Hepatocellular carcinoma is the sixth most common cancer and the third leading cause of cancer-related death1. Unlike most solid cancers, future incidence and mortality rates for hepatocellular carcinoma were projected to largely increase in several regions around the world over the next 20 years2. TACE has been established by a meta-analysis of randomised controlled trials as the standard of care for nonsurgical patients presenting with asymptomatic, multinodular, noninvasive tumour isolated to the liver and preserved hepatic function3.
The ideal TACE scheme should allow maximum and sustained concentration of the chemotherapeutic drug within the tumour with minimal systemic exposure combined with calibrated tumour vessel obstruction. While conventional TACE with administration of an anticancer-in-oil emulsion followed by embolic agents has been the most popular technique, the introduction of embolic, drug-eluting beads has provided an attractive alternative to lipiodol-based regimens4. Experimental studies have shown that TACE with drug-eluting beads has a safe pharmacokinetic profile and results in effective tumour killing in animal models.
Early clinical experiences have confirmed that drug-eluting beads provide a combined ischaemic and cytotoxic effect locally with low systemic toxic exposure5. Recently, the clinical value of a TACE protocol performed by using the embolic microsphere DC Bead (from BTG/Biocompatibles) loaded with doxorubicin (DEBDOX; drug-eluting bead doxorubicin) has been shown by a randomised trial6. In the multicentre PRECISION V study including 201 European patients with HCC, use of DEBDOX resulted in a statistically significant reduction in liver toxicity and drug-related adverse events compared with conventional TACE with Lipiodol and doxorubicin6,7. Contrary to the observation in the conventional TACE arm, high-dose doxorubicin treatment could be applied according to the planned schedule in the whole DEBDOX group, resulting in consistently high rates of objective response and disease control in subgroup analyses6. As a result of these investigations, DEBDOX has been increasingly used as the first-line transcatheter treatment for hepatocellular carcinoma8,9. A recent publication has reported an impressive median survival of 48 months in a cohort of 104 hepatocellular carcinoma patients treated with DEBDOX10. Despite the continuous progress in techniques and protocols11. TACE has inherent limitations12. TACE exerts therapeutic effects only in the treated territory; thus, other areas of tumours—undetected at the time of the procedure—may progress, or new tumours may develop. Moreover, by interrupting blood flow to the tumour, TACE induces necrosis at the tumour site, but may create conditions that permit or encourage angiogenesis. Surrogate markers of tissue hypoxia that increase after TACE include hypoxia-inducible factor 1 alpha and both plasma and hepatic vascular endothelial growth factor (VEGF)12.
Hypoxia can lead to neoangiogenesis, suggesting that inhibition of angiogenesis may be synergistic with TACE in patients with hepatocellular carcinoma12. Treatment with an anti-angiogenic agent might curtail the post-TACE rise in VEGF-mediated signalling and prevent or delay tumour progression. In addition, systemically active anti-angiogenic agents may target tumour foci distant from the site of TACE.
DEBDOX and sorafenib together represent a potentially powerful therapeutic approach, based on mechanisms that are theoretically synergistic. DEBDOX has been shown to be safe and effective, with significantly reduced systemic drug exposure compared to conventional TACE regimens. Sorafenib has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma, with activity on both tumour cells and endothelial cells. In a prospective, single-centre phase II study conducted at the Johns Hopkins University School of Medicine, safety and response of a combined protocol involving sorafenib 400mg twice per day and DEBDOX were assessed in 35 patients13. Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% vs .grade 3 to 4, 17%), and preliminary efficacy data were promising.
The phase 2 randomised, double-blind, placebo-controlled SPACE study (Sorafenib or placebo in combination with TACE with DEBDOX for intermediate-stage hepatocellular carcinoma) is the first global trial ever on the use of TACE in the treatment of hepatocellular carcinoma14. The objective of the study was to evaluate the efficacy and safety of sorafenib in combination with DEBDOX in patients with intermediate-stage hepatocellular carcinoma. The study was conducted at 85 sites across Europe, North America, and the Asia-Pacific region. Patients were eligible if they had asymptomatic, unresectable, multinodular tumours without vascular invasion or extrahepatic spread; Child-Pugh A liver functional status; and Eastern Cooperative Oncology Group (ECOG) performance status 014.
Patients were randomised to receive sorafenib 400mg bid or matching placebo continuously (one cycle = four weeks) until progression. All patients received DEBDOX (150mg doxorubicin) 3–7 days after first dose of study drug, and then on day 1 (± 4 days) of cycles 3, 7, and 13, and every six cycles thereafter. Patients allowed optional DEBDOX sessions between cycles 7 and 13 and cycles 13 and 19, if deemed necessary by the investigator. The primary endpoint was time to radiologic progression (TTP) by independent review (predefined alpha = 0.15). Secondary endpoints were overall survival (OS), time to vascular invasion or extrahepatic spread, time to untreatable progression (TTUP), and safety14.
Of 452 patients screened, 307 were randomised to sorafenib (n=154) or placebo (n=153). The hazard ratio (HR) for TTP was 0.797 (95% CI, 0.588, 1.080; p=0.072). Median TTP (50th percentile) was 169 days/166 days in the sorafenib and placebo groups, respectively; TTP at the 25th and 75th percentiles (preplanned) was 112 days/88 days and 285 days/224 days in the sorafenib and placebo groups, respectively. There were no unexpected safety findings. Median treatment duration in the sorafenib and placebo groups was 4.8 and 6.3 months, respectively, and median daily dose of study drug was 566mg and 791mg, respectively14. Table 1 shows a summary of the efficacy data.
The SPACE study met its primary endpoint of improving TTP when sorafenib was added to a regimen of TACE with DEBDOX, compared with TACE with DEBDOX alone.
The combination was well tolerated and no new safety findings that would preclude use of the combination were observed. Nevertheless, the encouraging efficacy signal requires confirmation with data from ongoing phase 3 trials. In fact, several questions remain as we attempt to improve treatment outcome in hepatocellular carcinoma patients.
The pathophysiologic complexity of hepatocellular carcinoma, balanced with a goal of providing effective tumour therapy with preservation of organ function, makes optimal treatment choice a clinical challenge. An understanding of exactly which features of hepatocellular carcinoma and patient health may predict the clinical outcome of combination regimens is essential for prescribing individualised, evidence-based therapeutic strategies.
In summary, because of the efficacy and safety of DEBDOX in the treatment of hepatocellular carcinoma, there is great interest in its potential use in combination with systemically-active drugs with antiangiogenic properties. A growing body of clinical evidence suggests that the combination of DEBDOX and sorafenib may be safe and effective, supporting the further clinical investigation of this emerging combination regimen.
Riccardo Lencioni is director, Diagnostic Imaging and Intervention, Pisa University School of Medicine, Pisa, Italy.
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