Systemic treatment for advanced

hepatocellular carcinoma
INTRODUCTION — Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently occurs in the setting of chronic liver disease
and cirrhosis. It is typically diagnosed late in the course of patients with chronic liver disease [1]. The patient's hepatic reserve, as indicated
by the Child-Pugh classification, often dictates therapeutic options (table 1).

Treatment options for HCC are divided into surgical therapies (ie, resection, cryoablation, and liver transplantation) and nonsurgical
therapies, which may be liver-directed (ie, percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization,
radiation and radioembolization) or systemic (chemotherapy, molecularly targeted therapy, hormone therapy). A general approach to the
treatment of HCC is shown in the figure (algorithm 1). An alternative treatment algorithm has been proposed by the Barcelona group (figure
1) [2].

Attempts to generate algorithmic approaches to the treatment of HCC are difficult since new treatments and indications for various
treatments are evolving rapidly. Furthermore, therapeutic approaches tend to vary based upon the available expertise as well as variability
in the criteria for hepatic resection and liver transplantation. These issues and a general approach to treatment of HCC are discussed in
detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma".)

Here we will discuss systemic treatment approaches for patients with advanced, unresectable HCC for whom liver-directed therapy is not
appropriate. Surgical treatment, liver-directed nonsurgical therapies, and the epidemiology, clinical manifestations, and diagnosis of HCC
are reviewed separately. (See appropriate topic reviews).

GENERAL CONSIDERATIONS — Palliative chemotherapy has not been used routinely for patients with advanced HCC for a number of
reasons:

 HCC has been considered to be a relatively chemotherapy-refractory tumor. This may be in part due to the high rate of
expression of drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in
p53.
 It can be difficult to gauge survival benefits from a systemic therapy regimen in patients with advanced HCC since survival is
often determined not by tumor aggressiveness or the impact of a systemic treatment, but by the degree of hepatic dysfunction.
Systemic chemotherapy is usually not well tolerated by patients with significant underlying hepatic dysfunction.
 Clinical investigations of chemotherapy in advanced HCC have been undertaken in diverse patient populations. As an example,
patients in Asian studies tend to be significantly younger, with well compensated cirrhosis due to chronic hepatitis B or C, while
North American or European patients with HCC are typically over 60, with alcoholic cirrhosis and comorbid illnesses. Not only
does this interfere with chemotherapy tolerance, dose, and the reported side effect profile, but in studies applying strict entry
criteria, the results may be applicable only to the small minority of Western patients who have well preserved hepatic function.
Moreover, chemotherapy may have less efficacy in patients with significant cirrhosis.

There has been a resurgence of interest and enthusiasm for systemic therapy of HCC with the emergence of data showing that single
agentsorafenib improves survival over best supportive care alone. These results established sorafenib monotherapy as the new reference
standard systemic treatment for advanced HCC and formed the basis for approval of sorafenib for unresectable HCC in the United States.
(See 'Sorafenib' below.)

However, there still may be a role for cytotoxic chemotherapy in selected medically appropriate patients who fail or are intolerant
of sorafenib, and who have adequate hepatic function and a reasonable remaining life expectancy.

Estimating life expectancy — Several staging or prognostic systems have been developed to guide the prognosis and treatment of
patients with HCC. These include the American Joint Committee on Cancer (AJCC) TNM, Okuda, CLIP (Cancer of the Liver Italian
Program), CUPI (Chinese University Prognostic Index), GETCH (Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire) and the
BCLC (Barcelona Clinic) staging systems. These systems were developed based upon both surgical and nonsurgical patients, and they
generally aim to classify patients with HCC broadly into those with early, intermediate, and advanced stage disease. (See "Staging and
prognostic factors in hepatocellular carcinoma".)

Patients with advanced HCC are a heterogeneous group. There are substantial differences in overall survival that are due to factors not
captured within the subgroups identified by these staging systems, and it is not clear that any of these staging systems provides meaningful
prognostic discrimination among those with advanced disease [3,4].

However, there is some evidence that outcomes of nonsurgical HCC can be predicted by both patient and tumor characteristics [5,6]. As an
example, a prognostic scoring system for patients with advanced HCC not amenable to locoregional therapy has been proposed (the
ALCPS, Advanced Liver Cancer Prognostic System), which allows a separation of three prognostic groups with significantly different three-
month survival [5]. The stratification is based upon the assignment of a weighted point value to 11 different patient and tumor
characteristics, with the total number of points corresponding to an estimated likelihood of three month survival (table 2).
While a prognostic scoring system such as this can objectively help clinicians to select appropriate candidates for evaluation of treatment
efficacy in clinical trials of new agents, there are no prospective data addressing its ability to predict which patients might benefit from any
form of therapy.

Response assessment — Conventionally, treatment response of HCC to systemic therapy has been assessed by radiologic imaging
using conventional response criteria such as that of the World Health Organization or RECIST (Response Evaluation Criteria in Solid
Tumors) (table 3) [7,8]. However, criteria such as these may not accurately reflect response to treatment or tumor viability, particularly in
the era of targeted therapy with agents such as sorafenib that are cytostatic rather than cytotoxic. It is not uncommon to observe patients
without a significant radiographic response who have evidence of reduced tumor viability or even a pathologic complete response in a
resected specimen [9,10]. Furthermore, in patients with HCC treated with sorafenib, tumor necrosis may initially be manifested as an
enlarging rather than a shrinking lesion [11].

An HCC expert consensus proposed the use of modified RECIST criteria, which mainly measure tumor viability in assessing response for
patients with HCC treated with targeted agents such as sorafenib (table 4) [2,12,13].

Similarly, guidelines from the European Association for Study of the Liver (EASL) suggest that estimated reduction in viable tumor burden
using dynamic imaging techniques be incorporated into definitions for response for patients receiving local ablation therapies for HCC
[14] (see "Nonsurgical therapies for localized hepatocellular carcinoma: Radiofrequency ablation, percutaneous ethanol injection, thermal
ablation, and cryoablation", section on 'Assessing response to locoregional therapies'):

 Complete response (CR) — Absence of enhanced tumor areas, reflecting complete necrosis
 Partial response (PR) — A >50 percent decrease in enhanced areas, reflecting partial tissue necrosis
 Progressive disease (PD) — An increase >25 percent in the size of ≥1 measurable lesion or appearance of a new lesion
 Stable disease — Any tumor response between PR and PD

Although not used widely for patients receiving systemic chemotherapy, response monitoring using functional criteria such as the EASL
criteria or modified RECIST may provide a more accurate reflection of vital tumor burden and treatment benefit than standard RECIST,
particularly for cytostatic treatments targeting angiogenesis, such as sorafenib [2,11,13,15]. (See 'Sorafenib' below.)

Serial measurements of the serum tumor marker alpha fetoprotein (AFP) appear to be a valid surrogate endpoint for the identification of
patients who would derive benefit from systemic chemotherapy, including sorafenib [16-19]. In one study, AFP responders (arbitrarily
defined as patients whose serum AFP decreased by more than 20 percent after a minimum of two cycles of chemotherapy) had better
median survival than did nonresponders (13.5 versus 5.6 months), and AFP response was strongly associated with radiographic response
[16]. Furthermore, an AFP response was frequently observed in patients with radiographically stable disease, and served to identify a
subgroup of these patients with better survival.

SYSTEMIC CHEMOTHERAPY — Chemotherapy has not been used routinely for patients with advanced HCC for a number of reasons:

 HCC has been considered a relatively chemotherapy refractory tumor. This may be in part due to the high rate of expression of
drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in p53 [20-22].
 It can be difficult to gauge benefit from chemotherapy in patients with advanced HCC since survival is often determined not by
tumor aggressiveness or the impact of a systemic treatment, but by the degree of hepatic dysfunction. Systemic chemotherapy
is usually not well tolerated by patients with significant underlying hepatic dysfunction.
 Clinical investigations of chemotherapy in advanced HCC have been undertaken in diverse patient populations. As an example,
patients in Asian studies tend to be significantly younger, with well-compensated cirrhosis due to chronic hepatitis B or C, while
North American or European patients with HCC are typically over 60, with alcoholic cirrhosis and comorbid illnesses. Not only
does this interfere with chemotherapy tolerance, dose, and the reported side effect profile, but in studies applying strict entry
criteria, the results may be applicable only to the small minority of Western patients who have well preserved hepatic function.

Furthermore, chemotherapy may be less effective overall in patients with significant cirrhosis. This was illustrated in an evaluation of
predictive factors among 147 patients receiving chemotherapy for HCC [23]. There were no objective responses among patients with a
poor performance status, ascites, portal vein tumor thrombus, or serum bilirubin >2.0 mg/dL [23].

Monotherapy

Doxorubicin and mitoxantrone — Single agent doxorubicin has been the most studied chemotherapy agent for advanced HCC. Although
an early trial in 1975 reported dramatic clinical activity and a 79 percent response rate [24], subsequent work suggests that the true
2 2
objective response rate with doxorubicin monotherapy is 20 percent or less with doses of 75 mg/m [25-30]. Lower doses (≤60 mg/m per
cycle) are associated with even lower objective response rates [31,32].

Despite the modest objective response rate, at least two controlled trials involving 106 and 445 patients, respectively, suggest
that doxorubicin is associated with a small survival advantage compared to either best supportive care alone (median survival 10.6 versus
7.5 weeks) [28] or nolatrexed (median survival 32 versus 22 weeks) [32]. The reason for the disparate survival outcomes in these two trials
is unclear, but patient selection may have played a role.

A limited number of phase III studies note higher response rates but no survival benefit with doxorubicin monotherapy compared to non-
oxaliplatin 5-FU-based regimens and single agent etoposide [29,33,34].
Both epirubicin and mitoxantrone have an approximately similar level of antitumor efficacy as doxorubicin (response rates 10 to 25 percent)
[35-38]. In contrast, the single agent activity of pegylated liposomal doxorubicin (PLD) is limited [39-41]. Combination regimens containing
PLD are discussed below. (See 'Gemcitabine-based' below.)

High-dose tamoxifen may potentiate the antitumor effect of doxorubicin [42]. In an open-label trial in which 38 patients with advanced HCC
2
received doxorubicin plus tamoxifen (120 mg/m per day), 12 (32 percent) achieved a response [43]. However, the median progression free
survival was only seven months.

Fluoropyrimidines — 5-Fluorouracil (5-FU) has acceptably low toxicity and broad antitumor efficacy. Although there is extensive hepatic
metabolism, adequate doses can usually be administered in the setting of hepatic dysfunction or jaundice.

Response rates with 5-FU monotherapy have been low. However, when given in combination with leucovorin, response rates as high as 28
percent have been reported [44], although lower rates have been noted by others [45].

Single agent treatment with the orally active fluoropyrimidine capecitabine [46] was associated with an objective response in nine of 37
patients (25 percent) in one study, including one complete response. However, a lower objective response rate (three partial responses
among 50 treated patients) was noted in a subsequent phase II study evaluating the same dose of capecitabine in combination
2
with oxaliplatin (130 mg/m every three weeks) [47]. (See 'Oxaliplatin-based' below.)

Gemcitabine, irinotecan, and thalidomide — Single agent gemcitabine has modest activity at best. In one report, 5 of 28 patients with
2
locally advanced or metastatic disease who received gemcitabine (1250 mg/m once weekly) had a partial response of short duration
(median 13 weeks) [48]. However, two other trials were disappointing [49,50]; one showed no objective responses in 30 patients treated
2
with gemcitabine 1000 mg/m , although nine achieved stable disease for a median of 7.4 months [50].

Irinotecan monotherapy resulted in one partial response for seven months among 14 patients with advanced HCC [51]. A second trial in 29
patients documented no objective partial responses but 12 disease stabilizations [52].

In early reports, thalidomide, an agent with antiangiogenic activity, [53-55] has been associated with low rates of objective antitumor activity
but disease stabilization in up to one-third of patients.

Combination chemotherapy regimens — Multiple combination cytotoxic regimens have been tested in patients with advanced HCC.

Cisplatin-based — Cisplatin-based combination regimens appear to result in higher objective response rates than non-cisplatin-containing
regimens, although it is not clear that any regimen confers a survival benefit. Response rates with several two and three-drug regimens are
approximately the same:

 Cisplatin plus doxorubicin – Response rates 18 and 49 percent in two studies, one conducted in children (with predominantly
HCC rather than the more chemosensitive hepatoblastoma) [56,57]
 Cisplatin, mitoxantrone, and continuous infusion 5-FU – Objective response rate 24 and 27 percent in two different studies
[58,59]
 Cisplatin, epirubicin and infusional 5-FU – Response rate 15 percent [60]
 Cisplatin, doxorubicin plus capecitabine – Response rate 24 percent [61]
 Sequential low-dose infusional cisplatin plus infusional 5-FU – Response rate 47 percent [62]
 Cisplatin plus capecitabine – Response rate 6 and 20 percent in two studies [63,64]

Gemcitabine-based

 2
Gemcitabine and cisplatin – In one phase II study, the combination of gemcitabine (1250 mg/m on days 1 and 8) and cisplatin
2
(70 mg/m on day 1 of every 21-day cycle) was associated with an overall response rate of 20 percent [65]. Grade 3 to 4
toxicities included anemia (37 percent), neutropenia (13 percent), thrombocytopenia (7 percent), transaminitis and mucositis (3
2
percent each). A second trial using a slightly different dosing regimen (cisplatin 25 mg/m on days 1 and 8, gemcitabine 1000
2
mg/m on days 1 and 8) reported a more favorable toxicity profile but a lower response rate (one partial response among 15
patients) [66].
 Gemcitabine plus pegylated liposomal doxorubicin – Pegylated liposomal doxorubicin (PLD) in combination with gemcitabine is
2
modestly active. In a phase II trial, 41 patients received gemcitabine (1000 mg/m days 1 and 8) plus pegylated
2
liposomal doxorubicin (30 mg/m on day 1) every 28 days [67]. There were three complete and seven partial responses (overall
response rate 24 percent), the median TTP was 5.8 months, and median overall survival was 22.5 months. Treatment was well
tolerated, with grade 3 to 4 toxicity limited to neutropenia (17 percent) and thrombocytopenia (2 percent).

Oxaliplatin-based — Combinations of oxaliplatin with either gemcitabine or a fluoropyrimidine are active in patients with advanced HCC.

GEMOX — Activity has been suggested for gemcitabine plus oxaliplatin (GEMOX), a regimen that lacks substantial renal and hepatic
toxicity [68,69]. In a phase II study involving 32 cirrhotics with previously untreated advanced HCC (lung metastases in 10, multifocal liver
2
disease in 18, the rest node-positive), gemcitabine (1000 mg/m by fixed dose rate infusion) on day 1 was followed by oxaliplatin (100
2
mg/m ) on day 2, with both drugs repeated every two weeks [68]. Grade 3 or 4 toxicities included thrombocytopenia (27 percent),
neutropenia (24 percent with two cases of febrile neutropenia), anemia (9 percent) and neuropathy (9 percent). The objective response rate
was 18 percent, and an additional 58 percent had disease stabilization. Median survival was 11.5 months. For unclear reasons, treatment
seemed to be more effective in patients with nonalcoholic rather than alcoholic cirrhosis. Combinations of GEMOX
with bevacizumab and cetuximab are discussed below. (See 'Molecularly targeted therapy' below.)
 2
XELOX — In a phase II study evaluating capecitabine (1000 mg/m twice daily for 14 of every 21 days) in combination with oxaliplatin (130
2
mg/m every three weeks), there were only three partial responses among 50 treated patients (objective response rate 6 percent) [47].
However, 29 additional patients had stable disease, and the disease control rate was 72 percent. Median overall and progression-free
survival were 9.3 and 4.1 months, respectively.

FOLFOX — Regimens containing oxaliplatin plus short-term infusional 5-FU and leucovorin are most commonly used in the treatment of
advanced colorectal cancer. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials".)
2
Modified FOLFOX4 (table 5) was directly compared to single agent doxorubicin (50 mg/m every three weeks) in an Asian trial of 371
patients with advanced or metastatic HCC, 90 percent of whom had HBV infection as the underlying etiology of cirrhosis [70]. In a
preliminary report of the most mature data (after 305 events had occurred), which were presented in an oral abstract session of the 2010
ASCO annual meeting, the median survival in the FOLFOX arm, although significantly better than that with doxorubicin monotherapy, was
short (6.5 versus 4.9 months, p = .00425). FOLFOX was also associated with significantly better median PFS (3 versus 1.8 months),
objective response rate (9 versus 3 percent), and disease control rate (partial response plus stable disease, 53 versus 33 percent).
Although the rate of sensory neuropathy was higher in the FOLFOX group (15 versus 0.6 percent), most cases were mild, and there were
no significant differences in the rate of grade 3 or 4 toxicities (either hematologic or nonhematologic) between the groups.

Interpretation of these results is hampered by the use of a relatively low dose of doxorubicin in the control arm. Furthermore, whether these
results can be extrapolated to American patients, who have alcohol or HCV rather than HBV as the underlying cause of cirrhosis, is
unclear.

Summary — The efficacy of cytotoxic chemotherapy is modest in patients with HCC, and in general, the duration of benefit is limited. No
single regimen has emerged as superior to any other, although few randomized trials have been conducted. Despite objective responses
that are occasionally complete, median survival in all of these studies has been short (4.4 to 11.6 months), with the exception of those in
which resection/transplantation is attempted after chemotherapy [57].

Interferon alfa and chemoimmunotherapy — IFNa is an immunomodulatory cytokine that has demonstrated activity in preclinical models
against several tumor types including HCC. At least three controlled trials have evaluated IFNa monotherapy for patients with advanced
HCC, with conflicting results:

 An early Chinese randomized trial of 75 patients suggested superior response rates and better tolerability of IFNa compared to
single agentdoxorubicin [71].
 A possible survival benefit for IFNa compared to BSC was suggested in a second trial in which 75 patients with inoperable HCC
2
were randomly assigned to receive IFNa (50 mU/m IM three times weekly) or no antitumor therapy [72]. Objective responses
were noted in 11 of 35 patients (31 percent) and median survival was significantly improved in the IFNa treated group (14.5
versus 7.5 weeks, respectively). Treatment was surprisingly well tolerated; dose reduction was required in only 34 percent,
predominantly because of fatigue.
 In contrast, these results were not confirmed in a second trial in which 58 patients were randomly assigned to IFNa (3 mU three
times weekly for one year) or symptomatic treatment only [73]. Only two of 30 evaluable patients (6.6 percent) achieved a
partial response, and the survival at one and two years was not different between the two groups (58 and 38 percent versus 36
and 12 percent, respectively). Despite the markedly lower dose than in the previous study, IFNa was associated with side
effects in 23 of 30 patients (77 percent), leading to discontinuation in 13.

Combinations of chemotherapy with interferon-alfa (IFNa) appear active.

The PIAF regimen — Cisplatin, IFNa, doxorubicin, and infusional 5-FU (PIAF) is an active, albeit toxic, combination regimen for advanced
HCC [9,74,75]. In one uncontrolled study, for example, PIAF was associated with an objective response in 13 of 50 patients (26 percent)
with advanced HCC [9]. Furthermore, histologic examination revealed no evidence of tumor cells in four of nine patients (44 percent) who
underwent surgical resection after achieving a partial response. Overall median survival of the entire population was nine months, and eight
of the resected patients remained in complete remission from eight to 26 months. Toxicity was mainly myelosuppression and mucositis, and
there were two treatment-related deaths from neutropenic sepsis.

Whether results with PIAF are better than with single agent doxorubicin was the subject of a multinational trial in which 188 unselected
2
patients with chemotherapy-naive unresectable HCC were randomly assigned to doxorubicin monotherapy (60 mg/m every three weeks)
2 2 2
or PIAF (cisplatin 20 mg/m on days 1 through 4, IFNa 5 MU/m subcutaneously on days 1 through 4, doxorubicin 40 mg/m on day 1, and
2
5-FU 400 mg/m on days 1 through 4) [30]. While objective response rates were higher with PIAF (21 versus 11 percent), this difference
was not statistically significant, nor was the difference in median survival duration (8.7 versus 6.8 months, p = 0.83). Not surprisingly,
treatment-related toxicity was more pronounced with PIAF (neutropenia 82 versus 63 percent grade 3 or 4, thrombocytopenia 57 versus 24
percent grade 3 or 4, hypokalemia 7 versus 0 percent grade 3 or 4).

One potential explanation for a failure to show a survival benefit in this trial may have been the lack of patient selection. The importance of
baseline liver function to outcomes with the PIAF regimen was illustrated in a series of 149 patients with unresectable HCC who were
treated with PIAF [74]. The objective response rate was significantly higher in patients with a normal bilirubin and a non-cirrhotic liver
compared to those with cirrhosis and a serum bilirubin >0.6 mg/dL (50 versus 6 percent). Of note, eight of 16 patients with a partial
response to PIAF who underwent surgical exploration had a complete pathologic response.

The place of the PIAF regimen in the treatment of unresectable HCC remains uncertain. However, due to its toxicity profile, it should be
considered only for fit patients with a good performance status and minimal hepatic dysfunction.

5-FU plus IFNa — The benefit of combining IFNa with just 5-FU alone is unclear; some data suggest that efficacy is schedule-dependent:
  2
In a report in which 43 patients (nine with the fibrolamellar variant of HCC) received infusional 5-FU (200 mg/m daily for 21 of
2
every 28 days) plus IFNa (4 MU/m three times weekly), an objective response was demonstrated in 14 (33 percent) [76]. Two
of four patients with HCC who were subsequently resected had a complete histologic response. Despite the presence of
cirrhosis in 71 percent of the patients with HCC, toxicity was moderate, with grade 3 or 4 stomatitis, fatigue, and hematologic
toxicity in 33, 5, and 9 percent of patients, respectively.
 A similar level of benefit (objective response rates between 33 and 50 percent, one-third to one-half complete) has been seen
with combinations of systemic IFNa with intrahepatic arterial 5-FU in patients with advanced HCC and major portal vein
thrombus (a contraindication to transhepatic arterial chemoembolization) [77-79]. Overall survival and chemotherapy response
have been significantly correlated with tumor expression of the type I interferon receptor [78,79]. Transhepatic arterial
chemoembolization for HCC is discussed elsewhere. (See "Nonsurgical therapies for localized hepatocellular carcinoma:
Transarterial embolization, radiotherapy, and radioembolization", section on 'Transarterial embolization'.)
 2
In contrast, less favorable results were noted in a small series of 10 patients receiving systemic 5-FU 750 mg/m weekly plus
IFNa (9 MU three times weekly); treatment was associated with substantial toxicity and no sustained antitumor responses [80].

Summary — The above data suggest that combination chemotherapy may play a minor role in the treatment of advanced HCC. However,
there are insufficient data to routinely recommend any standard regimen, and no drug or regimen has been approved for the treatment of
HCC [81]. Newer data on the efficacy of molecularly targeted agents for HCC have brought these agents, particularly sorafenib, to the
forefront of therapy. (See 'Molecularly targeted therapy' below.)

Nevertheless, systemic chemotherapy may still be considered for patients whose tumors progress while on sorafenib and whose
performance status and baseline liver function are sufficient to tolerate it. The side effect profile of any chemotherapy regimen should be
considered carefully in patients with advanced liver disease and a short life expectancy. Pending the results of several ongoing phase II
clinical trials, we recommend that cytotoxic therapy be reserved for medically appropriate patients with adequate hepatic function and
preferably administered within the context of a clinical trial.

For patients who are not eligible for clinical trials or if they are not available, we usually recommend cisplatin plus gemcitabine for fit
patients. Cisplatin, interferon alpha, doxorubicin, and 5-FU (PIAF) or infusional doxorubicin and cisplatin are reasonable choices for young
and healthy patients if more aggressive therapy is desired [82]. Weekly low-dose doxorubicin is an acceptable option for older or more frail
patients as is oral capecitabine or weekly high-dose 5-FU and leucovorin for sick or jaundiced individuals.

Reactivation of viral hepatitis may occur in patients with HCC who are undergoing intensive systemic chemotherapy, so it is important to
maintain antiviral medications. This topic and the use of lamivudine to prevent reactivation of hepatitis B during chemotherapy is discussed
elsewhere. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Impact of preexisting liver
disease' and "Lamivudine monotherapy for chronic hepatitis B virus infection", section on 'With immunosuppression'.)

MOLECULARLY TARGETED THERAPY — Treatment approaches that are directed against a specific molecular defect are termed
"molecularly targeted therapies". While the molecular pathogenesis of HCC remains poorly understood, the following results have been
noted:

 Several lines of evidence point to a possible role for the epidermal growth factor receptor (EGFR)/EGF (HER1) signaling
pathway in the carcinogenesis and proliferative behavior of HCC [83-91]. These data have led to the exploration of agents that
inhibit the EGFR, such as the small molecule tyrosine kinase inhibitor erlotinib and the anti-EGFR monoclonal
antibody cetuximab.
 HCCs are highly vascular tumors, and high levels of expression of vascular endothelial growth factor (VEGF) have been
observed, raising the possibility that agents targeting VEGF and/or the VEGF receptor (VEGFR) might be of therapeutic value.
 The Raf/MAP kinase-ERK kinase (MEK)/extracellular signal regulated kinase (ERK) pathway has been implicated in HCC
tumorigenesis [92]. Raf (receptor activation factor) kinase is an essential component of the MAP kinase pathway, which is a key
signaling mechanism that regulates many cellular functions such as growth, transformation, and apoptosis [93]. ERK is the
downstream enzyme of the MAP kinase pathway that is directly activated by Raf kinase to phosphorylated ERK.

Overexpression of activated MEK1 in HCC cell lines enhances tumor growth and survival by preventing apoptosis. Furthermore, the core
proteins of hepatitis C virus (HCV), a major risk factor for HCC, elicit high basal levels of Raf-1 activity in hepatocytes, increasing the risk of
neoplastic transformation [93,94]. Taken together, these data suggest therapeutic potential for drugs that inhibit Raf kinase.

Sorafenib — Sorafenib (Nexavar) is a multi-targeted orally active small molecule tyrosine kinase inhibitor (TKI) that inhibits Raf kinase and
the vascular endothelial growth factor receptor (VEGFR) intracellular kinase pathway [95]. Efficacy in HCC was initially suggested by a
phase I trial in which a single patient with HCC had an objective partial response, as assessed by standard RECIST [96]. Subsequent
phase II and III studies did not confirm a high level of objective measurable antitumor activity as measured using standard RECIST [11,97];
however, results from the phase III SHARP trial suggest a survival benefit compared to best supportive care alone [97]. Considerations for
response assessment in patients receiving molecularly targeted agents such as sorafenib are discussed above. (See 'Response
assessment' above.)

 In the phase II trial of 137 chemotherapy-naive patients with inoperable HCC and Child-Pugh A or B cirrhosis treated
with sorafenib (400 mg twice daily), there were only three objective responses (2.2 percent), eight minor responses (5.8
percent), and 46 (34 percent) with stable disease for at least 16 weeks [11]. The median time to tumor progression (TTP) was
5.5 months and median overall survival, 9.2 months.
  The multicenter European SHARP trial randomly assigned 602 patients with inoperable HCC and Child-Pugh A cirrhosis
to sorafenib (400 mg twice daily) or placebo [97]. Overall survival, the primary endpoint, was significantly longer in the
sorafenib-treated patients (10.7 versus 7.9 months), as was time to radiologic progression (5.5 versus 2.8 months). Similar to
the phase II trial described above, objective response rates were low, according to RECIST (7 partial responses [2 percent]).
(See 'Response assessment' above.)

Treatment was well tolerated with manageable side effects. The only grade 3 or 4 adverse effects that occurred significantly
more often in the treated group were diarrhea (8 versus 2 percent) and hand-foot skin reaction (8 versus <1 percent). There
were no differences in liver dysfunction or bleeding. The overall incidence of sorafenib-reelated side effects (particularly
dermatologic) was low compared to that reported by others [98]. (See "Cutaneous complications of molecularly targeted therapy
and other biologic agents used for cancer therapy", section on 'Hand-foot skin reaction'.)

These results established sorafenib monotherapy as the new reference standard systemic treatment for advanced HCC and
formed the basis for approval of sorafenib for unresectable HCC in the United States.
 The efficacy of sorafenib in Asian patients was the subject of a second placebo-controlled phase III trial in which 226 patients
with Child-Pugh A cirrhosis and no prior systemic therapy for HCC received sorafenib 400 mg twice daily or placebo [99].
Patients receiving sorafenib had significantly better median overall survival (6.5 versus 4.2 months) and TTP (2.8 versus 1.4
months). Grade 3 or 4 side effects included hand-foot skin reaction (11 percent), diarrhea (6 percent) and fatigue (3 percent).

The magnitude of benefit was markedly less in this trial than seen in the SHARP trial. In fact, the treated group in the Asian trial
had a shorter survival duration than the control group in the SHARP trial (6.5 versus 7.9 months), despite the fact that both trials
used the same entry criteria. Nevertheless, patients accrued to the Asian study were more ill at the start of therapy than those in
the SHARP trial, with a generally worse performance status and more advanced stage of disease [100].

An important unanswered question is whether there are differences in response to sorafenib based upon the etiology of the HCC. Asian
patients have a higher prevalence of infection with hepatitis B virus (HBV) as compared to Western populations; 73 percent of the patients
enrolled to the Asian trial had HBV infection versus 18 percent of those enrolled to SHARP [97,99]. At least some exploratory analyses
suggest that patients with HCV infection as the etiology of their cirrhosis may have a better response to sorafenib as compared to those
with other underlying causes of cirrhosis [101,102]. As an example, in an exploratory analysis of the phase III SHARP trial, although a
survival benefit was seen in all subgroups treated with sorafenib, the difference in median overall survival between sorafenib and placebo-
treated patients was highest in those with HCV-related cirrhosis (6.6 months, 14 versus 7.4 months); it was 3.6 months (9.7 versus 6.1
months) in patients with HBV-related cirrhosis, and 2.3 months (10.3 versus 8 months) in those with underlying alcohol-related liver disease
[102]. These differences in outcome according to hepatitis virus type could potentially explain some of the survival differences between the
SHARP and Asian trials of sorafenib. However, the available data are scant, and further study is needed to establish the influence of
underlying liver disease on sorafenib treatment responsiveness.

Taken together, these findings underscore the differences in prognosis of HCC depending on ethnicity and cause of cirrhosis, and have led
some to question the role of sorafenib as mandatory standard therapy in all patients.

Safety in patients with liver disease — The patients enrolled in the above trials had predominantly (over 95 percent) Child-Pugh A
cirrhosis. However, the majority of patients with HCC have underlying cirrhosis, and therefore, competing causes of death from progressive
HCC versus worsening cirrhosis. In a systematic review of 118 studies of patients with cirrhosis and no HCC, the one- and two-year
survival rates for patients with Child-Pugh A, B, or C cirrhosis were 95 and 90, 80 and 70, and 45 and 38 percent, respectively [103]. Death
from cirrhosis could potentially mask treatment-related antitumor effect.

Despite the specific population studied in the SHARP trial, the original FDA approval of sorafenib for HCC in the United States did not
specify the underlying cirrhosis state. However, there is only limited clinical experience and few published data regarding the safety and
efficacy of sorafenib in patients with Child's Pugh B or C cirrhosis:

 One report consisted of a subset analysis of 38 patients with Child Pugh B cirrhosis and 98 patients with Child Pugh A cirrhosis
who were enrolled in the phase II sorafenib trial described above [104]. Drug pharmacokinetics were similar in both groups, as
were rates of drug discontinuation and dose reduction. Despite a more than 50 percent shorter course of therapy in the Child
Pugh B patients (median duration of therapy 1.8 versus 4 months), outcomes were similar.

However, outcomes were poorer in the Child-Pugh B group (median overall survival 3.2 versus 9.5 months in those with Child-
Pugh A cirrhosis). Furthermore, certain adverse effects were more common in those with Child-Pugh B cirrhosis (grade 3 or 4
elevated bilirubin in 53 versus 14 percent, grade 3 or 4 encephalopathy in 13 versus 3 percent), which could have been drug
related or due to disease progression.
 A similar conclusion was reached in a retrospective report of experience with sorafenib in 59 patients with HCC, 26 with Child-
Pugh A, 29 with Child-Pugh B, and 10 with Child-Pugh C cirrhosis [105]. The median survival time in the three groups was 8.3,
4.3, and 1.5 months, respectively. These data support the view that sorafenib is unlikely to benefit patients with Child-Pugh C
cirrhosis.
 The safety and efficacy of sorafenib in patients with liver dysfunction was also addressed in an analysis of 1586 patients
receiving sorafenib and registered in the international GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular
Carcinoma and of its Treatment with Sorafenib) prospective database [106]. In a preliminary report presented at the 2011
ASCO meeting, the safety profile of sorafenib was similar in patients with Child-Pugh A and B cirrhosis, but a greater
percentage of Child-Pugh B patients discontinued therapy due to adverse effects; they also had a higher rate of deaths during
 treatment up to 30 days from the last sorafenib dose (34 versus 15 percent) and a shorter overall median survival (5 versus
10.5 months).

The analysis also highlighted interspecialty differences in treating HCC with sorafenib. Hepatologists and gastroenterologists
were more likely to use full starting doses of sorafenib and to treat patients for a longer period of time. Despite this variation in
treatment practice, toxicity rates (hand-foot syndrome, hematologic toxicities) were similar among all three specialties.

Underlying cirrhosis also makes it more difficult to clear drugs for which there is significant hepatic metabolism, like sorafenib. There is
controversy as to whether the initial dose of sorafenib needs to be modified in patients with hepatic dysfunction, as evidenced by the
following reports:

 The safety of sorafenib in patients with elevated transaminase levels was studied in a subgroup analysis of data from the
SHARP trial [107]. Patients with mild or moderate liver dysfunction (≥1.8 times the upper limit of normal) did not experience
increased hepatic or other toxicity. Although median overall survival was diminished in both placebo and sorafenib-treated
patients with moderate liver dysfunction, median TTP and overall survival favored the sorafenib group regardless of
transaminase levels. The authors concluded that treatment was safe and effective, even in patients with mild or moderately
elevated baseline transaminase levels and that hepatic function remained stable over the course of sorafenib therapy.
 On the other hand, results from a phase I study suggest that dose reduction to 200 mg twice a day is required in patients with a
bilirubin 1.5 to 3 times the upper limit of normal and that the drug cannot be tolerated with more severe hyperbilirubinemia.
(See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Sorafenib'.)

The manufacturer recommends no dose adjustment for Child-Pugh class B impairment, and makes no recommendation for Child-Pugh
class C cirrhosis (table 1). Nevertheless, we recommend an initial dose reduction to 200 mg twice daily in patients with a total bilirubin 1.5
to 3 times the upper limit of normal and that the drug not be administered to patients with more severe degrees of hyperbilirubinemia. For
other patients with Child-Pugh B cirrhosis, standard dosing from the onset with dose modification as needed is appropriate.

Given the poor prognosis of patients with HCC and Child-Pugh C cirrhosis, the associated significantly abnormal liver function, and the high
risk of treatment-related toxicity, most physicians would not prescribe sorafenib to these patients.

Side effects — Side effects of VEGF TK inhibitors such as sorafenib may include hypertension, renal toxicity, arterial thromboembolism,
cardiotoxicity, thyroid dysfunction, hand-foot syndrome, rash, pruritus, alopecia, problems with wound healing, hepatotoxicity, and muscle
wasting. As with other VEGF TK inhibitors, hypertension has been associated with treatment benefit in HCC, but this has not been seen in
all studies [108,109]. (See "Overview of angiogenesis inhibitors", section on 'Hypertension'.)

Sorafenib has been associated with potentially fatal liver toxicity, which is characterized predominantly by a hepatocellular pattern of liver
damage with significant increases in transaminases; uncommonly elevations in the international normalized ratio (INR) or
hyperbilirubinemia may occur. Liver function tests should be monitored regularly during treatment. The US FDA-approved labeling
for sorafenib recommends that if transaminases are “significantly increased” without alternative explanation, such as viral hepatitis or
progressing underlying malignancy, that the drug be discontinued.

Details about side effects and their management are discussed in detail elsewhere. (See "Cutaneous complications of molecularly targeted
therapy and other biologic agents used for cancer therapy", section on 'Sorafenib and sunitinib' and "Cardiotoxicity of nonanthracycline
cancer chemotherapy agents", section on 'Sorafenib and sunitinib' and "Anti-angiogenic and molecularly targeted therapy for advanced
renal cell carcinoma" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease" and "Chemotherapy
hepatotoxicity and dose modification in patients with liver disease", section on 'Sorafenib'.)

Sorafenib plus doxorubicin — The benefit of adding sorafenib to doxorubicin was studied in a phase II trial in which all patients received
2
doxorubicin (60 mg/m every 21 days), and they were randomly assigned to sorafenib 400 twice daily for a maximum of six cycles or
placebo [110]. Combination therapy was associated with a similarly low objective response rate (4 versus 2 percent with doxorubicin alone),
but a significantly longer time to tumor progression (6.4 versus 2.8 months) and median overall survival duration (13.7 versus 6.5 months).
The side effect profile was not significantly worse with combined therapy, although one in five patients receiving sorafenib plus doxorubicin
had a decrease in left ventricular ejection fraction.

The degree to which this improvement represents synergism between sorafenib and doxorubicin remains to be defined. Before this
approach can be considered standard, this combination must be compared to sorafenib alone in a large-scale phase III trial, which is
ongoing (Cancer and Leukemia Group B [CALGB] trial 80802) [111].

Other agents targeting VEGF

Bevacizumab — Bevacizumab (Avastin, a monoclonal antibody [MoAb] directed against VEGF) alone is active in HCC. Efficacy was
shown in a trial in which 46 patients with nonmetastatic HCC received single agent bevacizumab at a dose of either 5 mg/kg or 10 mg/kg
doses once every other week [112]. An objective response was documented in six (13 percent, one complete), and the median
progression-free survival was 6.9 months. The most common grade 3 or 4 toxicities were hypertension (15 percent), thrombosis (6 percent)
and major bleeding (11 percent).

A similar level of efficacy was seen in a second trial, reported in abstract form only [113]. Using bevacizumab 5 to 10 mg/kg every 14 days,
there were three partial responses and 13 disease stabilizations among 30 patients; six had to discontinue therapy because of variceal
bleeding.
The combination of bevacizumab with gemcitabine and oxaliplatin (GEMOX) was safe and moderately effective in a small phase II trial in
2 2
which 30 patients received gemcitabine (1000 mg/m ) followed by oxaliplatin (85 mg/m ) on days 2 and 16, plus bevacizumab (10
2
mg/m on day 1 of the first cycle and thereafter, on days 1 and 15 of each cycle) [114]. The objective response rate was 20 percent, the six-
month progression-free survival rate was 48 percent, and median overall survival was 9.6 months. However, whether these results are
superior to GEMOX alone [68] or bevacizumab alone can only be determined in a randomized trial. (See 'Combination chemotherapy
regimens' above.)

The combination of bevacizumab plus capecitabine with or without oxaliplatin is also tolerable and modestly active [115,116]. Whether any
combination regimens are better than bevacizumab alone or the chemotherapy regimen alone will require a randomized trial. The
combination of bevacizumab pluserlotinib is discussed below.

Sunitinib — Sunitinib (Sutent) is another orally active TKI that targets a variety of TKs in addition to VEGFR, including platelet-derived
growth factor receptors (PDGFRs), KIT, RET, and FLT3. Experience with sunitinib is illustrated by the following observations:

 An initial phase II study included 37 patients with unresectable HCC who were treated with sunitinib (50 mg daily for four of
every six weeks) and assessed by monthly CT scans [117]. There was one confirmed partial response, and 35 percent had
stable disease for over three months. However, grade 3 to 4 toxicity was prominent (thrombocytopenia, neutropenia, asthenia
and hand-foot skin reaction in 38, 24, 14, and 11 percent, respectively). Four patients had a fatal treatment-related adverse
event (renal failure, bleeding, thrombocytopenia, and hepatic encephalopathy).
 Two other phase II studies administered a lower dose of sunitinib (37.5 mg daily for four of every six weeks) to 34 and 45
patients, respectively [118,119]. In both studies, there was only one objective response, but about 40 to 45 percent of patients
achieved stable disease [118]. Fewer grade 3 or 4 toxicities were reported than in the prior study (there were no grade 5
toxicities).

A phase III trial directly compared this lower daily dose of sunitinib versus sorafenib in 1073 previously untreated patients with
advanced HCC [120]. In a preliminary report of an interim analysis presented at the 2011 meeting of the American Society of
Clinical Oncology (ASCO), sunitinib was associated with an inferior median survival (8.1 versus 10 months) and more frequent
treatment-related toxicity. An Independent Data Monitoring and Safety Committee recommended closure of the study.

Based upon these data, sunitinib cannot be considered an appropriate alternative to sorafenib for initial systemic treatment of advanced
HCC.

Anti EGFR strategies

Small molecule TK inhibitors — Limited activity for erlotinib (Tarceva), a small molecule TKI with specificity for EGFR, has been
suggested in phase II studies:

 In one study of 38 patients with unresectable or metastatic HCC, one-half of whom had previously received cytotoxic
chemotherapy, EGFR/HER1 expression was found in 88 percent [121]. Twelve patients (32 percent) were progression-free at
six months, while three had a radiographic partial response that lasted for two, 10, and 11 months, respectively. The median
survival of the entire cohort was 13 months.
 A second trial included 40 patients with previously untreated unresectable HCC who received erlotinib 150 mg daily as
monotherapy [122]. There were no objective responses, but 17 achieved stable disease with 16 weeks of continuous therapy.
The median overall survival was 11 months.

Additional studies with other receptor TKIs, both as monotherapy [11] and in combination with cytotoxic chemotherapy are ongoing.

Erlotinib plus bevacizumab — Antitumor activity for a unique combination of agents that modify growth factor signaling was suggested in
a phase II trial in which 59 patients with advanced HCC not amenable to surgical or regional therapies were treated with bevacizumab (10
mg/kg every two weeks) pluserlotinib (150 mg orally daily, continuously), with assessment of antitumor response at the end of 16 weeks
[123]. There were 14 objective partial responses (response rate 24 percent), and 33 other patients (56 percent) had stable disease. The
median progression-free and overall survival durations were 7.2 and 13.7 months, respectively.

However, antitumor activity with this same regimen could not be confirmed in a second multi-institutional phase II trial that enrolled 27
patients with advanced HCC, an ECOG performance status of 0 or 1, Child-Pugh A or B cirrhosis, and no more than one prior systemic
therapy [124]. There was only one confirmed objective partial response, time to disease progression was only three months, and median
overall survival was 9.5 months.

The efficacy of this regimen is uncertain. Particularly in view of the substantial cost of this regimen (over $10,000 per month), randomized
trials will be needed to confirm the superiority of erlotinib and bevacizumab over other systemic regimens. Such a trial is underway [125].
(See 'Sorafenib' above.)

Cetuximab — Cetuximab (Erbitux) is a MoAb that binds to the EGFR of both tumor and normal cells, competitively inhibiting ligand binding
and inducing receptor dimerization and internalization. Early results suggest activity for cetuximab in combination with GEMOX [126]. In a
2 2
preliminary report of 44 patients who received gemcitabine 1000 mg/m on day 1 and oxaliplatin 100 mg/m on day 2 every 14 days, in
2 2
combination with cetuximab (400 mg/m initially, then 250 mg/m weekly), there were eight partial responses, and the total disease control
rate (partial response plus stable disease) was 65 percent. Treatment was well tolerated with only one grade 4 toxicity (thrombocytopenia)
and no grade 5 toxicities. Grade 2 and 3 neurotoxicity occurred in 16 and 5 percent of patients, respectively.
Investigational approaches — Newer molecularly targeted approaches that show promise in early studies include inhibitors of the
mammalian target of rapamycin (mTOR), such as everolimus [127,128], and inhibitors of hepatocyte growth factor/c-Met, such as tivantinib
and cabozantinib [129,130].

HORMONE THERAPY — Several hormone agents have been studied in advanced HCC, including tamoxifen, megestrol, octreotide,
and lanreotide.

Tamoxifen — Since estrogen receptors (ERs) are present in approximately one-third of HCCs, these tumors could potentially benefit from
ER blockade withtamoxifen. Several prospective randomized trials and a systematic review of tamoxifen in patients with advanced HCC
have failed to show a survival benefit or improved functional status [131-135]. One possible reason for the lack of efficacy may be the
presence of variant ERs in some of these tumors [136,137].

Tamoxifen may also function as a potential inhibitor of p-glycoprotein, the MDR (multidrug resistance) gene product, and this has led to
trials of tamoxifen combined with various chemotherapeutic agents. Unfortunately, these studies have also failed to demonstrate any
benefit for the addition of tamoxifen [43,138-140]. (See 'Doxorubicin and mitoxantrone' above.)

Megestrol — Modest benefit has been suggested for megestrol in uncontrolled trials [136,141,142], but the results of two randomized trials
are conflicting:

 In a trial of 24 patients with advanced HCC who were randomly assigned to megestrol (160 mg daily) or supportive care only,
median survival was significantly better with megestrol (18 versus 7 months) despite no objective responses [136].
 On the other hand, a survival benefit could not be shown in a larger placebo-controlled trial of megestrol 320 mg per day in 200
patients with treatment-naïve HCC; in fact, there was a trend towards worse overall survival in the treated group (median 1.88
versus 2.14 months) [143]. The markedly different survival durations in the placebo group compared to the supportive care arm
of the previously described trial (2 versus 7 months) suggests that therapeutic outcomes may be strongly dependent on factors
such as baseline liver function and performance status.

Octreotide and lanreotide — The identification of somatostatin receptors in liver tissue from patients with HCC [144,145] provided the
rationale for a controlled trial in which 58 patients with advanced HCC were randomized to the somatostatin analog octreotide (250
micrograms twice daily subcutaneously) or placebo [146]. Treated patients had significantly better median survival (13 versus 4 months),
but no objective responses. Efficacy did not correlate with the tissue somatostatin receptor concentration.

These results could not be confirmed in two subsequent placebo-controlled randomized trials using a long-acting form
of octreotide (Sandostatin LAR) [147,148].

Lanreotide is a long acting somatostatin analog that is available in a depot formulation that has comparable efficacy to octreotide when
injected intramuscularly two to three times per month. Although limited antitumor activity has been suggested in nonrandomized studies
[145,149], a randomized trial of lanreotide versus placebo in 272 patients with advanced HCC failed to show any advantage for drug
treatment in terms of progression-free or overall survival, and treatment was associated with worse quality of life [150].

Thus, routine administration of octreotide or lanreotide cannot be recommended, particularly in view of the high cost of these drugs.

HEPATITIS B REACTIVATION — Immunosuppressive therapy is a risk factor for reactivation of hepatitis B virus infection (HBV). Issues
related to screening and prophylaxis are described separately. (See "Overview of the management of hepatitis B and case examples",
section on 'Who should be tested' and"Hepatitis B virus reactivation associated with immunosuppression".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The
th th
Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles
th th
are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You
can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

 Basics topic (see "Patient information: Liver cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS — Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently occurs in the setting of
chronic liver disease and cirrhosis. Hepatic reserve, as indicated by Child-Pugh class (table 1), often dictates the therapeutic options.
(See 'Introduction' above.)

Systemic therapy is appropriate for patients with advanced unresectable disease who are unsuitable for locoregional therapy.
(See "Surgical management of potentially resectable hepatocellular carcinoma" and "Liver transplantation for hepatocellular
carcinoma" and "Nonsurgical therapies for localized hepatocellular carcinoma: Radiofrequency ablation, percutaneous ethanol injection,
thermal ablation, and cryoablation".)

Systemic therapy for HCC is an evolving field. In general, efficacy with conventional cytotoxic chemotherapy is modest at best, and the
duration of benefit is limited. Although few randomized trials have been conducted, no single regimen has emerged as superior to any
other, and no drug or regimen has been unequivocally shown to improve survival. (See 'Systemic chemotherapy' above.)
 Newer data on the efficacy of molecularly targeted agents has brought these agents, particularly sorafenib, to the forefront of therapy for
advanced HCC. Molecularly targeted therapy offers the potential for prolonged survival, although objective tumor remissions are rare.
(See 'Sorafenib' above.)

The following represents our recommended approach to these patients:

 Our preferred approach is participation in an ongoing clinical trial testing new therapeutic strategies.
 For patients who are not eligible for a clinical trial or for whom protocol therapy is not feasible, we recommend initiating therapy
with the orally active tyrosine kinase inhibitor sorafenib 400 mg twice daily (Grade 1B). (See 'Sorafenib' above.) To improve
early tolerability, we typically start at 200 mg twice a day and increase the daily dose in 200 mg increments approximately every
five days until the target dose is reached. We recommend against initiating sorafenib in patients with Child-Pugh C cirrhosis
(Grade 1B). (See 'Safety in patients with liver disease' above.)
 Systemic chemotherapy is an option for patients whose tumors progress while on sorafenib and whose performance status and
liver function are sufficient to tolerate it. The best regimen is not established. The side effect profile of each individual regimen
must be carefully considered in patients who have advanced liver disease and/or a short life expectancy.

We prefer that eligible patients be enrolled on clinical trials testing new treatment strategies, if possible. For patients who are
not eligible for clinical trials or if they are not available, we suggest gemcitabine plus cisplatin for fit patients (Grade 2C).
Acceptable alternatives include doxorubicin plus cisplatin, or gemcitabine plus either oxaliplatin or pegylated liposomal
doxorubicin.

Weekly low-dose doxorubicin may be preferred for older or more frail patients, and oral capecitabine or weekly high-dose 5-FU
and leucovorin are appropriate choices for sick or jaundiced individuals. (See 'Systemic chemotherapy' above.)

The safety and benefit of combining molecularly targeted therapy (sorafenib or bevacizumab) and cytotoxic chemotherapy is not
yet definitively established, and we suggest not pursuing these strategies outside of the context of a clinical trial (Grade 2C).
(See 'Molecularly targeted therapy' above.)
 Tamoxifen is ineffective as monotherapy or in combination with doxorubicin and octreotide. Likewise, routine administration of
octreotide orlanreotide cannot be recommended outside of the context of a clinical trial. (See 'Hormone therapy' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP)
investigators. Hepatology 1998; 28:751.
2. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;
100:698.
3. Cabibbo G, Enea M, Attanasio M, et al. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular
carcinoma. Hepatology 2010; 51:1274.
4. Huitzil-Melendez FD, Capanu M, O'Reilly EM, et al. Advanced hepatocellular carcinoma: which staging systems best predict prognosis? J
Clin Oncol 2010; 28:2889.
5. Yau T, Yao TJ, Chan P, et al. A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to
locoregional therapy: implication for patient selection in systemic therapy trials. Cancer 2008; 113:2742.
6. Llovet JM, Bustamante J, Castells A, et al. Natural h