Condition

Hepatocellular carcinoma (HCC) is the most common primary liver tumor. It is the fifth most common cancer and the third leading cause of cancer death worldwide.¹ Overall 5-year survival rates for HCC are less than 10 percent in Europe and the United States.¹ The main etiology of HCC is chronic infection with the hepatitis B and hepatitis C viruses. Approximately 4 million individuals in the United States are chronically infected with hepatitis C virus, and the annual incidence rate of HCC among patients with hepatitis C-related cirrhosis is estimated to be between 2 and 8 percent. Unlike most solid tumors, the incidence of and mortality rate due to HCC are projected to increase worldwide in the next 20 years, primarily due to the dissemination of hepatitis C virus infection.² Other causes include cirrhosis due to any cause (e.g., alcohol), hereditary hemochromatosis and iron overload syndromes, nonalcoholic fatty liver disease, obesity, diabetes, and environmental toxins (e.g., aflatoxin, chewing of betel quid, and contaminated water).³

While there are several causes of HCC, etiology is not an independent prognostic factor for HCC;^4,5 rather, the underlying cirrhosis impacts prognosis and treatment decisions. In the United States, most cases of HCC occur in patients with cirrhosis.¹ A small proportion, approximately 5 percent, of all HCC cases in Western countries occurs in patients without cirrhosis.⁶ For patients with early-stage HCC without underlying cirrhosis, surgical resection is the preferred treatment and offers a high probability of a cure. The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend hepatectomy for patients with a single lesion less than 5 cm in size and mild or no underlying cirrhosis.⁷ In contrast, patients with severe cirrhosis are not considered resectable and receive supportive care instead.⁷

This report focuses on the approximately 80 percent of patients who are not surgical candidates due to advanced-stage disease at diagnosis, inadequate hepatic reserve to tolerate resection, tumors in unresectable locations, or medical comorbidities that result in a high surgical risk.¹

Classification/Staging of Hepatocellular Carcinoma

Both tumor stage and underlying liver function are key considerations in diagnosis, treatment selection, and prognosis of HCC. The BCLC classification system takes both tumor stage and underlying liver function into account and is widely used as the basis of treatment algorithms in Europe and North America.⁷ This system considers factors related to tumor stage, liver function, performance status, and cancer-related symptoms. HCC is staged from 0 to D.

Other staging systems are used regionally, such as Okuda staging developed in Japan, American Joint Committee on Cancer (AJCC) TMN staging, Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and Cancer of the Liver Italian Program (CLIP).^8-10 The set of prognostic factors considered in each of these systems varies and includes various measures and combinations of hepatic function, performance status, and tumor characteristics. Given the wide array of prognostic factors across the staging systems, a direct translation from one system to another is inexact. For example, though the BCLC staging system and the Okuda staging system both include a measure of tumor size, the numeric parameters of tumor size differ between the systems. Additionally, the BCLC system takes into account performance status and underlying liver function using Child-Pugh classification, whereas the Okuda system does not and instead includes other factors (presence of ascites and serum levels of albumin and bilirubin). Despite the apparent discrepancies, efforts have been made to designate equivalent stages between the two systems, albeit with some overlap (Table 1).⁸

Table 1

Comparison of Barcelona Clinic Liver Cancer (BCLC) and Okuda staging systems.

Classification of Underlying Liver Function

The Child-Pugh classification is a commonly used method to assess the prognosis of patients with underlying liver disease. The system employs five clinical factors: total bilirubin, serum albumin, international normalized ratio (INR; measure of clotting tendency of the blood), ascites (accumulation of fluid in the abdomen), and hepatic encephalopathy (declining brain function caused by toxin accumulation in the brain). Each is scored on a scale of 1–3, from lowest to highest severity. Patients are classified as class A, B, or C based on the total score. HCC patients with class A hepatic impairment have the best prognosis and would be candidates for surgical resection, although many would require local hepatic therapies such as ablative, transarterial, and radiotherapies. HCC patients with class B are not candidates for resection and are typically offered transarterial therapy, ablative therapy, radiotherapy, or systemic therapy. Class C patients typically are not candidates for local hepatic therapies, with rare exceptions, and usually receive supportive care. Transplantation can be offered to patients of all Child-Pugh classifications if they meet the listing criteria.^7,11

Another scoring system for chronic liver disease is the Model for End-Stage Liver Disease (MELD) score, which is based on serum bilirubin, serum creatinine, and INR. The MELD score ranges from 6 to 40, with a higher score corresponding to a higher severity of hepatic dysfunction. This score serves as a numerical scale for adult liver transplant candidates.¹²

Treatment Strategies

Table 2 through Table 4 present the mechanism of action, treatment setting, personnel involved, and specific harms reported for each of the 13 local hepatic therapies (ablative therapies, transarterial embolization therapies, and radiotherapies) included in this review.

Table 2

Local ablative therapies for primary hepatocellular carcinoma reviewed in this report.

Table 3

Transarterial embolization therapies for primary hepatocellular carcinoma reviewed in this report.

Table 4

Local radiotherapies for primary hepatocellular carcinoma reviewed in this report.

Potential Benefits and Drawbacks of Local Hepatic Therapies

Several patient and institutional factors may dictate the choice of local hepatic therapy for particular patients. Patient factors such as vascular anatomy, proportion of liver parenchyma involved with tumor, presence of shunts (e.g., pulmonary shunting), and performance status may influence the decision to use local hepatic therapies such as radioembolization and chemoembolization. For example, in patients with multifocal disease throughout both hepatic lobes, external-beam radiation may not be optimal due to radiation toxicity.

Ablative therapies such as radiofrequency ablation (RFA) and external beam radiation strategies are typically used in patients with unifocal or limited multifocal disease, whereas transarterial strategies such as chemoembolization (TACE) and radioembolization (RE) are typically offered to patients with more advanced, multifocal disease.^7,11 When examining the comparative efficacy of local hepatic therapies it is important to establish that patient groups are comparable. In general, patients treated with ablative therapies and those treated with transarterial strategies represent two distinct patient populations, and as a result when considering comparisons for this review we compared only ablative therapies to one another, embolization therapies to one another, and external-beam therapies compared to one another. TACE, RE, and RFA are performed by an interventional radiologist experienced in these techniques, though RFA can also be performed by surgeons. External-beam radiation is widely available at most centers;¹³ however, it may not be the best treatment option for some patients, such as those who may be candidates for other modalities such as RE.

Discussions in the literature of the potential benefits or harms from any single local hepatic therapy for a given patient group are limited in their usefulness. In this report (KQ3 below), we will review differences in comparative effectiveness of various local hepatic therapies in patients with unresectable HCC for specific patient and tumor characteristics, such as age, sex, disease etiology, and Child-Pugh score.

The National Comprehensive Cancer Network guidelines state that local hepatic therapies should not be used in place of liver resection or transplantation for patients who meet surgical criteria.¹⁴ The National Institutes of Health consensus recommendation suggests the use of locoregional therapies for selected patients with HCC confined to the liver and whose disease is not amenable to resection or transplantation.¹⁵ The existing guidelines do not provide specific guidance on the comparative effectiveness of the therapies. Providers and patients faced with treatment decisions need comparative evidence on which to base these decisions.

Scope of the Review

The objective of this systematic review is to examine the comparative effectiveness and harms of various local hepatic therapies for unresectable primary HCC in patients who meet all of the following criteria:

• No extrahepatic spread
• No portal invasion
• Child-Pugh class A or B disease
• Eastern Cooperative Oncology Group (ECOG) status ≤1 and/or
• BCLC stage A or B, or equivalent

Candidates for liver resection or transplant, as well as patients with advanced and terminal disease, are outside the scope of this review, as the treatment options for these patients are vastly different. Children are also excluded from this review as their disease presentation and prognosis are quite different from those of adults.

Nonsurgical candidates eligible for local hepatic therapies are a heterogeneous group. Patient selection criteria are critical for attaining optimal outcomes with the most appropriate local hepatic therapy, and patient selection for these procedures depends on how “medically or technically inoperable patients” are defined. We reviewed studies with any length of followup and in both inpatient and outpatient settings.

Table 5 lists the relevant populations, interventions, comparators, outcomes timeframes of assessment, and settings (PICOTS) relevant for this review.

Table 5

PICOTS (population, intervention, comparator, outcome, timing, and setting) for the Key Questions.

Key Questions

KQ1. What is the comparative effectiveness of the various local hepatic therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation with no evidence of extrahepatic disease regarding survival and quality of life?

KQ2. What are the comparative harms of the various local hepatic therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation with no evidence of extrahepatic disease regarding adverse events?

KQ3. Are there differences in comparative effectiveness of various local hepatic therapies in patients with HCC who are not otherwise candidates for surgical resection or transplantation for specific patient and tumor characteristics, such as age, gender, disease etiology, and Child-Pugh score?

Analytic Framework

We developed the analytic framework shown in Figure 1 based on clinical expertise and refined it with input from our Key Informants and Technical Expert Panel (TEP). The diagram is a revised version of those posted with the review protocol; the revisions are intended to make the core elements of our final analyses clearer, given the actual literature available for the review. Figure 1 outlines potential areas where patients who are not eligible for liver resection or transplantation are using local hepatic therapy. These therapies may affect intermediate health outcomes such as TTP, local recurrence, LOS, and days of work missed as well as final health outcomes of overall survival and quality of life (KQ1 and KQ3). In addition, we attempted to assess the occurrence of adverse effects of local hepatic therapies (KQ2).

Figure 1

Analytic framework for comparative effectiveness of local therapies for treatment of unresectable primary hepatocellular carcinoma. Abbreviations: HCC = hepatocellular carcinoma; 3D-CRT = External-beam three-dimensional conformal radiation therapy; IMRT (more...)