C u r ren t A p p ro a c h to Hepatocellular C a rc i n o m a

Peter Abrams,
KEYWORDS  Hepatocellular carcinoma  Partial hepatectomy  Liver transplantation  Locoregional therapy  Transarterial chemoembolization  Radiofrequency ablation
MD,

J. Wallis Marsh,

MD, MBA*

Hepatocellular carcinoma (HCC), an epithelial tumor derived from hepatocytes, accounts for 80% of all primary liver cancers and ranks globally as the fourth leading cause of cancer-related deaths. Annual mortality rates of HCC remain comparable to its yearly incidence, making it one of the most lethal varieties of solid-organ cancer.1 A retrospective study using the population-based registries of the Surveillance, Epidemiology, and End Results (SEER) program found that 11,547 cases of HCC were diagnosed in the United States between 1975 and 1998. Attributed at least in part to the hepatitis C (HCV) epidemic beginning in the 1960s, the overall age-adjusted incidence rates of HCC in the United States have steadily increased over the past 2 decades, from 1.3 per 100,000 persons from 1981 to 1983, to 3.0 per 100,000 persons from 1996 to 1998, increasing again to 4.1 per 100,000 persons from 1998 to 2000.24 Well-established risk factors for the development of HCC include hepatitis B carrier state, chronic hepatitis C infection, hereditary hemochromatosis, and cirrhosis of any etiology, as well as certain environmental toxins. Men are more prone to develop HCC, especially in high-incidence regions such as sub-Saharan Africa and Southeast Asia, with a mean male-to-female ratio of 3.7 to 1.0. Although not completely understood, the disparity in gender distribution is thought to be related to variations in hepatitis carrier states, exposure to environmental toxins, and the trophic effect of androgens.5 Most cases occur in patients with chronic liver disease or cirrhosis, affecting older persons disproportionately.
DIAGNOSIS

The diagnosis of HCC commonly involves radiology, biopsy, and alpha fetoprotein (AFP) serology testing. Individual evaluations are guided by the context of the patient
Department of Surgery, Thomas East Starzl Transplantation Institute, Montefiore Hospital, University of Pittsburgh School of Medicine, N755.8, 3459 Fifth Avenue, Pittsburgh, PA 15215, USA * Corresponding author. E-mail address: marshw@upmc.edu Surg Clin N Am 90 (2010) 803816 doi:10.1016/j.suc.2010.04.010 surgical.theclinics.com 0039-6109/10/$ see front matter 2010 Elsevier Inc. All rights reserved.

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presentation. In almost every instance, some form of high-resolution imaging, usually triphasic CT scan or MRI with gadolinium injection, is indicated to measure the extent of disease. Percutaneous fine-needle biopsy (2%3% rate of needle tract seeding) may be indicated in the setting of inconclusive imaging.6,7 At diagnosis, 20% to 60% of small lesions are found to be multifocal and, despite adequate preoperative assessment, up to 30% of tumors in patients with cirrhosis are understaged.810 In the setting of a patient presenting with significant risk factors, the detection of a liver mass requires a high index of suspicion for HCC. The sequence and type of tests used to diagnose HCC depend mainly on the radiologic characteristics and dimensions of the liver mass. Lesions measuring smaller than 1 cm, particularly in the context of cirrhosis, have a low likelihood of being HCC. If these subcentimeter lesions do not enhance on contrast imaging, their likelihood of being HCC is further diminished.11 This low likelihood of malignancy, however, is tempered by the ability over time to transform into HCC.12 Therefore, these lesions must undergo surveillance over the first 1 to 2 years to confirm lack of growth and, by implication, the absence of HCC. The current consensus guidelines regarding surveillance of subcentimeter liver lesions is to perform ultrasound follow-up at intervals from 3 to 6 months over the first 24 months, followed by routine surveillance after documenting no interval growth.13 Alternative imaging to ultrasound, CT, and/or MRI (such as lipiodol angiography) is not recommended as standalone surveillance in this subset of patients owing to lower sensitivity for small lesions. Lesions measuring 1 to 2 cm in a cirrhotic liver have been shown to have a significant likelihood of HCC. Many investigators have argued that this size range in the context of chronic liver disease requires biopsy.14,15 Although obtaining reliable biopsy specimens from these small lesions can be challenging, adequate characterization of lesions smaller than 2 cm by imaging techniques alone appears similarly burdened by likelihood of error. The characteristic arterial-phase enhancement and venousphase wash-out of HCC lesions are more difficult to identify with certainty in nodules smaller than 2 cm. Other non-HCC lesions smaller than 2 cm (eg, dysplastic nodules) may demonstrate similar characteristics to HCC, such as arterial enhancement without venous washout. In cirrhotic livers, it has been estimated that up to 25% of lesions smaller than 2 cm in diameter with arterial uptake but without venous washout will either not increase in size or regress over time and thus do not represent HCC disease.13,1618 Biopsy, therefore, remains a critical tool in identifying HCC with sufficient confidence in 1- to 2-cm lesions. Any liver lesion measuring larger than 2 cm in a cirrhotic liver is HCC until proven otherwise. In the setting of a larger than 2-cm lesion demonstrating characteristic HCC findings on high-resolution, contrast-enhanced imaging along with an AFP higher than 200 ng/ml, the diagnosis of HCC is made with sufficient confidence that biopsy confirmation is rarely indicated.15,16 Lesions larger than 2 cm with incongruous imaging characteristics in a cirrhotic liver or with classic HCC characteristics in a noncirrhotic liver may require biopsy to achieve sufficient diagnostic confidence.13 Current consensus guidelines reiterate the lack of necessity for biopsy in patients with cirrhosis with a lesion larger than 2 cm with characteristic HCC findings on 2 high-resolution, contrast-enhanced imaging studies, irrespective of AFP level, as the positive predictive value of the combination of clinical context and imaging findings exceeds 95%.13,14
STAGING

The staging of HCC is complicated twofoldby a lack of global consensus on any given HCC staging system and the significant impact of underlying liver function on

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prognosis. Most US physicians and surgeons use the modified TNM staging system (Table 1); however, this system fails as a robust predictor of tumor-free survival after transplantation in patients with HCC.13,19,20 The United Network for Organ Sharing (UNOS) uses an alternative staging system based on the American Liver Tumor Study Group (ALTSG), allowing certain patients with HCC to be prioritized on the transplant candidate waiting list (Table 2).21 Like the modified TNM system, the ALTSG classification system does not take into consideration the extent of underlying liver disease or tumor biology.
INDICATIONS FOR PARTIAL HEPATECTOMY

Partial hepatectomy (PH) is the standard treatment for resectable HCC in patients without cirrhosis, irrespective of extent of liver fibrosis; however, these criteria are met in only 5% of cases in Western countries, but in up to 40% in Asia. Earlier diagnosis, better patient selection, and advances in operative and postoperative management have increased the long-term survival of patients undergoing PH for HCC, with reported 1- and 5-year survival rates of 55% to 90% and 10% to 50%, respectively.22,23 Operative mortality rates in patients with cirrhosis and without

Table 1 TNM staging system for hepatocellular carcinoma T TX T0 T1 T2 Primary Tumor Primary tumor cannot be assessed No evidence of primary tumor Solitary, %2 cm, no vascular invasion Solitary, %2 cm, vascular invasion Multiple, one lobe %2 cm, no vascular invasion Solitary, >2 cm, no vascular invasion Solitary, >2 cm, vascular invasion Multiple, one lobe, <2 cm, vascular invasion Multiple, one lobe, >2 cm, with/without vascular invasion Multiple, more than one lobe Invasion of major branch of portal or hepatic vein Invasion of adjacent organs other than gallbladder Perforation of visceral peritoneum NX N0 N1 M MX M0 M1 Stage grouping Stage I Stage II Stage IIIA Stage IIIB Stage IVA Stage IVB T1N0M0 T2N0M0 T3N0M0 T1N1M0, T2N1M0, T3N1M0 T4, any N, M0 Any T, any N, M1 Regional lymph nodes Regional lymph nodes cannot be assessed No regional lymph node metastases Regional lymph node metastases Distant metastasis Distant metastasis cannot be assessed No distant metastasis Distant metastasis

T3

T4

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Table 2 American liver tumor study group modified TNM staging classification T0, N0, M0 T1 T2 T3 T4a T4b N1 M1 Stage I Stage II Stage III Stage IVA1 Stage IVA2 Stage IVB Not Found 1 nodule <1.9 cm 1 nodule 2.05.0 cm 23 nodules, all <3.0 cm 1 nodule >5.0 cm 23 nodules, at least 1>3.0 cm R4, any size T2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or US Regional (portal hepatitis) nodes involved Metastatic disease, including extrahepatic portal or hepatic vein involvement T1 T2 T3 T4a T4b Any N1, any M1

Abbreviation: US, ultrasound.

cirrhosis are 7% to 25% and less than 3%, respectively.8 Recorded deaths after the perioperative period are most frequently associated with tumor recurrence. Patients without cirrhosis but demonstrating compromised hepatic function must be carefully selected for PH to avoid postoperative liver failure and its accompanying high mortality. A clear departure has occurred from the historical use of the Child-Pugh classification as a predictor of postresection liver function, and most US liver surgeons today use clinical and diagnostic imaging to screen for portal hypertension to determine whether PH is a safe option. Multiple studies have demonstrated that a normal serum bilirubin level and the absence of clinically significant portal hypertension (ie, hepatic vein pressure gradient <10 mm Hg) are the best available indicators of acceptably low risk of postoperative liver failure after PH.24,25 In the absence of an elevated serum bilirubin and portal hypertension, survival after PH can exceed 70% at 5 years.24 In patients with an elevated serum bilirubin and significant portal hypertension, survival after PH drops to less than 30% at 5 years, regardless of Child-Pugh score. Survival after PH in patients with significant portal hypertension alone decreases to less than 50% at 5 years.24 Direct measurement of portal pressure is not necessary in patients with clinical signs of severe portal hypertension, including esophageal varices, ascites, or splenomegaly associated with a platelet count less than 100,000/mL. Experienced liver centers are now performing advanced laparoscopic liver resections, including right hepatectomy, left hepatectomy, and even extended right and left hepatectomy. A recent review of the international experience with laparoscopic liver resection found that 3- and 5-year survival rates for select patients were comparable with open PH.26 Reported advantages of laparoscopic liver resection include less analgesic requirements, smaller incisions with preservation of the abdominal wall, shorter inpatient stays, fewer transfusion requirements, accelerated postoperative recovery, and fewer postoperative adhesions. Potential limitations and disadvantages of laparoscopic liver resection include a significant learning curve, delayed

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control of major bleeding, insufficient assessment of the liver for additional lesions, and increased risk for gas embolism.26 As liver surgeons become more proficient with laparoscopic liver surgery as a component of the overall approach to HCC in patients without cirrhosis, we anticipate an increasing number of resections will be performed in a minimally invasive fashion. Similar to transitions occurring in the practice of vascular surgery, expertise in performing large open resections will likely contract and eventually be limited to a relatively small number of experienced liver centers. Exclusion from PH for multiple HCC lesions is a common but not universal practice among US liver surgeons. Notwithstanding evidence that increasing diameter does increase the likelihood of vascular invasion, increased size (>5 cm) of HCC tumors is not an absolute contraindication for PH. A wealth of anecdotal evidence demonstrates that some tumors may grow into very large, single lesions without vascular invasion, and thus represent no increased risk of recurrence after resection as compared with smaller lesions.25,27 Despite the many advances in patient selection and management leading to increased rates of long-term survival, the 5-year recurrence rates of HCC following PH range from 60% to 100%.28 The great majority (>80%) of recurrences are intrahepatic. Multivariate statistical analyses demonstrate the presence of microvascular invasion and multifocal disease as the strongest predictors of recurrence.25,27,29 These risk factors imply that dissemination, rather than de novo lesions, accounts for most recurrences.30 Undetected dissemination as the predominant mechanism of early recurrence also explains the preponderance of recurrences occurring within the first 3 years of follow-up.31 There have been no reports of neoadjuvant or adjuvant therapy causing significant reductions in recurrence rates after PH.32 Treatment of recurrence after PH remains an individualized practice with little in the way of outcomes data to support a more or less aggressive approach. Repeat resection may be indicated in the setting of a solitary recurrence. However, as dissemination appears to be the predominant cause of early recurrence, one might reasonably remain skeptical that a single lesion detected on high-resolution imaging does truly represent a solitary recurrence.33 Nonetheless, repeat resection in selected cases is warranted.
INDICATIONS FOR LIVER TRANSPLANTATION

Although complete surgical resection or ablation can provide cure for select patients, most patients with HCC have underlying cirrhosis, which itself behaves as a premalignant condition.34,35 Although PH treats localized HCC, it may fail to treat multifocal HCC and has no efficacy in preventing de novo HCC occurring in the remnant cirrhotic liver. Liver transplantation (LT) addresses HCC along with its multifocal potential, and treats the underlying liver disease itself. The accumulation of outcomes data has clearly established LT as the gold standard for early-stage HCC in the setting of cirrhosis. Initially poor outcomes were observed from LT for unresectable HCC in unselected patients (recurrence rates >60% within 2 years and 5-year survival rates <20%).3638 Much lower recurrence rates after LT were demonstrated for incidentally detected HCC in pathologic explants, providing the impetus for evaluating the role of LT for patients with small HCC.39,40 A provocative report by Bismuth and colleagues39 demonstrated that patients with 3 or fewer tumors each 3 cm or smaller in greatest diameter had a 3-year, disease-free survival of 83% after LT, compared with 18% after PH. A seminal retrospective study by Mazzaferro and colleagues10 established that favorable results could be achieved in patients with cirrhosis with either a solitary

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HCC smaller than 5 cm or with up to 3 nodules smaller than 3 cm, criteria that came to be called the Milano criteria. The 5-year survival of these early-stage patients exceeded 70%. Recipient age, gender, type of viral infection, or Child-Pugh score did not affect survival after transplantation. Liver transplantation demonstrates not only the best survival and recurrence-free rates, but also provides the longest recurrence-free survival, which in one retrospective analysis was as high as 77% at 5 years, compared with 20% after PH.41 In a multivariate analysis of a single-center experience at the University of Pittsburgh involving 307 patients undergoing LT for HCC between 1981 and 1997, the senior investigator of this review (J.W.M) found that independent predictors of tumor-free survival included lymph node status, depth of vascular invasion, greatest tumor dimension, lobar distribution, and tumor number (Table 3).20 There was no direct correlation between the current modified TNM staging system for HCC and tumor-free survival after LT (Table 4). In an effort to prioritize for LT those candidates with the highest short-term risk of mortality, the model for end-stage liver disease (MELD) scoring system was implemented in 2002. Although numerous studies have demonstrated the systems efficacy in predicting mortality in the setting of chronic viral and alcoholic liver disease, others have found that MELD is less robust in predicting mortality related to cholestatic liver disease and has no predictive power for HCC. To impart more urgent access to LT for select patients with HCC (eg, those with early-stage disease), additional points within the scoring system were allotted to patients with HCC to equilibrate their risk of death in comparison with the mortality of end-stage cirrhosis.42 The original scoring exception, which included lesions smaller than 2 cm, resulted in the overdistribution of donor
Table 3 Univariate analysis of all variables included in the current pathologic TNM staging system Risk Factor (no.) Lymph node status Neg (231) Pos (6) Vascular invasion None (133) Micro (67) Macro (37) Tumor size (cm) %2 (101) 24 (71) >4 (65) Lobar distribution Unilobar (161) Bilobar (76) Tumor number Single (120) Multiple (117) 168.8 9.2 (150.9186.8) 98.2 8.3 (81.9114.4) P<.0001 169.9 7.2 (155.9183.9) 49.7 6.2 (37.561.8) P<.0001 123.6 6.8 (110.3137.0) 142.7 11.8 (119.5165.8) 70.2 9.8 (51.089.5) P12<.0001 P13<.0001 P23<.0001 178.4 7.5 (163.8192.9) 112.4 11.2 (90.4134.4) 15.3 3.5 (8.522.1) P12<.00001 P13<.00001 P23<.00001 140.6 6.8 (127.2154.0) 5.3 1.0 (3.37.3) P<.00001 Tumor-Free Survival in Months (mean SE) 95% CI Significancea

Abbreviations: CI, confidence interval; Neg, negative; Pos, positive; SE, standard error; , failed to reach statistical significance. a Pxy expresses the significance between level x and level y.

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Table 4 Multivariate analysis of all variables included in the current pathologic TNM staging system Risk Factor Vascular invasion None Micro Macro Tumor size (cm) <2 24 >4 Lymph node status Negative Positive Lobar distribution Unilobar Bilobar J21 5 3.1 1.805.60 J21 5 2.95 0.988.9 J31 5 5.37 J32 5 1.55 J21 5 3.46 1.8115.9 0.852.81 2.135.66 J31 5 14.0 J32 5 3.96 J21 5 3.54 6.2331.35 2.676.92 2.334.5 Relative Riska 95% CI

Abbreviation: CI, confidence interval; , failed to reach statistical significance. a Jxy expresses the relative risk of level x to level y.

livers to patients with HCC (with many expected small tumors turning out not to be HCC on explanted pathology) and was therefore modified by a reduction in allocated points for Stage II patients and an elimination of the upgrade for Stage I.43 Using the American Liver Tumor Study Group Modified TNM staging system (see Table 2), current UNOS guidelines do not allow upgrading of candidates with Stage I disease, irrespective of biopsy confirmation; only candidates with Stage II HCC disease are upgraded on the waiting list to a MELD score of 22 (equivalent to a 15% probability of candidate death within 3 months) with the intent to shorten their waiting time. Owing to widely varying degrees of benefit from LT, patients with Stage III to IVa are not allocated extra points while on the UNOS waiting list, a blanket policy with which we disagree. Moreover, we believe that patients with Stage I disease should have the option of undergoing a biopsy, which, if positive for HCC, should qualify for an immediate MELD upgrade, as patients in Stage I are in their most curable stage. The strict application of the Milano criteria by UNOS for MELD upgrade allocation disadvantages patients with HCC with tumor profiles exceeding the criterias maximal size or multifocal parameters but in whom favorable outcomes after LT have been demonstrated.20,44,45 There is an ongoing debate within the liver transplantation community regarding whether and to what extent the indications for LT as primary therapy for HCC should be expanded.46 For patients with HCC disease beyond standard listing criteria in whom there is no macroscopic evidence of vascular invasion or extrahepatic spread, the survival rates after LT are generally comparable with patients transplanted for disease within the standard listing criteria. Most groups report a 5-year survival of more than 50% in patients transplanted for extended criteria HCC,41 which many investigators have argued is the minimum acceptable survival rate. In 2001, using explant pathologic data, Yao and colleagues44 at the University of California, San Francisco (UCSF) defined an expanded set of HCC criteria (solitary tumor %6.5 cm, or %3 nodules with the largest tumor %4.5 cm and total tumor diameter %8 cm) for which 1- and 5-year survival rates after LT were 90% and 75%,

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respectively. Retrospectively evaluating post-LT survival for patients with tumors beyond Milano criteria but within these UCSF expanded criteria by pretransplantation imaging and explant pathology, the group at the University of California, Los Angeles (UCLA) confirmed acceptable 1-, 3-, and 5-year survival rates of 82%, 65%, and 52%, respectively.47 Moreover, the difference in 5-year recurrence-free survival after LT for HCC in the UCLA study did not reach statistical significance between Milano criteria and UCSF expanded criteria tumor groups (74% vs 65%, P 5 .09). The Barcelona Clinic Liver Cancer Group4850 has demonstrated 5-year post-LT survival of greater than 50% using expanded criteria including 1 tumor size smaller than 7 cm, 3 tumors smaller than 5 cm, 5 tumors smaller than 3 cm, or downstaging to conventional Milano criteria with pre-LT adjuvant therapies. In the absence of more precise markers of HCC, biologic behavior that might better predict which patients with HCC would benefit from LT, it remains to be seen whether the overly restrictive UNOS tumor size and numberbased criteria for HCC will be expanded to allow access to LT to carefully selected patients who otherwise face certain death. The major limitation for LT as therapy for early-stage HCC is the insufficient number of donor livers. Without a living donor, there is always a waiting period between candidate listing and transplantation. If the waiting period extends over a sufficient length of time, the tumor will grow and eventually manifest absolute contraindications to LT (eg, macroscopic vascular invasion or extrahepatic spread). In a study by Yao and colleagues51 of patients with HCC on the waiting list, a 6-month waiting period for LT was associated with a 7.2% cumulative dropout probability, increasing to 37.8% and 55.1% at 12 and 18 months, respectively. Efforts to address the large waiting list of LT candidates and to decrease the dropout rate have included new strategies such as living donor LT, domino LT, split LT, the use of extended criteria donors, and donors after cardiac death. Living donor LT appears to be an effective option for patients with HCC within the Milano criteria, essentially equivalent in terms of survival to cadaveric LT, and should be especially considered if the anticipated waiting period is sufficient that tumor progression is likely. There are few data to support the use of living donor LT for patients with HCC who exceed the Milano criteria, although its use for this purpose is becoming increasingly common. We disagree with this practice. Because living donation puts a healthy individual at risk, it is our opinion that livers donated from living donors should be reserved for early-stage disease, whereas cadaveric livers should be used for more advanced but acceptable cases. Some investigators have suggested that patients with recurrent HCC after PH might be candidates for salvage transplantation.52 This option continues to lack support from clinical outcomes data. Alternatively, because the most strongly predictive factors for recurrence attributable to dissemination (eg, vascular invasion and satellite lesions) can be identified on pathologic examination, other investigators have proposed that a pathology-specific subset of patients lacking these findings on explant pathology be listed for LT immediately after PH, as the results of LT in this population appear favorable.53
INDICATIONS FOR ALTERNATIVE THERAPIES

Local regional therapy (LRT) is indicated for select patients who are not candidates for either PH or LT. LRT modalities include percutaneous ethanol injection (PEI), transarterial chemoembolization (TACE), and radiofrequency ablation (RFA), as well as transarterial radioembolization with Yttrium-90 (TARE-90Y). Although PH remains the standard for resectable HCC in the patient without cirrhosis, a growing body of clinical

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evidence demonstrates LRT survival rates, and outcomes after RFA in particular, are comparable with PH for HCC tumors 3 cm or smaller in diameter.54 Despite its increasingly common use as bridge therapy before LT, it remains to be determined whether LRT provides a survival benefit to those LT candidates facing a prolonged waiting time. Multiple LRT modalities have been used with mixed and controversial efficacy to decrease tumor burden and downstage HCC patients to Stage II disease. In the United States, RFA has become the predominant LRT for small HCCs, as it can achieve complete necrosis with fewer treatment sessions compared with PEI.55 The results of a meta-analysis of published randomized controlled studies indicate that TACE versus conservative management may provide a significant survival benefit to select patients with advanced-stage disease.50 In response to improving survival results with LRT, there are many centers outside the United States that offer local ablation as first-line therapy to select patients with small HCC.56 To date there are no randomized trials comparing PEI or RFA to PH. For treatment of small HCC in patients with cirrhosis, a single European cohort study demonstrated similar overall survival and recurrence rates between PEI and PH.57 Multicenter outcomes data from Japan demonstrate that Childs A patients with successful tumor necrosis may achieve 50% survival at 5 years, which appears to compare favorably with PH outcomes in nonoptimal surgical candidates.58 Reported HCC recurrence rates after LRT vary widely, with most long-term studies involving patients with unresectable disease, but in general are at least as high as for PH.13,59 Recurrences after ablation occur either from dissemination or the persistence of microscopic satellite nodules outside the ablation zone. With respect to tumor puncture by RFA and PEI, concerns over seeding are restricted mainly to either poorly differentiated HCC or peripheral tumors.60,61 Apart from reasonable concerns about iatrogenic spread of tumor cells, tumor tract seeding is not synonymous with metastatic disease and has not been found to affect survival. LRT remains an attractive modality for its ability to induce tumor necrosis and provide temporary control of tumor spread.14 Preliminary data from several centers have suggested a possible benefit of LRT in reducing rates of candidate drop-out because of tumor progression when the waiting period extends beyond 6 months.51,62,63 Given the risk of tumor progression, it is the practice of many transplant centers to treat HCC with LRT upon listing and before LT. The most common bridge therapy is TACE, as it has been shown to decrease tumor burden and delay tumor progression.64 The utility of pretransplant TACE as a means of improving survival after LT remains controversial. A case-control series reported by Decaens and colleagues65 showed that pre-LT TACE did not impact 5-year survival (59% TACE vs 59% no TACE, P 5 .7). Olthoff and colleagues66 similarly showed no difference in survival at 3 years post-LT if patients received pre-LT TACE. However, other centers have studied the outcomes of pathologic stage-specific patients with HCC undergoing TACE followed by LT and reported encouraging preliminary results. In a retrospective analysis of a small number of nonrandomized patients with T2 and T3 HCC within UCSF expanded criteria, treatment with TACE before LT resulted in a significant survival benefit versus no treatment, with 5-year recurrence-free survival rates of 85% versus 51% and 96% versus 87% for T3 and T2 HCC, respectively.67 To increase access to LT for patients with HCC, all major modalities of LRT have been used in an attempt to downstage excess tumor burden to within Milano criteria.67,68 Some investigators have suggested that the process of downstaging helps to identify aggressive disease, providing a window into an individual tumors probability of dissemination, thereby improving patient selection for LT and potentially

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post-LT survival.69 In a prospective study of a small number of patients reported by Yao and colleagues,70 70% of patients with tumor burden outside Milano criteria were successfully downstaged using multiple LRT modalities. Which modality or combination of LRT modalities to use and whether downstaging of HCC by any modality leads to better outcomes after LT remain critical questions to be clarified by randomized prospective studies.
SUMMARY

The incidence of HCC in the United States and worldwide continues to increase. Despite many significant advances, most patients continue to face a dismal prognosis, with a median survival after diagnosis of 6 to 20 months. In select patients, PH remains the best treatment option for HCC in the noncirrhotic liver. LT represents the gold standard for patients with HCC and cirrhosis in the absence of extrahepatic spread and macrovascular invasion. The scarcity of liver donors requires that national guidelines ensure outcomes for HCC remain comparable with results for other LT indications; nonetheless, favorable outcomes for patients with HCC exceeding the current national guidelines for LT should motivate expanded access to LT through prospective studies. The inability to offer LT as an immediate treatment option to patients with HCC undoubtedly jeopardizes the outcome in many patients. Living donor LT is emerging as a major strategy to address this dilemma but, in our opinion, should be reserved for patients with early-stage disease given the substantial risk to the donor. In select patients with unresectable HCC, the use of TACE may lead to significant survival benefit. The role of LRT as adjuvant therapy in the setting of LT for HCC continues to evolve and should be further clarified by prospective studies.
REFERENCES

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