Jennifer Gregg, PhD

To date, the only curative options available to patients are resection and transplantation, though only about 10% of patients are eligible. For patients with unresectable disease, locoregional therapies using minimally invasive techniques, such as ablation, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE), are preferred and have been used in patients with early-stage disease or as a palliative therapy.

Despite these additional treatment options, clinical outcomes vary significantly, and the 5-year survival rate for patients with HCC remains at less than 20%, indicating the need for additional, effective therapies.

Recent clinical evidence with embolization has drawn attention to the changing therapeutic landscape in HCC management, and is forcing clinicians to re-evaluate treatment options for primary and secondary HCC.

Conflicting Evidence for Chemoembolization for HCC

Conventional TACE, most commonly used with doxorubicin, has been used extensively in the treatment of unresectable HCC. Its popularity grew, in part, from randomized trials that demonstrated a survival advantage with chemoembolization versus best supportive care or bland hepatic artery embolization (HAE).

However, a direct head-to-head comparison of outcomes in a prospective trial showing the superiority of conventional TACE over bland embolization, embolization using microspheres alone, or radioembolization was lacking.

In a recent study, Karen T. Brown, MD, Memorial Sloan Kettering Cancer Center, New York City, and colleagues reported their findings in the February 1, 2016, issue of

The goal of the randomized phase II trial was to determine the effect of doxorubicin on response and outcomes after embolization by specifically comparing doxorubicin-eluting microspheres (LCB group) with microspheres alone (BB group). Eligible patients (N = 101) had HCC that was either localized or had limited extrahepatic disease. The primary endpoint was response to treatment using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria and liver computed tomography. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS).

RECIST responders had similar response rates between treatment groups (5.9% BB vs 6% LCB [95% CI, -9% to 9%;

= 1.0]). No difference in response rates was observed throughout the duration of the study. Similarly, no differences were observed in PFS (6.2 months BB vs 2.8 months LCB [HR, 1.36; 95% CI, 0.91-2.05;

= .11]) or OS (19.6 months BB vs 20.8 months LCB [HR, 1.11; 95% CI, 0.71-1.76;

=.64]). Similar rates of adverse events (AEs), serious adverse events, and postembolization syndrome were observed between treatment groups.

The results of this study coincide with a previous meta-analysis and systematic review, both of which failed to demonstrate the clinical benefit of chemoembolization over that of embolization without a drug.

The effect of embolization alone may contribute to hepatic ischemia resulting from arterial obstruction and subsequent tumor necrosis; the systematic review of 40 studies indicated that the effects of TACE were independent of the type or number of chemotherapies applied, suggesting some degree of nonspecificity in the response.

&ldquo;The results serve as a cautionary reminder of the potential pitfalls that may be encountered with the informal application of therapies available for HCC outside of the domain in which they were defined,&rdquo; Brown and the other researchers concluded. &ldquo;These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.&rdquo;

Emergence of Selective Internal Radiation Therapy for Primary or Secondary HCC

Over half of patients with colorectal carcinoma (CRC) will develop liver metastases (mCRC) during the course of their disease. Liver failure resulting from metastasis is a major cause of mortality for many patients. As nearly 25% of patients will present with liver metastases at diagnosis, treatment of CRC has remained a significant clinical challenge.

While chemotherapy and biologics are typically the first-line choice of therapy for patients with mCRC, a recent clinical trial investigated the effects of selective internal radiation therapy (SIRT) in combination with standard chemotherapy as a first-line treatment.

Professor Guy A. van Hazel, MD, University of Western Australia, Perth, and colleagues reported their findings in the February 22, 2016, issue of

Selective internal radiation therapy is a radiotherapy technique that delivers a single, targeted dose of radiation to hepatic tumors through injection into the hepatic artery, while sparing radiation exposure to normal liver tissue. Resin microspheres are commonly loaded with Yttrium-90 (

Y), a high-energy beta-emitter with a limited tissue-penetration range (average, 2.5 mm) and short half-life (2.67 days).

As with conventional embolization or TACE, SIRT requires the selective catheterization of blood vessels that feed the tumor. However, while embolization or TACE requires an ischemic environment for maximal effect, SIRT has a unique mechanism of action that contributes to its effectiveness. Resin microspheres used with SIRT are significantly smaller than those used with other embolization techniques, usually ranging from 20 to 60 microns in size, to permit continual blood flow. The presence of oxygen generates free radicals through the ionization of water from the emitted beta radiation. The free radicals in turn produce irreversible DNA damage and subsequent apoptosis in surrounding tissues.

There are two types of SIRT therapies currently available, resin-based particles, SIR-Spheres (Sirtex Medical); and glass-based particles, TheraSpheres (BTG Medical). SIR-Spheres have a specific activity of 50 Bq per sphere, and typically require 40 to 60 million spheres to treat the average patient.

In the SIRFLOX study, investigators performed a randomized controlled trial of fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy with or without SIR-Spheres as a first-line treatment in 530 patients with liver-only or liver-dominant mCRC. The primary outcome was PFS at any site, and secondary outcomes included PFS in the liver, OS, tumor response rates in the liver and at any site, and toxicity and safety.

Although the primary endpoint, PFS at any site, was not met (10.2 months control vs 10.7 months SIRT [HR, 0.93; 95% CI, 0.77-1.12;

=.43]), PFS in the liver was significantly extended with SIRT treatment (12.6 months control vs 20.5 months SIRT [HR: 0.69; 95% CI 0.55-0.90;

=.002]). These results indicated a 31% risk reduction in tumor progression in the liver for patients treated with additional SIRT compared with chemotherapy alone.

The objective response rate in the liver was also significantly improved with SIRT treatment (68.8% control vs 78.7% SIRT;

=.042), as was the complete response rate (1.9% vs 6.0%;

=.020) and first progression only in the liver (77% vs 52.4%;

<.001). Grade 3 or above AEs were 73.4% and 85.4% in the control and SIRT treatment arms, respectively (

Co-principal researcher of the study, Peter Gibbs, MD, explained, &ldquo;This finding matters a great deal because the liver is almost invariably the organ where colorectal cancer spreads to first. While half the patients initially diagnosed with colorectal cancer survive thanks to surgical removal of the primary tumor before the disease has spread elsewhere in the body, liver metastases eventually cause the death of the majority of the remaining hundreds of thousands of patients each year whose tumors spread but are inoperable."

Professor van Hazel commented, &ldquo;SIRFLOX gives us the data to validate the first-line use of&hellip;SIR-Spheres Y-90 resin microspheres in mCRC. Until now, we have not had a randomized clinical study large enough to provide Level One evidence supporting first-line use of this treatment."

He added, "This step forward matters to medical oncologists and their patients, because until the development of Y-90 resin microspheres, there was essentially no place for radiation therapy in the treatment of liver tumors. There was never a question that radiation would work in the liver, but the problem of administering the radiation in a way that spared healthy liver tissue from its effects prevented it from being an 'equal partner' with surgery and chemotherapy in treating mCRC, as it is in almost all other forms of cancer."

OS data from the SIRFLOX study will be combined with data obtained from 2 additional trials, FOXFIRE and FOXFIRE Global, which together enrolled over 1100 patients. Results are expected to be released in 2017.

Sorafenib, an oral multikinase inhibitor, is the only FDA-approved systemic agent currently available to treat metastatic HCC. Phase III trials of sorafenib, including the pivotal SHARP randomized controlled trial, established sorafenib as the standard treatment for patients with advanced HCC worldwide. Sorafenib improved clinical outcomes, with an extension in OS of nearly 3 months over placebo.

At this time, the clinical utility of SIR-Spheres in advanced HCC has not been clearly defined because of a lack of randomized clinical trials. Two ongoing, phase III studies will directly compare the efficacy of SIR-Spheres to sorafenib in patients with advanced HCC: SARAH and SIRveNIB.

The primary outcome measure for both studies is OS. The SARAH trial (France) has enrolled nearly 500 participants, and the SORveNIB trial (Singapore/Asia-Pacific) is slated to enroll 360 participants.

The principal investigator of the SARAH study, Val&eacute;rie Vilgrain, MD, PhD, Paris Diderot University, France, stated, &ldquo;SARAH is the largest randomized study ever to compare selective internal radiation therapyor any liver-directed therapy&mdash;against the standard-of-care systemic therapy in the treatment of primary liver cancer. The SARAH study team is delighted that enrolment is now complete, with results expected in late 2016.&rdquo;

SIR-Spheres are approved for unresectable HCC in the European Union, Australia, Argentina, Brazil, and several countries in Asia.

A recent retrospective analysis evaluated the safety and efficacy of sorafenib plus SIR-Spheres in patients with advanced HCC. Together with colleagues, Armeen Mahvash, MD, from MD Anderson Cancer Center in Houston, Texas, reported their findings in the February 5, 2016, issue of

In the analysis of 19 patients, Mahvash et al found that the combination of sorafenib and SIR-Spheres improved both OS and PFS compared with the previous SHARP trial of sorafenib alone (OS: 19.5 vs 10.7 months; PFS: 6.6 vs 5.5 months).

The combination treatment was well tolerated, with 21% of patients experiencing grade 3 AEs. The safety results were similar to those of the phase II SORAMIC study, which randomized patients to receive either sorafenib alone or SIR-Spheres followed by sorafenib, and concluded that treatments had similar tolerability and safety profiles.

The researchers of the retrospective analysis concluded that &ldquo;prospective, randomized controlled trials are warranted to evaluate the merit of our findings in patients with advanced HCC.&rdquo;

HCC affects the quality of life of hundreds of thousands of patients worldwide and is a difficult disease to treat. In spite of recent advances, such as the approval of sorafenib, the treatment of advanced HCC has remained unsatisfactory. Although locoregional therapies, such as TACE and conventional embolization, have improved survival in certain patients, they are associated with some risks and may not be suitable for patients with multiple, large tumors. Treatment with SIRT may provide a viable therapeutic option for those with advanced disease.

"Physicians have been performing SIRT procedures with Y-90 resin microspheres, in the United States and around the world, for more than 10 years. We have always felt that this procedure was a unique approach to deliver large doses of radiation to liver tumors, targeted in a way that spares healthy liver tissue,&rdquo; said Navesh K. Sharma, MD, University of Maryland Medical Center. He added that studies, such as SIRFLOX, have shown &ldquo;that not only can we deliver high doses of radiation to the liver safely with this approach, but we can do so using concurrent chemotherapy. Concurrent chemoradiation has been one of the most effective ways to treat cancer in general, especially those of gastrointestinal origin."

Khajornjiraphan N, Thu NA, Chow PKH. Yttrium-90 microspheres: a review of its emerging clinical indications.

Lee EW, Thakor AS, Tafti BA, Liu DM. Y90 selective internal radiation therapy.

National Cancer Institute. Cancer of the Liver and Intrahepatic Bile Duct - SEER Stat Fact Sheets. 2015.

Llovet JM, Real MI, Monta&ntilde;a X, et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.

Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.

Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone [published online February 1, 2016].

Camm&agrave; C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials.

Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.

Eadens MJ, Grothey A. Curable metastatic colorectal cancer.

van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer [published online February 22, 2016].

Mosconi C, Cappelli A, Pettinato C, Golfieri R. Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma: role and perspectives.

PR Newswire. SIRFLOX Study Presented at ASCO 2015 Annual Meeting. May 30, 2015.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma.

Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.

ClinicalTrials.gov. SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma (SARAH). ClinicalTrials.gov Identifier: NCT01482442. https://clinicaltrials.gov/ct2/show/NCT01482442.

ClinicalTrials.gov. Study to Compare Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (HCC) (SIRveNIB). ClinicalTrials.gov Identifier: NCT01135056. https://clinicaltrials.gov/ct2/show/NCT01135056.

PR Newswire. Treatment of Primary Liver Cancer: SARAH Study Completes Enrolment, Results Expected Late 2016 [press release].

Assistance Publique - H&ocirc;pitaux de Paris

Mahvash A, Murthy R, Odisio B, et al. Yttrium-90 resin microspheres as an adjunct to sorafenib in patients with unresectable hepatocellular carcinoma.

Ricke J, Bulla K, Kolligs F, et al. Safety and toxicity of radioembolization plus sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

Articles

Despite the widespread prevalence of hepatocellular carcinoma (HCC), effective treatment options for both primary and secondary liver tumors have remained elusive, as these tumors are difficult to manage, especially in cases where the tumor is unresectable.

Moving Forward: Examining the Evolving Role of Embolization in HCC

An estimated 10% to 40% of patients with HCC will present with PVT at the time of diagnosis. Portal vein thrombosis is an independent predictor of mortality, and, when left untreated, patients with HCC and PVT have a median overall survival (OS) of just 2 to 4 months.

Using the Barcelona Clinic Liver Cancer (BCLC) staging, most patients with PVT are classified as having advanced-stage disease (class C). As such, treatments are extremely limited, and curative options, such as liver transplantation and surgical resection, are generally contraindicated or controversial, and not performed in most centers.

Sorafenib (Nexavar) currently remains the only therapy specifically recommended for HCC with PVT by the American Association for the Study of Liver Diseases (AASLD). In the pivotal phase III SHARP trial, sorafenib demonstrated a median OS of 10.7 months versus 7.9 months with placebo, a benefit that was maintained across subgroups of patients with aggressive disease.

Because of the relatively short survival expectancy, ongoing efforts have continued in the detection and development of locoregional therapeutic options for patients with HCC and PVT.

Accurate and timely assessment of patients with malignant PVT in HCC is vital for both tumor staging and subsequent treatment selection. A relatively novel detection technique, gadoxetic acid‒enhanced magnetic resonance imaging (MRI), represents one potential option for the evaluation of thrombosis in HCC.

In a recently published retrospective study, Jae H. Kim, MD, and colleagues, Seoul National University College of Medicine, South Korea, reported their analysis of patients with HCC and PVT using gadoxetic acid-enhanced MRI in the January 14, 2016, issue of

Current imaging techniques used to evaluate HCC include dynamic computed tomography (CT) and nonspecific extracellular contrast material (ECCM)‒enhanced liver MRI. Both have shown clinical accuracy in diagnosis of PVT with HCC, though study cohorts have been small and did not include non-PVT control groups.

Previous reports have indicated that MRI with gadoxetic acid had superior diagnostic sensitivity and specificity for HCC in patients eligible for liver transplantation compared with dynamic CT or MRI with ECCM.

Whether MRI with gadoxetic acid was useful and advantageous for the evaluation of PVT was unknown.

Gadoxetic acid is a liver-specific contrast agent that exhibits certain characteristics that are beneficial for evaluating liver lesions. Hepatocytes take up nearly half of the injected dose of gadoxetic acid with a delayed enhancement that lasts for about 2 hours.

After administration, normal liver tissues demonstrate T1 shortening, but focal liver lesions typically do not, increasing the likelihood of HCC tumor detection through this exclusion. Tumors as small as 2 cm have been detected with this agent. Meta-analysis of gadoxetic acid‒enhanced MRI studies has shown 91% sensitivity and 94% specificity for HCC detection, rates that are higher than dynamic CT and ECCM MRI.

In the present study, 183 patients with malignant (n = 134) or benign (n = 49) PVT were matched with patients without PVT for age and sex. Of those with PVT, 125 patients had a complete occlusion and 58 had a partial occlusion. PVT was located in either the major portal vein (n = 159) or segmental portal vein (n = 24). Most patients, whether positive or negative for PVT, were classified as Child-Pugh A status.

Gadoxetic acid‒enhanced MR images were analyzed for sensitivity, specificity, and accuracy in the detection and characterization of PVT by location (major vs segmental) and type (complete vs partial). Two radiologists who were blinded to clinical and pathologic information analyzed images independently.

Patients with PVT exhibited a number of characteristics that were consistent with a worse clinical prognosis. Compared with those without PVT, patients with PVT had a significantly higher rate of liver cirrhosis (81% vs 66%;

<.0001), larger HCC diameters (7.15 cm &plusmn; 4.90 vs 5.32 cm &plusmn; 2.92;

<.0001), and a higher incidence of multiple tumors (52% vs 21%;

The diagnostic performance of gadoxetic acid‒enhanced MRI demonstrated comparable rates of sensitivity, specificity, and accuracy in PVT detection as when used to detect HCC. Using MRI with gadoxetic acid, reviewers were able to detect PVT with a sensitivity of 70% to 84%, specificity of 89% to 96%, and accuracy of 83% to 87%. The sensitivity of detection with gadoxetic acid for malignant PVT was 81% to 93%, with similar sensitivity of detection for the segmental and major branches. The sensitivity for benign PVT was significantly lower (41%-60%;

The sensitivity for detecting partial PVT was significantly lower than the detection of complete PVT (36%-59% vs 86%-96%, respectively;

<.0001). Similarly, sensitivity was significantly lower for patients eligible for liver transplantation than for other treatments, and in patients with Child-Pugh class B or C cirrhosis. The researchers hypothesized that these results may have been due to portal hypertension and weaker enhancement of the portal vein, the higher likelihood of partial benign PVTs in those groups, or the potential for severe hepatic dysfunction to impair the diagnostic performance.

The detection of characteristic imaging features of malignant PVT was common; detection of tumor continuity, vessel expansion, enhancement, increased T2 signal intensity, and diffusion restriction was found in more than 76% of patients for each reviewer. Conversely, these characteristics were rare, 10% or less, in patients with benign PVT. Importantly, MRI with gadoxetic acid distinguished malignant and benign PVT with accuracies of 92% to 95%.

A randomized trial compared gadoxetic acid‒enhanced MRI with ECCM MRI and contrast-enhanced CT as a first-line imaging method in patients suspected of having colorectal cancer with liver metastases (mCRC). Investigators concluded that diagnostic confidence was higher for MRI with gadoxetic acid than with the other 2 methodologies because additional imaging was not required prior to surgery. Fewer imaging tests ultimately resulted in similar overall costs among the imaging strategies evaluated.

Christoph Zech, MD, University of Basel, Switzerland, the lead researcher of the study commented, &ldquo;The potential clinical benefits shown at similar costs suggest that gadoxetic acid-enhanced MRI should be the preferred procedure to evaluate hepatic resectability in patients with colorectal cancer liver metastases."

Taken together, these results indicate the utility of gadoxetic acid‒enhanced MRI in HCC with PVT, and also in secondary metastases to the liver. Accurate diagnosis of HCC can help to improve treatment strategies and guide optimal clinical management of this progressive disease.

Ablation Techniques in the Clinical Management of HCC With PVT

For unresectable HCC, local ablation is considered a suitable alternative nonsurgical therapy option. Thermal ablation techniques effectively induce solid tumor cell death by raising the temperature above a lethal threshold. The technique is used in the treatment of many different tumor types, and is considered a favorable alternative to surgery because of its minimal invasiveness, acceptable tolerability and safety profile, efficacy, and cost-effectiveness. Furthermore, surgery is often an unsuitable treatment option for HCC with main portal vein involvement.

The 2 most commonly used thermal ablation techniques are microwave ablation (MWA) and radiofrequency ablation (RFA). They differ in their energy sources: non-ionizing electromagnetic fields with a frequency of 1 GHz are typically used with MWA, and alternating electric currents with a frequency of 400-500 kHz are typically used with RFA. In patients with HCC tumors less than 3 cm, RFA is effective and has shown a 5-year OS rate of nearly 40%.

Conversely, MWA is better suited for HCC tumors larger than 3 cm. Multiple reports have indicated complete ablation rates greater than 90% and OS rates greater than 50% at 3 years, although response rates often correlate directly with the size of the lesion.

Despite promising OS rates with ablation techniques, the recurrence rates of larger HCCs is still high. As such, combination therapies, such as MWA with transarterial chemoembolization (TACE), have been investigated. Not only does TACE create an ischemic environment that increases the local effect of the chemotherapeutic agent, it also creates synergy with thermal ablation by enhancing the sensitivity of tumor cells to hyperthermia.

A limited number of studies have examined the clinical efficacy of MWA with TACE in the setting of HCC with PVT, which may be attributed in part to concerns of hepatic necrosis and worsening liver function.

A recent prospective analysis examined the use of MWA following TACE in patients with HCC with malignant PVT. Jian Long, MD, and colleagues at Capital Medical University in Beijing, China, reported their findings in the January 7, 2016, issue of

In this study, the clinical characteristics, survival outcomes, and complications of patients treated with MWA after TACE (n = 60) were compared with those treated with TACE alone (n = 54), using data from a previous retrospective study. All patients in the prospective cohort had BCLC stage C disease, with one-half having more than 1 tumor. The mean size of the largest tumor was over 6.0 cm.

Compared with those treated with TACE alone, patients who were treated with MWA plus TACE showed improvement in 1- and 3-year OS rates (48% vs 33%, 1-year OS; 23% vs 20%, 3-year OS). Similarly, median survival times were also improved with combination therapy (13.5 months vs 9.5 months, respectively). Comparatively, in previous studies of patients with HCC and PVT treated with sorafenib, the 3-year survival rate was 15% and median survival was 4.3 months.

Additionally, changes in bioclinical markers were significantly associated with patient survival. Changes in the neutrophil-to-lymphocyte ratio (NLR; HR, 0.331;

=.031), Cancer of the Liver Italian Program (CLIP) score (HR, 2.632;

=.025), and treatment efficacy (HR, 36.848;

=.000) were all prognostic indicators of survival, indicating that these factors may be clinically useful predictors of patient outcomes in the context of HCC with PVT. Patients who were treated with MWA plus TACE and who had a decrease in NLR posttreatment showed improved survival compared with those with increased NLR. Within 4 weeks of treatment, no patients developed posttreatment hepatic failure, a significant finding given the controversial nature of MWA use with TACE. Other complications were rare, and only pneumothorax (n=2) and biliary tract injury (n=5) were noted posttreatment.

Although data are limited, these results were consistent with a previous study that showed improved clinical outcomes for patients who were treated with TACE followed by MWA compared with TACE alone in patients with unresectable, large-sized HCC. Superior tumor reduction rates (88% vs 39%) and longer survival times (11.6 vs 6.1 months) were observed.

Arthur Winer, MD, NYU Langone Medical Center, New York City, and colleagues presented a retrospective study of the comparative effectiveness of combination therapy of TACE plus ablation (RFA/MWA) versus TACE monotherapy in patients with HCC, at the 2016 ASCO Gastrointestinal Cancers Symposium. The 5-year survival rates for combination therapy, TACE, and ablation were 42.1%, 11.9%, and 13.3%, respectively. Similarly, survival at 5 years, as determined by Kaplan Meier analysis, was significantly longer with combination therapy than with ablation or TACE alone (

Although the latter studies did not evaluate the subpopulation of patients with HCC patients and PVT specifically, they demonstrated the potential clinical efficacy in an advanced HCC setting. The positive clinical results of the study by Long et al

may be of particular interest because of the large mean tumor size and multinodularity among patients. These clinical characteristics have traditionally been difficult to treat effectively, especially in patients with PVT.

&ldquo;The great progress of oncology over the past few years now permits the treatment of more patients with advanced disease who were previously considered unfit for surgery, or indeed, any kind of palliative treatment. Locoregional treatments such as RFA and MWA constitute the backbone of interventional treatment in HCC, a malignancy that affects up to a million people per year worldwide,&rdquo; wrote Loukia Poulou, MD, PhD, National and Kapodistrian University of Athens, Greece, and colleagues. Poulou added, &ldquo;The evolution of devices and instruments coupled with the progress of multidisciplinary patient management may allow a better stratification that would maximize treatment benefit.&rdquo;

Rajani R, Bj&ouml;rnsson E, Bergquist A, et al. The epidemiology and clinical features of portal vein thrombosis: a multicentre study. Aliment Pharmacol Ther. 2010;32(9):1154-1162.

Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol. 2006;12(47):7561-7567.

Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022.

Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57(4):821-829.

Kim JH, Lee JM, Yoon JH, et al. Portal vein thrombosis in patients with hepatocellular carcinoma: diagnostic accuracy of gadoxetic acid-enhanced MR imaging. Radiology. January 2016:150124.

Mitchell DG, Bruix J, Sherman M, Sirlin CB. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology. 2015;61(3):1056-1065.

Rossi S, Ghittoni G, Ravetta V, et al. Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma. Eur Radiol. 2008;18(8):1749-1756.

Chen L, Zhang L, Liang M, et al. Magnetic resonance imaging with gadoxetic acid disodium for the detection of hepatocellular carcinoma: a meta-analysis of 18 studies. Acad Radiol. 2014;21(12):1603-1613.

Ba-Ssalamah A, Uffmann M, Saini S, et al. Clinical value of MRI liver-specific contrast agents: a tailored examination for a confident non-invasive diagnosis of focal liver lesions. Eur Radiol. 2009;19(2):342-357.

Zech CJ, Justo N, Lang A, et al. Cost evaluation of gadoxetic acid-enhanced magnetic resonance imaging in the diagnosis of colorectal-cancer metastasis in the liver: results from the VALUE trial [published online February 24, 2016]. Eur Radiol. DOI: 10.1007/s00330-016-4271-0.

Harrison P. Cost of Expensive Imaging Balances Out in Liver Metastases. Medscape Conference News; March 10, 2015.

Poggi G, Tosoratti N, Montagna B, Picchi C. Microwave ablation of hepatocellular carcinoma. World J Hepatol. 2015;7(25):2578-2589.

N&rsquo;Kontchou G, Mahamoudi A, Aout M, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology. 2009;50(5):1475-1483.

Han K, Kim JH, Ko G-Y, et al. Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: a comprehensive review. World J Gastroenterol. 2016;22(1):407-416.

Long J, Zheng JS, Sun B, Lu N. Microwave ablation of hepatocellular carcinoma with portal vein tumor thrombosis after transarterial chemoembolization: a prospective study. Hepatol Int. 2016;10(1):175-184.

European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908-943.

Takizawa D, Kakizaki S, Sohara N, et al. Hepatocellular carcinoma with portal vein tumor thrombosis: clinical characteristics, prognosis, and patient survival analysis. Dig Dis Sci. 2007;52(11):3290-3295.

Liu C, Liang P, Liu F, et al. MWA combined with TACE as a combined therapy for unresectable large-sized hepotocellular carcinoma. Int J Hyperthermia. 2011;27(7):654-662.

Winer A, Rosen Y, Lu F, et al. Comparative effectiveness of combination TACE/ablation vs. monotherapy in hepatocellular carcinoma. J Clin Oncol. 2016;34(4_suppl; abstr 350).

Poulou LS, Botsa E, Thanou I, et al. Percutaneous microwave ablation vs radiofrequency ablation in the treatment of hepatocellular carcinoma. World J Hepatol. 2015;7(8):1054-1063.

The hepatic portal vein is critical to normal liver function and supplies approximately 75% of the blood supply to the liver. In the general population, portal vein thrombosis (PVT) is relatively rare, occurring with an incidence of about in 1 in 100,000 people.

New Approaches to the Detection and Treatment of HCC With Portal Vein Thrombosis

Despite sorafenib&rsquo;s ability to improve clinical outcomes, the average overall survival (OS) is limited to between 7 and 11 months.

Given that clinical trials of first- and second-line therapies have not provided suitable alternatives,

additional novel therapies are urgently needed in order to improve patient outcomes for patients with HCC.

Ongoing Clinical Trials of New Agents in the First-Line Setting

Nivolumab (Opdivo) is a monoclonal antibody that targets PD-1 on activated T cells, allowing the immune system to attack the tumor. In this way, nivolumab blocks negative regulators of T-cell activation, the PD-1 ligands, and serves as an immune checkpoint blockade. The FDA-approved uses for nivolumab include unresectable or metastatic melanoma, metastatic nonsmall cell lung cancer, and advanced renal cell carcinoma. Nivolumab has not been extensively studied in HCC.

In May 2015, lead investigator Anthony El-Khoueiry, MD, University of Southern California Norris Comprehensive Cancer Center, and colleagues presented phase I/II clinical data on the safety and antitumor activity of nivolumab in patients with advanced HCC, at the 2015 ASCO Annual Meeting.

The study of 42 patients demonstrated that nearly 20% had a tumor response (reduction beyond 30%) with nivolumab treatment, including a complete response (CR) in 2 patients. Stable disease (SD) was observed in nearly 50% of patients, with the longest duration lasting over 17 months; the OS rate after 12 months was 62%.&nbsp;In comparison, sorafenib response rates are typically 2% to 3%, with an OS rate of about 30% after 12 months. Grade 3 or above adverse events (AEs) occurred in less than 20% of patients.

"While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer," Dr. El-Khoueiry said in a press statement.

An ongoing randomized phase III trial, CheckMate-459, of nivolumab versus sorafenib as a first-line treatment in advanced HCC is currently under way with over 700 patients enrolled. The primary outcomes of the study are time to progression (TTP) and OS, with an estimated completion date of May 2017.

Lenvatinib is a receptor TKI with activity against multiple receptors, including those of VEGF and fibroblast growth factor (FGF). Lenvatinib is currently approved for use in patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer and is pending an FDA decision for use in patients with renal cell carcinoma.

The phase I/II safety and efficacy study of lenvatinib in patients with advanced HCC was presented by Kiwamu Okita, MD, PhD, Yamaguchi University, Japan, and colleagues at the ASCO Gastrointestinal Cancers Symposium in 2012.

Among the 42 patients who were enrolled in the study, 33% had a partial response (PR). Grade 3 AEs included hypertension, anorexia, proteinuria, and thrombocytopenia.

A multicenter, randomized phase III clinical trial of lenvatinib versus sorafenib as first-line therapy in nearly 1000 patients with unresectable HCC is ongoing, with completion estimated for later this year.

Novel Second-Line Therapies Following First-Line Therapy Failure

Other agents, such as regorafenib (Stivarga), cabozantinib (Cometriq), ramucirumab (Cyramza), and tivantinib, are being investigated in patients who have progressed following first-line treatment with sorafenib. Sorafenib is commonly used in the frontline setting, and remains effective across various prognostic factors and liver function scores,

making this the standard frontline therapy that most patients will have received in second-line trial.

Regorafenib is a multikinase inhibitor of VEGF receptors, c-kit, Ret, and FGF receptor, and targets various pathways important for angiogenesis, oncogenesis, and the tumor microenvironment. The FDA has previously approved regorafenib for the treatment of advanced gastrointestinal stromal tumors and previously treated metastatic colorectal cancer.

Jordi Bruix, MD, University of Barcelona, Spain, and colleagues reported phase II findings of regorafenib in the November 2013 issue of

The analysis evaluated the safety and efficacy of regorafenib as a second-line therapy following sorafenib failure in 36 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC.

Adverse events related to treatment were mostly mild and occurred in 39% of patients; 14% of patients experienced serious AEs. During the median treatment duration of nearly 20 weeks, 72% of patients exhibited disease control, reaching a TTP of 4.3 months and OS of 13.8 months.

The results of the phase II trial prompted further investigation in a phase III trial, RESOURCE, which is currently ongoing. Eligible patients, who have failed prior sorafenib therapy, will be randomly assigned to receive either regorafenib or placebo in a 2:1 ratio. The primary endpoint is OS, and the anticipated trial completion is later in 2016.

Cabozantinib is a small-molecule inhibitor of multiple receptor tyrosine kinases, including HGF receptor (MET), Ret, and the VEGF receptor. The FDA has approved the agent for the treatment of progressive, metastatic medullary thyroid cancer, and an application is pending for metastatic renal cell carcinoma.

In advanced HCC, cabozantinib has shown promising results in a phase II trial, and ongoing data are being gathered in a phase III trial. The phase II data were presented by Chris Verslype, MD, PhD, University Hospital Gasthuisberg, Leuven, Belgium, and colleagues at the 2012 ASCO annual meeting.

In the phase II randomized discontinuation trial, 41 patients with HCC who had received 1 line of prior systemic therapy and classified as Child-Pugh score A were eligible to participate. Among patients who received cabozantinib in the lead-in phase of the trial, 5% achieved a PR, 78% achieved SD, and 7% had progressive disease. The median OS was 15.1 months, and the median progression-free survival (PFS) was 4.4 months, independent of prior sorafenib therapy. The most common grade 3 or higher AEs were diarrhea, palmar-plantar erythrodysesthesia, and thrombocytopenia.

The ongoing phase III trial, CELESTIAL, will compare the OS of cabozantinib versus placebo in patients who have received prior sorafenib therapy. The primary completion date is estimated for late 2016.

&ldquo;Patients with advanced HCC who have progressed on sorafenib have few therapeutic options, and new approaches to managing their disease are much needed,&rdquo; said Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York City, the lead investigator of CELESTIAL. &ldquo;Phase II data investigating cabozantinib in this patient population are worthy of more study, and cabozantinib&rsquo;s target profile, which includes inhibition of both MET and VEGFR, is highly relevant in HCC.&rdquo;

Tivantinib is a receptor TKI that is selective for MET. Ongoing studies are evaluating MET as a prognostic and predictive indicator of tumor progression and response to tivantinib. Lorenza Rimassa, MD, Humanitas Cancer Center, Rozzano, Milan, Italy, and colleagues recently presented their findings at the 2016 ASCO Gastrointestinal Cancers Symposium.

In the phase II analysis, 107 patients who had previously failed prior first-line treatment were randomized to receive tivantinib or placebo. Patients were stratified by high or low circulating levels of MET and hepatocyte growth factor (HGF), and also by levels of alpha-fetoprotein (AFP). Circulating levels of MET were prognostic (OS: 4.6 months high vs 8.9 months low; HR, 0.61;

=.023). MET expression also correlated with sorafenib treatment; 40% of patient biopsies prior to treatment were MET-high compared with 82% of biopsies after sorafenib. A significant interaction in OS between tivantinib and MET expression was observed (

=.039). The other biomarkers examined were not predictive of tivantinib response.

An ongoing phase III, randomized, double-blind clinical trial of over 350 patients with inoperable, high-expressing MET tumors who have been treated previously with systemic therapy is currently under way. The primary endpoint is OS, and secondary outcomes are PFS and safety. The anticipated study completion date is mid-2017.

Ramucirumab is an anti-VEGFR-2 antibody that binds to the receptor with high affinity and prevents ligand activation. VEGF, among other angiogenic factors, is highly expressed in HCC and associated with worse outcomes, making it a highly attractive therapeutic target.

Andrew X. Zhu, MD, Massachusetts General Hospital, Boston, and colleagues reported their initial phase III findings of ramucirumab in the June 18, 2015, issue of

The randomized, double-blind trial, REACH, examined 565 patients who were refractory or not amenable to locoregional therapy and who had previously received sorafenib. The primary endpoint, OS, was not significantly different with ramucirumab when compared with placebo (9.2 months vs 7.6 months; HR, 0.87; 95% CI, 0.72-1.05;

=.14). However, improvements were noted in the secondary endpoints of PFS, TTP, and objective response rate (ORR). The most common grade 3 or above AEs included ascites, hypertension, asthenia, malignant neoplasm progression, and increased aspartate aminotransferase concentration.

Although the primary endpoint was not reached, additional analysis that stratified patients by AFP concentration demonstrated a significant difference in OS between ramucirumab and placebo in patients with AFP levels greater than 400 ng/mL (7.8 months vs 4.2 months; HR, 0.67; 95% CI, 0.51-0.90;

=.006). Similarly, in patients with a baseline AFP 1.5 times the upper limit of normal or greater, the median OS was 8.6 versus 5.7 months for ramucirumab and placebo, respectively (HR, 0.749; 95% CI, 0.603-0.930;

These results suggested that patients with elevated AFP, a diagnostic and prognostic marker of HCC, might be more likely to benefit from ramucirumab.

A follow-up prospective phase III trial, REACH 2, will examine the safety and efficacy of ramucirumab as a second-line therapy specifically in patients with elevated baseline AFP. The estimated primary completion date is late 2017.

Oncolytic Immunotherapeutic Viruses  A New Class of Agents in HCC

The majority of agents that are currently in phase III trials specifically target and bind to various RTKs expressed on the tumor cell surface. A new class of agents, oncolytic immunotherapies, function through a unique mechanism of action, and selectively replicate within and lyse tumor cells. JX-594, also known as Pexa-Vec, is an oncolytic and immunotherapeutic vaccinia virus that is currently being investigated in patients with advanced HCC.

Jeong Heo, MD, PhD, Pusan National University Hospital, Busan, Korea, and colleagues reported the results of an initial phase II dose-finding trial of JX-594 in the February 10, 2013, issue of

JX-594 uses a dual-pronged approach to target cancer cells. First, JX-594 targets tumor cells with active epidermal growth factor receptor (EGFR)/RAS signaling and uses that kinase pathway to replicate and induce oncolysis. Second, the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) triggers an anti-tumor immune response.

In the phase II study, investigators compared low-dose with high-dose (10x greater) JX-594 in 30 patients with advanced HCC. Survival duration was directly related to dosage; patients achieved a median survival of 6.7 months and 14.1 months on the low and high dose, respectively (HR, 0.39;

=.020). Treatment was generally well tolerated in both cohorts, and the rate of AEs was similar in both treatment groups, with flu-like symptoms being the most common.

Trials of JX-594/Pexa-Vec are ongoing. A phase III randomized study, PHOCUS, will compare JX-594 followed by sorafenib with sorafenib alone in patients with advanced HCC who have not received prior systemic therapy. The primary outcome measure is OS, and secondary outcome measures include TTP, PFS, ORR, and disease control rate. The study is expected to reach its primary completion in late 2017.

Abou-Alfa, lead investigator of the phase III trial, stated, "We are still desperately in need of additional treatment options for advanced liver cancer. Cancer immunotherapy holds much promise, and I'm greatly looking forward to having the opportunity to evaluate Pexa-Vec in patients with advanced liver cancer." &nbsp;

Overall, numerous therapies are in late-stage clinical development that show promise for patients with advanced HCC. Because most will present with advanced-stage disease at diagnosis, only liver resection and transplantation are considered curative. Thus, there is a critical need to improve the therapeutic landscape. The alternative first-line and second-line therapies described may provide hope for patients in the near future.

Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-1255.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.

Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34.

Villanueva A, Hernandez-Gea V, Llovet JM. Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat Rev Gastroenterol Hepatol. 2013;10(1):34-42.

El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015;33(15_suppl; abstr LBA101).

Mulcahy N. Add Liver Cancer to Nivolumab&rsquo;s List of Victims. Medscape Medical News; May 29, 2015.

ClinicalTrials.gov. A Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma. ClinicalTrials.gov Identifier: NCT02576509. https://clinicaltrials.gov/ct2/show/NCT02576509.

Okita K, Kumada H, Ikeda K, et al. Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Initial assessment of response rate. J Clin Oncol. 2012;30(4_suppl; abstr 320).

ClinicalTrials.gov. A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma. ClinicalTrials.gov Identifier: NCT01761266. https://clinicaltrials.gov/ct2/show/NCT01761266.

Lencioni R, Kudo M, Ye S-L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609-617.

Bruix J, Tak W-Y, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 1990. 2013;49(16):3412-3419.

ClinicalTrials.gov. Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma. ClinicalTrials.gov Identifier: NCT01774344. https://clinicaltrials.gov/ct2/show/NCT01774344.

Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma patients (pts): results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2012;30(4_suppl; abstr 261).

ClinicalTrials.gov. Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL). ClinicalTrials.gov Identifier: NCT01908426. https://clinicaltrials.gov/ct2/show/NCT01908426.

Exelixis. Exelixis Initiates Phase 3 Clinical Trial of Cabozantinib in Patients With Advanced Hepatocellular Carcinoma [press release]; September 10, 2013.

Rimassa L, Abbadessa G, Personeni N, et al. Tumor and plasma biomarker analysis from the randomized controlled phase II trial (RCT) of tivantinib in second-line hepatocellular carcinoma (HCC). J Clin Oncol. 2016;34(4_suppl; abstr 197).

ClinicalTrials.gov. Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy. ClinicalTrials.gov Identifier: NCT01755767. https://clinicaltrials.gov/ct2/show/NCT01755767.

Zhu AX, Park JO, Ryoo B-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870.

Zhu AX, Ryoo B-Y, Yen C-J, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated {alpha}-fetoprotein (AFP) from the randomized phase III REACH study. J Clin Oncol. 2015;33(3_suppl; abstr 232).

ClinicalTrials.gov. A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (REACH-2). ClinicalTrials.gov Identifier: NCT02435433. https://clinicaltrials.gov/ct2/show/NCT02435433.

Both in the United States and worldwide, the incidence of hepatocellular carcinoma (HCC) is on the rise, and, despite extensive research, sorafenib (Nexavar) remains the only FDA-approved systemic therapy available for advanced tumors.

Jennifer Gregg, PhD | Authors

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