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.
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.2
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.3Recent 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).4,5However, 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 ofJournal of Clinical Oncology.6
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%;P= 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;P= .11]) or OS (19.6 months BB vs 20.8 months LCB [HR, 1.11; 95% CI, 0.71-1.76;P=.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.7,8The 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.8
“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,” Brown and the other researchers concluded. “These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.”
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.9While 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 ofJournal of Clinical Oncology.10
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 (90Y), a high-energy beta-emitter with a limited tissue-penetration range (average, 2.5 mm) and short half-life (2.67 days).11
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.11
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.2,11
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.10
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;P=.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;P=.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;P=.042), as was the complete response rate (1.9% vs 6.0%;P=.020) and first progression only in the liver (77% vs 52.4%;P<.001). Grade 3 or above AEs were 73.4% and 85.4% in the control and SIRT treatment arms, respectively (P=.516).10
Co-principal researcher of the study, Peter Gibbs, MD, explained, “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."12
Professor van Hazel commented, “SIRFLOX gives us the data to validate the first-line use of…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 2017.10
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.13,14
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.15,16The 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, Valérie Vilgrain, MD, PhD, Paris Diderot University, France, stated, “SARAH is the largest randomized study ever to compare selective internal radiation therapyor any liver-directed therapy—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.”17SIR-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 ofJournal of Hepatocellular Carcinoma.18
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).13,18
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.19The researchers of the retrospective analysis concluded that “prospective, randomized controlled trials are warranted to evaluate the merit of our findings in patients with advanced HCC.”
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,” said Navesh K. Sharma, MD, University of Maryland Medical Center. He added that studies, such as SIRFLOX, have shown “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."