the median PFS andedian survival were not reported.240

Targeting the VEGF pathway, bevacizumab has been explored inombination with gemcitabine-oxaliplatin.241 A phase II study wasndertaken to define efficacy and toxicity profiles in HCC patients. Theedian OS was 9.6 months (95% CI, 8.0 months to “not available”) andedian PFS was 5.3 months (95% CI, 3.7 to 8.7 months). GEMOX-B was

oncluded to have moderate antitumor activity for patients with advancedCC with an especially high 6-month PFS of 48% (95% CI, 31-65). A

imilar study by Sun and colleagues used capecitabine-oxaliplatin withevacizumab, and the PFS was similar, at 5.4 months.242 These PFSesults are similar to the sorafenib arm of the SHARP study.Other Antiangiogenic Agents. Other phase II trials with other antian-iogenic agents have been performed with limited success (Table 7).Thalidomide. Thalidomide monotherapy was studied in a cohort of 37CC patients.244 Thirty-one percent showed disease stability (CI 95%,6-51) and 61% had disease progression (95% CI, 42-78). There was aoncerning incidence of neurotoxicity. The authors concluded that tha-idomide monotherapy, at the doses studied (400-1000 mg/day), could not

ABLE 6. Phase II randomized study of sorafenib and doxorubicin (S � D) versus placebo �

oxorubicin (P � D) in patients with hepatocellular cancer65

S � D (n � 47) P � D (n � 49)

TP (months) 8.6 4.8S (months)* 13.8 6.5FS (months)** 6.9 2.8bjective response (CR � PR), n (%) 2 (4) 1 (2)esponse (SD) 36 (77) 27 (55)

TP, time to tumor progression; OS, overall survival; PFS, progression-free survival; CR,omplete response; PR, partial response; SD, stable disease.P � 0.013; **P � 0.012.

e recommended for the treatment of HCC.


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In the same year, Zhu and colleagues published a study on the use ofhalidomide and epirubicin in unresectable HCC patients.245 The lowerose of thalidomide (200 mg) was better tolerated. No full or PR wasbserved, but 7 patients (41%) had stable disease with a median durationf 6 months (range, 5-14). The authors concluded that the combination ofhalidomide and epirubicin was well tolerated at the studied doses and hadimited benefit in patients with unresectable and metastatic HCC.Cediranib. Cediranib is an orally available potent small molecule

eceptor tyrosine kinase inhibitor of VEGF-A. An interim report of a-stage study was presented at American Society of Clinical OncologyASCO) 2007.246 Patients with unresectable HCC, meeting eligibilityriteria, received this drug, 45 mg, by mouth once daily using a 28-dayreatment cycle. The primary endpoint was 6-month survival. With anccrual goal of 40, promising activity was defined as 22 or more patientsurviving at least 6 months. Data on 28 patients (25 males, 3 females)ere presented. Thirteen had extrahepatic disease and 14 had cirrhosis.he median age was 75 years (range, 48-84). Nineteen patients werevaluable for toxicity; the major toxicities were fatigue, anorexia,ypertension, and jaundice (all grade 3), and there were no side effectsttributable to bone marrow suppression. Overall, 16 (84%) patientseveloped grade 3 toxicity and no grade 4-5 toxicity was observed. Datan efficacy is pending.Brivanib Alaninate. At the 2009 ASCO Gastrointestinal Cancersymposium, another promising antiangiogenic molecule was presented.rivanib alaninate is a selective dual inhibitor of VEGF and fibroblastrowth factor (FGF) signaling pathways. It has been shown to inhibitngiogenesis and tumor growth in xenograft models of HCC. It has alsohown clinical activity and good tolerability in patients with unresectableCC.247 The objective of this study was to assess the efficacy and safetyf brivanib alaninate in patients with advanced HCC who have failed one

ABLE 7. Antiangiogenesis therapy in hepatocellular cancer

Agents Author (Year) N RR (%) SD (%) MS (m)

evacizumab* Schwartz (2005)243 11 10% 72% —EMOX-bevacizumab** Zhu (2006) 33 20% 27% 9.6 mhalidomide Patt (2005) 32 5% 6.8 mpirubicin-thalidomide Zhu (2005) 19 0% 6.5 m

EMOX, gemcitabine and oxaliplatin; RR, response rate; SD, stable disease; MS, medianurvival.5 mg/kg; **10 mg/kg.

rior antiangiogenic therapy. This was a second cohort of an ongoing


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hase II single-agent study of brivanib alaninate in patients with unre-ectable, locally advanced or metastatic HCC who had failed sorafenib,unitinib, bevacizumab, or thalidomide treatment. The primary efficacyndpoint was a 6-month PFS rate. Additional endpoints included overallesponse rate by modified WHO criteria, time to response, OS, andisease control rate. Of the 22 patients, 20 had failed sorafenib and 2,halidomide. The most frequently reported AEs (�25%) were fatigue64%), diarrhea and anorexia (41% each), vomiting and hypertension36% each), and constipation and nausea (27% each). Nineteen patientsad an investigator assessment of efficacy, and 11 (58%) had stableisease. Twenty-one patients had measurements of AFP levels (82% hadlevated AFP at baseline) and 43% had a greater than 50% reduction ontudy. The authors concluded that that brivanib alaninate is generally wellolerated in patients who have failed sorafenib or thalidomide treatment.arly review of scans and AFP levels indicated encouraging signs ofctivity in this population for which there is currently no approvedherapy.Sunitinib. Another promising oral multikinase inhibitor that targets

ngiogenesis factors is sunitinib. Specifically, the receptor tyrosineinases VEGFR1, VEGFR2, PDGFR-�/�, FLT3, and c-KIT are targeted.hase II studies examined tolerability and efficacy of this molecule indvanced HCC.248 Of the 37 study subjects, one had a confirmed PR and9% had stable disease as their best response. Grade 3 and 4 toxicitiesere primarily bone marrow related, including thrombocytopenia (43%)

nd neutropenia (24%). Additional toxicities included central nervousystem symptoms (24%), asthenia (22%), and hemorrhage (14%). Doseeductions were required in 27% of patients.mTOR Inhibitors in HCC. In addition to antiangiogenic targets, otherolecular agents for HCC target mTOR (mammalian target of rapamy-

in). Activation of this pathway induces cell proliferation and prolongsell survival. The mTOR protein regulates phosphorylation of the p70 S6erine-threonine kinase and the translational repressor protein 4E-BP1.249

hese agents include everolimus, temsirolimus, and sirolimus; phase Ind II trials are currently under way. Investigators have studied total andhosphorylated mTOR and S6K protein expression by immunohisto-hemistry in hepatocellular carcinomas (n � 73), fibrolamellar carcino-as (n � 13), and hepatic adenomas (n � 15). Results were correlatedith tumor growth pattern as defined by the WHO (trabecular, pseu-oglandular/acinar, compact, and scirrhous), tumor size, Ki-67 prolifer-tion index, and the modified Edmondson nuclear grade, which has a
cale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin

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twCl5sroam(3mmdeaa

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o see the effect on proliferation and S6K phosphorylation. They foundhat the increased expression of total mTOR was seen in 5% ofepatocellular carcinoma, whereas overexpression of phospho-mTORas evident in 15% of hepatocellular carcinoma. Phospho-mTOR posi-

ivity correlated with increased expression of total S6K, which was foundn 45% of cases. Total S6K overexpression was positively correlated withumor nuclear grade, inversely with tumor size, and was unassociatedith the proliferation index or WHO growth pattern. Rapamycin treat-ent of HepG2 and Hep3B cell lines markedly inhibited cell proliferation

nd reduced S6K phosphorylation in both cell lines.250

Targeting EGFR Pathway in HCC. In a normal liver, epidermalrowth factor receptor (EGFR), EGF, and transforming growth factorTGF)-� are involved in the proliferation of hepatocytes. It is suspectedhat the TGF-�/EGFR signaling pathway contributes to hepatocarcino-enesis and proliferation of established HCC.251 In HCC tumor speci-ens, the TGF-� and EGFR axis is acknowledged to be activated in 70%

o 80% of cases. Therefore, EGFR inhibitors such as cetuximab252 andrlotinib253 have been proposed to patients with advanced HCC in severalrials. However, results of single agent studies were disappointing, withesponse rates below 5% and no significant improvement of survival inomparison to historical controls.Combining VEGFR and EGFR. Recent studies have increased the

esting of the combination of 2 drugs affecting 2 different path-ays.254,255 One such study included biopsy-proven unresectable HCC,hild-Pugh class A or B cirrhosis, bilirubin less than 2.0 mg/dL, TA

evels less than 5 times the upper limit of normal, platelets greater than0,000/�L, and ECOG PS less than 2.255 Prior allowed therapies areurgery, external RT, ablation, TACE, and 1 systemic therapy. Patientseceived bevacizumab 10 mg/kg every 14 days plus erlotinib 150 mgrally daily. The primary endpoint was the percentage of patients alivend progression-free after 16 weeks of therapy (PFS16) based on historicedian PFS of 3 to 5 months. Fourteen patients (24.6%) had prior therapy

6 sorafenib). Of the 57 patients enrolled, 14 (28%) had confirmed PRs,1 (62%) had stable disease, and 5 (10%) had progressive disease. Theedian PFS was 7.9 months (95% CI 5.7, 9.5) and the OS was 12.8onths, 95% CI (9.5, 17.9). Grade 3 or 4 toxicities were TA elevation,

iarrhea, fatigue, hyperkalemia, hypertension, proteinuria, pulmonarymbolus, leukoencephalopathy, and GI bleed. The combination of bev-cizumab and erlotinib appears to have significant clinically meaningful
ctivity in HCC and further studies are under way.

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ummaryIn conclusion, systemic therapy is appropriate for patients with advancednresectable disease who are unsuitable for surgical or locoregional therapy.xperience with chemotherapy as a treatment for HCC has been disappoint-

ng, with response rates typically less than 20%, and there is no therapeuticdvantage of combination chemotherapy compared with single agents.204,227

ue to underlying hepatic dysfunction, treatment side effects often dictatehat the risk of therapy outweighs the benefit in OS.This is a field in evolution, however. The development of molecularly

argeted therapy using agents like sorafenib provides reason for optimismor HCC patients and clinicians alike. The survival benefit shown by thisultikinase inhibitor has brought to bear a gold-standard option whereby

uture comparative trials can be compared. Careful patient selection androperly powered trials will be needed to prove the efficacy of theseewer treatments. In view of the highly vascular nature of HCC, theontinued evaluation of antiangiogenic agents is anticipated, with higherpecificity for predominant molecular pathways.

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