Multidisciplinary Management of Hepatocellular Carcinoma

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:354 –362

Multidisciplinary Management of Hepatocellular Carcinoma JENNIFER GUY,*,‡ ROBIN K. KELLEY,*,§ JOHN ROBERTS,㛳,¶ ROBERT KERLAN,#,** FRANCIS YAO,*,‡ and NORAH TERRAULT*,‡ *Department of Medicine, ‡Division of Gastroenterology, §Division of Oncology, 㛳Department of Surgery, ¶Division of Transplant Surgery, #Department of Radiology, **Division of Interventional Radiology, University of California San Francisco, San Francisco, California

Hepatocellular carcinoma is a leading cause of death in patients with cirrhosis. Management algorithms continually are increasing in sophistication and involve application of single and multimodality treatments, including liver transplantation, hepatic resection, ablation, transarterial chemoembolization, radioembolization, and systemic chemotherapy. These treatments have been shown to increase survival times. As many as 75% of patients with limitedstage disease who are given curative therapies survive 5 years, whereas less than 20% of untreated patients survive 1 year. Treatment can be optimized based on the patient’s tumor stage, hepatic reserve, and functional status. However, because of the heterogeneity in presentation among patients, a multidisciplinary approach is required to treat hepatocellular carcinoma, involving hepatologists, surgeons, interventional radiologists, and oncologists. We present each specialist’s viewpoint on controversies and advances in the management of hepatocellular carcinoma. Keywords: Hepatocellular plantation.

T

Carcinoma;

Resection;

Trans-

he incidence of hepatocellular carcinoma (HCC), a common complication of cirrhosis, continues to increase in the United States.1 The number of hospitalizations and economic burden attributable to HCC are substantial.2,3 The 1-year survival rate for untreated HCC is less than 20%, but improves to more than 75% for patients with limited-stage disease who undergo curative treatments.4,5 Only 30% of patients with HCC present with limited-stage disease, and data indicate underuse of curative and palliative therapies for these patients.6,7 The risk of HCC recurrence is an important consideration that influences choice of HCC therapy and surveillance strategies.8 Options available to treat HCC have become increasingly complex; a multidisciplinary approach to patient care is required by a team of providers with complementary expertise and skill sets that includes hepatologists, radiologists, interventional radiologists, surgeons, and oncologists. Available therapies, used alone or in combination, include liver transplantation (LT); hepatic resection; liver-directed therapies such as ablation (alcohol, microwave, and radiofrequency), transarterial chemoembolization (TACE), radioembolization, and conformal or stereotactic radiation; and systemic chemotherapy with sorafenib and investigational agents. The type of treatment most appropriate for an individual patient with HCC is based on tumor stage, hepatic reserve, and functional status. Multiple cancer-staging systems have been proposed.9 The Barcelona Clinic Liver Cancer (BCLC) staging system (Figure 1)

is the only one that links treatment and prognosis with cancer stage, degree of liver dysfunction as assessed by the Child–Pugh scoring system, and patient functional status; use of the BCLC therefore is advocated by the American Association for the Study of Liver Disease guideline on HCC management.10,11 Multimodal treatments that use combination therapies are not outlined within the BCLC schema but often are used in clinical practice, with good effects.12 A multidisciplinary approach is required to manage patients with HCC because of the heterogeneity in presentation, variation among patients who are candidates for recommended treatments, and diversity of responses to therapy in clinical practice. We present perspectives from hepatology, surgery, interventional radiology, and oncology specialties on the controversies and advances in HCC management.

Very Early Stage Disease Very early stage HCC is defined by a BCLC stage of 0, a single tumor of less than 2 cm in size, normal functional status, and preserved hepatic function (Child–Pugh class A). The diagnosis of HCC is covered in-depth in the American Association for the Study of Liver Disease guideline for HCC management and will not be discussed here.11 Patients with a single HCC lesion that is less than 2 cm have tumors of the T1 stage, according to the modified American Joint Committee on Cancer (AJCC)-TNM staging system, and therefore are not eligible for HCC model for end-stage liver disease (MELD) exception points for LT in the United States.13 There is controversy about whether these patients should receive immediate therapy for HCC or be monitored until they meet T2 criteria, when they can be considered for LT with HCC exception status. In patients with very early stage disease, hepatic resection or ablation offers equivalent treatment response and survival rates; however, disease recurrence remains high within 5 years.14 –20

Surgical Perspective Hepatic resection or ablation of HCC lesions less than 2 cm have the same 5-year survival rates.14 –20 The type of therapy chosen is determined based on tumor location, hepatic Abbreviations used in this paper: AJCC, American Joint Committee on Cancer; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; LT, liver transplantation; MELD, model for end-stage liver disease; RCT, randomized clinical trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing. © 2012 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.11.008

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Figure 1. BCLC staging system. CLT, cadeveric liver transplant; LDLT, living donor liver transplant; PS, performance status; RF, radiofrequency ablation. Reprinted with permission from Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373:614–616.81

function, functional status, other comorbidities, and local patterns of practice. Resection should be limited to patients with compensated cirrhosis (defined by a bilirubin level of ⬍2 mg/ dL, the absence of portal hypertension, and more than 100,000 platelets/mL).21 In studies of cirrhotic patients with Child– Pugh class A disease who underwent resection for HCC (including patients with lesions ⬍2 cm), the 5-year survival rates ranged from 49% to 93%; 5-year recurrence rates were as high as 80%.14 –17 Although multiple studies have evaluated the effects of ablation of tumors of 3 cm or larger, only a few studies specifically have evaluated ablation of HCC lesions less than 2 cm.18 –20 In a prospective cohort study of 218 patients of Child–Pugh class A who received radiofrequency ablation (RFA) for lesions that were 2 cm or less, 97% had a complete response over a median 31-month follow-up period.18 The overall 5-year rate of survival was 69% and the complication rate was 1.8%. Although the rate of local recurrence was low, the estimated overall 5-year rate of recurrence was as high as 80%. There has been no randomized controlled trial (RCT) to compare resection with RFA specifically in patients with lesions less than 2 cm, probably because the sample size and length of follow-up evaluation required to perform such a study are prohibitive. A Markov model simulating 10,000 patients with compensated cirrhosis and HCC smaller than 2 cm who are treated by percutaneous RFA, resection, or percutaneous RFA, followed by resection among those who do not respond, estimates the overall survival times for each approach to be more than 7 years.22

Interventional Radiology Perspective Of the ablative techniques, RFA is better for patients with very early or early stage HCC than percutaneous ethanol ablation or microwave catheter ablation. A meta-analysis of 4 RCTs that included studies of patients with lesions larger than

2 cm found that RFA had better 3-year survival rates than percutaneous ethanol ablation (63%–91% vs 48%– 61%).23 Percutaneous ethanol ablation and RFA resulted in equivalent survival times for patients with lesions smaller than 2 cm, although RFA requires fewer treatment sessions and has a more predictable response. There has been no RCT to compare RFA and TACE for potentially resectable HCC, including lesions smaller than 2 cm. In a small study of 40 patients with unresectable small HCC (median size, ⬍3 cm), 80% of patients who received either TACE or RFA survived 1 year.24 Although no single RCT has shown that combination therapy with TACE and RFA increases survival times of patients with very early stage disease, compared with either therapy alone, a metaanalysis of 4 RCTs reported that combination therapy did increase survival time, regardless of tumor size.25,26 TACE should not be used alone as first-line therapy in patients who can be treated with ablation or resection.

Hepatology Perspective There is controversy over the optimal management strategy for compensated cirrhotic patients with a single HCC that is smaller than 2 cm. HCCs smaller than 2 cm are classified as T1 by modified AJCC–TNM staging and therefore are not eligible to receive MELD HCC exception points for LT listings in the United States. A Markov model of cirrhotic patients of Child–Pugh class A, with a single lesion smaller than 2 cm, found that immediate treatment with RFA or TACE had equivalent survival times, and was more cost effective, than waiting until the lesion was larger than 2 cm so the patient could be placed on the LT wait list with HCC exception status.27 However, this model did not include important factors such as hepatic decompensation or the development of recurrent or new tumors. A recent study of 159 patients with tumors smaller than 2 cm found that 56% developed recurrent HCC after RFA

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Figure 2. Percentage of patients undergoing liver transplantation within 3 months of listing by UNOS region in 2007.30

during a median follow-up period of 29 months, and that 18% of these had advanced-stage tumors.28 Geographic differences in wait times, which vary by United Network for Organ Sharing (UNOS) region, are another important factor to consider in determining whether to chose LT for patients with very early stage disease29,30 (Figure 2). Further data are needed to better characterize the risk:benefit ratio of early versus late HCC treatment in this group of patients. Patients who receive resection or ablation therapy should be monitored closely for HCC recurrence and signs of decompensation. There are not much data to define an optimal surveillance protocol after treatment, but multiphase, cross-sectional image analysis 1 month after treatment, and then at 3-month intervals, has been proposed for at least the first 2 years after treatment, with possibly longer intervals (up to 6 mo) thereafter.11 Hepatologists also must treat underlying liver diseases; patients with hepatitis B who receive antiviral therapies have been shown to have decreased rates of cirrhosis, decompensation, and HCC.31 The efficacy of interferon therapy in reducing HCC recurrence after resection in patients with hepatitis C is controversial.32,33

Early Stage Disease Patients with early stage disease are assigned BCLC stage A and have a single lesion or up to 3 lesions, none greater than 3 cm in size, no evidence of extrahepatic spread of disease

or vascular invasion, normal performance status, and are of Child–Pugh classes A or B. These patients have tumors of the T2 stage, based on the modified AJCC-TNM staging system, and also are within Milan criteria if the single lesion is not greater than 5 cm in size. In management of these patients, there are controversies over the relative risks and benefits of LT to candidates eligible for resection, the role of salvage transplantation in patients previously treated with resection, whether ablation is equivalent to resection of lesions that are 3 to 5 cm, and the use of liver-directed therapies in patients awaiting LT.

Surgical Perspective First-line therapy for patients with Child–Pugh class A cirrhosis but no portal hypertension and a single HCC lesion traditionally has been hepatic resection.11 Fifty percent to 75% of cirrhotic patients with a single lesion and no portal hypertension, but less than 55% in those with portal hypertension or multiple or large lesions, survive for 5 years.15,16,34,35 HCC recurs within 5 years in up to 80% of patients treated by resection.15,36 Factors that increase the risk of recurrence include larger size and number of HCC lesions, higher histologic tumor grade, higher levels of ␣-fetoprotein, and macrovascular and microvascular invasion.15,37,38 Adjuvant therapies have not been shown to reduce recurrence; however, a multicenter, placebo-controlled trial is underway to determine whether sorafenib reduces the recurrence of HCC after resec-

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tion (NCT00692770, available at: www.clinicaltrials.gov). Gene expression signatures associated with high or low probabilities of recurrence have been identified and may have future clinical application in predicting the relative benefits of various therapies for an individual patient.39,40 It is not clear if patients with HCC lesions 3 to 5 cm have comparable outcomes after ablation or resection. In an RCT conducted in China of 186 Child–Pugh class A patients, with HCCs that were less than 5 cm, there were no statistically significant differences in rates of 4-year overall and disease-free survival between patients treated with resection (64% and 52%, respectively) versus RFA (66% and 48%, respectively).41 Observational studies have reported variable results with RFA versus resection, with outcomes dependent on tumor size.20,42– 44 The response to RFA is 70% to 95% among patients with lesions less than 3 cm, but decreases to approximately 50% in patients with lesions greater than 3 cm.20 Among patients with lesions more than 3 cm who were treated with RFA, the overall 5-year survival rate was 30% to 50% and the 5-year recurrence rate reached 80%.42– 44

Hepatology Perspective Patients with early stage HCC that cannot be treated by resection, or who have portal hypertension or decompensated cirrhosis, should be considered for LT. In a landmark study, Mazzaferro et al45 reported excellent outcomes from LT among patients with HCC that was within the Milan criteria (a single lesion that is 5 cm or less or 3 lesions that are all 3 cm or less and absence of portal vein invasion or extrahepatic spread of disease), with an overall 4-year survival rate of 75% and a recurrence rate of 8%. In the United States, 60% of patients with HCC within the Milan criteria who undergo LT survive to 5 years.5,46 Patients with HCC within the Milan criteria are given MELD exception points because of the risks of tumor progression and wait-list drop out; they are given a MELD exception score of 22, which is adjusted every 3 months to reflect a 10% increase in mortality. Wait times for LT for patients listed with HCC MELD exception points vary among UNOS regions29,30 (Figure 2). Despite conflicting evidence about whether liver-directed therapy reduces the number of patients who drop off the wait list or improves post-transplant survival, physicians are recommended to treat patients whose wait-list time exceeds 6 months.47– 49 Ablation and TACE each have been shown to be effective in patients awaiting LT, and combination therapy might be used for this group, based on limited data.12,50,51 LT increases the rate of 5-year, disease-free survival compared with resection or ablation, raising the question of whether LT should be the first-line therapy for all patients with HCC, regardless of resection candidacy. Disadvantages to this approach include organ shortages in certain regions.29 LT after resection is termed salvage transplant, and single-center experiences vary.52–54 Resection is not considered to be a bridging procedure to transplant in the United States. Patients are not eligible for HCC exception points for LT unless they develop recurrent or new disease that is within Milan criteria.55 Recurrent HCCs are within the Milan criteria at the time of diagnosis in 50% to 80% of patients.56 Live-donor liver transplant is an attractive option for patients with HCC because of decreased wait-list times, com-

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pared with deceased-donor liver transplant. HCC within the Milan criteria is an accepted indication for live-donor liver transplant; patients have comparable overall survival rates with those who receive a deceased-donor liver transplant. There are conflicting data about whether live-donor liver transplant is associated with increased recurrence.57–59

Intermediate-Stage Disease Patients with intermediate-stage disease are assigned BCLC stage B, have multinodular HCC with no extrahepatic disease or vascular invasion and preserved functional status, and are Child–Pugh class A or B. Traditionally, these patients have been classified as outside LT criteria because of tumor burden beyond Milan criteria. However, modest expansion of the tumor burden permissible for LT has been proposed to allow these patients to receive LT. Treatment of lesions initially beyond Milan criteria with locoregional therapy, to allow these patients to be eligible for LT, is called down staging. TACE is considered first-line therapy for patients with intermediate-stage disease and a tumor burden beyond consideration for down-staging protocols, or who are cared for in centers where expanded criteria for LT are not performed. Radioembolization is emerging as a promising alternative to TACE.

Hepatology Perspective Liver transplantation is a treatment option for patients with tumor burden beyond the Milan criteria in certain regions of the United States and worldwide. There are expanded criteria for LT, such as the University of California at San Francisco criteria and the Up-to-7 criteria, which allow for larger size or number of HCC tumors yet maintain equivalent 5-year survival rates of more than 70%.60 – 63 Data from a large retrospective analysis of more than 1000 patients who exceeded the Milan criteria indicated that the probability of HCC recurrence in patients within the University of California at San Francisco or Up-to-7 criteria was as much as 15% within 5 years of LT, compared with more than 40% for patients who underwent LT with tumors beyond these criteria.64 Tumor response to down staging has been proposed as an important surrogate marker of tumor biology and risk for recurrence after LT.65– 67 A study by Yao et al67 followed up patients who were treated with TACE or RFA for tumor size that was beyond that of the Milan criteria and were monitored for tumor response for at least 3 months before LT.67 After this ablate-and-wait approach, 30% of the patients had tumors with aggressive biology and therefore were not good candidates for LT, whereas the remaining patients had 4-year, post-transplant survival rates of 92%, without any evidence of recurrence.67 The UNOS-sponsored HCC consensus conference recommended waiting at least 3 months before performing LTs for down-staged patients.55 An even longer wait period (eg, up to 6 mo) might better identify patients with aggressive tumors who are not good candidates for LT.30

Interventional Radiology Perspective TACE is considered the best treatment for intermediate-stage multifocal HCC without portal vein invasion or ex-

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trahepatic disease. RCTs and meta-analyses have shown that TACE increases survival times compared with no treatment; 42% to 82% of patients treated with TACE survived 1 year.68 Cohort studies and 1 RCT have shown that conventional TACE and doxorubicin-eluting beads have similar levels of efficacy in patients with Child–Pugh class A or B cirrhosis. However, doxorubicin-eluting beads have a better toxicity profile, possibly because patients have less systemic exposure to the drug.69,70 Advanced hepatic dysfunction is a contraindication to chemoembolization. Radioembolization with yttrium-90 microspheres has been compared with TACE in several observational studies; cirrhotic patients of Child–Pugh class A were found to have equivalent

median survival times of 16 and 17 months, after therapy.71,72 There is evidence for a trend of higher response rates and longer time to progression among patients who received radioembolization, compared with TACE.71 Radioembolization was well tolerated in patients with branch or lobar portal vein thrombosis, although their overall survival times were shorter than those of patients without portal vein thrombosis.73 An RCT to compare the effects of ablation, TACE, and radioembolization is underway (NCT00956930, available at: www.clinicaltrials. gov). Exclusion criteria for radioembolization therapy include the presence of a lung-shunt fraction more than 20% and a total level of bilirubin greater than 2 mg/dL, to avoid development of radiation-induced lung and liver disease.

Table 1. Selected Ongoing Randomized Phase 3 Studies of Targeted Therapies in Advanced HCC Study numbera

Title

Sponsor(s)

VEGF plus EGFR

NCT00881751

Brivanib

VEGFR, FGFR

NCT00858871

Medical University of South Carolina Bristol-Meyers Squibb

Linifanib (ABT-869)

VEGFR, PDGFR

NCT01009593

Sorafenib plus doxorubicin (IV)

BRAF, VEGFR, PDGFR, plus DNA damage

NCT01015833

Sorafenib plus erlotinib

BRAF, VEGFR, PDGFR, plus EGFR

NCT00901901

Bevacizumab and erlotinib or sorafenib as firstline therapy in treating patients with advanced liver cancerb A randomized, double-blind, multicenter, phase III study of brivanib vs sorafenib as first-line treatment in patients with advanced HCCc Efficacy and tolerability of ABT-869 vs sorafenib in advanced HCC Sorafenib tosylate with or without doxorubicin hydrochloride in treating patients with locally advanced or metastatic liver cancer (CALGB 80802) A phase III, randomized, placebo-controlled, double-blind trial of sorafenib plus erlotinib vs sorafenib plus placebo as first-line systemic treatment for HCCc

Arginine deprivation

NCT01287585

Polaris Group

Brivanib

VEGFR, FGFR

NCT00825955

Brivanib

VEGFR, FGFR

NCT01108705

Everolimus (RAD001)

mTORC1

NCT01035229

Ramicirumab (IMC-1121B)

VEGFR

NCT01140347

A randomized, double-blind, multicenter phase 3 study of ADI-PEG 20 plus BSC vs placebo plus BSC in subjects with advanced HCC who have failed prior systemic therapy A randomized, double-blind, multicenter, phase III study of brivanib plus BSC vs placebo plus BSC in subjects with advanced HCC who have failed or are intolerant to sorafenib: the BRISK PS studyc A randomized, double-blind, multicenter phase III study of brivanib plus BSC vs placebo plus BSC in Asian subjects with advanced HCC who have failed or are intolerant to sorafenib (BRISK-APS) Global study looking at the combination of RAD001 plus BSC and placebo plus BSC to treat patients with advanced HCC A multicenter, randomized, double-blind, phase 3 study of ramucirumab (IMC-1121B) drug product and BSC vs placebo and BSC as second-line treatment in patients with HCC after first-line therapy with sorafenib (REACH)

Investigational agent(s) First-line therapy trials Bevacizumab plus erlotinib

Second- or later-line therapy and/or sorafenib-intolerant/ineligible trials ADI-PEG 20

Therapeutic target(s)

Abbott CALGB/NCI

Bayer

Bristol-Meyers Squibb

Bristol-Meyers Squibb

Novartis Pharmaceuticals ImClone, LLC

NOTE. This table does not include studies of novel techniques or devices. BRAF, v-raf murine sarcoma viral oncogene homolog B1; CALGB, Cancer and Leukemia Group B; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; mTOR, mammalian target of rapamycin; NCI, National Cancer Institute; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Adapted from Villanueva et al80 and http://www.clinicaltrials.gov. aStudies may be searched by number on the NCI website, http://www.clinicaltrials.gov. bRandomized phase II study. cOngoing, no longer recruiting.

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Advanced-Stage Disease Patients with advanced-stage disease are of BCLC class C, have evidence of portal invasion or extrahepatic spread of HCC, are of Child–Pugh class A or B, and have impairment of functional status. Treatment options focus on controlling cancer progression and providing palliation. Sorafenib is the first-line therapy for patients with advanced HCC who have well-compensated cirrhosis.74,75 Combination therapies with multiple chemotherapeutic agents or chemotherapy with liver-directed therapies are promising and under investigation. In patients with decompensated liver disease (defined by Child–Pugh class C) and/or significant impairment in functional status (Eastern Cooperative Oncology Group, ⬎2), treatment options are limited because treatments are not well tolerated. These patients are considered to have end-stage disease (BCLC class D), with overall survival times of less than 3 months; the goals of care therefore predominantly are symptom control.10

Oncology Perspective Systemic therapy options for advanced HCC are evolving. Sorafenib has been shown to be the first systemic therapy to increase survival times of patients with advanced HCC.74

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Patients treated with the oral multikinase inhibitor sorafenib (400 mg twice daily) had an overall median survival time of 10.7 months, compared with 7.9 months for patients who received placebo (hazard ratio, 0.63). Most patients were Child–Pugh class A with an Eastern Cooperative Oncology Group performance status of 0 to 1. Hepatitis C virus infection and alcohol use were the most common causes of liver disease. An identically designed RCT of Asian patients (70% with hepatitis B–related liver disease) showed a median survival time of 4.2 months for patients who received placebo and 6.5 months for those treated with sorafenib (hazard ratio, 0.68).75 The most common side effects from sorafenib, based on the National Cancer Institute Common Terminology Criteria version 3.0, are weight loss, hand or foot skin reactions, and diarrhea. Potentially life-threatening effects include severe hypertension, myocardial infarction, bleeding, bowel perforation, hepatic decompensation, and significant interactions with other drugs. The dose of sorafenib should be adjusted for the baseline levels of bilirubin and albumin—patients with total bilirubin levels 1.5 to 3 times the upper limit of normal tolerated a maximum dose of 200 mg twice daily, whereas patients with total bilirubin levels more than 3 times the upper limit of normal might not even tolerate a dose of 200 mg every third

Table 2. Selected Ongoing Randomized Phase 3 Studies of Adjuvant Therapy After Locoregional Treatments or Surgery in HCC Investigational agent(s)

Therapeutic target(s)

Study numbera

Title

Brivanib

VEGFR, FGFR

NCT00908752

Sorafenib

BRAF, VEGFR, PDGFR

NCT01004978

Sorafenib

BRAF, VEGFR, PDGFR

NCT00692770

Sorafenib

BRAF, VEGFR, PDGFR

NCT01324076

Sunitinib

VEGFR, PDGFR, KIT

NCT01164202

Thalidomide

Angiogenesis

NCT00921531

Thymopentin

Immune modulation

NCT00460681

A randomized, double-blind, multicenter, phase III study of brivanib vs placebo as adjuvant therapy to TACE in patients with unresectable HCC (the BRISK TA study) A phase III, randomized, double-blind trial of chemoembolization with or without sorafenib in unresectable HCC in patients with and without vascular invasion (ECOG 1208) A phase III, randomized, double-blind, placebocontrolled study of sorafenib as adjuvant treatment for HCC after surgical resection or local ablation (STORM)b TACE-2: a randomized, placebo-controlled, double-blinded, phase III trial of sorafenib in combination with transarterial chemoembolization in HCC A double-blind, randomized, phase II/III study Comparing the use of chemoembolization combined with sunitinib against chemoembolization combined with a placebo in patients with HCC (SATURNE) Phase III study of adjuvant therapy with thalidomide for chemoembolization in advanced HCC Study of thymopentin in patients after curative resection of small HCC

Sponsor(s) Bristol-Meyers Squibb

ECOG/NCI

Bayer

University College, London

Federation Francophone de Cancerologie Digestive

Fudan University

Fudan University

NOTE. This table does not include studies of novel techniques or devices. BRAF, v-raf murine sarcoma viral oncogene homolog B1; ECOG, Eastern Cooperative Oncology Group; FGFR, fibroblast growth factor receptor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; NCI, National Cancer Institute; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor. Adapted from Villanueva et al80 and http://www.clinicaltrials.gov. aStudies may be searched by number on the NCI website, http://www.clinicaltrials.gov. bOngoing, no longer recruiting.

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day.76 The US Food and Drug Administration label for sorafenib says it should not be given to patients with liver dysfunction of Child–Pugh class C. Several prospective trials have evaluated the efficacy and tolerability of sorafenib in realworld clinical settings, these trials have shown that adverse events and dose reduction are common (NCT00812175, available at: www.clinicaltrials.gov).77,78 Sorafenib (estimated wholesale retail price of approximately $4500 per month) has been shown to be cost effective by standard US dollar thresholds.79 Multiple pathways that contribute to HCC pathogenesis have been identified; several targeted therapies are being evaluated in phase 1 to 3 trials, as first-line alternatives to sorafenib, as first-line therapies in combination with sorafenib, or as second- or later-line therapies (Table 1).80 Sorafenib also is being studied in combination with transarterial chemoembolization or with surgery (Table 2). Given the increasing number of trials of drugs for advanced HCC, it is important to consider whether patients might be candidates for clinical trials before they are given sorafenib.

Hepatology Perspective The hepatologist has an opportunity to have an important role in directing the continuum of care for patients with HCC, from diagnosis to coordination of HCC treatment, to evaluation for LT, to management of the underlying liver disease and complications of cirrhosis. Patients with advanced HCC who are being treated with sorafenib must be followed up closely for signs of toxicity that necessitate dose reduction or therapy discontinuation. Providers for patients with advanced HCC should be knowledgeable about end-of-life care, including pain and symptom management and referrals to hospice care.

Conclusions HCC is an increasingly common and complex disease with multiple treatment options, which can be used alone or in combination. The application of and tolerability of treatment depend on cancer stage, hepatic reserve, and functional status. LT, ablation, resection, chemoembolization, radioembolization, and chemotherapy all increase survival time compared with no treatment. LT has the best survival rates for patients who meet the Milan criteria; 75% survive for 5 years and only 10% have disease recurrence. Modest expansion of the criteria required for LT can result in equivalent rates of survival, with overall small increments in rates of recurrence. Among patients who did not receive LT but were selected appropriately for resection or ablative treatment, 50% to 70% survived 5 years; however, HCC recurred in as many as 80%, regardless of initial stage at presentation, indicating the need for careful surveillance. Patients with intermediate-stage disease treated with TACE have a median survival time of 2 years. Radioembolization has been studied in observational cohorts; response and survival rates are similar to those of TACE. Sorafenib and chemotherapeutic trials are available for patients with advanced disease. New technologies are improving our understanding of HCC pathogenesis and progression, leading to new systemic therapies and providing tools to predict responses to therapies. The amount of heterogeneity among patients who present with HCC and the rapid pace of advances in multiple, related disciplines require a multidisciplinary approach to HCC care.

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Reprint requests Address requests for reprints to: Jennifer Guy, MD, MAS, California Pacific Medical Center, Department of Transplantation, 2340 Clay Street, 3rd Floor, San Francisco, California 94115. e-mail: guyj@ sutterhealth.org; fax: (415) 600-1200. Conflicts of interest The authors disclose no conflicts. Funding This study was supported by grants from the University of California San Francisco Liver Center (P30 DK-26743).