Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be? Andrew X. Zhu

Transcription

1 Hepatobiliary Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be? Andrew X. Zhu Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA Key Words. Hepatocellular carcinoma Molecularly targeted agents Systemic therapy Learning Objectives After completing this course, the reader will be able to: 1. Describe the epidemiologic trend of HCC. 2. Discuss the inherent difficulty and challenge of developing systemic therapy for HCC. 3. Outline the history and current status of systemic therapy for HCC. 4. Describe the rationale and current status of developing molecularly targeted agents for HCC. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com Abstract Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC. The Oncologist 2006;11: Introduction Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death [1]. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths [2]. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period [3, 4]. Unresectable Correspondence: Andrew X. Zhu, M.D., Ph.D., Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114, USA. Telephone: ; Fax: ; azhu@partners.org Received April 3, 2006; accepted for publication May 10, AlphaMed Press /2006/$20.00/0 The Oncologist 2006;11:

2 Zhu 791 or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit [5]. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC. Why Is It Difficult to Develop Effective Systemic Therapy for HCC? Despite extensive efforts by many investigators, systemic chemotherapy for HCC has been quite ineffective, as evidenced by low response rates and no demonstrated survival benefit. Although many molecular changes have been identified in HCC, we are just beginning to identify the key molecular pathways involved in hepatocarcinogenesis and to assess the relevance of these as potential therapeutic targets. HCCs are heterogeneous as a result of the multiple etiologies and risk factors that may determine different pathways in hepatocarcinogenesis. Underlying cirrhosis in many patients may lead to portal hypertension with hypersplenism, platelet sequestration, varices and gastrointestinal bleeding, hepatic encephalopathy, hypoalbuminemia, differential drug binding and distribution, and altered pharmacokinetics, limiting the selection and adequate dosing of most cytotoxic agents. HCCs are inherently chemotherapy-resistant tumors [6] and are known to express the multidrug-resistant gene MDR-1 [6 8]. The ability to conduct controlled clinical trials of systemic regimens in this patient population has been hampered by the aggressive nature of the disease, the selection of appropriate end points, controversies about choosing appropriate controls, and the distribution of many patients in developing nations where access to clinical trials may be difficult. Hormonal Therapy The finding that various hormone receptors are present in HCC has led many investigators to examine the role of hormonal manipulation in this disease. Several lines of evidence have suggested an association between estrogen and HCC. Estrogen receptors are expressed in normal human liver, in chronic hepatitis, in benign hepatic tumor tissues, and rarely in HCC at a low concentration [9]. In preclinical models, estrogens are involved in stimulating hepatocyte proliferation in vitro and may promote liver tumor growth in vivo [10]. The persistent administration of estrogens, particularly in the form of oral contraceptives, has been associated with an increased incidence of hepatic adenomas and with a slightly increased incidence of HCC [9]. The antiestrogenic compound tamoxifen has been shown to reduce the level of estrogen receptors in the liver [11]. HCC affects men more often than women with a male:female ratio of 4:1. The presence of wild-type or variant estrogen and androgen receptors in the tumors may alter the sensitivity of HCC to hormonal manipulations. Table 1 summarizes the results of tamoxifen studies. In the 1990s, three controlled studies showed significantly longer survival times in patients treated with tamoxifen [12 14]. However, all of these studies were small, two studies were nonblinded, and one was not randomized. From , five large, negative, randomized studies (four of which were double-blind trials) with a total of 1,144 patients failed to demonstrate longer survival with tamoxifen [15 20]. Recently, Barbare and colleagues reported their results of a randomized phase III study [21]. Four hundred twenty patients with advanced HCC were randomly assigned to two groups: 210 in the control group and 210 in the tamoxifen group (20 mg daily). The estimated median survival times were 4.8 and 4.0 months in the tamoxifen and control groups, respectively (p =.25). In a Cox proportional hazards model, they found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda stage I or II. The authors concluded that tamoxifen did not improve the overall survival of patients with advanced HCC. It is worth noting that a variant form of the wild-type estrogen receptor (wter) that maintains a constitutive transcriptional activity has been described [22]. Compared with HCCs expressing wter, HCCs with variant ER (ver) had more aggressive clinical features and insensitivity to tamoxifen [23, 24]. In a preliminary, prospective, randomized study of 45 patients with HCC characterized by ver, patients treated with megestrol had a significantly longer median survival time than untreated patients (19 months vs. 7 months; p =.0090) [25]. Antiandrogen therapies have also failed to improve survival in randomized studies in patients with advanced HCC [16, 26]. Clinical experience in advanced HCC with octreotide, a somatostatin analogue, has also been controversial. In an initial small randomized study by Kouroumalis and colleagues, 58 patients with advanced HCC were randomized to receive either subcutaneous octreotide (250 μg twice daily) or no treatment [27]. Patients treated with octreotide had a median survival time of 13 months, compared with those who received no treatment, who had a median survival time of only 4 months (p =.002, log-rank test). However, in

3 792 Systemic Therapy of Advanced HCC Table 1. Studies with tamoxifen in hepatocellular carcinoma Study Treatment No. of patients Survival Farinati et al. [12] T vs. C month survival rate: T 22% vs. C 5% Martinez Cerezo et al. [13] T vs. C month survival rate: T 48.5% vs. C 9.1% (p =.01) Elba et al. [14] T vs. C 22 Median survival (wks): T 74 vs. C 52 (p =.04) Castells et al. [15] T vs. C and 2-year actuarial survival rate: T 51% and 27% vs. C 43% and 29% (p =.75) CLIP group [17] T vs. C 496 Median survival (mos): T 15 vs. C 16 (p =.54) Riestra et al. [18] T vs. C month survival rate: T 30% vs. C 37.8% (p =.31) Liu et al. [19] T vs. C 119 Median survival (days): T 44 vs. C 41 (p =.703) Chow et al. [20] T (120) vs. T (60) vs. C another randomized, placebo-controlled study, 70 patients with advanced HCC were randomized to receive a 2-week course of 250 μg of short-acting octreotide twice daily followed by a long-acting octreotide (Sandostatin LAR ; Novartis Pharmaceuticals Corp., East Hanover, NJ) 30-mg injection once every 4 weeks for six doses (n = 35) or placebo (n = 35) [28]. There was no difference in median survival time between the Sandostatin LAR -treated group and the control group (median survival, 1.93 months vs months, respectively). The poor survival in the control arm raised the concern of poor patient selection or an aggressive clinical course in the study population. In another study, 41 patients with advanced HCC were treated with octreotide [29]. The median survival time in that group of patients was 571 days. Recently, Barbare and colleagues reported their preliminary results of a randomized placebo-controlled trial [30]. Two hundred seventy-two patients with unresectable HCC were randomized to receive either octreotide (monthly i.m. injection of 30 mg of long-acting octreotide) or a placebo. No survival benefit was seen in the results of the interim analysis after the occurrence of 150 deaths: the median overall survival time was 6.5 months in the octreotide arm and 7.3 months in the placebo arm. Whether octreotide may have limited benefits in advanced HCC patients whose tumors express somatostatin receptors remains to be defined month survival rates: T (120) 35% vs. T (60) 41% vs. C 44% Barbare et al. [21] T vs. C 420 Median survival (mos): T 4.8 vs. C 4 (p =.25) Abbreviations: CLIP, Cancer of the Liver Italian Programme; C, control; T, tamoxifen; T (120), tamoxifen 120 mg daily; T (60), tamoxifen 60 mg daily. Chemotherapy Although large numbers of controlled and uncontrolled studies have been performed with most classes of chemotherapeutic agents, no single or combination chemotherapy regimen has been found to be particularly effective in HCC. Response rates are low, and the response duration is typically short. Studies have also been difficult to interpret because response criteria used in some of the earlier studies were poorly defined. Most of the earlier studies did not stratify patients based on the severity of underlying cirrhosis or other factors, making comparison of study results difficult. More important, any survival benefit of systemic chemotherapy for HCC remains to be determined. Table 2 summarizes some of the results with single agents in advanced HCC. Doxorubicin is perhaps the most widely used agent in HCC. Despite the initial encouraging reports from Uganda using single-agent doxorubicin, subsequent studies have failed to confirm these data. In a large study of doxorubicin in advanced HCC, no responses were noted among 109 patients [31]. Among 475 patients who received doxorubicin in various studies, a 16% response rate was documented, with a median survival time of 3 4 months [32]. Recent large phase III studies have shown a 4% 10.5% response rate in HCC patients treated with doxorubicin in the control group [33, 34]. Significant grade The Oncologist

4 Zhu 793 Table 2. Systemic chemotherapy for hepatocellular carcinoma (single agents) Study Agent No. of patients Response rate (%) Johnson et al. [103] Doxorubicin Sciarrino et al. [31] Doxorubicin Melia et al. [104] VP Hochster et al. [35] Epirubicin Lai et al. [105] Mitoxantrone 20 0 Falkson et al. [106] Cisplatin Chao et al. [45] Paclitaxel 20 0 Patt et al. [49] Capecitabine Yang et al. [47] Gemcitabine Fuchs et al. [48] Gemcitabine 30 0 O Reilly et al. [46] Irinotecan 14 7 Halm et al. [50] Pegylated liposomal doxorubicin 16 0 Stuart et al. [52] Nolatrexed 26 8 Leung et al. [55] T Falcon-Lizaraso et al. [107] Irofulven or above hematologic and gastrointestinal toxicities were encountered in patients treated with doxorubicin, and these included neutropenia (63%), febrile neutropenia (17%), thrombocytopenia (24%), elevation of transaminase (13%), and diarrhea (7%) [34]. Epirubicin is the 4ʹ-epimer of doxorubicin, with its structure differing from that of doxorubicin only in the reorientation of a single hydroxyl group at the 4ʹ position. Epirubicin was identified following the screening of a series of doxorubicin derivatives as having the potential for a better therapeutic index than the parent compound. It was predicted to have a more favorable toxicity profile with less myelosuppression and cardiotoxicity than with doxorubicin. However, several small studies have shown that epirubicin has limited activity in HCC [35 37]. Other drugs, such as cisplatin, 5-fluorouracil (5-FU), mitoxantrone, etoposide, and fludarabine, have failed to demonstrate meaningful activity [38 44]. Newer chemotherapy drugs, including paclitaxel, irinotecan, gemcitabine, capecitabine, and pegylated liposomal doxorubicin, have been studied in HCC with disappointing results [45 50]. Nolatrexed (Thymitaq ; Agouron Pharmaceuticals, La Jolla, CA) is a novel thymidylate synthase inhibitor that is not polyglutamated and does not require facilitated transport for uptake into cells. Following several phase II studies showing limited activity of nolatrexed [51, 52], a large phase III randomized controlled study was conducted comparing nolatrexed with doxorubicin in 446 patients with unresectable HCC from North America, Europe, and South Africa [33]. The median survival times for patients treated with nolatrexed and doxorubicin were only 20.7 weeks and 31 weeks, respectively. Patients treated with nolatrexed had more treatment-related toxicities and withdrawal. Another potentially promising new drug was T This agent inhibits microtubule formation by binding irreversibly and specifically to isotypes of β-tubulin, causing cell arrest at G 2 /M and inducing apoptosis. Based on the initial preclinical and clinical experience of antitumor activity [53 56], a phase II/III open-label, randomized trial was performed comparing T with doxorubicin in chemotherapy-naïve, unresectable HCC [57]. Unfortunately, that study was closed early after recommendation from the External Data Monitoring Committee because of a lack of survival benefit for T Of 339 patients with available data, 169 were randomized to T at a 250-mg/m 2 weekly infusion and 170 were randomized to doxorubicin at a 60-mg/m 2 infusion every 3 weeks. No overall survival difference was seen, with a median survival time of 6 months in each arm [57]. A variety of combination chemotherapy regimens has been studied in HCC, and results from some of the recent studies are summarized in Table 3. Although a few of the combination chemotherapy regimens have shown superior response rates, most of these have not been validated in large randomized phase III studies. Because of the heterogeneity of the disease and patient selection bias, the relevant clinical significance of these regimens remains unknown. Moreover, the combination chemotherapy regimens also had greater toxicity than single agents. Taieb and colleagues examined the combination of gemcitabine and oxaliplatin (GEMOX) in advanced HCC and

5 794 Systemic Therapy of Advanced HCC Table 3. Systemic chemotherapy for hepatocellular carcinoma (combination regimens) Study Regimen No. of patients Response rate (%) Al-Idrissi et al. [108] Doxorubicin, 5-FU, mitomycin C Ravry et al. [109] Doxorubicin, bleomycin Patt et al. [63] 5-FU, interferon Ji et al. [110] Cisplatin, interferon Bobbio-Pallavicini et al. [111] Epirubicin, etoposide Leung et al. [59] PIAF Taieb et al. [58] GEMOX Lee et al. [112] Cisplatin, doxorubicin Ikeda et al. [113] Mitoxantrone, 5-FU, cisplatin Abbreviations: 5-FU, 5-fluorouracil; GEMOX, gemcitabine and oxaliplatin; PIAF, cisplatin, interferon, doxorubicin, and 5- fluorouracil. demonstrated antitumor activity, with a 19% clinical response rate and an acceptable toxicity profile [58]. The most impressive result of combination chemotherapy comes from a Hong Kong study using the combination of cisplatin, interferon-α, doxorubicin, and 5-FU (PIAF) [59]. This regimen produced a partial response rate of 26%. Nearly half the patients with pretreatment elevated alphafetoprotein (AFP) levels achieved a 50% decrease in AFP level. In 9 of the 50 patients, the initially unresectable tumors became resectable following the chemotherapy. In four of these patients, the resected specimens had a pathologic complete response and the AFP level fell to within the reference range. Yeo et al. [34] recently reported the results of a randomized phase III study comparing PIAF with single-agent doxorubicin. One hundred eighty-eight patients with unresectable HCC were enrolled in the study, and 94 patients in each arm were randomly assigned to receive either single-agent doxorubicin (60 mg/m 2 ) on day 1 every 3 weeks for up to six cycles or PIAF, which consisted of cisplatin (20 mg/m 2 ) on days 1 4, interferon-α2b (5 MU/m 2 ) on days 1 4, doxorubicin (40 mg/m 2 ) on day 1, and 5-FU (400 mg/m 2 ) on days 1 4 every 3 weeks for up to six cycles. The overall response rates in the doxorubicin and PIAF groups were 10.5% (95% confidence interval [CI], 3.9% 16.9%) and 20.9% (95% CI, 12.5% 29.2%), respectively. Neutropenia, thrombocytopenia, and hypokalemia were statistically significantly more common in patients treated with PIAF than in patients treated with doxorubicin. The median survival durations of the doxorubicin and PIAF groups were 6.83 months (95% CI, ) and 8.67 months (95% CI, ), respectively (p =.83), failing to reach statistical significance for the study s primary end point. It should be noted that patients who receive combination chemotherapy in clinical studies, in general, have a good performance status, adequate hepatic function, and no evidence of portal hypertension with severe thrombocytopenia. At the present time, there is no drug or regimen that can be clearly defined as the standard for treating HCC. Biologic and Biochemical Therapy Interferon has been tested extensively in HCC. Earlier studies showed small but significant beneficial effects in Asian patients with hepatitis B virus-related HCC [60, 61]. Unfortunately, this has not been confirmed in Europe in controlled studies, and the tolerance to interferon has been poor [62]. Combinations of interferon and different schedules of 5-FU administration have been studied in HCC with conflicting results [39, 63]. Thalidomide has poorly understood mechanisms of action, and it might exert its therapeutic properties through antiangiogenic activity and modulation of cytokines, including tumor necrosis factor-α, interferon, interleukins 10 and 12, cyclooxygenase-2, and nuclear factor κb [64]. Several studies have examined the efficacy and toxicity of thalidomide in HCC (Table 4). Hsu and colleagues conducted a study using thalidomide in 68 HCC patients. Of the 63 evaluable patients, one complete and three partial responses were seen, for a response rate of 6.3% (95% CI, 0% 12.5%). Ten patients had a dramatic decrease in their AFP levels. Interestingly, all responders received thalidomide at 300 mg or less per day [65]. In another study, involving 99 patients with advanced HCC, responses were seen in six patients in response to single-agent thalidomide [66]. Several recent phase II studies from the U.S. have examined the use of thalidomide either as a single agent or in combination with epirubicin or interferon and have shown limited activity in HCC [67 70]. Fatigue and somnolence were the most common side effects associated with thalidomide administration. Based on the observation that a large number of human HCC cell lines were auxotrophic for arginine, an amino aciddegrading enzyme arginine deiminase (ADI) conjugated The Oncologist

6 Zhu 795 Table 4. Studies with thalidomide in hepatocellular carcinoma Study Treatment No. of Patients RR (%) PFS (mos) Hsu et al [65] Thalidomide NA 4.3 Wang et al [66] Thalidomide NA 2.7 Lin et al [67] Thalidomide Patt et al [68] Thalidomide NA 6.8 Zhu et al [69] Thalidomide/ Epirubicin Schwartz et al [70] Thalidomide/ Interferon a a Five patients had interferon. Abbreviation: NA, not available. Median Survival (mos) to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine was studied in HCC in a phase I/II study [71]. In that study, an ADI-SS PEG 20,000 mw dose level of 160 U/m 2 was sufficient to lower plasma arginine from a resting level of approximately 130 μmol/l to below the level of detection (<2 μmol/l) for more than 7 days. The treatment was well tolerated. Of the 19 patients enrolled, two and seven patients had complete and partial responses, respectively. An additional seven patients had stable disease (SD). The median survival time was 410 days. The promising results from this preliminary study warrant further confirmation in future studies. Molecularly Targeted Therapy Improved understanding of the mechanisms of hepatocarcinogenesis coupled with the arrival of many newly developed molecularly targeted agents has provided the opportunity to study some of these novel agents in advanced HCC. Many key carcinogenic pathways [72], such as increased angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, seem to be involved in HCC development. Several excellent reviews have summarized the state of knowledge of the most common and important molecular aberrations in HCC [73 76]. Many of the molecular changes found in HCC are attributed to underlying cirrhosis, and others are found in dysplastic nodules and the HCC lesions themselves. Several early clinical studies have examined the efficacy and safety of targeting some of these pathways in advanced HCC (Table 5). Increasing evidence has highlighted the importance of epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER-1) and its ligands EGF and transforming growth factor alpha (TGF-α) in hepatocarcinogenesis. The expression of several EGF family members, specifically EGF, TGF-α, and heparin binding-epidermal growth factor, as well as EGFR, has been described in several HCC cell lines and in tissue [77 82]. In one study, expression of EGFR/HER-1 was present in 9 of 11 HCCs. Morimitsu and colleagues examined the expression of TGF-α and its receptor, EGFR, in HCC and adjacent nontumorous livers from 25 Japanese patients using immunohistochemistry [83]. TGF-α was detected in 24 of 25 (96%) HCCs and 23 of 24 (96%) available adjacent nontumorous livers. EGFR was detected in 16 of 25 (64%) HCCs and 17 of 24 (71%) adjacent nontumorous livers. Studies have supported the theory of an autocrine, paracrine, and endocrine mechanism of TGF-α and EGFR/HER-1 on the proliferation of human HCC [84]. Recent data from two clinical trials have demonstrated the safety and modest efficacy of erlotinib (Tarceva ; Genentech, Inc., South San Francisco, CA), an oral EGFR tyrosine kinase inhibitor, in advanced HCC [85, 86]. In a study by Philip and colleagues, 3 of 38 patients (9%) achieved partial responses, and 12 of 38 patients (32%) were progression free at 6 months [85]. In another preliminary report by Thomas et al. [86], 8 of 25 patients (32%) achieved progression-free survival (PFS) at 4 months. We have recently reported our preliminary experience using cetuximab, a chimeric monoclonal antibody against EGFR, in advanced HCC [87]. Of the 30 patients enrolled, no patient achieved a response, and the PFS time was only 41 days. In light of earlier experiences with erlotinib, our results were somewhat surprising. Current studies are ongoing using EGFR antagonists in combination with other targeted agents in HCC. The use of EGFR inhibitors as potential chemopreventive agents or in the adjuvant setting may represent other potential opportunities for the further development of these agents. HCCs are vascular tumors and increased levels of vascular endothelial growth factor (VEGF) and microvessel density (MVD) have been observed [88]. High VEGF expression has been associated with inferior survival [89 91]. Therefore, VEGF represents a potential therapeutic target in HCC. Bevacizumab (Avastin ; Genentech, Inc.), a recombinant, humanized monoclonal antibody that targets VEGF,

7 796 Systemic Therapy of Advanced HCC Table 5. Recent studies with molecularly targeted agents No. of Study Regimen patients Response rate (%) Median PFS/TTP (mos) Median survival (mos) Philip et al. [85] Erlotinib Zhu et al. [96] GEMOX-B Eckel et al. [114] Imatinib a NR Abou-Alfa et al. [97] Sorafenib Thomas et al. [86] Erlotinib Schwartz et al. [95] Bevacizumab NR a Time to treatment failure. Abbreviations: GEMOX-B: gemcitabine, oxaliplatin, and bevacizumab; NR, not reported; PFS, progression-free survival; TTP, time to tumor progression. has emerged as an important therapeutic agent in several malignancies [92]. In addition to its direct antiangiogenic effects, bevacizumab may enhance chemotherapy administration by normalizing tumor vasculature and decreasing the elevated interstitial pressure in tumors [93, 94]. Recent data for bevacizumab in HCC indicate that this agent can be administered safely in carefully selected HCC patients and has demonstrated modest clinical activity [95, 96]. Schwartz et al. [95] reported their preliminary experience using single-agent bevacizumab in HCC in a phase I study. Of the first 24 patients treated, partial responses were seen in two patients, and SD of more than 4 months duration was noted in 17 patients; the median time to progression in these 24 patients was 6.4 months. We have recently completed our phase II study using bevacizumab in combination with gemcitabine and oxaliplatin (GEMOX-B) in advanced HCC. This regimen had moderate antitumor activity in HCC, with an overall response rate of 20% in evaluable patients and an additional 27% of patients with SD [96]. The median overall survival time was 9.6 months, and the median PFS time was 5.3 months, with the PFS rates at 3 and 6 months approaching 70% and 48%, respectively. The most common treatment-related grade 3 4 toxicities included leukopenia/ neutropenia, transient elevation of transaminases, hypertension, and fatigue. BAY (sorafenib) is a novel signal transduction inhibitor that targets the Raf/mitogen-activated protein kinase extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway and the VEGF receptor VEGFR-2 and PDGF receptor PDGFR-β. It showed promising clinical activity in HCC in a large phase II study with 137 patients [97]. Five patients had partial responses, and 49% of patients had SD for at least 4 months. A large, randomized phase III trial just completed accrual comparing sorafenib with placebo in advanced HCC patients. The retinoic acid receptor (RAR) and retinoid X receptors (RXR) belong to the superfamily of nuclear ligand-activated transcriptional regulators. Increased RAR-α expression and downregulation of RAR-β have been observed in HCC tissue [98]. The retinoids, all-trans retinoic acid (RA), 9-cis RA, and acyclic retinoid may promote apoptosis in HCC, as measured by evaluation of DNA cleavage patterns in several studies performed in HCC cell lines [99]. Muto et al. [100] demonstrated a reduction in new tumors in HCC patients who received adjuvant acyclic retinoid, a polyprenoic acid (3,7,11,15-tetramethyl1-2,4,6,10,14-hexadecapentaenoic acid), following either surgical resection or tumor ablation via percutaneous ethanol injection of the primary HCC. In a study reported by Meyskens and colleagues in 29 HCC patients treated with an oral beta-all trans-ra, no responses were seen and the median survival time was 4 months [101]. A recent study by Thomas and colleagues reported the use of TAC-101 (4-[3,5-bis (trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid with selective binding affinity for RAR-α in a phase I/II study [102]. Of the 28 patients treated at 20 mg daily for 14 days every 3 weeks, disease stabilization was noted in 42% of patients, with tolerable safety profiles. Whether this represents inherent anti-hcc activity of TAC-101 or patient selection bias remains to be determined in future studies. Given the relatively favorable safety profiles of the newer targeted agents and the strong rationale of inhibiting multiple pathways in hepatocarcinogenesis, efforts are ongoing to combine these agents in HCC trials. Future Directions Effective systemic therapies for HCC patients are urgently needed. Future research should continue to unravel the mechanisms of hepatocarcinogenesis and identify key relevant molecular targets for therapeutic intervention. While we are continuing our efforts to develop more active systemic regimens in HCC, because of the heterogeneity and the aggressive nature of the disease, we should initially focus on testing the promising agents/regimens in patients with relatively preserved hepatic function and good performance status. Because most HCC patients have The Oncologist

8 Zhu 797 underlying cirrhosis with impaired hepatic function, we should carefully assess the safety and toxicity profiles of the newer agents/regimens in this population. A diseasespecific quality of life measurement should be developed and validated in HCC. We should establish the necessary infrastructure and methodology to conduct clinical trials in HCC so that large trials can be performed more efficiently and patient resources can be optimally used. While testing the newer molecularly targeted agents in HCC, it is imperative to incorporate imaging studies and surrogate markers in an attempt to understand the potential mechanisms of action of these agents. Once we have identified more active agents and regimens in the advanced disease setting, we can then assess them in the adjuvant setting following surgical resection or liver transplantation for HCC in an attempt to further improve the outcomes of these patients. Hopefully, we will witness meaningful progress in the development of systemic therapy for HCC in the coming years. Disclosure of Potential Conflicts of Interest A. X. Z. has worked as a consultant for Genentech and Bristol Myers-Squibb. References 1 Parkin DM, Bray F, Ferlay J et al. Estimating the world cancer burden: Globocan Int J Cancer 2001;94: Jemal A, Siegel R, Ward E et al. Cancer statistics, CA Cancer J Clin 2006;56: El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: El-Serag HB, Davila JA, Petersen NJ et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139: Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol 2005;23: Huang M, Liu G. The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. Cancer Lett 1999;135: Kato A, Miyazaki M, Ambiru S et al. Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection. J Surg Oncol 2001;78: Kuo MT, Zhao JY, Teeter LD et al. Activation of multidrug resistance (Pglycoprotein) mdr3/mdr1a gene during the development of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell Growth Differ 1992;3: Claviere C, Bronowicki JP, Hudziak H et al. [Role of sex steroids and their receptors in the pathophysiology of hepatocellular carcinoma.] Gastroneterol Clin Biol 1998;22: French. 10 Francavilla A, Polimeno L, DiLeo A et al. The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro. Hepatology 1989;9: Jiang SY, Shyu RY, Yeh MY et al. Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism. J Hepatol 1995;23: Farinati F, Salvagnini M, de Maria N et al., Unresectable hepatocellular carcinoma: a prospective controlled trial with tamoxifen. J Hepatol 1990;11: Martinez Cerezo FJ, Tomas A, Donoso L et al. Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. J Hepatol 1994;20: Elba S, Giannuzzi V, Misciagna G et al. Randomized controlled trial of tamoxifen versus placebo in inoperable hepatocellular carcinoma. Ital J Gastroenterol 1994;26: Castells A, Bruix J, Bru C et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology 1995;109: Manesis EK, Giannoulis G, Zoumboulis P et al. Treatment of hepatocellular carcinoma with combined suppression and inhibition of sex hormones: a randomized, controlled trial. Hepatology 1995;21: Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet 1998;352: Riestra S, Rodriguez M, Delgado M et al. Tamoxifen does not improve survival of patients with advanced hepatocellular carcinoma. J Clin Gastroenterol 1998;26: Liu CL, Fan ST, Ng IO et al. Treatment of advanced hepatocellular carcinoma with tamoxifen and the correlation with expression of hormone receptors: a prospective randomized study. Am J Gastroenterol 2000;95: Chow PK, Tai BC, Tan CK et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology 2002;36: Barbare JC, Bouche O, Bonnetain F et al. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol 2005;23: Villa E, Camellini L, Dugani A et al. Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma. Cancer Res 1995;55: Villa E, Moles A, Ferretti I et al. Natural history of inoperable hepatocellular carcinoma: estrogen receptors status in the tumor is the strongest prognostic factor for survival. Hepatology 2000;32: Villa E, Colantoni A, Camma C et al. Estrogen receptor classification for hepatocellular carcinoma: comparison with clinical staging systems. J Clin Oncol 2003;21: Villa E, Ferretti I, Grottola A et al. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer 2001;84: Grimaldi C, Bleiberg H, Gay F et al. Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial. J Clin Oncol 1998;16: Kouroumalis E, Skordilis P, Thermos K et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42:

9 798 Systemic Therapy of Advanced HCC 28 Yuen MF, Poon RT, Lai CL et al. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 2002;36: Plentz RR, Tillmann HL, Kubicka S et al. Hepatocellular carcinoma and octreotide: treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage. J Gastroenterol Hepatol 2005;20: Barbare JC, Bouché O, Bonnetain F et al. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: preliminary results of a randomized placebo-controlled trial (FFCD-ANGH CHOC). Proc Am Soc Clin Oncol 2005;23:4036a. 31 Sciarrino E, Simonetti RG, Le Moli S et al. Adriamycin treatment for hepatocellular carcinoma. Experience with 109 patients. Cancer 1985;56: Nerenstone SR, Ihde DC, Friedman MA. Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treat Rev 1988;15: Porta C, Ruff P, Feld R et al. Results of a phase III, randomized controlled study, the largest ever completed in hepatocellular carcinoma (HCC), comparing the survival of patients with unresectable HCC treated with nolatrexed (NOL) or doxorubicin (DOX). American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, January 26 28, Yeo W, Mok TS, Zee B et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005;97: Hochster HS, Green MD, Speyer J et al. 4 Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma. J Clin Oncol 1985;3: Dobbs NA, Twelves CJ, Rizzi P et al. Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity. Cancer Chemother Pharmacol 1994;34: Shiu W, Mok SD, O SK et al. Phase II trial of epirubicin in hepatoma. Cancer Treat Rep 1986;70: Okada S, Okazaki N, Nose H et al. A phase 2 study of cisplatin in patients with hepatocellular carcinoma. Oncology 1993;50: Stuart K, Tessitore J, Huberman M. 5-Fluorouracil and alpha-interferon in hepatocellular carcinoma. Am J Clin Oncol 1996;19: Tetef M, Doroshow J, Akman S et al. 5-Fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial. Cancer Invest 1995;13: Davis RB, Van Echo DA, Leone LA et al. Phase II trial of mitoxantrone in advanced primary liver cancer: a Cancer and Leukemia Group B Study. Cancer Treat Rep 1986;70: Shiu W, Mok SD, Leung N et al. Phase 2 study of high dose etoposide (VP16-213) in hepatocellular carcinoma. Jpn J Clin Oncol 1987;17: Yoshino M, Okazaki N, Yoshida T et al. A phase II study of etoposide in patients with hepatocellular carcinoma by the Tokyo Liver Cancer Chemotherapy Study Group. Jpn J Clin Oncol 1989;19: Harvey WH, Fleming TR, Beltran G et al. Phase II study of fludarabine phosphate in previously untreated patients with hepatoma: a Southwest Oncology Group Study. Cancer Treat Rep 1987;71: Chao Y, Chan WK, Birkhofer MJ et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer 1998;78: O Reilly EM, Stuart KE, Sanz-Altamira PM et al. A phase II study of irinotecan in patients with advanced hepatocellular carcinoma. Cancer 2001;91: Yang TS, Lin YC, Chen JS et al. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2000;89: Fuchs CS, Clark JW, Ryan DP et al. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2002;94: Patt YZ, Hassan MM, Aguayo A et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 2004;101: Halm U, Etzrodt G, Schiefke I et al. A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma. Ann Oncol 2000;11: Mok TS, Leung TW, Lee SD et al. A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 1999;44: Stuart K, Tessitore J, Rudy J et al. A phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma. Cancer 1999;86: Shan B, Medina JC, Santha E et al. Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors. Proc Natl Acad Sci U S A 1999;96: Molpus K, Schwartz G, O Dwyer P et al. A phase I study of the anti-microtubule agent T sodium administered daily x 5 every 3 weeks. Proc Am Soc Clin Oncol 2002;21:415a. 55 Leung TW, Feun L, Posey J et al. A phase II study of T sodium in patients (pts) with unresectable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2002;20:572a. 56 Venook AP, Rowinsky EK, Donehower RC et al. Safety and pharmacokinetics (PK) of T (T67) administered as a weekly 3-hour infusion in subjects with hepatocellular carcinoma (HCC) in a phase 1 study. Proc Am Soc Clin Oncol 2004;22:4087a. 57 Posey J, Johnson P, Mok T et al. Results of a phase 2/3 open-label, randomized trial of T versus doxorubicin (DOX) in chemotherapy-naïve, unresectable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2005;23:4035a. 58 Taieb J, Bonyhay L, Golli L et al. Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules. Cancer 2003;98: Leung TW, Patt YZ, Lau WY et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 1999;5: Lai CL, Lau JY, Wu PC et al. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology 1993;17: Lai CL, Wu PC, Lok AS et al. Recombinant alpha 2 interferon is superior to doxorubicin for inoperable hepatocellular carcinoma: a prospective randomised trial. Br J Cancer 1989;60: Llovet JM, Sala M, Castells L et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000;31: Patt YZ, Hassan MM, Lozano RD et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 2003;21: The Oncologist

10 Zhu Eleutherakis-Papaiakovou V, Bamias A, Dimopoulos MA. Thalidomide in cancer medicine. Ann Oncol 2004;15: Hsu C, Chen CN, Chen LT et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65: Wang TE, Kao CR, Lin SC et al. Salvage therapy for hepatocellular carcinoma with thalidomide. World J Gastroenterol 2004;10: Lin AY, Brophy N, Fisher GA et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005;103: Patt YZ, Hassan MM, Lozano RD et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005;103: Zhu AX, Fuchs CS, Clark JW et al. A phase II study of epirubicin and thalidomide in unresectable or metastatic hepatocellular carcinoma. The Oncologist 2005;10: Schwartz JD, Sung M, Schwartz M et al. Thalidomide in advanced hepatocellular carcinoma with optional low-dose interferon-alpha2a upon progression. The Oncologist 2005;10: Izzo F, Marra P, Beneduce G et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 2004;22: Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100: Sheu JC. Molecular mechanism of hepatocarcinogenesis. J Gastroenterol Hepatol 1997;12:S309 S Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31: Bergsland EK. Molecular mechanisms underlying the development of hepatocellular carcinoma. Semin Oncol 2001;28: Thomas MB, Abbruzzese JL. Opportunities for targeted therapies in hepatocellular carcinoma. J Clin Oncol 2005;23: Ito Y, Takeda T, Higashiyama S et al. Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep 2001;8: Yeh YC, Tsai JF, Chuang LY et al. Elevation of transforming growth factor alpha and its relationship to the epidermal growth factor and alphafetoprotein levels in patients with hepatocellular carcinoma. Cancer Res 1987;47: Carlin CR, Simon D, Mattison J et al. Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines. Mol Cell Biol 1988;8: Kira S, Nakanishi T, Suemori S et al. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver 1997;17: Kiss A, Wang NJ, Xie JP et al. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met,tgf-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997;3: Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999;19: Morimitsu Y, Hsia CC, Kojiro M et al. Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: relative expression of transforming growth factor-alpha and its receptor in the different areas of tumor. Hum Pathol 1995;26: Yamaguchi K, Carr BI, Nalesnik MA. Concomitant and isolated expression of TGF-alpha and EGF-R in human hepatoma cells supports the hypothesis of autocrine, paracrine, and endocrine growth of human hepatoma. J Surg Oncol 1995;58: Philip PA, Mahoney MR, Allmer C et al. Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23: Thomas MB, Dutta A, Brown T et al. A phase II open-label study of OSI- 774 (NSC ) in unresectable hepatocellular carcinoma. Proc Am Soc Clin Oncol 2005;23:4083a. 87 Zhu AX, Blaszkowsky L, Enzinger PC et al. Phase II study of cetuximab in patients with unresectable or metastatic hepatocellular carcinoma. American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, January 26 28, Yamaguchi R, Yano H, Iemura A et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28: Chao Y, Li CP, Chau GY et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 2003;10: Poon RT, Ho JW, Tong CS et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 2004;91: Jeng KS, Sheen IS, Wang YC et al. Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study. World J Gastroenterol 2004;10: Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7: Willett CG, Boucher Y, di Tomaso E et al. Direct evidence that the VEGFspecific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10: Schwartz JD, Schwartz M, Sung M et al. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, January 26 28, Zhu AX, Blaszkowsky LS, Ryan DP et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24: Abou-Alfa G, Ricci S, Amadori D et al. Phase II study of BAY in patients with advanced hepatocellular carcinoma (HCC). Eur J Cancer 2004;S2: Sano K, Takayama T, Murakami K et al. Overexpression of retinoic acid receptor alpha in hepatocellular carcinoma. Clin Cancer Res 2003;9: Kim DG, Jo BH, You KR et al. Apoptosis induced by retinoic acid in Hep 3B cells in vitro. Cancer Lett 1996;107: Muto Y, Moriwaki H, Ninomiya M et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334: Meyskens FL Jr, Jacobson J, Nguyen B et al. Phase II trial of oral betaall trans-retinoic acid in hepatocellular carcinoma (SWOG 9157). Invest New Drugs 1998;16: