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Transarterial therapies play an important role in the treatment of hepatocellular carcinoma, both in a palliative setting and as an adjunct to surgery. These therapies exploit the dual blood supply of the liver to selectively target tumors via the hepatic artery, while sparing nontumorous liver. Currently available therapies include transarterial embolization; chemoembolization, with or without drug-eluting beads; and radioembolization. Transarterial techniques are also being used in the development of novel therapies. This article provides an outline of the technical and clinical applications of intraarterial therapies in the treatment of HCC and highlights pertinent future directions.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and results in a third of cancer deaths. Most cases are found in Asia and sub-Saharan Africa, but the incidence in the United States has drastically increased over the past two decades, in part because of the prolonged survival of cirrhotic patients, the prevalence of chronic hepatitis C, and associations with the metabolic syndrome of obesity and diabetes.1,2
Despite improved surveillance of patients with underlying liver disease, most HCCs are diagnosed at nonoperable stages. Transarterial therapies have been developed to provide local control for HCC both in a palliative setting and as an adjunct to surgery. Transarterial therapies exploit the fact that HCC derives most of its blood supply from the hepatic artery, whereas nontumorous liver receives most if its blood supply from the portal vein.3 After a catheter is directed into the hepatic artery, vasculo-occlusive (embolic) or nonembolic agents are delivered preferentially to the tumor while limiting exposure to normal hepatic parenchyma. Current available therapies include transarterial embolization (TAE), transarterial chemoembolization (TACE), and radioembolization (Table 1). In addition, transarterial techniques hold promise for the future, as they allow for the selective tumor delivery of therapy. This article is a review of the technical and clinical applications of transarterial therapies for the treatment of HCC and ends with a brief discussion of possible future directions.
TAE or “bland” embolization originated during the 1970s and has since evolved, with more refined catheter techniques and embolic materials.4 The goal of TAE is to cause ischemic tumor necrosis through terminal arteriolar occlusion. Embolic agents, such as gelatin sponge, acrylic copolymer gelatin, and polyvinyl alcohol, have been used. More recently, submillimeter spherical embolic particles have been developed to access and achieve better terminal arteriole blockade.5 TAE has been used as primary treatment for unresectable HCC and to treat disease recurrence after partial hepatectomy.6,7 Proponents of bland embolization argue that the addition of chemotherapy for chemoembolization adds cost and toxicity without an established survival benefit.7 Opponents hold that some studies have demonstrated that hypoxic change alone can lead to tumor progression by inhibiting apoptosis and stimulating angiogenesis, therefore implying the need for adjuvant chemotherapy.8,9
TACE, first described by Yamada et al.10 in 1977, involves the transarterial administration of chemotherapy in combination with embolization. Embolization limits vascular washout of chemotherapy. In addition, the subsequent hypoxic injury is likely to inhibit the tumor cells' ability to clear intracellular chemotherapy. This technique allows for much higher levels of local chemotherapy compared with systemic dosing with decreased systemic exposure. An iodized oil derived from poppy seeds (Lipiodol Ultra-fluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) became an important addition to the chemotherapy mixture after it was found to increase retention within the tumor, providing longer exposure to chemotherapy agents.11 Recent data for studies in which TACE was used to treat HCC are found in Table 2.
In 2002, two seminal prospective randomized trials established a survival benefit for highly selected patients with unresectable HCC treated with TACE vs. best supportive care. Llovet et al12 compared the results of fixed-interval doxorubicin TACE or TAE with best supportive care in patients with unresectable HCC and well-preserved liver function. This study was stopped early after a clear survival benefit was established for patients undergoing TACE or TAE vs. best supportive care. At the time of study termination, no clear benefit of TACE vs. TAE was established. Lo et al13 also found a survival benefit for selected patients receiving cisplatin TACE vs. best supportive care. TACE has subsequently become the de facto accepted clinical standard of care for local therapy in HCC patients with relatively preserved liver function that is not amenable to surgical resection or transplant.17
There is a lack of data to support the use of one chemotherapeutic agent or combination of agents over another. Single-agent doxorubicin is the most common monotherapy worldwide. Within the United States, combination therapy is more commonly used, typically consisting of doxorubicin, mitomycin C, and cisplatin. Portal vein thrombosis (PVT) was once considered a theoretic contraindication to TACE. However, Georgiades et al14 demonstrated successful TACE in 32 patients with PVT without any hepatic infarct or failure. They found Child-Pugh nominal liver staging to be the best predictor of survival.
In addition to prolonging survival of patients with inoperable tumors, TACE has shown promising results in downstaging patients before liver transplant. Orthotopic liver transplant (OLT) is an attractive surgical option for HCC, as it treats both the malignancy and underlying cirrhosis. However, early experience with OLT for HCC was discouraging, owing to high mortality and recurrence rates.18,19 OLT was therefore not considered a mainstay of HCC treatment until a landmark publication in 1996 established favorable survival data for selected patients with early-stage disease, defined as a solitary tumor ≤5 cm or three or fewer tumors ≤3 cm without gross vascular invasion and since labeled the Milan criteria.20 A subsequent review of 2898 transplants found that patients whose disease exceeded the Milan criteria had a 5-year survival rate which was half that of patients who fell within Milan criteria (32% vs. 61%, P < .0001).21
Several studies have since demonstrated that patients who are successfully downstaged with protocols involving TACE have posttransplant survival time similar to that of patients who initially meet the Milan criteria.16,22–23 In one such study from the University of California, San Francisco, 70.5% of patients were successfully downstaged, with resulting 4-year posttransplant survival of 92%.16 Overall Kaplan-Meier intention-to-treat survival was 87.5% and 69.3% at 1 and 4 years. These findings have resulted in the acceptance of TACE as an established means of determining eligibility for transplant for tumors that fall outside the Milan criteria.24
A shortage of liver donors has resulted in prolonged waiting times for patients in the United States who are scheduled for transplant. Despite efforts to prioritize transplants for eligible patients with HCC, median waiting times of 64 days resulted in an attrition rate of 18% due to tumor progression or death.21 TACE has been implemented as a bridge to transplant, to prevent disease progression beyond transplant criteria. Although TACE before transplant is widely practiced, a survival benefit has not been established, and evaluation is limited by lack of randomized, prospective trials.24 However, results in several studies suggest that response to TACE correlates well with transplant outcomes and therefore may be useful in identifying patients with aggressive tumors who are unlikely to benefit from transplant.25
Similar results were found in a prospective study in which TACE vs. hepatic resection was examined as a first-line treatment for patients with large (>5 cm), multiple tumors without vascular invasion or distant metastasis.26 This intermediate-stage disease, when resectable, is associated with a high rate of recurrence. Among these patients, no survival benefit was established for primary resection vs. TACE (P = .26). In addition, the primary-resection group had higher rates of complications (P < .01). However, the subgroup of patients who responded to TACE and went on to resection had better survival than patients who underwent up-front resection (P = .04). The authors concluded that TACE may have a role in identifying optimal patients for hepatic resection.
Drug-eluting beads (DEBs) are microspheres that can be loaded with chemotherapeutic agents and used for chemoembolization (DEB-TACE). They have the advantage of providing controlled, sustained release of chemotherapy at decreased peak plasma levels within the systemic circulation.27 There are several commercially available products. PVA microspheres (DC Bead; Biocompatibles, Farnham, UK), which imbibe doxorubicin by immersion, are the most commonly investigated product thus far. Acrylic copolymer microspheres (SAP Quadrophere [Hepasphere in Europe]; BioSphere Medical, Rockland, MA) are beads that can also imbibe doxorubicin or cisplatin.
Several phase I and II studies have demonstrated safety and efficacy of DEB-TACE. Poon et al28 completed a phase I dose-escalation study between 25 and 150 mg and found no dose-limiting toxicity. The phase II trial at the 150-mg dose found a partial response rate of 63% and a complete response rate of 7%, according to modified Response Evaluation Criteria in Solid Tumor (RECIST) standards, with a complication rate of 11%. A prospective phase II trial in the United States included 27 patients with unresectable HCC treated with 34 embolizations.29 In this study, response rates were 60% and 10% by EASL (European Association for the Study of the Liver) and RECIST criteria, respectively, with the remainder of patients having stable disease. Results of several other studies are summarized in Table 3.
The first prospective, multicenter, randomized trial (PRECISION V) compared conventional TACE (c-TACE) with doxorubicin vs. DEB-TACE with DC Bead microspheres in 212 patients with Child-Pugh A/B cirrhosis and unresectable HCC.30 The DEB-TACE group demonstrated decreased severe liver toxicity (P < .001) and lower doxorubicin-related side effects such as alopecia and marrow suppression (P = .0001), despite a higher total mean dose of doxorubicin (295 vs. 223 mg). The DEB-TACE group demonstrated overall trends toward higher objective response, complete response, and disease control, although these results were not statistically significant. However, for a subgroup of patients with more advanced disease (Child-Pugh B, ECOG 1, and bilobar or recurrent disease), the objective response and control rates were significantly higher in the DEB-TACE groups (P = .0038 and P = .0026, respectively).
Comparison of survival data is pending. A retrospective case–control study from a single academic institution in the United States demonstrated a survival benefit for patients undergoing DEB-TACE vs. c-TACE.32
Radioembolization involves the transarterial administration of embolic microspheres labeled with Yttrium-90 (Y90). Y90 is a beta admitter with a half-life of 64.2 hours and a maximum tissue penetration of 10 mm within the liver. Because of the selective permeation of the tumor vascular plexus, Y90 radioembolization can deliver extremely high levels of radiation (up to 150 Gy), with tolerable exposure to normal parenchyma.33 Two FDA-approved products are currently available that involve glass (TheraSphere; MDS Nordion, Kanata, ON, Canada) and resin-based (SIR-Spheres; Sirtex Medical, Lane Cove, Australia) microbeads. Both products have mean diameters <60 μm and lodge within terminal arterioles, making them particularly susceptible to systemic shunting to the lungs or abdominal viscera. Extensive pretreatment planning includes mesenteric and visceral angiography; dosimetry planning, including a transarterial 99tc macroaggregated albumin (MAA) study to evaluate for pulmonary shunting; and meticulous occlusion of potential enteric conduits, such as the gastroduodenal artery.34
The largest series in the United States examined the results of 526 treatments performed on 291 patients in a single-center, longitudinal cohort study of patients with unresectable HCC.35 Response rates of 42% and 57% were reported, according to World Health Organization (WHO) and EASL criteria, respectively. The reported 30-day mortality was 3%. Median survival was significantly higher in patients with Child-Pugh A disease vs. those with Child-Pugh B (17.2 months vs. 7.7 months, P = .002). The authors concluded that the patients with Child-Pugh A disease, regardless of portal vein thrombosis, derived the most benefit from radioembolization, whereas those with Child-Pugh B and portal vein thrombosis had poor outcomes.
For patients with unresectable HCC, retrospective studies (Table 4) found similar efficacy and toxicity between radioembolization and TACE.37–39 For patients with main portal vein thrombosis, radioembolization may be considered advantageous over TACE, owing to its relatively decreased embolic effect.17 Radioembolization has also demonstrated favorable outcomes for downstaging tumors to meet the Milan criteria. Lewandowski et al36 retrospectively compared transarterial radioembolization with Y90 (TARE-90) with TACE in patients with T3 disease. The TARE-90 group demonstrated a trend toward higher partial response and higher percentage of downstaging from T3 to T2 (58 vs. 31%, P = .028), thus falling within the Milan criteria.
The combination of transcatheter therapies with radiofrequency ablation or systemic therapy represents the quintessential step in the natural evolution of therapies in the management of HCC, especially after the availability of sorafenib. In a recent phase II trial, the safety and efficacy of DEB-TACE with doxorubicin plus sorafenib were evaluated in 35 consecutive patients with HCC.40 The results showed the combination to be safe with manageable toxicity, owing mainly to sorafenib. Efficacy was evaluated, with an objective response rate of 58% and disease control rates of 95% and 100% according to RECIST and EASL criteria, respectively. Prospective, multicenter, randomized control trials are currently under way comparing TACE with sorafenib vs. placebo.41,42
Transcatheter technique also holds promise for the selective delivery of other novel therapies. Intra-arterial administration of the antiglycolytic agent 3-bromopyruvate (3-BrPA), or related analogues, is one such potential therapy currently being investigated, with human clinical trials pending.43,44 This therapy exploits the phenomenon, termed the Warburg effect,45 that cancer cells tend to rely more heavily on glycolysis than on oxidative phosphorylation to meet their energy demands.
Gene therapy is another potential locoregional approach to treating HCC. Genes can be introduced into tumor cells by either viral vectors or nonviral carriers. Both strategies lend themselves to selective administration, as viral vectors can cause systemic inflammatory response, and nonviral carriers require high concentrations to achieve transmission.46 Potential strategies under investigation include tumor-suppressor genes, such as p53, and suicide genes, such as thymidine kinase from the herpes simplex virus, followed by ganciclovir.47,48 In one recent study, iodized oils appeared to improve transarterial delivery of nonviral gene vectors, similar to their effect in TACE.49
Future prospective, randomized trials are needed to further compare catheter-directed modalities for both locoregional control and as a bridge to transplant. The prevalence of HCC and the complex nature of the disease suggest that transarterial therapies will continue to play a pivotal role in treatment for the foreseeable future.