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Diagnosis and Treatment of Hepatocellular Carcinoma


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Diagnosis and Treatment of Hepatocellular Carcinoma

  1. 1. GASTROENTEROLOGY 2008;134:1752–1763Diagnosis and Treatment of Hepatocellular Carcinoma Hashem B. El–Serag* Jorge A. Marrero‡ Lenhard Rudolph K. Rajender Reddy§*Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; ‡Division of Gastroenterology, University of Michigan, Ann Arbor,Michigan; and §Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania and Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, University of Ulm, Ulm, GermanyThe diagnosis and treatment of hepatocellular carci- although rarely erythrocytosis can be seen because ofnoma (HCC) have witnessed major changes over the extrarenal synthesis of erythropoeitin.6 In addition topast decade. Until the early 1990s, HCC was a rela- signs of cirrhosis (eg, jaundice, palmar erythema, gyneco-tively rare malignancy, typically diagnosed at an ad- mastia) and portal hypertension (eg, ascites, varices), avanced stage in a symptomatic patient, and there were hepatic bruit could be detected in 10%–20% of patientsno known effective palliative or therapeutic options. with HCC.7 With the increased awareness of HCC, moreHowever, the rising incidence of HCC in several re- asymptomatic patients are being diagnosed as part ofgions around the world coupled with emerging evi- active surveillance. Unfortunately, the majority of pa-dence for efficacy of screening in high-risk patients, tients still presents with signs and symptoms suggestiveliver transplantation as a curative option in select of liver decompensation and/or tumor spread.patients, ability to make definitive diagnosis usinghigh-resolution imaging of the liver, less dependency HCC Screeningon obtaining tissue diagnosis, and proven efficacy of HCC screening is recommended in high-risk pa-transarterial chemoembolization and sorafenib as tients (Table 1). In a randomized controlled trial of nearlypalliative therapy have improved the outlook for 19,000 HBV-infected patients in China, it was shown thatHCC patients. In this article, we present a summary of HCC surveillance with testing of serum -fetoproteinthe most recent information on screening, diagnosis, (AFP) and performance of abdominal ultrasound (US) atstaging, and different treatment modalities of HCC, repeated 6-month intervals improves survival.8,9 Al-as well as our recommended management approach. though adherence to surveillance was relatively low ( 60%), a 37% reduction in HCC-related mortality was reported. A similar, randomized clinical trial study in Diagnosis of Hepatocellular Carcinoma China, however, reported that surveillance for HCC is notC irrhosis is the strongest and the most common known risk factor for hepatocellular carcinoma(HCC), particularly cirrhosis related to hepatitis C virus beneficial in the absence of curative therapies after the cancer was diagnosed.10 In addition, several nonrandom- ized trials, as well as observational studies, have observed(HCV) and hepatitis B virus (HBV) infections.1–3 In addi- a survival benefit in those identified with small and earlytion, HBV acquired in the perinatal period and early tumors.11childhood is associated with increased risk of HCC even AFP and liver US are the most widely used tools forin the absence of cirrhosis. HCC surveillance. Based on the estimated HCC doubling time, the recommended surveillance interval is 6 months, Clinical Features Patients with HCC present with one or more of Abbreviations used in this paper: AFP, -fetoprotein; HCC, hepato-several clinical features including right upper quadrant cellular carcinoma; BCLC, Barcelona-Clinic Liver Cancer; CTP, Child-pain, weight loss, and/or worsening liver enzymes in a Turcotte-Pugh; LDLT, living donor liver transplantation; OTL, orthotopicpatient known to have cirrhosis. Rare presenting features liver transplantation; PEI, percutaneous ethanol injection; RFA, radio-include acute abdominal catastrophe from rupture of frequency ablation; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing; US, ultrasound.HCC with intraabdominal bleeding or extra hepatic man- © 2008 by the AGA Instituteifestations (eg, hypercalcemia, hypoglycemia, thyrotoxi- 0016-5085/08/$34.00cosis).4,5 Anemia is present in more than half of cases, doi:10.1053/j.gastro.2008.02.090
  2. 2. May 2008 DIAGNOSIS AND TREATMENT OF HCC 1753Table 1. Groups in Whom HCC Screening and Surveillance is very important for the diagnosis and staging of this Is Recommended tumor. The most reliable diagnostic tests are triple-phaseHepatitis B carriers (HBsAg positive) helical CT and triple-phase dynamic contrast enhanced Asian males 40 y magnetic resonance imaging (MRI),24,25 whereas hepatic Asian females 50 y angiography has fallen out of favor in most practice All cirrhotic hepatitis B carriers settings. HCC derives its blood supply predominantly Family history of HCC Africans over age 20 y from the hepatic artery, whereas the remainder of theNonhepatitis B cirrhosis nontumorous liver receives both arterial and portal Hepatitis C blood. The hallmark of HCC during CT scan or MRI is Alcoholic cirrhosis the presence of arterial enhancement followed by delayed Genetic hemochromatosis hypointensity of the tumor in the portal venous and Primary biliary cirrhosis Possibly: 1-antitrypsin deficiency, nonalcoholic steatohepatitis, delayed phases, ie, washout26 (Figure 1). The presence of autoimmune hepatitis arterial enhancement followed by washout has a sensitiv- ity and specificity of 90% and 95%, respectively. However, 71% of patients with HCC will have arterial enhancementalthough a 1-year interval may be equally effective.8,12,13 and washout on more than one test, whereas the rest doThe performance of US depends on the experience of the not have these features and, therefore, will require liverexaminer, the technology used, the body habitus, the biopsy for the diagnosis of HCC. There have been at leastpresence of cirrhosis, and the size of the tumor. Recent 4 studies that have compared the accuracy of CT andstudies generally indicate a 60% sensitivity, and 90% MRI for HCC diagnosis, using the explanted liver as thespecificity.14 The sensitivity of US to detect tumor nod- gold standard.27–30 These show that MRI is slightly betterules in cirrhotic livers is particularly low.15–17 The serum in the characterization and diagnosis of HCC when com-AFP level of 20 ng/mL commonly used as the upper limit pared with CT scan (Table 2). The performance of CTof normal18,19 has low sensitivity (25% to 65%) for detect- and MRI is affected by the size of the lesions. For exam-ing HCC and is therefore considered inadequate as the ple, in tumors larger than 2 cm, MRI is reported to havesole screening test. Patients with chronic liver disease, an accuracy 90%; however, in tumors smaller than 2 cm,especially those with a high degree of hepatocyte regen- this level is reduced to 33%.31eration (eg, HCV), can express elevated serum AFP in the Currently, AFP serum levels above 200 ng/mL areabsence of malignancy.20,21 Other tests such as des- highly specific for HCC diagnosis in patients with cirrho-carboxy prothrombin and lectin-bound AFP (AFP-L3) are sis and coinciding radiologic evidence of focal hepaticavailable, but there are no reliable prospective data on lesions.8 However, the sensitivity of AFP is much lowertheir effectiveness in HCC screening. because it has been reported that only one third of The cost-effectiveness of HCC surveillance strategies patients with HCC have AFP levels higher than 100using both AFP and US have been evaluated in retrospec- ng/mL.32,33tive studies as well as mathematical models,1,8 –10,14 andgenerally reported surveillance for HCC in patients with Diagnostic Approach to HCCcompensated cirrhosis might be associated with a modest A diagnostic approach to HCC has been devel-gain in quality adjusted life years at acceptable costs. One oped based on the literature and expert consensus andstudy also reported that the effectiveness of surveillance incorporates serology, cytohistology, and radiologic char-depends mostly on the outcomes and costs of HCC acteristics.8,34 Diagnosis of HCC can be confidently es-treatments.22 In patients undergoing HCC screening tablished if (1) a focal hepatic mass 2 cm is identifiedwhile awaiting liver transplantation, screening with com- on one imaging technique wherein characteristic contrastputerized tomography (CT) is associated with the great- enhancement features on the arterial phase with venousest gain in life expectancy and is possibly cost-effective in washout on an MRI or CT can be demonstrated; (2) athis setting.23 focal hepatic mass with atypical imaging findings (no Therefore, current guidelines advocate the use of US at arterial enhancement with washout), or a focal hepatic6 –12 months frequency to screen for HCC in high-risk mass detected in a noncirrhotic liver, should undergo apatients. The use of AFP alone is strongly discouraged, biopsy.and its use in addition to US is controversial. High-risk Noninvasive diagnosis of HCC is best limited to patientspatients include virtually all patients with cirrhosis and with cirrhosis and to patients with a focal hepatic mass 2some HBV-infected patients irrespective of cirrhosis ( 40 cm. On the other hand, the recommended diagnostic ap-years in men and 50 years in women).8 proach for tumors 2 cm or tumors that do not meet above criteria8 is such that (1), when nodules within 1–2 cm Diagnostic Imaging on screening of a cirrhotic liver are typical of HCC (hyper- Once a screening test is abnormal or there is a vascular with washout) on 2 imaging modalities, the lesionclinical suspicion that a patient may have HCC, imaging should be treated as HCC. In an atypical lesion where the
  3. 3. 1754 EL–SERAG ET AL GASTROENTEROLOGY Vol. 134, No. 6 Figure 1. MRI features of HCC. The left top panel shows an arte- rial phase MRI examination of the liver and an enhancing mass in the right lobe, which further in- tensifies in the left bottom panels indicated by the arrowheads. The right top panel shows a 2-minute delayed MRI examina- tion that shows the mass in the right lobe, but this is hypointense compared with the rest of the liver as well as when compared with the arterial phase. This is the phenomenon of washout of con- trast. The right lower panel shows a 5-minute examination that highlights washout of con- trast in the delayed phase com- pared with the arterial phase examination.vascular profile is not consistent among techniques, a bi- ventional radiology, oncology, and pathology. One has toopsy of the lesion should be considered. (2) Nodules smaller consider several patient and tumor factors including thethan 1 cm should be followed with US at 3- to 6-month severity of underlying liver disease, tumor bulk, and associ-intervals. If, over a period of 2 years, growth has not been ated comorbidities as well as several practice-setting factorsobserved, a return to routine surveillance at 6-month inter- including availability and expertise in surgical resection,vals is suggested.35 transplantation, and ablative therapies. Percutaneous liver biopsy under radiologic guidancehave sensitivities and specificities of 90% and 91% for US Staging of HCCand 92% and 98% for CT scan guidance, respectively.36 A A precise staging of the disease may help decidenegative biopsy result, although highlight suggestive, on prognosis as well as choice of therapy with the great-does not completely rule out malignant disease, and the est survival potential. There are several prognostic scor-nodule should be further studied at 3- to 6-month inter- ing systems including Barcelona-Clinic Liver Cancervals until the nodule disappears, enlarges, or displays (BCLC), Cancer of the Liver Italian Program, the Chinesediagnostic characteristics of HCC. If the lesion enlarges University Prognostic Index and Japanese Integratedbut remains atypical for HCC, a repeat biopsy is recom- Staging. They use different permutations of variablesmended.36 related to the severity of liver disease, number and size of tumor nodules, and cancer spread (Table 3). Although Treatment of HCC there is no one universally accepted HCC staging system, The management of HCC involves multiple disci- many have adopted the BCLC group’s proposal of 5plines including hepatology, surgery, diagnostic and inter- stages, further validated in a large North American expe-Table 2. Summary of Several Studies That Compared the Accuracy of CT Scan and MRI Scan in HCC CT scan MRI Author Gold standard No. patients No. nodules HCC (n) Sens Sp Sens SpDe Ledinghen et al28 Explanted liver 34 88 54 51 61 84 93Rode et al30 Explanted liver 43 69 13 53 77 92 58Burrel et al27 Explanted liver 50 127 76 61 76 66 75Libbrecht et al29 Explanted liver 49 136 77 50 70 79 82Sens, sensitivity (%); Sp, specificity (%).
  4. 4. May 2008 DIAGNOSIS AND TREATMENT OF HCC 1755Table 3. Several Commonly Used Staging Systems for HCC Okuda Staginga Negative: Positive: Stage:Tumor size 50% of liver 50% of liver I: No positive factorsAscites Absent Present II: 1–2 positive factorsBilirubin 3 mg/dL 3 mg/dL III: 3–4 positive factorsSerum albumin 3 g/dL 3 g/dL Child–Turcotte–Pugh (CTP) 1 Point: 2 Points: 3 Points: Class:Encephalopathy None Grade I–II Grade III–IV A 5–6 ptsBilirubin (mg/dL) 2 2–3 3 B 7–9 ptsPT/INR 1.7 1.71–2.20 2.20 C 10–15 ptsAscites None Controlled RefractoryAlbumin (g/L) 35 28–35 28 BCLC Staging and correlation with Okuda StagingStage: PS: Tumor stage: Okuda: pH: Bilirubin: Classification: A1 0 Single I No Normal Very early A2 0 Single I Yes Normal Early A3 0 Single I Yes Altered A4 0 3 3 cm I–II Yes Altered B 0 5 cm or multinodular I–II Intermediate C 1–2 Vascular invasion I–II Advanced D 3–4 Any stage III Terminal CLIP Stagingb Portal veinPoints: CTP: Tumor morphology: AFP: thrombosis: 0 A Uninodular 50% of liver 400 ng/dL No 1 B Multinodular 50% of liver 400 ng/dL Yes 2 C Massive 50% of liverCLIP, Cancer of the Liver Italian Program; PH, portal hypertension; PS, performance status; PT, prothrombin time; INR, international normalizedratio.aMedian survival without therapy: Stage I: 8.3 years, Stage II: 2 years, Stage III: 0.7 years.bThe median survival is 36, 22, 9, 7, and 3 months for total CLIP points of 0, 1, 2, 3, and 4 to 6, respectively.rience.37,38 The BCLC staging and prognostic system ac- Despite some degree of overlap, several stages of HCCcounts for variables related to tumor stage, physical and can be identified, and each has different clinical featuresliver functional status, and cancer-related symptoms and as well as treatment and prognosis (Figure 2). Very earlyalso provides a link to a treatment algorithm. Patients in HCC is currently very difficult to diagnose, presentingstage A can undergo resection, transplantation, or abla- with a single HCC lesion 2 cm. Affected patients havetion. Child–Turcotte–Pugh (CTP) class, which provides CTP class A, display no signs or symptoms, and thean assessment of the synthetic function, may serve com- tumor displays no vascular invasion. Resection and ra-plementary to the BCLC staging in providing a more diofrequency ablation (RFA) likely offer similar 5-yearrefined treatment algorithm.39 The Okuda classification survival rates. The choice of therapy depends on thetakes into account radiologic tumor size and liver func- tumor location, degree of portal hypertension, and pres-tion (ascites, total serum bilirubin, and serum albumin) ence of medical helpful in identifying patients with advanced HCC but Patients presenting as early stage HCC exhibit preservedmay be less adequate for staging patients with early or liver function (CTP A and B) with a solitary HCC or upintermediate stage disease. Another commonly used stag- to 3 nodules, each 3 cm in size. These patients can being system is the Cancer of the Liver Italian Program,21,40 effectively treated by resection, liver transplantation (or-which uses a mathematical score based on the CTP, thotopic liver transplantation [OLT]), or ablation withtumor morphology, AFP, and presence of vascular inva- the possibility of long-term cure, with 5-year survivalsion; however, it does not adequately assess populations figures up to 75%. The choice of therapy is dictated by theundergoing radical therapies, such as resection or trans- severity of the liver function, portal hypertension, andplantation. medical comorbidities.
  5. 5. 1756 EL–SERAG ET AL GASTROENTEROLOGY Vol. 134, No. 6 Figure 2. A proposed algo- rithm for treatment of HCC (adapted from BCLC algo- rithm)103 PS, performance sta- tus; OLT, orthotopic liver trans- plantation; PEI, percutaneous ethanol injection; RFA, radiofre- quency ablation. Patients with compensated cirrhosis and without 5% of patients in Western countries but nearly 40% inHCC-related symptoms or vascular invasion that are out- HBV-endemic Asian countries.14 HBV has several cancer-side of the criteria of very early or early stage correspond to promoting actions including insertional mutagenesisthe intermediate stage HCC. In this group, transarterial and p53 inhibition that explain its potential to inducechemoembolization (TACE) leads to a 23% improvement HCC in noncirrhotic liver.48 Patients with HCC and con-in the 2-year survival compared with conservative ther- comitant cirrhosis are not suitable for resection becauseapy. of the potential for hepatic decompensation after surgi- Patients with mild cancer-related symptoms and/or cal resection. Hepatic resection for HCC in patients withvascular invasion or extrahepatic spread are considered as cirrhosis, therefore, requires careful selection. A funda-advanced stage (BCLC stage C). TACE may increase sur- mental problem is not only the stage of cirrhosis but alsovival in well-selected candidates. However, a recently com- the diminished regenerative reserve at the cirrhosis stage.pleted randomized trial showed that soranefib improved Hepatocyte regeneration decreases at the cirrhosis stage,the overall survival for patients at the BCLC stage C which has been linked to telomere shortening, senes-compared with placebo. This therapy is likely to become cence, and DNA damage checkpoint activation.49 Thethe main option for patients at this stage. development of molecular markers indicating the regen- Patients with advanced stage present with cancer erative reserve of hepatocytes may help to better selectsymptoms, related to progressed liver failure, tumor HCC patients with underlying cirrhosis for surgical re-growth with vascular involvement, extrahepatic spread, section in the future.or physical impairment (performance status 2).41 Trials Historically, the selection of candidates was based onof tamoxifen,42– 44 octreotide,45 interferon,46 or antian- the CTP classification; however, this often does not ac-drogenic therapy47 have shown no clear benefit for these count for some of the symptoms of advanced liver dis-agents. ease. A normal bilirubin concentration and the absence Unfortunately, patients who present with or have pro-gressed into terminal stage have a 1-year survival less than of significant portal hypertension are probably the best10%. This group does not benefit from treatments men- predictors of excellent short- and long-term outcomes.50tioned above. Therefore, to prevent unnecessary suffering, Significant portal hypertension can be inferred fromthe patient should receive symptomatic treatment. signs of esophageal varices and platelet counts below 100,000/mm3 related to splenomegaly or can be deter- Treatment Modalities mined by indirect portal pressure measurements (hepatic A summary of the main treatment modalities, venous pressure gradient 10 mm Hg). The 5-year sur-their indications, and reported outcomes is shown in vival is less than 30% in patients with elevated bilirubinTable 4. ( 1 mg/dL) and portal hypertension. Surgical resection. Hepatic resection is the treat- In patients with cirrhosis, 5-year recurrence rates fol-ment of choice for HCC in noncirrhotic patients because lowing resection exceed 50%.14,34 Utilization of tools suchof the fact that the residual liver has well-preserved he- as comparative genomic hybridization, integration pat-patic reserve. This group, however, accounts for less than tern of HBV, DNA fingerprinting using loss of heterozy-
  6. 6. May 2008 DIAGNOSIS AND TREATMENT OF HCC 1757Table 4. Summary of Therapeutic Modalities for HCC and Their Outcomes Treatment Survival Special issuesSurgical resection 1 y: 97% Choice of therapy for patients without cirrhosis (low morbidity) 3 y: 84% 5%–15% of HCC patients eligible 5 y: 26%–57% Right hepatectomy has higher risk than left hepatectomy Pre/postresection adjunct therapy not recommendedTransplantation (LT) 1 y: 91% Curative treatment for chronic disease and HCC 2 y: 75% MELD exception points for HCC 5 y (MILAN): 70% Effective corresponding to UNOS criteria (1 tumor 5 cm; up 5 y (extended): 50% to 3 tumors 3 cm Liver donor LT considered for HCC progression outside MILAN criteria UCSF criteria not implemented in current MELD exception allocation policyRadiofrequency ablation (RFA) 1 y: 90% Effect is more predictable in all tumor sizes than following PEI 3 y: 74% Superior to PEI in larger tumors; equivalent in small tumors 5 y: 40%–50% Requires fewer treatment sessionsPercutaneous ethanol injection (PEI) 1 y: 85% Early HCC patients not suitable to resection or OLT or RFA not 3 y: 50% available or contraindicated 5 y: 40%–50% Highly effective for small HCC ( 2 cm) Low rate of AEsTransarterial chemoembolization (TACE) 1 y: 82% Nonsurgical patients with large/multifocal HCC w/o vascular 2 y: 63% invasion or extrahepatic spreadNOTE. The 1-year survival rates are reported from different studies and thus may not be used to compare directly the different therapeuticmodalities.AE, adverse events; OLT, orthotopic liver transplantation.gosity assays, or DNA microarray has allowed researchers currently recommended United Network for Organ Shar-to determine that 60% to 70% of recurrences correspond ing (UNOS) criteria (1 lesion 5 cm or maximum 3to intrahepatic metastases and that 30% to 40% are de lesions 3 cm in diameter) have shown tremendousnovo tumors.51–53 promise, with reported 5-year survival rates of 70% and Several variables affect the risk of recurrence following recurrence rates of 15%.59 – 61 The tumor burden criteriaresection: these include tumor size, number of tumors, for transplantation for HCC as established by the UNOSvascular invasion, and the width of the resection margin. are largely accepted. Expanded selection criteria (a singleThe recommended upper limit of tumor size for consid- lesion of 6.5 cm or up to 3 lesions, none of which areeration of resection has been argued, noting that there is larger than 4.0 cm, with a maximum combined tumora significant difference in the 5-year recurrence rates in bulk of 8.0 cm), have been proposed by University ofpatients with tumors 5 cm that is considerably greater California in San Francisco.62 Liver transplantation inthan those with 5 cm (43% vs 32%, respectively).54 such candidates has been associated with outcomes sim-Similarly, multinodular tumors have been determined to ilar to those who are within the UNOS criteria. However,have an increased tendency to recur.55 A large study of given the large number of HCC cases considered for liver1000 HCC patients reported a 5-year survival after resec- transplantation, the struggle is to keep a balance betweention of single tumors to be 57% and 3 or more nodules to HCC and non-HCC 26%.56 Resectable tumor-free margins vary on a case- The UNOS oversees liver allocation in the Unitedby-case basis to balance tumor removal to reduce recur- States. Based on the radiologic diagnosis of the numberrence with preservation functioning liver parenchyma to and size of lesions, Model for End-Stage Liver Diseaseallow survival. A recent prospective randomized trial (MELD) exception points are awarded for HCC, with thecompared wide ( 2 cm) and narrow ( 1 cm) resection expectation that liver transplantation is accomplished inmargins for solitary HCC.57 Although recurrence rates a reasonable period of time. The exception points forremained high in both groups, the overall survival rates HCC are based on the 3-month pretransplantation mor-were higher for the wide margin group. tality rates. For solitary lesions 2 cm and 5 cm, as well Liver transplantation. Liver transplantation, in as up to 3 lesions, each 3 cm, patients currently receivetheory, is the optimal therapeutic option for HCC; it a MELD score of 22, unless their calculated MELD scoresimultaneously removes the tumor and underlying cir- is otherwise greater. For each 3-month interval that theyrhosis thus minimizing the risk of HCC recurrence. Ear- remain on the wait list, a greater number of exceptionlier selection criteria for liver transplantation were broad, points are awarded based on an expected increase of 10%leading to poor results with recurrence rates of approxi- for the 3-month pretransplantation mortality rate (eg,mately 50% and 5-year survival rates of 40%.58,59 The extension No. 1: 25 points for 25% mortality; extension
  7. 7. 1758 EL–SERAG ET AL GASTROENTEROLOGY Vol. 134, No. 6No. 2: 28 points for 35% mortality, . . .). The challenges HCC 3 cm24 and in almost 100% in tumors less than 2encountered in HCC pertain to the degree of MELD cm. Tumor necrosis is less likely to be achieved in largeexception points that should be assigned to HCC pa- tumors; 70% necrosis is reported for tumors between 2tients so that the number of transplantations done for and 3 cm and 50% necrosis for HCC between 3 and 5HCC patients are reasonable relative to other indications, cm.70 –72 It is a well-tolerated, inexpensive procedure withthat there is an acceptable and comparable mortality few adverse effects. In nonrandomized studies of patientsfrom all indications while awaiting transplantation, and with small HCC, PEI has been shown to carry the samethat the outcomes are similar after transplantation. overall survival and recurrence-free survival as surgical The role of downstaging of tumors that are outside of resection.73,74 In a large series of 3225 patients withconventional UNOS criteria for OLT has been explored. solitary tumors 3 cm reported by Ryu et al,75 there wereDownstaging is HCC-directed therapy that aims at re- no significant differences in survival between resectionducing the size and/or number of HCC lesions. Studies and PEI. The best survival for PEI has been shown forhave shown that successful tumor downstaging can be tumors 3 cm and 3 lesions.75achieved in up to 70% of the patients treated in a proto- RFA, which has largely replaced PEI, provides morecol with one or more therapeutic modalities including complete ablation with fewer sessions than PEI (FigureTACE, radiofrequency ablation (RFA), or percutaneous 3).76,77 The efficacy of RFA in ablating tumors 2 cm isethanol injection (PEI). Subsequently, successful liver similar to that of ethanol; however, in tumors 2 cm,transplantation was accomplished in nearly half of these efficacy is better than with ethanol.78patients.63,64 Although encouraging, longer follow-up is Several recent randomized trials compared RFA andneeded to assess further the risk of HCC recurrence after PEI in treating patients with small HCC 4 cm (TableOLT before downstaging can be recommended and 5)71,77–79 and demonstrated the superior efficacy of RFAadopted. The role of salvage liver transplantation after in terms of less operator variability, lower local recur-initial resection of HCC is less clear. Overall, suboptimal rence, and longer overall as well as disease-free survival.outcomes have been observed with this strategy com- Local tumor control was reported to range between 90%pared with primary liver transplantation for HCC.65 and 96%, with a mean of 1.1–2.1 sessions for RFA vs Given the shortage of donors and in attempts to 4.8 – 6.5 for ethanol injection (Table 5). Local recurrenceshorten the waiting time for cadaveric liver transplanta- rates have ranged between 8% and 14% at 2–3 years intion, living donor liver transplantation (LDLT) has been patients treated with RFA compared with 22%–34% inshown to be an alternative to cadaveric liver transplanta- those treated with PEI. Overall survival rates for patientstion, with approximately 3000 cases done worldwide for treated with RFA were 100% and 98% for 1 and 2 years,all indications. LDLT is a complex procedure that is respectively, compared with 96% and 88%, respectively, inassociated with a morbidity of 20%– 40% and a donor the PEI trials. Recurrence-free survival rates at 1 and 2mortality of 0.3%– 0.5%.66,67 With that, consideration of years were 86% and 64% for the RFA group and 77% andethical, societal, and legal issues are vital to successful 43% for the PEI group, respectively.79 Adverse events wereimplementation of LDLT for HCC treatment. A recent generally similar for the 2 treatment groups. There hasretrospective analysis of a United States experience noted been a large experience reporting RFA safety even inthat the disease-free survival following LDLT was lower those with lesions close to vascular structures.80 Thesethan that of cadaveric liver transplantation. LDLT recip- data indicate that RFA leads to better local tumor andients had a higher rate of HCC recurrence within 3 years longer overall survival for patients with very early as wellthan deceased donor OLT recipients, 30% vs 0%, respec- as early stage HCC. Therefore, RFA is the preferredtively. However, there was no difference in mortality or method of local ablation for patients with tumors 4the combined outcome of mortality or recurrence.68 cm. RFA should be considered for patients with very earlyThus, the role of LDLT, particularly for those outside of stage HCC when resection cannot be applied and also forideal criteria, needs further evaluation. patients with early stage HCC who are not candidates for Percutaneous ablation. Minimally invasive per- OLT and possibly for those with long waiting times 3cutaneous treatments are the best treatment alternatives months.for early HCC patients who are not eligible for surgical There are at least 2 prospective, randomized controlledresection or transplantation. The most widely utilized trials comparing RFA with surgical resection. Both foundmethods to induce tumor necrosis are PEI and RFA. no significant differences in overall survival or recur-Other, less utilized methods include the injection of rence-free survival and expectedly lower complicationacetic acid, boiling saline, cryotherapy, microwave ther- rates and lower hospitalization in patients treated withapy, and laser therapy.8,58,69 RFA.81,82 A recent Italian cohort study of 218 patients PEI consists of injecting absolute ethanol directly into with HCC tumors 2 cm in diameter showed a sustainedthe HCC lesions. PEI performed under US guidance response in 97% during a median follow-up of 31 monthsachieves complete tumor necrosis in 70%– 80% of solitary and a 5-year survival rate of 68%.83 It seems that these 2
  8. 8. May 2008 DIAGNOSIS AND TREATMENT OF HCC 1759Figure 3. Percutaneous abla-tion of HCC using radiofrequency.procedures offer similar efficacy, and the choice of ther- 12% of the 903 patients evaluated for HCC were suit-apy for very early stage HCC should depend on candidacy able for TACE.84for surgery in terms of performance status, severity of The basis of embolization is to induce ischemic tumorportal hypertension, and feasibility of RFA in terms of necrosis via acute arterial occlusion. Embolization maytumor location. be done alone (transarterial embolization) or combined Transarterial embolization/chemoembolization. with selective intraarterial chemotherapy (TACE) such asTACE may offer palliative benefits for patients with doxorubicin, mitomycin, or cisplatin and a contrastintermediate stage HCC with 5-year survival rates after agent, lipiodol.treatment exceeding 50%. TACE has been shown to TACE induces extensive tumor necrosis in 30% to upimprove survival in patients outside of the early stage to 50% of those treated patients, but with fewer than 2%criteria, especially in those who have not presented achieving a complete response.84 A meta-analysis of 7with cancer-related symptoms or vascular invasion.69 randomized controlled trials comparing in that meta-However, its safe and effective use is limited to patients analysis, arterial embolization and/or chemoemboliza-with preserved liver function, absence of extrahepatic tion as a primary treatment for HCC in comparison withspread or vascular invasion, and no significant cancer- conservative management and/or suboptimal therapies.85related symptoms. A European study revealed that only Arterial embolization improved 2-year survival comparedTable 5. Summary of Several Studies That Compared PEI and RFA for HCC Treatment Complete Sessions necrosis rate (%) (average number) Author N Tumor size PEI RFA PEI RFA Survival differenceLivraghi et al71 86 3 cm 80 90 4.8 1.2 NoLencioni et al79 102 Milan criteria 82 91 5.4 1.1 Yes Recurrence freeLin et al78 157 4 cm 88 96 6.5 1.6 YesShiina et al77 232 Milan criteria NA 6.4 2.1 YesNOTE. The 1-year survival rates are reported from different studies and thus may not be used to compare directly the different therapeuticmodalities.PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
  9. 9. 1760 EL–SERAG ET AL GASTROENTEROLOGY Vol. 134, No. 6with that in control subjects (odds ratio, 0.53; 95% CI: icas, Europe, and Australia/New Zealand. The overall sur-0.32– 0.89). vival (46.3 weeks, 95% CI: 40.9 –57.9, vs 34.4 weeks, 95% CI: In a large, prospective cohort study of 8510 patients 29.4 –39.4, respectively, P .058) and time to symptomwho received TACE for unresectable HCC, the median progression (24 weeks, 95% CI: 18 –30, vs 12 weeks, 95% CI:survival was 34 months with 1-, 2-, 3-, 5-, and 7-year 11.7–17.1, respectively, P .007) were significantly longer insurvivals of 82%, 47%, 26%, and 16%, respectively.86 There patients administered Nexavar vs those patients adminis-is currently little data to guide the choice of the chemo- tered placebo.88 Approximately 83% of the patients in thetherapeutic agent or the retreatment schedule for TACE. sorafenib trial had portal vein invasion and were classifiedThe current evidence does not support the use of transar- as Barcelona stage C, with 20% having extrahepatic metas-terial embolization without chemotherapeutic agent. tases. The 17% without portal vein invasion were patients Transarterial embolization/TACE are associated with who did not respond to TACE and were classified as Bar-adverse events in approximately 10% of treated patients; celona stage B in the study. Most patients had mild tothese events include ischemic cholecystitis, nausea, vom- moderate performance status. Therefore, it is reasonable toiting, bone marrow depression, and abdominal pain.58 A recommend sorafenib for patients with advanced stage orpostembolization syndrome is reported in 50% of pa- intermediate stage HCC with portal vein thrombosis. Prom-tients treated with TACE and includes fever, abdominal ising results89 on progression-free survival have also beenpain, and moderate degree of intestinal obstruction. reported for Erlotinib, an inhibitor of endothelial growthTreatment-related mortality is less than 5%. factor receptor signalling.90 TACE is clearly the first-line therapy for patients at the Telomerase inhibition. Telomerase is active inintermediate stage who exceed the criteria for liver trans- 90% of human HCC, and it appears to be necessary for theplantation (Figure 2). In addition, TACE can be per- immortal proliferation capacity of HCCs.49 Preclinical stud-formed in patients at the early stage in whom RFA ies show that telomerase inhibition can impair proliferationcannot be performed because of tumor location (proxim- of human HCC in nude mice.91 Phase I/II clinical studiesity to a gallbladder, biliary tree, or blood vessel) or med- are currently underway in patients with lymphoma. In ad-ical comorbidities. TACE is also the first-line therapy for dition to the above approaches, antibody treatment againstdownstaging tumors that exceed the criteria for HCC surface markers have been reported to lower recur-transplantation.64 rence rates after liver transplantation.92 Other options. Radionuclide Yttrium-90, a pure Another important factor to improve future therapiesemitter, is a form of hepatic artery-directed therapy. Mi- in HCC is the development of new markers to improvecrospheres of approximately 25 m in diameter contain- screening of cirrhosis patients for early lesions,93 selec-ing Yttrium-90 are lodged via a catheter insertion into tion of HCC patients that could benefit from surgery orthe lobar or segmental level of either hepatic artery and chemotherapy,94 –97 or diagnosis of HCC.98 However, theemit local radiation with limited exposure to adjacent utility of these tests remains unproven and will have to behealthy tissue.87 Currently, there are no data to suggest tested in translational and clinical studies.its superiority over ablative therapies. HCC Treatment: Effectiveness vs Efficacy Molecular Therapies Population-based studies in the United States indi- There are a growing number of clinical studies cate that the overall 1- and 3-year survival rates for patientsevaluating the efficacy of molecular therapies in HCC, with HCC are approximately 20% and 5%, respectively (me-alone or in combination with classical chemotherapy. dian survival of 8 months).99 These figures accommodate Angiogenesis inhibitors. Several studies (phase I, for a 20% improvement in survival that was observed be-II, and III) are underway. Positive results have been ob- tween 1987 and 2001. To make a positive impact on thetained for therapies using Bevacizumab (vascular endo- effectiveness of treating HCC, several steps have to be suc-thelial growth factor inhibitor) in combination with cessfully accomplished so that more patients can be diag-Gemcitabine and Oxalliplatin. nosed at an early stage and receive timely potentially cura- Growth-receptor signaling. Studies have been tive therapy. However, there seems to be a serious chasmconducted targeting platelet-derived growth factor receptor, between efficacy and effectiveness of treatment of HCC.100 Aendothelial growth factor receptor, Raf, and other signaling United States population-based study reported that, inpathways controlling cell proliferation. Positive results were 2963 patients 65 years and older diagnosed between 1992reported for the use of Nexavar (Bayer Healthcare AG, and 1999 with HCC, only 13% received potentially curativeLeverkusen, Germany) (sorafenib), an oral multikinase in- therapy (transplant, 0.9%; resection, 8.2%; local ablation,hibitor, in patients with HCC. A phase III double-blind, 4.1%). Furthermore, only 34% of 513 patients with singlerandomized, placebo-controlled trial was designed to eval- lesions and 34% of 143 patients with lesions 3.0 cmuate Nexavar in patients with advanced HCC (BCLC stage received potentially curative therapy. There were geographicC) who had no prior systemic therapy. Six hundred two variations in the management of HCC that are at least aspatients were randomized and enrolled at sites in the Amer- significant as clinical and tumor-related features in deter-
  10. 10. May 2008 DIAGNOSIS AND TREATMENT OF HCC 1761mining the extent and type of HCC therapy.101 Another 10. Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer:United States population-based study of 1156 patients di- results of a randomised controlled trial in Qidong, China. J Med Screen 2003;10:204 –209.agnosed between 1998 and 2002 with small nonmetastatic 11. Wong LL, Limm WM, Severino R, et al. Improved survival withHCC in the United States found that liver transplantation screening for hepatocellular carcinoma. Liver Transpl 2000;6:yielded excellent overall survival, but only 21% of patients 320 –325.with localized HCC received a transplant. Marked geo- 12. Trevisani F, De NS, Rapaccini G, et al. Semiannual and annualgraphic and racial variations were seen in the use of trans- surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience).plantation for HCC after controlling for other tumor and Am J Gastroenterol 2002;97:734 –744.patient-related variables. For example, 25% of white pa- 13. Zhang B, Yang B. Combined -fetoprotein testing and ultra-tients, 21% of Hispanic patients, 17% of Asians patients, and sonography as a screening test for primary liver cancer. J Medonly 13% of African-American patients received a transplant. Screen 1999;6:108 –110.Patients with HCC were 2.2 times less likely to get a trans- 14. Bolondi L, Sofia S, Siringo S, et al. Surveillance programme ofplant in the South and 3.3 times less likely in the Northeast cirrhotic patients for early diagnosis and treatment of hepato- cellular carcinoma: a cost effectiveness analysis. 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Kulik LM, Atassi B, van Holsbeek L, et al. Yttrium-90 micro- cine, Houston, Texas 77030. e-mail:; fax: spheres (TheraSphere) treatment of unresectable hepatocellu- (713) 748 7359.