Systemic therapy in advanced hepatocellular carcinoma

Key points

Cytotoxic chemotherapy has not proven effective in hepatocellular carcinoma (HCC). Sorafenib is the only approved agent for advanced, unresectable disease.
Current studies are evaluating a wide range of targeted agents covering the spectrum of molecular aberrations in HCC. Currently, there are no effective alternatives for sorafenib-refractory HCC.
The combination of sorafenib and chemoembolization has not been shown to improve clinical outcomes. Combined systemic and liver-directed therapy in HCC remains investigational.

Introduction

Research and therapeutic development in advanced hepatocellular carcinoma (HCC) have evolved in recent years. New insights into the genetics and molecular biology of HCC have transformed the way it is studied and treated.

The management of HCC is generally determined by disease extent and performance status with the additional consideration of hepatic function. The prototypical Barcelona Clinic Liver Cancer (BCLC) algorithm considers these variables in separating patients into discrete groups for which specific lines of therapy are prescribed. However, these categories are more fluid in daily clinical practice, especially for locally advanced disease considered unresectable. These patients may be treated with locoregional and/or systemic therapies at different times during the clinical course rather than pursuing a strictly linear therapeutic sequence. The growing reality of an interdisciplinary management approach is reflected by the proliferation of clinical trials studying combined modality therapy.

This chapter will discuss the management of locally advanced HCC that is no longer amenable to surgical and liver directed ablative therapies, as well as metastatic disease. An overview of systemic therapies currently being investigated in HCC will be presented in addition to a discussion of aspects that are important for the interventional radiology domain.

Staging

The challenge of managing HCC arises from the dual nature of the disease: the malignancy itself and the underlying cirrhosis. Before embarking on any course of treatment, an assessment of the hepatic functional reserve is imperative, in view if its prognostic implications, and its impact on the management plan. The most commonly used scoring system for cirrhosis in clinical practice is the Child-Pugh classification, which uses three laboratory (serum bilirubin, albumin, international normalized ratio [INR]) and two clinical (ascites, encephalopathy) variables. Each variable is graded according to its severity. The total grades of all five variables are added and make up a score that ranges from the least decompensated category (A), through moderate (B), to the most decompensated (C) liver.

The key limitation of the Child-Pugh scoring system is its lack of any cancer-related parameters, which obviously are key contributors to HCC patients’ prognosis.

The objective of a staging system is to provide prognostic information that helps the clinician devise a management plan appropriate for the anticipated clinical outcome. Several different staging systems have been developed for HCC that include the purely anatomic American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM (tumor, node, metastasis) system to a variety of hybrid anatomic and functional systems such as the BCLC algorithm. Given that each of these systems were developed in populations of varying ethnicities, risk factors for cirrhosis, and treatment approaches, their general applicability and predictive potential, especially for patients with locally advanced or unresectable HCC, is a continued subject of debate. Although the BCLC algorithm is considered to be the most comprehensive of the hybrid staging systems and has been validated prospectively, ^, its discriminatory power among patients with advanced HCC is limited. A single-institution review of the different systems found that the Cancer of the Liver Italian Program (CLIP) which was developed in patients with hepatitis C, the Chinese University Prognostic Index (CUPI) developed primarily in patients with hepatitis B, and the Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire (GETCH) best predicted outcomes in patients with advanced HCC, whereas the BCLC and sixth edition TNM systems were not informative in this setting. These findings were consistent with an earlier study showing that the CLIP system outperformed the BCLC and Okuda systems in the palliative setting. Thus, although the BCLC algorithm serves as an important roadmap for prognostication and management, outcomes of patients with locally advanced or metastatic HCC may be better estimated by the CLIP, CUPI, or GETCH systems if the dominant underlying risk factor is hepatitis C, hepatitis B, or alcoholic cirrhosis, respectively.

Systemic chemotherapy

Several classes of chemotherapy agents exist, each exerting its cytotoxic effects through one or several of these mechanisms: alkylating agents, platinums, and topoisomerase inhibitors cause DNA strand breakage; fluoropyrimidines and other antimetabolites inhibit DNA synthesis; taxanes and vinca alkaloids prevent microtubule formation and cell division. Unlike molecularly targeted agents that will be discussed later, chemotherapy represents a less discriminatory form of therapy; normal cells rely on the same mechanisms to maintain DNA integrity, proliferate, and survive as their cancerous counterparts and are therefore subject to the same cytotoxic effects. Many of the toxicities of chemotherapy drugs result from the collateral damage incurred to normal cells in addition to cancer cells.

Studies of single-agent chemotherapy in HCC began during the 1960s–1970s. One of the earliest agents to be tested was doxorubicin (also known as adriamycin), from the anthracycline family of alkylating agents. In 1975, a phase 2 trial reported a striking objective response rate of 79% and median survival of 8 months. Subsequent studies of doxorubicin were unable to replicate these results; response rates ranged from 15% to 20% and median survival was only 4 months. Phase 3 studies also did not show doxorubicin to be superior to other chemotherapy regimens.

Clinical trials of 5-fluorouracil, a fluoropyrimidine used in the treatment of many gastrointestinal malignancies, as well as newer agents such as the topoisomerase I inhibitor irinotecan and the antimetabolite gemcitabine failed to produce durable response and survival outcomes. Although combination regimens such as gemcitabine + oxaliplatin (GEMOX) and oral 5-fluorouracil (capecitabine) + oxaliplatin (CAPOX) appeared to be more active on the basis of phase 2 data, their impact on survival has not been assessed in phase 3 studies. The strategy of combined chemoimmunotherapy has also been studied in advanced HCC. Interferon α-2b (IFN) was combined with cisplatin, doxorubicin, and 5-fluorouracil (PIAF) in a phase 2 study. Median survival was 8.9 months. Notably, 26% of patients had a partial response, 12% were converted to resectable disease, and 8% of patients had a pathologic complete response. PIAF was associated with significant hematologic toxicities; 34% of patients had grade 3/4 leukopenia, 22% had grade 3/4 thrombocytopenia and two patients died of neutropenic sepsis. Despite the considerable toxicities, the compelling clinical and pathologic responses reported in this study led to a phase 3 trial comparing PIAF with doxorubicin, which was still considered the most effective chemotherapy agent at the time. The primary endpoint, overall survival, was not statistically significantly different between the study arms (8.7 vs. 6.8 months, P = .83). Response rates were higher but not statistically significant in favor of PIAF (20.9% vs. 10.5%, P = .06), and one patient on each arm had a pathologic complete response. There was a significantly higher incidence of neutropenia, thrombocytopenia, and hypokalemia of any grade on the PIAF arm; however, there were no treatment-related deaths.

The limited impact of chemotherapy on responses and survival in HCC has several potential explanations. HCC tumors have been shown to overexpress the multidrug resistance gene-1 ( MDR-1 ) and P-glycoprotein drug extrusion molecule. Furthermore, the therapeutic index of chemotherapy, especially chemoimmunotherapy, is narrowed in a patient population with limited end-organ reserve. For these reasons, chemotherapy has been supplanted by molecularly targeted agents in HCC, though it may still be useful as an adjunct to these agents. The combination of sorafenib and doxorubicin has shown promising activity and will be discussed below.

Targeted therapies

In most cases, the initiating step in hepatocarcinogenesis is liver injury due to hepatotoxins, viral hepatitis, or other insults, leading to chronic inflammation, cirrhosis, and the formation of dysplastic nodules and ultimately HCC ( Figure 9-1 ). These steps are accompanied and driven by amplifications in oncogenes, losses in tumor suppressor function, and changes in signaling pathways that are normally responsible for maintaining hepatohomeostasis. Among the myriad factors that have been implicated in this process are the receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR) family, insulinlike growth factor receptor (IGFR), vascular endothelial growth factor receptor (VEGFR), and c-met. Interactions between these cell surface molecules and their specific ligands cause a conformational change in the RTK, leading to phosphorylation of their intracellular domains, and downstream activation of signaling cascades including the Ras/Raf/Mek/Erk (MAP kinase) and PI3K/Akt/mTOR cascades. Signal transmission through these intracellular conduits results in the transcriptional activation of genes that govern cell growth, proliferation, the evasion of apoptosis, angiogenesis, and invasive and metastatic capabilities. Established HCC tumors also continue to evolve and acquire additional aberrations that enable their survival through compensatory changes in the same pathways, or through the co-optation of associated networks. Therapeutic disruption of tumor cell signaling circuitry at its different levels is actively being studied in HCC.

Figure 9-1, Pathogenesis of hepatocellular carcinoma

Receptor tyrosine kinases

Epidermal growth factor receptor

The EGFR superfamily consists of four RTKs: EGFR, c-erbB-2, c-erbB-3, and c-erbB-4, which regulate key cellular functions including proliferation, survival, angiogenesis, and motility. Recognition of the primacy of EGFR as an oncogene in multiple malignancies has made it a leading therapeutic target. Aberrant EGFR activity in HCC appears to be primarily the result of overexpression, which also appears to correlate with more aggressive disease characteristics. ^, Anti-EGFR agents undergoing active clinical trial assessment in HCC include small-molecule tyrosine kinase inhibitors (TKIs) and anti-EGFR monoclonal antibodies.

Small-molecule TKIs target the intracellular signaling domain of the EGFR, preventing the activation of downstream cascades and the transcription of genes that promote malignant behavior. Three anti-EGFR TKIs have been assessed in HCC: erlotinib, gefitinib, and lapatinib.

Erlotinib, a selective inhibitor of EGFR/ErbB-1/Her-1, was evaluated in two phase 2 studies that enrolled fit patients with locally advanced/metastatic HCC, 70%–80% of whom had Child-Pugh A liver function. The first study enrolled 38 patients, 50% of whom previously received systemic therapy. Progression-free survival, defined as the proportion of patients without disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines or death, at 6 months was 32%. Nine percent of patients had a partial response lasting 2–11 months, 50% had stable disease, and median survival was 13 months. Similar findings were noted in a phase 2 study that enrolled 40 patients who were naÃ¯ve to systemic therapy. Although no objective responses were observed, 43% of patients had stable disease; progression-free survival at 4 months was 42.5% and median survival was 10.8 months. The most common grade 3/4 toxicities with erlotinib were fatigue, diarrhea, skin rash, nausea, vomiting, anorexia, and transaminitis, which occurred in up to 13% of patients. In both studies, neither the presence nor the intensity of tumor EGFR immunoreactivity correlated with responses, and the relationship between cutaneous toxicity and clinical outcomes was not explored. ^,

Gefitinib did not exhibit clinically relevant activity in a phase 2 study conducted in 31 patients with advanced disease naÃ¯ve to systemic therapy. Although treatment was well tolerated, there was only one partial response, and 7 patients had stable disease for a disease control rate of 26%. Median progression-free and overall survival were 2.8 and 6.5 months, respectively

The dual EGFR/c-erbB-1 and c-erbB-2/Her-2 inhibitor, lapatinib, was evaluated in a phase 2 trial conducted in a mixed population of patients with advanced HCC and biliary tract carcinomas. The practice of evaluating therapies in studies that include both HCC and biliary tract carcinomas is fading away as we learn more about the different biology of those two diseases. Regardless, the Ramanathan study did not show any activity in the HCC subgroup; 5% of patients had an objective response, and median progression-free and overall survival were 2.3 and 6.2 months, respectively. Results were somewhat better in another phase 2 trial that enrolled 26 patients with advanced HCC, 19% of whom were previously treated. Although there were no objective responses and median progression-free survival was only 1.8 months, 40% of patients had stable disease (lasting >3 months in six patients and >1 year in two patients) and median overall survival was 12.6 months. Factors associated with improved survival included the development of a skin rash, infection with hepatitis C, and the presence of ≥20 EGFR intron 1 (CA) _n16-23 repeats within tumor cells instead of <20 repeats.

Cetuximab is a chimeric monoclonal antibody that binds to the extracellular domain of the EGFR, preventing receptor-ligand interactions as well as intracellular domain phosphorylation. In a phase 2 study of cetuximab in HCC, there were no objective responses although 17% of patients had stable disease lasting a median of 4 months. Median progression-free and overall survival on that study were 1.4 and 9.6 months, respectively. Tumor EGFR expression did not correlate with responses to cetuximab. In another phase 2 study, 44.4% of patients had stable disease with a median time to progression of 8 weeks. Among patients who maintained stable disease for >8 weeks, the median time to progression was 22.5 weeks. Sixty percent of responders exhibited an upregulation of cell cycle inhibitory proteins compared to only 14% of nonresponders. The relationship between the development of skin rash, KRAS and BRAF mutation status, and responses to cetuximab has not been explored in HCC.

Taken together, anti-EGFR agents failed to show any meaningful activity in advanced HCC, although there appear to be subgroups of patients who might derive greater benefit from these agents compared to the unselected population. Characterization of these subgroups remains a work in progress.

Insulinlike growth factor

Obesity, dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) are features of the metabolic syndrome that is a recognized risk factor for the development HCC. The link between the metabolic syndrome and HCC is thought to be mediated by insulin, insulinlike growth factor (IGF) ligands and their receptors, in concert with reactive oxygen species, proinflammatory cytokines, and activation of the c-Jun amino-terminal kinase 1 (JNK1). These complex interactions result in a final common pathway of hepatocellular inflammation, apoptosis, compensatory proliferation and, ultimately, hepatocarcinogenesis. Targeting of the IGF axis using small-molecule TKIs and monoclonal antibodies is currently being evaluated in HCC.

A phase 2 study of the anti IGF-1 receptor (IGF-1R) antibody, cixutumumab (IMC-A12), in advanced HCC was terminated for inefficacy after 24 patients were enrolled. The primary endpoint, progression-free survival at 4 months, was 30% and median overall survival was 8 months. There were no objective responses, 29% of patients had stable disease, and 41% progressed. Therapy was complicated by grade 3 and 4 hyperglycemia in 46% of patients. High serum IGF binding protein-1 levels correlated positively with progression-free survival. The combination of cixutumumab and sorafenib in patients with advanced HCC naÃ¯ve to systemic therapy is undergoing evaluation in both a phase 1 and phase 2 study ( www.clinicaltrials.gov , NCT00906373, NCT01008566).

BIIB022 and AVE 1642 are two other anti-IGF-1R antibodies undergoing evaluation in HCC. A phase 1B study of sorafenib and BIIB022 has been completed and results are pending ( www.clinicaltrials.gov , NCT00956436). The combination of AVE1642 and sorafenib was found to be safe and tolerable in a phase 1 study that also reported stable disease lasting a median of 13 weeks in 85% of patients.

OSI-906 is an oral dual inhibitor of IGF-1R and the insulin receptor. A randomized phase 2 study in advanced HCC was terminated by the sponsor ( www.clinicaltrials.gov , NCT01101906), but another phase 2 study assessing the combination of OSI-906 and sorafenib is ongoing ( www.clinicaltrials.gov , NCT01334710).

C-met and the hepatocyte growth factor

The c-met receptor tyrosine kinase and its cognate ligand, hepatocyte growth factor (HGF), are potent mitogens that coordinate hepatogenesis in the developing embryo and promote regeneration and maintain the integrity of the mature liver. In preclinical models, aberrant c-met expression demonstrates tumorigenic potential, and inactivation of c-met/HGF signaling has shown antitumor activity. ^, Although data on the clinicopathologic characteristics and outcomes associated with c-met overexpression in human HCC are conflicting, ^, c-met targeting is actively being evaluated in clinical trials. Tivantinib (ARQ197), an oral non-ATP-competitive c-met TKI, is currently being studied in a phase 1B study of patients with Child-Pugh A or B cirrhosis and HCC, with preliminary data demonstrating acceptable toxicity ( www.clinicaltrials.gov , NCT00802555). A phase 1 dose escalation study of ARQ197 and sorafenib in HCC has shown that the combination is well tolerated and may be active in treatment-naÃ¯ve as well as pretreated disease ( www.clinicaltrials.gov , NCT00827177).

Several hybrid antiangiogenic and c-met inhibitors have also been developed and are being studied in HCC. Results from the HCC subset of a phase 2 discontinuation study of cabozantinib (XL184), a dual c-met/VEGFR-2 inhibitor were recently presented. Seventy-eight percent of patients experienced tumor regression with cabozantinib and median progression-free and overall survival were 4.4 months and 15.1 months, respectively. Tumor regression was associated with a ≥50% decrease in AFP from baseline in 35% of patients, and outcomes were not affected by prior therapy with sorafenib. Of note that tumor c-met expression was not assessed. Foretinib, another c-met/VEGFR-2 inhibitor, is also being studied in a phase 1/2 trial ( www.clinicaltrials.gov , NCT00920192).

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