Hepatocellular Carcinoma 2009

Hepatocellular Carcinoma: Current Management
Surgical Therapy for Hepatocellular Carcinoma

The age-adjusted incidence of hepatocellular carcinoma (HCC) has tripled in the United States over the past 2 decades, fueled by the dramatic increase of hepatitis C during that same time period. Currently, there are an estimated 3 million people with chronic hepatitis C and 1.2 million with chronic hepatitis B in the United States. These patients are estimated to develop HCC at a rate of 0.5% to 5% per year.1 The incidence of HCC in the United States still lags behind many parts of the world where hepatitis B is endemic, such as China, Southeast Asia, and southern Africa. Worldwide, HCC is the third most common cause of cancer death and there are an estimated 1 million cases worldwide.2 The median survival in unresectable cases is less than 4 months and under a year for untreated patients with less advanced disease.3-7 Fortunately, the longterm survival rates from HCC in the United States have doubled over the past 2 decades, and a part of this increase is likely due to advances in surgical therapy for HCC, particularly as cancers are being detected earlier and therefore are still localized.8 Both surgical resection and transplantation are highly effective in the treatment of patients with localized HCC. Typically these surgical modalities complement each other, as patients with preserved liver function are candidates for resection and those with poor underlying liver function would be directed toward transplantation. However, their relative roles in the treatment of HCC have generated quite a bit of debate. Ultimately, as the multitude of treatment modalities proliferate, HCC must be treated in a multidisciplinary fashion, involving hepatologists, oncologists, surgeons, radiologists, and pathologists, to come up with the best treatment plan for any individual patient.
Diagnosis
The diagnosis of HCC is typically made because of symptomatic disease or through screening of at-risk patients. Screening of high-risk
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patients involves the measurement of tumor markers such as alphafetoprotein (AFP), as well as periodic radiographic imaging modalities such as ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). Although the sensitivity and specicity of serum AFP are only approximately 50% and 80%, respectively, an AFP level greater than 200 ng/dL is highly suspicious for HCC.9-12 Although the cost effectiveness of intensive screening is debatable,13 several authors have reported that 30% to 60% of patients are found with resectable disease at the time of diagnosis, which is nearly double the rate encountered in an unscreened population. Furthermore, those patients who undergo intensive screening appear to have an improved long-term survival.14-16 Because of the characteristic imaging ndings of tumors on dynamic, contrast-enhanced CT scans and MRIs, the diagnosis of HCC is often possible without the need for biopsy. The classic nding of early arterial phase enhancement and contrast washout on the delayed venous imaging is highly specic for HCC. A mass larger than 2 cm in a patient with an AFP level greater than 200 ng/dL is also considered diagnostic of HCC. In at-risk patients with a newly discovered mass without typical arterial enhancement or elevated AFP, a biopsy is recommended.17
Evaluating Hepatic Reserve

Once a diagnosis of HCC has been made, the next most relevant determination is the severity of underlying liver dysfunction, since more than 80% of patients with HCC will have some degree of cirrhosis.18 The most common way to stratify patients according to hepatic reserve is the Child-Pugh classication. A normal liver can tolerate a resection of up to 80% of the parenchyma with regeneration occurring within weeks. In general, a Child A patient can be considered for resection of up to 50% of the liver parenchyma, a Child B patient, 25%, and a Child C classication would be a contraindication to resection.19,20 Child classication, in combination with clinical assessment, and biochemical blood tests (liver function tests [LFT], coagulation prole, and platelet count) provide the most simple, reliable, and reproducible method to identify patients at risk for liver insufciency.21,22 Other investigators have utilized the Model of End-Stage Liver Disease (MELD) score, developed to quantify liver insufciency before transplantation, as an assessment of liver reserve before resection as well, and have found it to be an independent predictor of perioperative mortality and long-term survival.23,24 However, Schroeder and colleagues found that the American Society of Anesthesiologists (ASA) class and Child class were superior to
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MELD score in predicting postsurgical mortality in patients with cirrhosis undergoing resection for HCC.25 Indocyanine green (ICG) is an anionic dye cleared by hepatocytes and excreted in bile. The clearance of ICG from the bloodstream at 15 minutes is used as a measure of hepatocyte function.26 In a normal liver, the value should be less than 10% retention, and a value above 15% to 20% retention is abnormal, demonstrating liver insufciency. A value of 40% retention at 15 minutes demonstrates severe liver dysfunction, suggesting that any type of resection would not be tolerated.27,28 Clinically relevant portal hypertension is also dened as a hepatic venous wedge pressure greater than 10 mm Hg, splenomegaly with a platelet count less than 100,000, or esophageal varices. Other less commonly used tests include the galactose elimination capacity and the technetium-99m-labeled asialoglycoprotein receptor quantity.29,30 Unfortunately, none of these methods of determining hepatic reserve is ideal, nor is there any test that is considered standard. None can accurately assess all of the numerous functions of the liver completely, nor has any single test been demonstrated to be superior to another in evaluating hepatic reserve or predicting postoperative outcome.
Staging
As opposed to other malignancies, long-term survival in patients with HCC depends on both pathologic stage of the disease as well as severity of underlying liver dysfunction, and therefore, an ideal staging system would take into consideration both pathological and clinical factors. Unfortunately, the exact interaction between tumor and liver disease on long-term patient outcome has never been well established, and there is no one standard staging system. Furthermore, variations between geography, etiology of disease, and genetic factors can make this standardization more difcult. By far, the most widely used staging system for HCC is the American Joint Committee on Cancer (AJCC) TNM (tumor, node, metastasis) staging system31 (Table 1). This classication system categorizes patients based on tumor size, number, vascular invasion, regional node status, and distant metastases. It follows the TNM model of other cancers, but requires tissue for adequate staging. The Okuda staging system, proposed by Okuda and colleagues in 19857 was the rst staging system to include variables of liver function such as ascites, albumin, and bilirubin levels in addition to tumor size. An alternative system was created in 1998 by the Cancer of the Liver Italian Program Investigators (CLIP), which incorporates Child stage, tumor morphology, AFP levels,
12 Curr Probl Surg, January 2010
TABLE 1. American Joint Committee on Cancer TNM staging system for hepatocellular cancer Stages for hepatocellular carcinoma Tumor T: Primary tumor Tx: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Solitary tumor without vascular invasion T2: Solitary tumor with vascular invasion or multiple tumors, none 5 cm T3: Multiple tumors 5 cm or tumor involving major branch or portal or hepatic vein T4: Tumor with direct invasion of adjacent organs Node N: Regional lymph nodes Nx: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis Metastasis M: Distant metastasis Mx: Distant metastasis cannot be assessed M1: Distant metastasis Staging Stage I: T1N0M0 Stage II: T2N0M0 Stage IIIA: T3N0M0 Stage IIIB: T4N0M0 Stage IIIC: Any T, N1M0 Stage IV: Any T, any N, M1
and the presence of portal vein thrombosis (PVT).32 The Japan Integrated Staging Score from the Cancer Study Group of Japan combines Child staging with a modied TNM staging and incorporates measures of functional capacity as well.33 Some investigators have proposed using the MELD score as a predictor of long-term outcome itself; however, it is a purely clinical scoring system that does not take tumor characteristics into account. Despite this, the MELD score has been demonstrated to predict both immediate postoperative outcome as well as long-term survival following hepatic resection.23,24,34,35 Other classications include the Chinese University Prognostic Index (CUPI), simplied Vauthey staging, and the Barcelona Clinic Liver Cancer (BCLC) staging classication. The BCLC system uses tumor characteristics and clinical features and links these data to suggested treatment modalities and their associated life expectancies. The American Association for the Study of Liver Diseases (AASLD) has adopted the BCLC algorithm as part of its practice guidelines.36 The American Hepato-Pancreato-Biliary Association has recommended the use of CLIP for clinical staging and AJCC for pathological staging.37
Surgical Treatment
The primary goal of therapy for HCC is to improve long-term survival in patients amenable to surgical therapy and possibly affecting cure, whether it is via resection or transplantation. Nonsurgical therapies such as radiofrequency ablation (RFA), cryoablation, microwave coagulation, percutaneous ethanol injection (PEI), and transarterial embolization have traditionally been used for local tumor control, particularly as a bridge to transplantation as well as for palliation. These modalities will be discussed further in the last section. More recently data have suggested that RFA can potentially be as effective as surgery, and potentially curative for small HCC. These data are provocative, but need to be conrmed on a larger scale before RFA can be considered a substitute for surgical therapy for HCC. Until then, surgical resection and transplantation can be considered the only potentially curative therapies in the treatment of HCC.
Liver Resection
Advances in surgical technique, anesthetic management, intraoperative US, and intensive care unit (ICU) care have improved the ability to perform surgical resection for HCC. Despite these advances, only 15% to 30% of patients with HCC are operative candidates, due to advanced disease, extrahepatic metastases, or inadequate liver reserve although these numbers nearly double with intensive screening.38 For those who are candidates for surgical resection, operative mortality is typically less than 5% and the 5-year survival rate is 40% to 70% depending on the stage of disease (Table 2). Determining who qualies as a resection candidate can vary from surgeon to surgeon, as the modality of assessment of liver dysfunction varies, and there are institutional, regional, and individual surgeon biases. For example, portal hypertension clearly affects postoperative complications and long-term survival,51 and some groups, including the Barcelona group, have advocated that any clinical evidence of portal hypertension be a contraindication to surgical resection. Others have demonstrated that portal hypertension alone should not be a contraindication to resection, with Ishizawa and colleagues demonstrating a 5-year survival rate as high as 68% in selected patients with portal hypertension.52,53 Although the type of resection in this population of patient tends to be limited to less than 2 segments, with good surgical judgment and reasonable hepatic reserve, portal hypertension alone may not be a contraindication to resection, but rather represents additional data that inuences the size and scope of resection possible.
TABLE 2. Results of resection for hepatocellular carcinoma Author Okuda, 1985 Japan Liver Survey, 1994*39 Bismuth, 1993, 199540,41 Fong, 199942 Grazi, 200143 Before 1992 After 1992 Poon, 200244 Milan Criteria Esnaola, 200345 USA France Japan Cha, 200346 Milan Criteria Ouside Milan Wu, 200547 Nuzzo, 200748 Katz, 200949 Nathan, 2009 SEER50 *Multi-institutional series.
7
N 153 468 3500 68 60 54 100 107 157 135 169 187 230 36 144 105 113 192 788
Operative mortality (%) 30 3 10 3.7 5 9.3 1.3 4 5.3 6.4 3.5 2.8 5 1 3 4.6
1 year 30 76 76 74 80 83 77 90
Survival 3 years 15 55 52 52 52 58 47 53 72 76
5 years 12 45 36 40 42 37 32 49 70 31 31 41
85 70 86
74 44 70
75
56
69 31 55 44 24 (10 years) 41 23 (10 years) 39
One of the ways to increase the safety of resection and expand the pool of patients eligible is portal vein embolization (PVE). PVE is a technique used to occlude the portal inow to the portion of liver that is destined to be removed, inducing hypertrophy in the portion of liver that will be left behind, known as the future liver remnant, over the period of 3 to 4 weeks.54 Although typically a procedure performed by interventional radiology using a percutaneous, transhepatic approach, the occlusion or ligation can also be performed open or laparoscopically at the time of another operation. In a cirrhotic liver, where only up to 40% of the liver can be resected, PVE increases the ability to resect the liver safely, reducing the incidence of complications, and decreasing the length of stay compared with patients without PVE.55-57 Resection for Early HCC. The reported survival rate following resection of HCC is approximately 40% to 70% in most series depending on the stage of disease and the amount of liver dysfunction (Table 2). A recent study by Katz and colleagues found the median overall survival
(OS) rate following resection was 40 months and the proportions of patients alive at 5 and 10 years were 41% and 23%, respectively. The median disease-specic survival (DSS) and recurrence-free survival (RFS) were 54 and 22 months, respectively. After resection of HCC, 76% of patients developed tumor recurrence by 5 years and 83% were found to have recurrent disease at 10 years.49 Nathan and colleagues reviewed the Surveillance, Epidemiology and End Results (SEER) database and identied 788 patients with HCC smaller than 5 cm who underwent resection.50 The authors found 5-year survival to be 39%, with tumor size greater than 2 cm, multifocality, and vascular invasion predicting worse survival; patients with all 3 factors still had a 5-year survival rate of 29%. In carefully selected patients with good prognostic factors such as no vascular invasion by tumor, solitary lesions without intrahepatic metastasis, tumor diameter smaller than 5 cm, and negative surgical margins, 5-year survival rates as high as 78% following resection have been reported.58-60 Recurrence after Resection. Recurrence of HCC following resection is clearly a common occurrence, with 50% to 80% of patients experiencing recurrence by 5 years after resection, and the majority within 2 years.46,61 The mechanism is typically not an inadequate resection, but rather de novo tumor formation in the cirrhotic liver, or intrahepatic metastases that were too small to be detected/identied at the time of resection. Tumor characteristics associated with recurrence include tumor size, number, vascular invasion, cirrhosis, and elevated AFP.46,62,63 When HCC does recur, it typically returns in the liver alone,63,64 with one large series demonstrating that 86% of recurrences were isolated to the liver only. Consequently, liver-directed therapies are often successful in recurrent disease. In particular, re-resection of HCC has been associated with long-term outcomes similar to primary resection of HCC, with 5-year survival rates reported up to 56%.65-70 Resection for Advanced HCC. With regard to patients with large tumors and preserved liver function, there are no other curative options available other than resection, as transplantation is contraindicated. One of the criticisms of the BCLC algorithm for treatment of patients with HCC is that there is no treatment designated for patients with tumors greater than 5 cm in size with good hepatic reserve. Although patients with larger tumors are more likely to have occult vascular invasion, survival following resection is similar to small tumors when vascular invasion is not identied. The OS rate for patients with tumors greater than 10 cm is still approximately 40% in several multi-institutional series,
which was not statistically different from survival in patients with tumors smaller than 10 cm.71-74 Tumor multifocality is a prognostic factor often associated with lower survival, but does not exclude a good outcome in selected patients. In several studies, resection of multifocal HCC is associated with 5-year survival rates of approximately 24%.75,76 Lymph node metastases have also been associated with lower long-term survivals in patients with HCC.77,78 Routine lymphadenectomy is not recommended as part of standard resection, and enlarged periportal lymph nodes are often noted on preoperative imaging due to underlying hepatitis. Minimally Invasive Resections. Minimally invasive approaches to both benign and malignant liver diseases are reported with increasing frequency and, as experience has increased, there has been interest to apply laparoscopic resection for HCC. A laparoscopic resection is especially appealing in patients with HCC, since they often cannot tolerate a major liver resection due to hepatic insufciency and are at risk for complications of ascites and ensuing wound complications associated with a large open incision. No prospective series is reported in the literature; however, in the largest published series, 116 patients underwent laparoscopic liver resection for HCC with the vast majority having less than 2 segments resected.79 There were no perioperative deaths, and the postoperative complication rate was less than 6%, with a 5-year survival rate of approximately 60%. In another series, the outcomes of 23 consecutive cirrhotic patients undergoing laparoscopic resection for HCC were compared with a historical group of 23 patients who underwent open resection and were matched for age, gender, tumor location and size, and severity of cirrhosis.80 One patient in the laparoscopic group was converted to an open procedure because of inadequate exposure. The mean operative time was longer in the laparoscopic surgery group (148 vs. 125 minutes), whereas the frequency of intraoperative blood transfusion (0% vs. 17%), mean hospital stay (8.3 vs. 12 days), and postoperative complication rate (13% vs. 48%) were better in the laparoscopic group. Perioperative mortality and 2-year survival rates were comparable in both groups. The initial success encountered with laparoscopic resections in HCC is largely due to the highly selected population of patients who undergo smaller, nonanatomic resections. This allows for resection in patients with marginal hepatic reserve who otherwise would not be eligible. Clearly, more prospective data are needed; however, the preliminary results are encouraging, and it appears that, in experienced hands, laparoscopic resection is feasible and safe. It is should be emphasized that
TABLE 3. Results of transplantation for hepatocellular carcinoma Operative mortality Recurrence Survival (%) rate (%) 3 years 5 6 13 4.7 4.5 57 54 10 10 11 10 45 39 47 69 63
Author Iwatsuki, 199187 Bismuth, 199340 Mazzaferro, 199682 Llovet, 199951 Hemming, 200184 Yao, 200185 De Carlis, 200383 Yoo, 200386 1987 to 1991 1992 to 1995 1996 to 2001
N 105 60 48
Notes
5 years 36 74 (4 years) 69 57 73 62 25.3 46.6 61.1
87 Intention to treat analysis 112 64 121 Review of UNOS 270 Database 282 433
UNOS, United Network for Organ Sharing.
laparoscopic resections for HCC are technically demanding and should be undertaken only with proper training and in high volume centers.
Transplantation
The idea of transplantation for HCC was initially proposed because, in theory, it completely removes the tumor and underlying diseased liver, while alleviating portal hypertension in the process. Initial investigators had to balance the unknown effect that immunosuppression would have on tumor growth with issues regarding the proper utilization of a limited resource such as a deceased donor liver. Success was measured not only in demonstrating long-term survival, but the survival had to match the results of transplantation in non-cancer-bearing patients with liver failure. The early experience with liver transplantation for HCC did not meet this standard, with 5-year survival rates following transplantation of only 18% and recurrence rates of approximately 50% at 2 years.81 However, Bismuth and associates rst recognized that patients with early or incidentally found HCC after transplantation had nearly equivalent survivals as their non-HCC counterparts.40 This eventually led to the landmark study by Mazzaferro and colleagues, who demonstrated that transplantation in patients with a solitary HCC lesion smaller than 5 cm in diameter or 3 tumors 3 cm or smaller (Milan Criteria) led to an OS rate of 75% at 4 years.82 On adopting these criteria, several investigators have conrmed this long-term survival benet of transplantation, with 5-year survival rates reported at approximately 60% to 70%51,83-86 (Table 3).
The United Network for Organ Sharing (UNOS) has adopted the Milan criteria and allocates organs based on the MELD scoring system. The UNOS criteria further specify that patients eligible for liver transplantation should not be resection candidates. Once they qualify for transplantation based on radiologic or pathologic criteria for diagnosis of HCC, patients are awarded MELD exception points (22 MELD points), provided that they have at least a solitary lesion that is greater than 2 cm in size. Based on the 20% to 50% dropout rate seen at 1 year due to progression of disease,21,51 the patients are awarded an additional point every 3 months that they remain on the list until they receive their transplantation. According to the UNOS Web site, in 2008, 18.1% of all liver transplantations performed in the United States were for HCC.88 Expanding Transplantation Criteria. Yao and associates85 from the University of California at San Francisco (UCSF) suggested a moderate expansion of the Milan criteria to include solitary tumors smaller than 6.5 cm or 3 or fewer nodules with the largest lesion less than 4.5 cm and total tumor diameter less than 8 cm. Using these UCSF criteria, the 5-year survival rate remained high at 75% after liver transplantation. A major criticism of the UCSF study is that the results were based on tumor explant characteristics, not preoperative imaging measurements. Therefore, Duffy and colleagues89 recently demonstrated that patients meeting UCSF criteria had similar 5-year posttransplant survivals as patients meeting Milan criteria both by preoperative imaging (UCSF 64%, Milan 79%) and explant pathology (UCSF 71% vs. Milan 86%). These authors have used these data to suggest that current transplantation criteria should be expanded. However, the current UNOS policy of limiting MELD points to those patients with tumors larger than 2 cm as a conscious attempt to minimize the rate of overallocation of organs to patients with HCC.90 Although some investigators feel the Milan criteria may be too restrictive, potentially denying deserving patients access to transplantation, the concern for the erosion of RFS rates and the understaging of patients by pretransplantation imaging have dampened enthusiasm for expansion of tumor guidelines. Although a moderate expansion of the Milan criteria does not appear to signicantly alter the long-term survival, there is a trend toward increased recurrence and decreased survival,89 and certainly any expansion of criteria will increase the proportion of patients with HCC receiving orthotopic liver transplantation, which already makes up nearly 20% of all liver transplantations currently performed in the United States. Salvage Transplantation. Salvage transplantation has been proposed as a possible option for patients with recurrent disease following resection
for HCC. Although it remains an unproven strategy, salvage transplantation may represent a practical means of rationing available organs.91 Some investigators have proposed this strategy as a feasible and costeffective approach that may provide a means of allocating organs to only those patients requiring transplantation.92-94 The true practicality of performing salvage transplantation is still a matter of debate.95-99 Although some see this approach as essentially using resection as a bridge to transplantation, approximately one half to one quarter of patients who undergo resection will not recur, avoiding the potential complications of liver transplantation and immunosuppression as well as preventing the unnecessary utilization of a liver graft. Living Donor Liver Transplantation for HCC. Advances in living donor liver transplantation (LDLT) over the past decade have made this a viable option for patients who otherwise face long waiting times for deceased donor liver grafts. Several retrospective reviews have demonstrated that LDLT for HCC has a similar survival to that of deceased donor transplantation.100-102 However, some authors have documented a higher rate of recurrence compared with deceased donor transplantation recipients.103-105 The reason for this is unknown, but perhaps it is due to the 20% to 50% dropout rate seen in patients on the wait list for deceased donor transplantation, which may serve to screen out biologically more aggressive tumors that would have had a propensity to metastasize or recur. Despite the paucity of data regarding live donor transplantation for HCC, some surgeons are already advocating the expansion of UNOS criteria for live donor transplantation to allow transplantation for larger tumors.106,107 Clearly, the question of utilizing live donor liver transplantation for HCC remains unresolved and requires further prospective analysis.
Transplantation versus Resection for HCC

The debate regarding the most appropriate surgical therapy for a patient with early stage localized HCC is largely a nonissue, since most patients who undergo resection are beyond the criteria for transplantation, and most patients transplanted for HCC have liver dysfunction that would not allow for safe resection. A small proportion of HCC patients have localized disease and good enough hepatic reserve to be eligible for both transplantation and the best primary therapy for these patients remains unclear. The question is partially answered by the UNOS criteria for transplantation, which states that patients who are resection candidates are excluded from eligibility for transplantation; however, the determination of whether a patient is a candidate for resection can also be a source of
debate as well, as discussed above. There are no randomized controlled trials (RCTs) comparing resection and liver transplantation for those patients who would be eligible for both: those with small, early stage disease with good hepatic reserve. Proponents of resection for this patient population point to the equivalent long-term survival between resection and transplantation while avoiding the utilization of a scarce resource and avoiding lifelong immunosuppression. Proponents of transplantation point to the high rate of recurrence in stage-matched resection patients undergoing resection. Transplantation is clearly associated with a much lower rate of recurrence (approximately 10%) and Schwartz noted recently that the disease-free survival following transplantation for HCC appears to level off at approximately 5 years, whereas following resection, the disease-free survival continues to trend downward at 5 and even 10 years.108 Sophisticated analyses of cost, quality of life, and length of wait list times have failed to resolve this debate satisfactorily, but local surgical expertise and individual and institutional biases play as big a role as any in determining whether these selected patients will undergo resection versus transplantation. Based on 5-year survival rates reported in most retrospective series, the survival following resection could be interpreted as being inferior to that of transplantation at 5 years for HCC (50% vs. 70%). However, this difference is explained by the fact that patients in resection series have more advanced disease than those in transplantation series, where patients are restricted by the Milan criteria. Accordingly, those patients who are resected and meet the Milan criteria have comparable survival to patients who are transplanted.59,94 Therefore, stage for stage, transplantation and resection appear to have equivalent OS rates. Furthermore, most transplantation series measure survival from the time of transplantation, rather than from the time of being listed for transplantation. Depending on the length of time on the wait list, up to 50% of patients will progress beyond the Milan criteria and become ineligible for transplantation.51 Schwartz proposed using a cutoff of 1 year average wait list time to determine whether surgery or transplantation should be the primary treatment modality, suggesting that dropouts occurring in the 1 year period negated any tumor recurrence advantage that transplantation may have.108 To properly utilize a limited resource such as a deceased donor liver for the treatment of HCC requires the balance of individual needs with societal concerns. The greatest difculty is determining how to fairly distribute a limited number of organs to those patients who will benet the most, particularly when other modalities such as resection and ablation are available and can provide similar results. Ultimately, the
treatment options for patients with HCC must be selected on an individual patient basis determined in a multidisciplinary fashion by assessing tumor characteristics, underlying hepatic function, the patients condition, and available resources.
Locoregional Therapy for HCC

HCC is the sixth most common cancer worldwide and is rising in incidence in the United States.109,110 HCC claims 500,000 lives worldwide annually.111,112 The majority of patients do not survive past 6 months after diagnosis.7 Although surgical resection is the gold standard for HCC, many patients are not surgical candidates due to cirrhosis with inadequate hepatic reserve, multiple lesions, extrahepatic disease, anatomic constraints of tumor, or medical comorbidities.113 Therefore, other liver-directed therapies are employed in the treatment of HCC, including thermal ablative techniques (RFA and microwave), ethanol injection, directed radiotherapy (RT), transcatheter arterial chemo- or bland embolization, and hepatic arterial infusion chemotherapy (HAIC). Depending on the extent of disease, these therapies can be employed alone or in combination.
Ablation
Ablative techniques improve the ability to treat patients with unresectable primary hepatic tumors.114 Ablative techniques destroy tumor via temperature changes associated with cell death while causing minimal damage to adjacent, normal liver.115 The most commonly used techniques include RFA and microwave ablation (MWA). Recurrence decreases with margins of at least 0.5 to 1.0 cm. The choice of technique depends on equipment availability and surgeon/radiologist preference. There are limited randomized prospective studies that demonstrate superior outcomes between modalities, so it is unclear which specic modality is best for a given application. Currently, the most commonly utilized modality in the United States is radiofrequency, whereas MWA is used more in Europe and Asia.
Ablation, RFA
Mechanism. RFA is the most frequently used thermoablative technique.115 It produces coagulative necrosis via an alternating highfrequency electric current in the radiofrequency range (460-500 kHz), delivered through an electrode placed in the center of a lesion.115 Ionic movement within the tissue creates frictional heat as the ions try to follow this alternating current, with local tissue temperatures exceeding
FIG 1. HCC in cirrhotic patient pre- (A), immediately before (B), and 9 months after RFA (C). Pre-RFA
AFP was 43.2 and 9 months later was 11.3.
100C.115 This ionic agitation leads to tissue destruction via tissue boiling and creation of water vapor. Once lethal temperatures ( 60C) are reached, protein denaturation, tissue coagulation, and vascular thrombosis result in a zone of complete ablation (Fig 1). A zone of partial tissue destruction up to 8 mm in diameter can be seen surrounding the zone of coagulation.114 Heat-based ablation modalities cause profound vascular thrombosis, making bleeding an unusual complication of RFA.114 RFA can be delivered 3 ways: percutaneously, laparoscopic, or open (laparotomy).114,115 The mode chosen is based on known advantages of each technique. Although percutaneous ablation avoids a laparotomy,
patients require an anesthetic due to the pain associated with the procedure. With percutaneous RFA, there is no ability to assess the abdomen for extrahepatic disease, and there is no access to intraoperative US, which can detect additional hepatic disease in 40% to 55% of patients.114,116,117 Laparoscopic ablation is technically difcult in its limited ability to image the liver in multiple planes, limiting accurate probe placement. Because of these limitations, open ablation is often the preferred mode of delivery for patients able to tolerate it.114 Indications. For HCC, RFA is currently indicated for unresectable disease, as a bridge to liver transplant for HCC, and as a substitute for surgical resection in those with medical contraindications to surgery.115 RFA is the favored modality for coagulopathic patients due to the intrinsic cautery effect decreasing bleeding complications.114 In addition, randomized studies have found short-term outcomes comparable to resection for small HCC.118 Limitations/Complications. The main limitation of RFA is attaining destruction of adequate tissue volume. Monitoring of the ablation zone is difcult due to the air that is released during heating, which limits the ability to visualize coagulated tissue in real time. Treating lesions in the perihilar area or near large vascular structures is also difcult due to the heat-sink effect of the blood ow in these areas and proximity to the bile duct. Complications occur in 8% to 35% of patients undergoing RFA and include abscess formation and biliary injury.114,115
RFA for Small, Resectable HCC

A recent RCT for RFA versus resection has demonstrated similar survival outcomes. In a prospective, randomized study comparing RFA with hepatectomy for small HCC, Chen and colleagues randomized 180 patients to receive either RFA (percutaneous) or resection.118 To be included, adult patients needed to have a solitary HCC smaller than 5 cm in diameter without metastases, no invasion into the major portal/hepatic veins, Pugh-Child Class A liver function, and no previous treatment for HCC. Preoperative demographics were similar between groups for age, gender, tumor size, AFP, bilirubin, albumin, and ICG-R15. The only signicant difference was in preoperative ALT levels, which were higher in the ablation group (P 0.046). The mean follow-up for ablation was 27.9 months versus 29.2 months for resection. Hopefully, after longer follow-up, the authors will analyze the data again to determine whether the conclusions remain the same. All 90 patients in each group, RFA or surgery, were included for analysis and in compliance with the intention-to-treat analysis. Of the 90
patients randomized to ablation, 19 patients withdrew their consent and underwent resection. There were 21 patients in the RFA group who needed additional ethanol injections or RFA due to incomplete tumor necrosis on follow-up CT, and 2 patients receiving additional transcatheter arterial chemoembolization (TACE) for residual tumors despite repeated RFA/PEI. There were 2 patients in the surgical group with liver dissemination who were therefore treated with ethanol, but were included in the analysis. The 1- and 4-year OS rates were 95.8% and 67.9%, respectively, and 93.3% and 64%, respectively, after resection (P NS). There was no difference between groups in 1- and 4-year disease-free survival rates (90% and 48% for ablation vs. 86% and 51% for resection). There was also no difference in survival rates between groups by tumor size. Major complications occurred signicantly more frequently after resection (50 of 90) than ablation (3 of 71, P 0.05). Complications in the resection group included liver failure (n 2), moderate/severe ascites (n 27), gastrointestinal (GI) bleeding (n 2), and jaundice 30 days after surgery (n 19). In the ablation group 8 patients developed postablation fevers higher than 38.5C and 3 patients developed mild burns to the sites of electrode pad placement, but no hemorrhage, infection, or tract seeding occurred. All patients required analgesia after resection, in comparison to 16 patients in the ablation group. Therefore, it appears that although the survival and recurrence endpoints were similar, 21 patients needed reintervention in the RFA group. However, the tradeoff is the higher complication rate following resection. Note also that this study had a relatively short follow-up, and survival and recurrence endpoints will need to be veried with longer follow-up.
RFA in Locally Advanced HCC

HCC is well suited for locoregional therapy due to its propensity to stay within the liver, and patients usually die of liver failure secondary to local tissue growth and liver decompensation instead of metastatic disease.119 Curley and colleagues evaluated 110 cirrhotics with unresectable HCC (Child class A-C) treated with RFA.120 The local recurrence rate was 3.6% (median follow-up, 19 months). New lesions (liver tumors or extrahepatic metastases) developed in 45% of patients. Twenty-ve percent of patients (n 28) died of recurrent HCC, and 26 patients with recurrence were alive at study termination. Sixty-ve patients had no radiographic evidence of HCC recurrence. These results demonstrated that hepatic RFA can be effective in appropriately selected patients, with
recurrence rates comparable to published data evaluating other ablation modalities.
Ablation, Microwave
Background. MWA refers to all electromagnetic methods of inducing tumor destruction by using devices generating frequencies of a minimum of 900 MHz.115,121 Under image guidance with CT, MRI, or US, a microwave antenna is placed intratumorally and an electromagnetic wave is emitted from the microwave generator through the exposed, noninsulated portion of the antenna. This leads to agitation of water molecules in tumoral tissue creating friction and heat, leading ultimately to coagulative necrosis and cell death.115,121 Although MWA shares many advantages with RFA, MWA has some theoretical advantages. Both offer exible treatment approaches, consistent necrotic areas, and excellent patient tolerability. With MWA, transmission is not limited by tissue desiccation and charring as in RFA, which relies on conduction of electricity. Intratumoral temperatures can be driven higher, leading to a larger ablation zone, less treatment time, and more complete tumor killing.121 Like RFA, MWA can be performed during laparoscopy, laparotomy, or percutaneously. US guidance is used to apply MWA to single or multiple tumors, inducing necrosis within the tumor and in a margin of normal hepatic parenchyma.115 Image ndings indicative of tumor necrosis include echogenic change on US, loss of contrast enhancement on CT and, on T2 MRI, there is decreased intensity.122 Indications. The indications for MWA include unresectable HCC, HCC in anatomically difcult locations, and HCC patients unsuitable for surgery.115,123 Complications. Complications are similar to those of RFA, including bile duct stenosis, intraperitoneal bleeding, liver abscess, colonic perforation, tumor seeding along the antennae track, and skin burns.121 Side effects include pain, postablative syndrome (fever/malaise), and asymptomatic pleural effusions that are self-limiting.121,122
Outcome for Unresectable HCC

MWA. Liang and colleagues evaluated prognostic factors for survival in 288 cirrhotic patients with HCC.123 Eligibility criteria included HCC smaller than 8 cm, less than 5 lesions with diameters less than 6 cm, and no extrahepatic disease. One-year and 5-year cumulative survival rates were 93% and 51% (mean follow-up, 31 months). On multivariate analysis, patients with a single nodule and tumors smaller than 4 cm had
signicantly improved survival rates. As expected, smaller tumors and less advanced disease were associated with improved outcomes after therapy. MWA versus RFA. In a Japanese randomized study in 2002, MWA was compared with RFA in cirrhotic patients with small HCC.124 There was no difference in patient or tumor characteristics between the groups, and 72 patients with 94 HCC lesions were randomly assigned to RFA or MWA with equivalent therapeutic effects, complication rates, and rates of residual foci observed between the two modalities.124 Unfortunately, there were no survival data obtained after a mean follow-up period of 18 months, nor have there been follow-up studies published to date. Clearly limited by small sample size, the results of these studies represent the only prospective trials evaluating the efcacy of MWA. Based on the results from these studies, the choice of ablative technique should be based on institutional and user experience and preference.
PEI for Unresectable HCC

Background. PEI was rst reported by Sugiura in 1983.125-127 Given the limited indications for surgical resection in patients with advanced cirrhosis,126 PEI is an accepted treatment for patients with small, unresectable HCC. Mechanism. PEI is performed under US guidance, where 2 to 8 mL of 95% ethanol is administered at a time. Ethanol penetrates tumor cells promptly, inducing coagulative necrosis and thrombosis in the tumor microcirculation through protein denaturation, platelet aggregation, and dehydration of both parenchymal and surrounding endothelium.127 Tumor tissue has a different consistency compared with the surrounding parenchyma, allowing homogeneous distribution of ethanol within the tumor nodule127 (Fig 2). PEI offers low cost and a favorable complication prole, with the best results demonstrated in patients with small HCC.128,129 Indications. As rst-line therapy, current indications include HCC lesions smaller than 3 cm.130,131 PEI is also indicated for small HCC lesions recurring at distant sites after previous treatment.126,129,132 Limitations. Complete tumor necrosis correlates inversely with tumor size; therefore, local recurrence increases when PEI is administered to larger tumors (demonstrated in studies comparing RFA to PEI).127,133
FIG 2. Before (A) and after (B) PEI in cirrhotic patient with HCC.
Intratumoral septa prevent homogeneous tumor distribution through larger tumors and multinodular tumors, leading to inadequate margins and recurrence at the peripheral aspect of the tumor.127 There are no denitive criteria for the quantity and interval of injections; however, the best
results occur when dispersion exceeds the maximal tumor diameter by 1 to 2 cm to create a 1-cm ablation ring around the HCC nodule.127 Since excessive ethanol increases side effects and results in unnecessary liver damage,127 there is a delicate balance to be considered when PEI is a potential therapy for larger tumors or in patients with severe hepatic dysfunction. Outcome PEI. Several studies have evaluated the effectiveness of PEI in HCC. The outcomes of patients who underwent PEI as rst-line treatment for HCC in Japan were evaluated in a recent observational study.126 Indications for PEI included HCC tumors smaller than 3 cm and a maximum of 3 tumors. Overall 5- and 10-year survival rates were 60% and 21%, respectively. The survival was best in Child A patients with a solitary HCC ( 2 cm), with 5- and 10-year survival rates of 74% and 31%, respectively. Results from a long-term follow-up of Korean patients demonstrate similar survival rates, where OS rate at 5 years was 39%, and 55% for patients with tumors smaller than 2 cm.132 Thus, long-term survival is possible after PEI alone for small HCC and likely correlates with tumor size. PEI versus resection. There are conicting survival data when PEI is compared with resection for small HCC.134-136 A recent RCT compared PEI with resection of HCC smaller than 3 cm in diameter and less than 2 lesions.129 All 38 patients in each group had hepatitis, with or without cirrhosis (Child class A or B). Patients with cirrhosis were without ascites or coagulopathy, and the majority had single tumors. There were 76 patients randomized, with no statistical difference between groups in either survival or recurrence. The 5-year tumor-free survival rates were 45% in the PEI group and 48% in the resection group. Although the sample size was small, these results suggest that in highly selected patients with small, accessible HCC due to hepatitis, PEI may result in outcome comparable to resection. PEI versus RFA. According to the AASLD practice guidelines, PEI should be the standard against which other nonsurgical therapies are compared.36,137 According to the AASLD guidelines, RFA offers better local disease control for HCC greater than 2 cm, but a question remains regarding survival benet.36,137 Thus, there have been several RCTs comparing PEI with RFA (Table 4). Recent meta-analyses evaluating these RCTs concluded that for small HCC, RFA signicantly improved 3-year survival compared with PEI, which may be due to the ability of RFA to provide a better margin of tissue destruction around the tumor.137,138
TABLE 4. Randomized controlled trials comparing percutaneous ethanol injection (PEI) to radiofrequency ablation (RFA) for hepatocellular carcinoma137-139 Results Tumor size Cohorts (cm)

Author
Follow-up
Complete necrosis Survival rate (%) (%)
Recurrence (%)
Brunello, 139 2008140
PEI RFA
Lin, 187 2005133
PEI PAI RFA
Shiina, 232 2005141
PEI RFA
Lin, 157 2004142 Lencioni, 102 2003143
PEI RFA PEI RFA
Median follow-up 1-year CR 3-year Distant, over PEI: 25.3 months PEI (36) PEI (59) follow-up RFA: 26.1 months RFA (65) RFA (63) PEI (50.7) RFA (45.7) Median follow-up PEI (88) 3-years 3-years, 35 months PAI (92) PEI (51) local RFA (96) PAI (53) PEI (34) RFA (74) PAI (31) RFA (14) Median follow-up PEI (100) 3-year 4-year PEI: 3 years RFA (100) PEI (57) overall RFA: 3 years RFA (74) PEI (85) RFA (70) Mean follow-up PEI (88) 3-year 3-year DSF PEI: 35 months RFA (96) PEI (50) PEI (17) RFA: 37 months RFA (74) RFA (37) Mean follow-up PEI (82) 2-year 2-year DFS PEI: 22.4 months RFA (91) PEI (88) PEI (62) RF: 22.9 months RFA (98) RFA (96)
PAI, percutaneous acetic acid injection; DFS, disease-free survival; CR, complete response.
Complications. In a 20-year observational study, complications after PEI primarily include hyperthermia ( 38C, 44%), elevated serum LFTs (47.7%), and pain (14.4%).126 Less common are seeding of HCC to the body wall (1.9%), pleural effusion (1.5%), biliary stricture (3.3%), portal vein thrombosis (0.7%), and bleeding in the biliary tract (0.7%). Death and emergency complications were not encountered. These results suggest that PEI can be used safely for the treatment of small HCC tumors, provided the dispersion area exceeds 1 to 2 cm of the maximal diameter of the tumor.127
Radiotherapy for Advanced HCC

Background. Exposure to radiation in excess of 40 Gy can lead to radiation-induced liver disease (RILD), a clinical syndrome characterized by ascites, anicteric hepatomegaly, and elevated liver enzymes weeks to months following therapy, therefore limiting the role for whole liver external beam irradiation for HCC.112,144 However, recent data suggest that local liver RT can be effective in abrogating the progression of HCC.145,146 In addition, RT can be highly effective in palliating pain.
Technique. Recent technological advances in image guidance and reduction of breathing artifact allow for delivery of radiation conformally to focal liver cancer, lessening the toxicity associated with whole liver radiation.147 Whole liver fractionated radiation is limited to 30 Gy, but higher doses can be applied if functional liver tissue can be spared from the high radiation.148,149 Stereotactic body radiation therapy (SBRT) refers to delivering radiation in few fractions, and has been utilized for both primary liver tumors as well as liver metastases.148,150-152 The dosage of RT to the tumor bed is important, since dose-response relationships have been demonstrative of improved tumor response rates with higher doses of localized RT.146,153 Therefore, studies have been performed in hopes of maximizing the amount of RT to localized areas of liver to protect the surrounding parenchyma and to maximize therapeutic outcome. Outcomes Localized RT for Unresectable HCC. In a recent report from Tse and colleagues, the authors performed a phase I study of individualized SBRT for unresectable HCC and intrahepatic cholangiocarcinoma (IHC).154 Of 41 patients in their study, 31 had unresectable HCC and 61% of those were AJCC TNM stage T3, N0. Patients underwent 6-fraction SBRT (24 to 54 Gy) during a 2-week period. The median survival was 11.6 months for HCC patients with large-vessel thrombosis versus 17.2 months for those without thrombosis (median follow-up, 17.6 months; P NS). In HCC patients, the response of large-vessel thrombosis was 6% complete response (CR), 19% partial response (PR), and 38% stable disease. Most sites of recurrence were extrahepatic. Park and colleagues evaluated the response to local RT for unresectable HCC in a retrospective study.145 Fifty-nine patients were treated with localized RT with a curative intent at doses of 30 to 55 Gy. Tumor responses were evaluated by the change in maximum tumor size on serial CT scans. The median age was 59 years, 78% were male, and no patients had extrahepatic metastases. Maximal tumor diameters were 9.6 4.2 cm. Thirty-three patients had portal vein thromboses conrmed on imaging. Patients were followed with serial CT scans 4 to 8 weeks after RT, and then at 2- to 3-month intervals. Eleven percent of patients had CRs, 61% had PRs (decreased tumor size 50%), stable disease (decrease 50%) in 25%, and 8% had progressive disease. There was a relationship between radiation dose and tumor responsiveness, with a 73% CR or PR rate for doses greater than 50 Gy (vs. 46.7% with dose larger than 50 Gy, P 0.0299). Tumor size also affected responsiveness, with tumors larger than 10 cm having 50%
response, and tumors smaller than 10 cm with 78.8% responsiveness (P 0.0109). The in-eld failure was signicantly correlated with RT dose (P 0.031), where 47% failed when the dose was less than 50 Gy, and only 16% failed when the dose exceeded 50 Gy. The median follow-up was 12.9 months after RT and 23 months after diagnosis. At the end of the study, 16 patients remained alive. The 2-year OS rate after diagnosis was 47% (median survival of 18 months) and, after RT, 27% (median survival 10 months). In-eld progression-free survival (PFS) at 2 years was 61%, with a median survival of 10 months. Toxicity/Complications. There were no RILD or dose-limiting toxicities seen in the Tse and colleagues study.154 Eight of the 31 HCC patients developed grade 3 elevated liver enzymes. There were 3 patients who developed transient asymptomatic right-sided pleural effusions 3 months after SBRT. One patient developed a tumor-duodenal stula 15 months after SBRT, and died 22 months after SBRT due to GI bleeding, believed to be related to disease persistence or progression, with a possible contribution from the radiation treatment.154 In the study by Park and colleagues, 62.7% of patients had nausea or vomiting that was transient and improved with medication.145 This study also noted that the incidence of morbidity was affected by which lobe was irradiated, where 55% of patients developed acute morbidity after RT to the right lobe, versus 92% of patients with RT to the left lobe. Late morbidities developed in 8 patients, where 3 suffered RILD, 2 gastritis, and 3 with gastroduodenal ulceration. There were no fatal complications, nor grade 4 adverse effects.
Radioactive Particles
Background. Given the risk of RILD with whole liver radiation and the need for doses of more than 40 Gy to inict lethal injury to malignant tissue, minimally invasive intra-arterial devices delivering high does of radiation internally to the tumor have emerged. This therapy utilizes radioactive yttrium-90 microspheres to deliver high tumoricidal doses while limiting the development of RILD.112 Technique. Yttrium-90 intra-arterial RT, also known as radioembolization, is a minimally invasive catheter-based therapy delivering internal radiation via the tumor-feeding arterial vessels. Since hepatic tumors derive their blood supply primarily from the hepatic artery and normal liver parenchyma is supplied by the portal system, treatment is relatively selective.155 Embolic particles are loaded with radionuclide containing the pure beta-emitter, yttrium-90, and lodge in malignant microvasculature, delivering high doses of ionizing radiation to the tumor compartment
while maintaining low radiation exposure of the normal liver. Currently, there are 2 commercially available yttrium-90 microsphere devices: TheraSphere (MDS Nordion; Ottawa, ON, Canada) (made of glass) and Selective Internal Radiation (SIR) spheres (Sirtex Medical, Sydney, Australia) (made of resin).112,155-157 TheraSpheres are used primarily for HCC. Contraindications. Absolute contraindications include signicant hepatopulmonary shunting demonstrated on a pretreatment 99mTc macroaggregated albumin (MAA) scan (results in 30 Gy being delivered to the lungs with a single infusion), and the inability to prevent deposition of microspheres to the GI tract with modern catheter techniques. Relative contraindications include compromised pulmonary function, inadequate liver reserve and kidney function (creatinine 2.0 mg/dL), and a platelet count of 75 109/L4. Morbidity. The most common clinical toxicity is a mild postembolic syndrome that includes fatigue, vague abdominal discomfort, pain, and fever. Other nontarget radiation-induced toxicities include cholecystitis, gastric ulceration, gastroduodenitis, pancreatitis, radiation pneumonitis, and RILD.112 Outcomes (TheraSpheres). TheraSpheres are used for HCC, and in a recent prospective study patients were stratied according to method of treatment, risk, Okuda classication, and Child class.156 Patients were treated by liver segment or dened by catheter placement and blood ow distribution. The treatment was dened as segmental when the catheter perfused less than two Couinaud liver segments. If all individual treatments were segmental, then patients were classied as being treated segmentally. All nonsegmental treatments were classied as lobar. The number of treatments depended on tumor distribution, hepatic function, and vascular ow dynamics. The patients were divided into groups including segmentally treated, lobar treated/low-risk, and lobar treated/ high risk. All patients treated in a lobar fashion with diffuse disease, tumor replacement of more than 70% of the liver, ascites, AST or ALT levels more than 5 times the upper limit of normal, or total serum bilirubin greater than 2 mg/dL, were deemed high risk. Forty-three patients were followed, and there was no difference among groups in terms of tumor response. Fifty-one percent of lesions demonstrated a more than 50% reduction in tumor size, and 79% of patients had a tumor response when percent reduction and/or tumor necrosis were used as measures. The median OS was signicantly different between groups (segmental, 47 months; low-risk lobar, 17 months; high-risk lobar, 11 months; P 0.0001). In non-high-risk patients, median survival was 21 months versus
11 months in high-risk patients (P 0.0001). Median survival also differed according to Okuda Stage (stage I, 24 months; stage II, 13 months; P 0.0001). There was improved survival in Childs class A patients with median survivals of 21 months versus 14 months in class B/C patients (P 0.006). Based on these results, despite similar tumor response rates, patients with better underlying liver function and less tumor burden have improved survival after directed RT for HCC. Further prospective studies are needed to compare outcomes to other standard therapies, given that results following this treatment have not yet been reported with long-term follow-up or in comparison to other therapeutic options.
Embolization
Background. As described above, given the dual blood supply144 various catheter-based, locoregional therapies exploit the preferential blood ow to hepatic tumors via the hepatic arterial system and sparing the nontumorous liver supplied by the portal system.115 TACE delivers chemotherapeutics followed by either embolization or various materials to decrease intratumoral blood ow.115 The reduced blood ow to the tumor leads to tumor ischemia as well as increased local concentrations of antitumor drug, therefore reducing systemic toxicity.115 Technique. Both TACE and bland embolization involve delivering vascular occlusive agents that occlude tumor inow via a temporary catheter placed in the hepatic artery.158 Chemotherapeutics may or may not be administered before embolization, resulting in either TACE or bland embolization, respectively. Embolization agents can be permanent (polyvinyl alcohol [Ivadon]) or temporary (microspheres, degradable starch microspheres [DSM], collagen and gelatin sponge [Gelfoam]).158 Specic to TACE, there are variations in protocols, including the chemotherapeutic used, the use of lipiodol, and the type of material used to decrease blood ow.115 Doxorubicin, cisplatin, and mitomycin are the drugs used most often in the United States. Lipiodol is an iodinated ethyl ester of fatty acids of poppyseed oil that is retained by liver tumor.115,159 Most protocols utilize this agent as a drug carrier and a tumor-seeking agent115 because it has a microvascular occlusive effect, and is preferentially retained by hepatic tumor cells.158 Some form of embolization with the agents mentioned above usually follows the administration of drug to reduce arterial blood ow and induce tumor ischemia. However, it is important to maintain some ow to tumor to repeat TACE treatments.115
Transcatheter Arterial Chemoembolization

Indications/Limitations. TACE is used for unresectable HCC and as bridging for transplantation.115,160,161 TACE also has palliative indications and offers symptomatic relief from tumors with invasion into Glissons capsule.158 Given the promising results in its palliative role, TACE has been evaluated as a neoadjuvant therapy with the hope of reducing tumor size, inducing tumor necrosis, and preventing tumor dissemination during resection.162 Results are inconclusive, but randomized trials demonstrate that preoperative TACE did not improve surgical outcomes and resulted in dropout from denitive surgery because of disease progression and liver failure.162-164 The data are also inconclusive regarding its adjuvant role after resection,165,166 but there are randomized data to suggest it may be benecial.166,167 Extensive intrahepatic metastases involving both lobes of the liver are limitations to TACE, precluding treatment of all feeding vasculature at the expense of normally perfused tissue.158 Adverse Effects/Complications. The most common adverse effect is postembolization syndrome (right upper quadrant pain, nausea, vomiting, and fever with elevated liver enzymes),115 which occurs transiently in approximately 4% to 10% of patients. Recovery normally occurs within 7 to 10 days.115 Mechanical complications can occur, and include catheter dislodgement, thrombosis, and occlusion, site infection, mesenteric ischemia, and inadvertent infusion embolization of the hepatic artery.158 Rare but serious complications include tumor rupture, acute liver failure, liver abscess, and pulmonary lipiodol embolism.115,158 Outcomes TACE in Unresectable HCC. TACE was the most frequent treatment for HCC as initial therapy as demonstrated by the Liver Cancer Study Group of Japan.168 An 8-year prospective study was performed by Takayasu and colleagues, and consisted of 8510 patients with unresectable HCC treated with TACE. The median survival was 34 months (mean follow-up, 19 months), and the 5-year survival rates, stratied by TNM stage (I, II, III, and IV), were 47%, 32%, 20%, and 10%, respectively (P 0.001). This demonstrates that the lower the stage, the better the survival rate after TACE therapy. Randomized trials have also demonstrated improved survival in patients with unresectable HCC undergoing TACE versus symptomatic treatment.160,161 In the study from Lo and colleagues, 80 patients with unresectable HCC were randomly assigned to TACE versus symptomatic
treatment.161 Survival was the main endpoint, with 1- and 2-year survival rates of 57% and 31% in the TACE group, respectively, versus 32% and 11%, respectively, in controls (P 0.002). For tumors smaller than 5 cm, survival was 29.8 months in the TACE group and 11.5 months in the controls (P 0.003). Again, TACE proves to be more effective than symptomatic control for unresectable HCC. TACE versus Transcatheter Arterial Embolization (Bland Embolization/TAE). Studies comparing TACE with TAE have shown no difference in survival in HCC patients.160 In a randomized study by Llovet comparing TACE, TAE, and symptomatic treatment of unresectable HCC, 112 patients received embolization with gelfoam, chemoembolization with gelfoam and doxorubicin, and symptomatic treatment.160 The primary endpoint was survival (mean follow-up, 22 months for embolization, 21 months for chemoembolization, and 15 months for control groups). The 2-year survival was 50% for embolization, 63% for chemoembolization, and 27% for control (P 0.009 control vs. chemoembolization, P NS embolization vs. chemoembolization). TACE improved survival compared with conservative therapy, but not bland embolization.160 Therefore, the choice of bland versus chemoembolization is institution-dependent, since no real differences in long-term outcome have been demonstrated. Combination TACE RFA. Since the rate of complete necrosis in RFA decreases as tumor size increases, combining RFA with therapies that occlude arterial supply or other local ablative therapy has been proposed and studied to increase the area of coagulative necrosis.119 Since TACE is commonly used for the treatment of unresectable HCC, researchers hypothesized that blood ow occlusion in the tumor can decrease heat dispersion by the bloodstream, and increase the size of the necrotic area produced with ablation.119 A randomized trial evaluated TACE combined with RFA versus TACE alone versus RFA alone in patients with large HCC ( 3 cm).169 OS was improved in patients receiving combination TACE-RFA compared with either treatment alone. The median survival was 24 months following TACE, 22 months following RFA, and 37 months following combination treatment (P 0.001 for TACE vs. the combination; P 0.001 for TACE vs. RFA). When subgroup analysis was performed according to lesion size, combination treatment increased survival over TACE (P 0.008) and RFA (P 0.001) in patients with lesions between 3 and 5 cm. For lesions larger than 5 cm, survival was highest in the combination group (P 0.001, TACE-RFA vs. RFA and TACE). Therefore, combination TACE-RFA may have survival benets over either therapy alone in HCC larger than 3 cm.
TACE RT (Unresectable HCC). TACE has been a primary treatment for patients with unresectable HCC.170 Recent advances in local RT have led to studies demonstrating improved response rates when added to TACE for unresectable HCC.171,172 Thus far, TACE is not globally accepted as a treatment for unresectable HCC with PVT.173,174 There is fear of liver failure attributable to ischemia after these procedures, with risk of necrosis of noncancerous hepatic parenchyma and deterioration of hepatic function.175 Although Yamada and colleagues demonstrated feasibility in combination therapy for patients with PVT when TACE is strictly administered to the intrahepatic tumor and RT to PVT,176 the majority of TACE RT is directed at advanced HCC without PVT. Patients with histologically proven unresectable HCC were included in a prospective study by Cheng and colleagues.170 Twenty-ve patients with a mean tumor size of 10.3 4.4 cm all underwent local RT (mean dose, 46.9 5.9 Gy), followed by TACE 1 month later unless contraindicated (main PVT, bilirubin 3 mg/dL, and intrahepatic arteriovenous shunting). Patients were classied as Childs class A or B. Median follow-up was 23 months. Median survival was 19.2 months, and 1- and 2-year survival rates were 54% and 41%, respectively. T4 patients receiving only RT had shorter survival at 2 years (21% vs. 64% in non-T4 patients). The 2-year survival rate was 13% for RT alone, and 55% for RT TACE (P 0.003). Although PVT had a nonsignicant impact on 2-year survival, all 5 patients with PVT developed regional progression after treatment, compared to 7 of 20 patients without PVT. These results are similar to a study from Seong and colleagues, in which 30 patients with unresectable HCC were enrolled in a prospective trial of combined TACE and RT.177 The median survival and 1-year survival rate were 17 months and 67%, respectively. Cheng concluded that TACE RT was associated with better control of HCC than RT alone, but acknowledged the bias of better patient selection in the combination group.
Hepatic Arterial Infusion Chemotherapy

Background. The role of systemic chemotherapy is limited, given poor response rates in advanced, unresectable HCC.178-180 Therefore, localized therapies have been implemented to improve the outcomes associated with unresectable HCC, including HAIC either as a single therapy or in combination with other localized therapies mentioned above. Multiple studies have evaluated HAIC via an implantable port system and have reported it to be a useful therapeutic modality for patients with advanced HCC.181,182 The advantages of HAIC compared with systemic chemotherapy include delivery of higher concentrations with less sysCurr Probl Surg, January 2010 37
temic toxicity, and different chemotherapeutic agents have been used alone or in combination.183 Technique. The indwelling catheter can be inserted percutaneously or intraoperatively. Percutaneously, the catheter is placed via the femoral or brachial artery using angiography. The tip of the catheter is placed at the common hepatic artery or the proper hepatic artery.184 The other end of the catheter is connected to the injection port, and, in the operative approach, the device is implanted subcutaneously in the right lower abdominal quadrant.183,184 Adverse Reactions. Most commonly nausea and loss of appetite occur in 35% of patients,184 and are controllable by medications and/or suspending HAIC. These adverse reactions are secondary to the chemotherapeutics used, and also include leukopenia/thrombocytopenia (13%), renal damage (2%), deterioration in hepatic function (13%), and auditory disturbances (2%).184 Complications. There are also rare technical problems associated with the catheter, including catheter obstruction (10%), catheter sepsis (4%), catheter dislocation (2%), and hepatic artery occlusion (2%).184 Outcome in Locally Advanced HCC. In a previous study by Ando and colleagues, 48 patients with HCC and PVT were treated with HAIC via an implantable port.184 Patients received 4 serial courses of chemotherapy, each consisting of daily cisplatin and 5-uorouracil (5-FU) for 5 days. Responders were dened as either undergoing CR or PR and nonresponders as having stable disease or progressive disease. Eight percent and 40% of patients had a CR and PR, respectively. The 1- and 5-year survival rates were 45% and 11%, respectively. The median survival for the 23 responders was 31.6 months, and 5.4 months for nonresponders. For the responders, the 1- and 5-year survival rates were 100% and 40%, respectively. In an attempt to shorten the duration of treatment without compromising the therapeutic effect, Park and colleagues performed a prospective study evaluating outcomes after repetitive short-course HAIC with high-dose 5-FU and cisplatin over 3 days every 4 weeks in patients with advanced HCC.183 Thirty-four of 41 patients had PVT. A median of 6 cycles were administered, with 9 patients (22%) achieving PR, and 14 with stable disease (34%). The OS was 12 months, and the time to disease progression was 7 months. Therefore, short-course HAIC is a safe alternative for patients and can be administered with systemic chemotherapy.
HAIC and Localized RT (for Locally Advanced HCC)

In advanced HCC with PVT, patients have a grave prognosis with often less than 6 months survival.7,185 Although resection is the gold-standard
treatment for suitable candidates, with 1-year survival reported at 72%,186 it has little role in advanced HCC given patients poor liver function, extensive liver and/or metastatic disease, and portal vein involvement. HCC has a high risk of PVT, which has been observed in 65% at autopsy.184,187 Unfortunately, most patients with locally advanced HCC are unresectable and have limited treatment options due to PVT. Given these limitations, there remains a need for effective therapeutics. With prior studies demonstrating improved outcome when chemotherapy is directed intrahepatically via HAIC, and localized RT potentially lessening the risk of RILD,188,189 investigators have utilized the combination of these 2 for patients with locally advanced HCC. In a recent study by Han and colleagues, 40 patients with unresectable HCC and associated PVT (main trunk or rst branch) participated in a trial of localized CCRT (intra-arterial chemotherapy plus external beam radiation therapy) after HAIC.188 The subjects had a median age of 50, were predominantly male (90%), hepatitis B-positive, and had adequate liver reserve with Child-Pugh scores up to 6, total bilirubin less than 2.0 mg/dL, and ICG R15 less than 20%. Forty-ve Gray (Gy) were delivered over 5 weeks to the target volume, and concurrent continuous-infusion hepatic arterial 5-FU was given during the rst and fth weeks of RT through a percutaneous chemoport. One month after CCRT, HAIC with 5-FU and cisplatin were administered every 4 weeks for 3 to 12 cycles according to tumor response. HAIC was stopped after 3 cycles if there was progressive disease. The primary endpoint of this study was OS and PFS. Mean follow-up was 18.2 months, with 1-year and 3-year OS being 58% and 24%, respectively. The median survival was 13.1 months from the start of RT. The median time to PFS was 6 months. Patients were divided into 2 groups based on their initial response after CCRT, and survival was signicantly improved in responders versus nonresponders (medial survival, 19.9 months vs. 11.4 months). In a phase II trial of high-dose conformal RT with concurrent HAIC with oxuridine in patients with unresectable intrahepatic malignancies, patients were included if they had Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2 and had life expectancies of more than 12 weeks. The median survival was 15.2 months for HCC patients compared with 8 months in historical controls (P 0.0001).189 The authors compared all subjects in the study demonstrating improved survival when localized RT 75 Gy, which improved median survival from 14.9 to 23.9 months. For all tumor types, PFS was also improved
FIG 3. HCC Algorithm. Locoregional therapy for HCC is dependent on Childs-Pugh classication, hepatitis B/C positivity, and tumor size and location. *Consider transplant particularly in hepatitis C or Child-Pugh B patients with hepatitis. Consider ablation if tumor(s) 3 cm.
with higher doses of RT of more than 75 Gy (20.7 vs. 10.9 months). These data suggest short-term survival benets with a combination of localized therapies.
Summary
Since most patients are inoperable at diagnosis, other liver-directed therapies are needed to treat patients with HCC. Currently, the most commonly utilized techniques include ablation (RFA and microwave), embolization, PEI, HAIC, and directed RT. These therapies can be administered alone, but can also be effective when utilized in combination or with other chemotherapeutic regimens. An algorithm to approach the initial steps in managing localized HCC is presented in Fig 3. Because there are many subtleties in treatment approaches dependent on patientspecic factors, as well as institutional-dependent resource differences, this is meant as a guide to treatment options rather than a denitive schema. Based on the limitations of the currently available options to treat localized HCC, there remains a need for randomized studies to better address which modalities are superior for treating HCC according to the specic clinical scenario.
Systemic and Emerging Therapies for HCC

HCC is a rapidly fatal disease in many patients190 and systemic therapy with cytotoxic agents has historically been of marginal benet. The median survival for patients with intermediate or advanced stage tumors, which make up 50% to 60% at diagnosis, is just 6 to 16 months when treated. An improved understanding of the mechanism of hepatocarcinogenesis provides us a unique opportunity to evaluate novel agents against this cancer. As more is learned about the heterogeneity of HCC from genomic and proteomic studies, the appreciation of its multidimensional nature has expanded, along with the ever-increasing armamentarium of therapeutic agents and targets. HCC is currently receiving a great deal of attention in the past few years as the era of molecularly targeted therapy continues. Agents against angiogenesis and hepatic growth factors are already in clinical use or are in development.
Cytotoxic Chemotherapy
Cytotoxic therapy has long been used locally and systemically for HCC. Although local therapy has proven to be of benet for OS, systemic therapy historically has demonstrated limited therapeutic efcacy and bears no gold-standard option.18 Results of a phase III randomized placebo-controlled trial with the multikinase inhibitor sorafenib showed a survival benet, giving the oncology community reason for optimism about the future of systemic therapy.
Is There a Role for Chemotherapy in HCC?

It is important to understand where the role of chemotherapy ts into the myriad of treatment options, which includes transplant, resection, ablation (RFA, cryo, PEI), and TACE.191 The majority of HCC patients present at an intermediate or advanced stage, for which curative surgical measures and ablative techniques are contraindicated. It is in this setting that systemic therapy takes on a potentially important role. In addition, systemic therapy may hold promise as an adjuvant therapy, but needs further evaluation to test efcacy, since the only promising therapy, sorafenib, has been tested only in patients with metastatic disease. A major challenge in patient selection for past chemotherapeutic trials is the heterogeneity of the disease. Unlike most other solid tumors, hepatomas arise in the setting of underlying organ dysfunction, and 80% occur in cirrhotic livers. It is well known that the degree of hepatic dysfunction correlates with the predicted OS. Accordingly, the benets of systemic agents are balanced against the risks related to morbidity and drug tolerance. Impaired renal function, ascites, and thrombocytopenia
are just 3 examples of factors that can reduce tolerance to chemotherapy. Indeed, varying degrees of dysfunction portend different prognoses, and when additional variables like geography, disease etiology/etiologies, and patient PS are taken into account, the reliability of statistical ndings are less sound. Nevertheless, the inclusion of chemotherapeutic agents has been an attractive option for clinical trials and patient care. Another major challenge has been that HCC has proven refractory to chemotherapy. Resistance could be intrinsic or acquired after chemotherapy. The length of exposure to chemotherapeutic drugs is crucial in determining response; poor tumoral perfusion, and consequently drug delivery, contributes to intrinsic resistance.192 The background of hepatic brosis, with its architectural distortion, may also account for these ndings. The drug resistance of HCC involves changes in the expression and metabolism of drug targets, and is caused by defects in effector mechanisms.193 An example of this is the altered expression of glutathione transferase, topoisomerase II, and DNA repair involving modulation of cellular response to chemotherapy. Another target with altered expression is p-glycoprotein, the product of the MDR1 gene. It has been shown to increase after drug exposure in vitro.194 Response to systemic chemotherapy was inversely related to the level of p-glycoprotein expression in patients with inoperable tumors. Another gene related to hepatoma formation is p53, whose pathway plays its part in cellular response to chemotherapeutic agents.195 Proteins have been identied that confer resistance to p53-induced apoptosis by inhibition of NF B activity.196
Doxorubicin and Topoisomerase II Inhibitors

Perhaps no chemotherapeutic agent for HCC has been studied more frequently than doxorubicin.197 It is an anthracycline with mechanism of action involving intercalation and topisomerase II inhibition. In 1 study of more than 475 subjects, a 16% response rate has been documented, with a median survival time of 3 to 4 months.198 In a prospective randomized trial by Lai and colleagues199 involving 106 patients who were randomized to receive either doxorubicin versus no antitumor therapy in advanced HCC patients, it was reported that the median survival time in patients receiving doxorubicin was 10.6 months versus 7.5 weeks in the no-therapy arm (P 0.036). A phase III trial that randomized HCC patients to doxorubicin as a single agent versus control group demonstrated a response rate of 10.5%.200 The median survival in patients treated with doxorubicin
was 6.83 months. Another phase III RCT compared the survival of 445 patients with unresectable HCC treated with nolatrexed or doxorubicin. In this trial, it was reported that the median OS was 22.3 weeks for nolatrexed and 32.3 weeks for doxorubicin (P 0.0068).200 Objective response rate (CR plus PR) was 1.4% for nolatrexed and 4.0% for doxorubicin. The studies with doxorubicin suffer from a heterogeneous patient population and study design. The major side effects observed with doxorubicin use in these studies have been GI or hematological (diarrhea, vomiting, anemia, thrombocytopenia, and neutropenia) along with fatigue and elevated LFTs.198-200 Clearly, the toxicity prole and poor response rate have led to decreased enthusiasm for its use. Doxorubicin has also been studied in combination with other chemotherapeutic agents including gemcitabine,201 cisplatin,202 bleomycin,197 and 5-FU plus mitomycin-C203 with response rates ranging from 11.8% to 18.9%. Pegylated liposomal doxorubicin (PLD), due to its liposomal formulation, is purported to have longer circulation time and specic accumulation in tumor tissue with benecial effects of reduced toxicity. It has been studied in the past as a single chemotherapeutic agent in HCC with mixed results. A study by Halm and colleagues in 2000204 showed neither objective response nor stable disease,204 and a small phase II study by Schmidinger and colleagues in 2001 involving 14 patients showed an objective response in 14% with 36% disease stabilization over 6 months.205 A study most recently published by Lind and colleagues206 from Sweden failed to detect a response rate greater than 20%, with the authors concluding that PLD appears ineffective in advanced HCC. The common side effect prole included palmoplantar erythrodysesthesia, grade 3 fatigue, and grade 3 hematological toxicity (thrombocytopenia/ neutropenia and anemia), which were relatively mild as compared with conventional doxorubicin. However, PLD, when used in conjunction with gemcitabine in a phase II trial involving 35 patients, showed CR in 2 patients and a PR in 6 patients, with an overall response rate of 24% (preliminary data) and a median survival rate of 8.8%.207 Epirubicin, which is a 4= epimer of doxorubicin, was thought to have the possibility of a better therapeutic index than doxorubicin. Epirubicin as a single agent in advanced HCC showed no tumor response and the authors concluded that it had no major impact on survival.208 Results of studies testing mitoxantrone were also disappointing.209
Other Chemotherapeutic Agents

There have been a variety of other chemotherapeutic agents used as a single agent against advanced HCC with disappointing results. These include 5-FU, cisplatin, etoposide, and udarabine.210-213 Irinotecan, paclitaxel, gemcitabine, capecitabine, and irofulven, which are relatively newer chemotherapeutic agents, have also been used as single agent against advanced HCC, but all have shown relatively low response rates.180,214-217
Combination Chemotherapy in HCC

Due to the dismal activity of single agents in treating advanced HCC, many combination chemotherapy regimens have been tried, with some trials showing better response rates compared with single agent therapy. However, considering the heterogeneity of HCC and the diversity in the patient population studied, the results of these studies need to be interpreted with caution. Also, combination chemotherapy seems to be associated with higher toxicity in various studies. One of the most notable regimens that has evoked much discussion is the combination of cisplatin, doxorubicin, 5-FU, and interferon- (PIAF) in advanced unresectable HCC. Leung and colleagues reported in 1999 that, among 50 patients treated with this regimen as part of a single-arm open-label phase II study, 13 patients (26%) had an objective response, with 9 of the 50 patients undergoing surgical resection secondary to the response.218 Of these 9 patients, 4 patients had no histological evidence of tumor cells, with a median survival of 8.9 months. A recent phase III RCT by Yeo and colleagues comparing doxorubicin to PIAF regimen was published in 2005.178 The trial involved 188 patients with unresectable HCC with the patients randomized to each arm. The overall response rates in the doxorubicin and PIAF groups were 10.5% (95% condence interval [CI], 3.9-16.9) and 20.9% (95% CI, 12.5-29.2), respectively. The median survival durations of the doxorubicin and PIAF groups were 6.83 months (95% CI, 4.80-9.56) and 8.67 months (95% CI, 6.36-12.00), respectively (P 0.83), which were not statistically signicant. Neutropenia (82% vs. 63%, grade 3/4), thrombocytopenia (57% vs. 24%), and hypokalemia (7% vs. 0%) were statistically signicantly more common in patients treated with PIAF than in patients treated with doxorubicin. Therefore, combination therapy with PIAF is not recommended due to the lack of signicant benet and increased toxicities compared with doxorubicin. Gemcitabine and oxaliplatin (GEMOX) have been recently investigated in their activity against advanced HCC.219 In a phase II study220 of
GEMOX administered every 2 weeks involving 32 patients with cirrhosis with previously untreated advanced HCC, the objective response rate was 18% (95% CI, 8-34) with 58% experiencing stable disease (this included 5 minor responses). Median progression-free and OS times were, respectively, 6.3 months (95% CI, 4.3-10.1) and 11.5 months (95% CI, 8.5-14.3). The main side effects experienced were thrombocytopenia (grade 3/4 in 27%), neutropenia (24%), anemia (9%) and neuropathy, grade 3 oxaliplatin induced (9%). They also reported that treatment using this regimen was more effective in patients with nonalcoholic cirrhosis than alcoholic cirrhosis. The authors attributed this nding to the differences in liver parenchymal damage caused by alcohol as opposed to viral hepatitis or steatohepatitis. A subsequent uncontrolled study by Loua and colleagues using GEMOX every 3 weeks219 involving 44 patients showed PR in 1 patient alone with stable disease in 20% (8 patients) for an average duration of 20.2 weeks. The authors concluded that the particular dosing schedule used in this study was ineffective and should therefore not be used in patients with advanced HCC. A study by Merlin and colleagues involving GEMOX administered every 2 weeks involving 15 patients showed 27% PR rate with 13% stable disease rate.221 The median OS was 7.7 months. It is likely that the GEMOX regimen has some antitumor activity, and the response rate is higher than the prior mentioned studies, but more patients are needed to conrm this. Epirubicin and VP-16 (etoposide) were used in an Italian phase II study222 reported by Bobio-Pallavicini and colleagues in the late 1990s. The study involved 36 patients with an objective response rate of 39% (95% CI, 23-55) with 31% exhibiting stable disease. The median OS time was 10 months and in the objective responders, the survival time was 13.5 months. The main side effect reported was hematological toxicity. However, there have been no phase III trials using this combination since subsequent studies showed poor response rates. Cisplatin, doxorubicin, and capecitabine were studied in a trial involving 29 patients in Korea with advanced HCC.223 The response rate was 24% (95% CI, 9-40) with 6 patients having stable disease. The median time to progression was 3.7 months. The main side effect was GI toxicities and approximately 17% patients had low-grade hand-foot skin reaction. The authors reported that despite the acceptable response rate and side effect prole, there was no survival benet. A Chinese phase II study evaluated the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX 4 regimen) in patients with unresectable HCC.224 This study involving 22 patients showed a response rate of
18.2% (including 1 CR and 3 PRs). The main side effects experienced included neutropenia, thrombocytopenia, liver transaminase (TA) elevations, and diarrhea. The authors conclusion was that since the response is encouraging, phase III trials are warranted.
Hormonal Therapy in HCC

Tamoxifen, an antiestrogen, has been extensively studied in advanced HCC as a potential therapy for HCC, since estrogen receptors are present in approximately one third of these tumors. There has also been evidence to suggest that estrogen can promote tumor growth in vivo and potentiates hepatocyte growth in vitro.225 However, various prospective randomized trials and a systematic review of the benets of tamoxifen in HCC patients have failed to show any advantage with tamoxifen use.226-229 A randomized controlled phase III trial published in 2005 by Barbare and colleagues227 evaluated the role of tamoxifen in advanced HCC with a total of 420 patients randomized to the control or therapy arm (20 mg tamoxifen daily). The estimated median survival times were 4.8 and 4.0 months in the tamoxifen and control groups, respectively (P 0.25). It was concluded that tamoxifen did not improve the OS of patients with advanced HCC. It is also postulated that tamoxifen might function as a potential inhibitor of p-glycoprotein, which is the MDR1 gene product. Therefore, tamoxifen has been combined with various chemotherapeutic agents to treat against advanced HCC and also failed to show a benet.230-232
Biotherapy in HCC
Octreotide, a somatostatin analog, has also been used as experimental therapy for advanced HCC due to the identication of somatostatin receptors in HCC.233 Prior studies have been reported with conicting data about the benet of this drug. A phase II study that evaluated the use of octreotide LAR in 17 patients with advanced HCC and a CLIP score greater than 3 showed PR in 6% (1 patient), stable disease in 60%, and a median OS of 10 months.234 Adverse reactions reported included symptomatic hypoglycemia (12%), small bowel obstruction/ileus (6%), thrombocytopenia (6%), and abdominal bloating (6%). Due to the improved median survival expected for this group of patients, updated data after more patients are enrolled are anticipated.
Need for Novel Agents in HCC

Despite the availability of a large number of clinical trials searching for an optimal therapy against advanced HCC, there is no single or combi46 Curr Probl Surg, January 2010
nation hormonal therapy or chemotherapy that is effective against advanced HCC. The heterogeneity, the aggressive nature of the disease, and the underlying hepatic dysfunction are some of the main reasons for the failure of systemic chemotherapy regimens to improve survival. Part of the answer to solve this difcult clinical problem lies in the development of molecularly targeted therapies and trials involving such therapies to assess their efcacy in HCC.
Targeting Angiogenesis in HCC

Sorafenib. There is at present a deluge of studies in genomic and proteomic medicine related to HCC, and scientists are nding more and more potential targets, cellular processes, and methods of categorizing HCC. Translating this information into clinical trials is paramount for the discovery of newer, targeted therapies. The SHARP Trial (Sorafenib HCC Assessment Randomized Protocol) was the rst to show a survival benet using one of the newer, molecularly targeted therapies. It was a phase III, international, multicenter, double-blind study sponsored by the drug manufacturers, involving patients with late stage HCC. The rationale behind the study was that Raf kinase is overexpressed and activated in HCC,235 and that the RAF/MEK/ERK signaling pathway is implicated in liver tumorigenesis. Sorafenib, approved in advanced renal cell carcinoma, is the only approved inhibitor of Raf kinase and is also a known inhibitor of RAF, vascular endothelial growth factor receptor (VEGFR), and other kinases.236 The clinicians based the study on the ndings of a phase II trial of sorafenib for patients with advanced HCC and Child class A and B liver function status,237 whereby the drug demonstrated antitumor activity and was well tolerated. The primary objective of the SHARP Trial was OS and time to symptomatic progression; the secondary objective was time to progression and disease control rate (overall response rate SD).5 Six hundred two patients, nearly all of Child class A and four fths in BCLC stage C, were randomized into a study or placebo arm. Of the primary outcomes, the median OS showed a marked advantage for sorafenib (46.3 weeks vs. 34.4 weeks for placebo; hazard ratio [HR], 0.00,058; P 0.0077). The median time to progression also favored sorafenib (5.5 months vs. 2.8 months for placebo; HR, 0.58; P 0.000007) (Table 5). The study was halted early when the international data monitoring committee determined that the OS endpoint had been met. Adverse events (AE) were relatively few and, surprisingly, were more common for placebo (54%) than for sorafenib (52%). In practice, however, some physicians believe the true incidence of AE with sorafenib
TABLE 5. Phase III sorafenib hepatocellular carcinoma assessment randomized protocol trial Variable Overall response, no. (%) CR PR SD PD Progression-free rate at 4 months, % TTP, weeks OS, weeks Time to symptom progression (FSHI8-TSP) Sorafenib (n 299) 0 7 (2.3) 211 (71) 54 (18) 62 24 46.3 Placebo (n 303) 0 2 (0.7) 204 (67) 73 (24) 42 12.3 34.4 0.58 0.69 .000007 .00058 .77 HR P
HR, hazards ratio; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TTP, time to tumor progression; OS, overall survival; FSHI8-TSP, the Functional Assessment in Cancer Hepatobiliary Symptom Index Time to Symptom Progression scoring system.
is higher than reported in this study. The most common AE for patients taking sorafenib were diarrhea, anorexia, nausea, and hand-foot skin reaction. The diarrhea is often tolerable but can be debilitating and can require discontinuation of the agent. One limitation to the study was the selection criteria: Child-Pugh class A disease patients, whose hepatic function should, in theory, tolerate the hepatically excreted study drug better than a liver with poorer function. The authors concluded that sorafenib is the rst systemic therapy to prolong survival in HCC patients, and has now become a reference standard for systemic therapy of HCC patients. Sorafenib activity is, in part, predicated on the highly vascular nature of HCC. Antiangiogenic targets are not new in the scope of chemotherapeutic trials, and several other biologic agents have been studied. Bevacizumab is a recombinant, humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). In addition to its direct antiangiogenic effects, it is also thought to enhance chemotherapy efcacy by decreasing the elevated interstitial pressure in tumors. Sorafenib improves OS in patients with HCC, yet the response rate is low (2%), with no CRs by Response Evaluation Criteria in Solid Tumors. Therefore, even though patients may not have a radiographic response, as long as they have stable disease and are tolerating therapy, they should continue treatment. A randomized phase II study of sorafenib and doxorubicin versus doxorubicin alone was reported by Abou-Alfa and colleagues.238 The combination arm of sorafenib and doxorubicin showed a higher median
TABLE 6. Phase II randomized study of sorafenib and doxorubicin (S doxorubicin (P D) in patients with hepatocellular cancer65 S TTP (months) OS (months)* PFS (months)** Objective response (CR Response (SD) D (n 8.6 13.8 6.9 2 (4) 36 (77) 47)
D) versus placebo
D (n 4.8 6.5 2.8 1 (2) 27 (55)
49)
PR), n (%)
TTP, time to tumor progression; OS, overall survival; PFS, progression-free survival; CR, complete response; PR, partial response; SD, stable disease. *P 0.013; **P 0.012.
time to progression of 8.6 months and median OS of 13.7 months over doxorubicin (Table 6). Bevacizumab. Siegel and colleagues used bevacizumab as a single agent in a phase II study.239 Two doses, 5 and 10 mg/kg administered IV every 2 weeks, were tested in patients with no overt metastases or local vascular invasion. Of the 46 subjects studied, only 6 had objective responses, although 65% were progression free at 6 months (median PFS was 6.9 months). As with the previously described studies, this study suffers from small sample size, a nonrandomized nature, and possible patient selection bias. Malka and colleagues also evaluated a bevacizumabonly single-arm trial, and report a 12.5% response rate; the median PFS and median survival were not reported.240 Targeting the VEGF pathway, bevacizumab has been explored in combination with gemcitabine-oxaliplatin.241 A phase II study was undertaken to dene efcacy and toxicity proles in HCC patients. The median OS was 9.6 months (95% CI, 8.0 months to not available) and median PFS was 5.3 months (95% CI, 3.7 to 8.7 months). GEMOX-B was concluded to have moderate antitumor activity for patients with advanced HCC with an especially high 6-month PFS of 48% (95% CI, 31-65). A similar study by Sun and colleagues used capecitabine-oxaliplatin with bevacizumab, and the PFS was similar, at 5.4 months.242 These PFS results are similar to the sorafenib arm of the SHARP study. Other Antiangiogenic Agents. Other phase II trials with other antiangiogenic agents have been performed with limited success (Table 7). Thalidomide. Thalidomide monotherapy was studied in a cohort of 37 HCC patients.244 Thirty-one percent showed disease stability (CI 95%, 16-51) and 61% had disease progression (95% CI, 42-78). There was a concerning incidence of neurotoxicity. The authors concluded that thalidomide monotherapy, at the doses studied (400-1000 mg/day), could not be recommended for the treatment of HCC.
TABLE 7. Antiangiogenesis therapy in hepatocellular cancer Agents Bevacizumab* GEMOX-bevacizumab** Thalidomide Epirubicin-thalidomide Author (Year) Schwartz (2005)243 Zhu (2006) Patt (2005) Zhu (2005) N 11 33 32 19 RR (%) 10% 20% 5% 0% SD (%) 72% 27% MS (m) 9.6 m 6.8 m 6.5 m
GEMOX, gemcitabine and oxaliplatin; RR, response rate; SD, stable disease; MS, median survival. *5 mg/kg; **10 mg/kg.
In the same year, Zhu and colleagues published a study on the use of thalidomide and epirubicin in unresectable HCC patients.245 The lower dose of thalidomide (200 mg) was better tolerated. No full or PR was observed, but 7 patients (41%) had stable disease with a median duration of 6 months (range, 5-14). The authors concluded that the combination of thalidomide and epirubicin was well tolerated at the studied doses and had limited benet in patients with unresectable and metastatic HCC. Cediranib. Cediranib is an orally available potent small molecule receptor tyrosine kinase inhibitor of VEGF-A. An interim report of a 2-stage study was presented at American Society of Clinical Oncology (ASCO) 2007.246 Patients with unresectable HCC, meeting eligibility criteria, received this drug, 45 mg, by mouth once daily using a 28-day treatment cycle. The primary endpoint was 6-month survival. With an accrual goal of 40, promising activity was dened as 22 or more patients surviving at least 6 months. Data on 28 patients (25 males, 3 females) were presented. Thirteen had extrahepatic disease and 14 had cirrhosis. The median age was 75 years (range, 48-84). Nineteen patients were evaluable for toxicity; the major toxicities were fatigue, anorexia, hypertension, and jaundice (all grade 3), and there were no side effects attributable to bone marrow suppression. Overall, 16 (84%) patients developed grade 3 toxicity and no grade 4-5 toxicity was observed. Data on efcacy is pending. Brivanib Alaninate. At the 2009 ASCO Gastrointestinal Cancers Symposium, another promising antiangiogenic molecule was presented. Brivanib alaninate is a selective dual inhibitor of VEGF and broblast growth factor (FGF) signaling pathways. It has been shown to inhibit angiogenesis and tumor growth in xenograft models of HCC. It has also shown clinical activity and good tolerability in patients with unresectable HCC.247 The objective of this study was to assess the efcacy and safety of brivanib alaninate in patients with advanced HCC who have failed one prior antiangiogenic therapy. This was a second cohort of an ongoing
phase II single-agent study of brivanib alaninate in patients with unresectable, locally advanced or metastatic HCC who had failed sorafenib, sunitinib, bevacizumab, or thalidomide treatment. The primary efcacy endpoint was a 6-month PFS rate. Additional endpoints included overall response rate by modied WHO criteria, time to response, OS, and disease control rate. Of the 22 patients, 20 had failed sorafenib and 2, thalidomide. The most frequently reported AEs ( 25%) were fatigue (64%), diarrhea and anorexia (41% each), vomiting and hypertension (36% each), and constipation and nausea (27% each). Nineteen patients had an investigator assessment of efcacy, and 11 (58%) had stable disease. Twenty-one patients had measurements of AFP levels (82% had elevated AFP at baseline) and 43% had a greater than 50% reduction on study. The authors concluded that that brivanib alaninate is generally well tolerated in patients who have failed sorafenib or thalidomide treatment. Early review of scans and AFP levels indicated encouraging signs of activity in this population for which there is currently no approved therapy. Sunitinib. Another promising oral multikinase inhibitor that targets angiogenesis factors is sunitinib. Specically, the receptor tyrosine kinases VEGFR1, VEGFR2, PDGFR- / , FLT3, and c-KIT are targeted. Phase II studies examined tolerability and efcacy of this molecule in advanced HCC.248 Of the 37 study subjects, one had a conrmed PR and 39% had stable disease as their best response. Grade 3 and 4 toxicities were primarily bone marrow related, including thrombocytopenia (43%) and neutropenia (24%). Additional toxicities included central nervous system symptoms (24%), asthenia (22%), and hemorrhage (14%). Dose reductions were required in 27% of patients. mTOR Inhibitors in HCC. In addition to antiangiogenic targets, other molecular agents for HCC target mTOR (mammalian target of rapamycin). Activation of this pathway induces cell proliferation and prolongs cell survival. The mTOR protein regulates phosphorylation of the p70 S6 serine-threonine kinase and the translational repressor protein 4E-BP1.249 These agents include everolimus, temsirolimus, and sirolimus; phase I and II trials are currently under way. Investigators have studied total and phosphorylated mTOR and S6K protein expression by immunohistochemistry in hepatocellular carcinomas (n 73), brolamellar carcinomas (n 13), and hepatic adenomas (n 15). Results were correlated with tumor growth pattern as dened by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modied Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin
to see the effect on proliferation and S6K phosphorylation. They found that the increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines.250 Targeting EGFR Pathway in HCC. In a normal liver, epidermal growth factor receptor (EGFR), EGF, and transforming growth factor (TGF)- are involved in the proliferation of hepatocytes. It is suspected that the TGF- /EGFR signaling pathway contributes to hepatocarcinogenesis and proliferation of established HCC.251 In HCC tumor specimens, the TGF- and EGFR axis is acknowledged to be activated in 70% to 80% of cases. Therefore, EGFR inhibitors such as cetuximab252 and erlotinib253 have been proposed to patients with advanced HCC in several trials. However, results of single agent studies were disappointing, with response rates below 5% and no signicant improvement of survival in comparison to historical controls. Combining VEGFR and EGFR. Recent studies have increased the testing of the combination of 2 drugs affecting 2 different pathways.254,255 One such study included biopsy-proven unresectable HCC, Child-Pugh class A or B cirrhosis, bilirubin less than 2.0 mg/dL, TA levels less than 5 times the upper limit of normal, platelets greater than 50,000/ L, and ECOG PS less than 2.255 Prior allowed therapies are surgery, external RT, ablation, TACE, and 1 systemic therapy. Patients received bevacizumab 10 mg/kg every 14 days plus erlotinib 150 mg orally daily. The primary endpoint was the percentage of patients alive and progression-free after 16 weeks of therapy (PFS16) based on historic median PFS of 3 to 5 months. Fourteen patients (24.6%) had prior therapy (6 sorafenib). Of the 57 patients enrolled, 14 (28%) had conrmed PRs, 31 (62%) had stable disease, and 5 (10%) had progressive disease. The median PFS was 7.9 months (95% CI 5.7, 9.5) and the OS was 12.8 months, 95% CI (9.5, 17.9). Grade 3 or 4 toxicities were TA elevation, diarrhea, fatigue, hyperkalemia, hypertension, proteinuria, pulmonary embolus, leukoencephalopathy, and GI bleed. The combination of bevacizumab and erlotinib appears to have signicant clinically meaningful activity in HCC and further studies are under way.
Summary
In conclusion, systemic therapy is appropriate for patients with advanced unresectable disease who are unsuitable for surgical or locoregional therapy. Experience with chemotherapy as a treatment for HCC has been disappointing, with response rates typically less than 20%, and there is no therapeutic advantage of combination chemotherapy compared with single agents.204,227 Due to underlying hepatic dysfunction, treatment side effects often dictate that the risk of therapy outweighs the benet in OS. This is a eld in evolution, however. The development of molecularly targeted therapy using agents like sorafenib provides reason for optimism for HCC patients and clinicians alike. The survival benet shown by this multikinase inhibitor has brought to bear a gold-standard option whereby future comparative trials can be compared. Careful patient selection and properly powered trials will be needed to prove the efcacy of these newer treatments. In view of the highly vascular nature of HCC, the continued evaluation of antiangiogenic agents is anticipated, with higher specicity for predominant molecular pathways.
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Hepatocellular Carcinoma: Current Management

Surgical Therapy for Hepatocellular Carcinoma

Curr Probl Surg, January 2010

Evaluating Hepatic Reserve

69 31 55 44 24 (10 years) 41 23 (10 years) 39

5 years 36 74 (4 years) 69 57 73 62 25.3 46.6 61.1

UNOS, United Network for Organ Sharing.

Transplantation versus Resection for HCC

Locoregional Therapy for HCC

RFA for Small, Resectable HCC

RFA in Locally Advanced HCC

recurrence rates comparable to published data evaluating other ablation modalities.

Outcome for Unresectable HCC

PEI for Unresectable HCC

Complete necrosis Survival rate (%) (%)

Brunello, 139 2008140

Lin, 187 2005133

PEI PAI RFA

Shiina, 232 2005141

Lin, 157 2004142 Lencioni, 102 2003143

PEI RFA PEI RFA

Radiotherapy for Advanced HCC

Transcatheter Arterial Chemoembolization

Hepatic Arterial Infusion Chemotherapy

HAIC and Localized RT (for Locally Advanced HCC)

Systemic and Emerging Therapies for HCC

Is There a Role for Chemotherapy in HCC?

Doxorubicin and Topoisomerase II Inhibitors

Other Chemotherapeutic Agents

Combination Chemotherapy in HCC

Hormonal Therapy in HCC

Need for Novel Agents in HCC

Targeting Angiogenesis in HCC

D (n 4.8 6.5 2.8 1 (2) 27 (55)

105. 106. 107. 108. 109. 110. 111. 112.

113. 114. 115. 116. 117. 118.

Curr Probl Surg, January 2010

145. 146. 147.

148. 149. 150.

151. 152. 153.

Curr Probl Surg, January 2010

174. 175. 176.

179. 180. 181.

Curr Probl Surg, January 2010

211. 212. 213.

Curr Probl Surg, January 2010

248. 249. 250. 251.

252. 253. 254.

Curr Probl Surg, January 2010

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