There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation.
Methods
We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770.
Findings
We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6–35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1–38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9–19·5) in the sorafenib group and 8·4 months (2·9–19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780–1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group.
Interpretation
Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.
Funding
Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals.
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally, and the global incidence is rising, with roughly 700 000 cases diagnosed worldwide in 2012 alone.1, 2 HCC usually occurs in the setting of liver cirrhosis, because of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, alcohol consumption, non-alcoholic steatohepatitis, or diabetes.3, 4, 5
In carefully selected patients diagnosed at an early disease stage, surgical resection, liver transplantation, and local ablation are potentially curative and are associated with 5-year survival rates of 60–80% (resection) and 40–70% (ablation).3, 4, 6 However, tumour recurrence is common and jeopardises overall survival in these patients. Surgical resection and ablation are associated with tumour recurrence rates of 50% at 3 years and 70% at 5 years.3, 4, 6, 7, 8, 9 Thus, the long-term prognosis after resection or ablation remains unsatisfactory, and prevention of recurrence via adjuvant treatments is an important unmet medical need in patients with HCC.
Adjuvant therapy in HCC represents a considerable challenge, in particular because of the underlying liver disease present in almost all patients. Currently, there is no standard of care for adjuvant therapy because no treatment has a proven benefit in randomised studies in patients with HCC after potentially curative treatment.3, 4, 10, 11, 12, 13 Although interferon is the most widely studied treatment in this setting, evidence is conflicting based on studies with small sample sizes, heterogeneous patient populations, and differing types and length of treatment.13 Studies of other potential adjuvant treatment options, such as vitamin K2, retinoids, and systemic chemotherapy, have also been inconclusive in terms of efficacy and safety,7, 13, 14, 15 and a phase 3 trial (NCT00568308) of the heparanase inhibitor PI-88, which showed promise in phase 2,16 was terminated.17
Research in context
Evidence before this study
We searched PubMed using combinations of the search terms ”hepatocellular carcinoma”, ”HCC”, “systemic”, ”adjuvant”, and”sorafenib”, with no time restriction. We also assessed major clinical practice guidelines for hepatocellular carcinoma (HCC) and associated references. Sorafenib is the established standard of care in patients with advanced HCC and the only systemic agent approved for HCC. To the best of our knowledge, before this study, no study of sorafenib in the adjuvant setting after resection or ablation had been done. However, more recently, two studies of sorafenib as an adjuvant therapy for HCC were published. One, a pilot study of 31 patients, reported a significantly longer time to recurrence in the sorafenib group, whereas the other, a retrospective study of 78 patients, noted that sorafenib prolonged overall survival, but not recurrence-free survival.
Added value of this study
Herein, we report the first, large-scale, randomised controlled trial assessing sorafenib as an adjuvant therapy for patients with HCC after resection or ablation.
Implications of all the available evidence
Although sorafenib has shown to be effective in the advanced setting, our findings, in combination with the additional evidence available, suggest that the drug is not an effective intervention in the adjuvant setting for HCC after resection or ablation.
The oral multikinase inhibitor sorafenib is approved in patients with unresectable HCC based on two phase 3 randomised trials,18, 19 and is the recommended treatment in patients with advanced HCC.3, 4, 10, 11, 12
Tumour recurrence can be caused by unrecognised microscopic metastases, or de-novo development of primary tumours because of the underlying liver disease.6, 20 Thus, based on the mechanism of action of sorafenib (namely, inhibition of tumour cell proliferation and angiogenesis21), in addition to its proven efficacy in advanced HCC, there is rationale for the study of sorafenib as an adjuvant therapy in HCC. The STORM trial was thus designed to assess the efficacy and safety of sorafenib versus placebo as an adjuvant therapy in patients with HCC with a complete radiological response after curative treatment by surgical resection (R0 on pathological report) or local ablation (complete response by imaging techniques).
Section snippets
Study design and participants
The STORM trial was a randomised, double-blind, placebo-controlled, phase 3 study undertaken throughout the Americas, Asia-Pacific, and Europe across 202 sites (hospitals and research centres) in 28 countries (appendix). Site distribution was as follows: Argentina (three centres), Australia (five centres), Austria (three centres), Belgium (four centres), Brazil (five centres), Bulgaria (two centres), Canada (five centres), Chile (two centres), China (27 centres), France (14 centres), Germany
Results
We recruited patients between Aug 15, 2008, and Nov 17, 2010. Of 1602 patients screened, 1114 met eligibility criteria and were randomly assigned: 556 to the sorafenib group and 558 to the placebo group (figure 1). 553 patients in the sorafenib group and 554 in the placebo group received treatment as initially assigned. Six patients assigned to placebo received one or more dose of sorafenib, and hence the safety analysis population consisted of 559 patients in the sorafenib group and 548 in the
Discussion
In this phase 3 randomised study of sorafenib as adjuvant therapy for early HCC after image-proven, successful surgical resection or local ablation, the primary objective of a significant improvement in RFS with sorafenib was not met. Similarly, we noted no significant treatment effect on the secondary endpoints of time to recurrence and overall survival.
Adjuvant therapy in HCC represents an area of high unmet medical need, and, up to now, attempts to address this need have proved largely
2024, Clinics and Research in Hepatology and Gastroenterology
The optimal management of unresectable hepatocellular carcinoma (uHCC) remains an unresolved challenge. There is ongoing debate regarding the efficacy and safety of drug-eluting bead TACE (DEB-TACE) with tyrosine kinase inhibitors (TKIs).
We searched PubMed, Embase, Web of Science and the Cochrane Library for eligible studies. The main endpoints under investigation were survival outcomes, including overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Secondary outcomes encompassed tumor response rates and adverse events (AEs). Two researchers conducted the data extraction independently and assessed the quality of the studies. After pooling and analyzing the data, we assessed the heterogeneity and performed both subgroup analysis and sensitivity analysis. Additionally, we evaluated the potential for publication bias.
Eight studies with 1513 patients were finally retrieved. Compared to monotherapy, although bigeminal therapy exhibited improved survival benefits (OS: HR: 0.56, 95 % CI 0.41–0.76, p < 0.001; TTP: HR: 0.72, 95 % CI 0.59–0.87, p = 0.001) and tumor response (ORR: RR: 1.59; 95 % CI 1.19–2.13, p = 0.002; DCR: RR: 1.14; 95 % CI 1.03–1.26, p = 0.010), the reliability of results was affected by significant heterogeneity. In the subgroup analysis, compared to DEB-TACE alone, the bigeminal therapy failed to show any statistical differences. Compared to TKIs, it demonstrated significant advantages in both survival (OS: HR: 0.49, 95 % CI 0.40–0.61, p < 0.001; TTP: HR: 0.60, 95 % CI 0.48–0.75, p < 0.001) and tumor response (ORR: RR: 2.40, 95 % CI 1.86–3.09, p < 0.001; DCR: RR: 1.36, 95 % CI 1.20–1.54, p < 0.001) while low heterogeneity was observed. Concerning safety, DEB-TACE provides no more severe AEs while TKIs-related AEs require close monitoring.
Our findings suggest that DEB-TACE combined with TKIs may be a safe and effective treatment for uHCC, which is more suitable for patients in the advanced stage.
Liver cancer, the sixth most common cancer globally and the second-leading cause of cancer-related deaths, presents a critical public health threat. Diagnosis often occurs in advanced stages of the disease, aligning incidence with fatality rates. Given that established treatments, such as stereotactic body radiation therapy and transarterial radioembolization, face accessibility and affordability challenges, the emerging focus on cancer cell metabolism, particularly arginine (Arg) depletion, offers a promising research avenue. Arg-depleting enzymes show efficacy against Arg-auxotrophic cancers, including hepatocellular carcinoma (HCC). Thus, in this review, we explore the limitations of current therapies and highlight the potential of Arg depletion, emphasizing various Arg-hydrolyzing enzymes in clinical development.
Despite being the first positive phase 3 trial in the adjuvant setting for early-stage hepatocellular carcinoma, the IMbrave050 study raises a number of questions regarding patient selection, endpoint robustness, and the balance between efficacy and acceptable toxicity.1
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumour burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of patient management. Randomised-controlled trials represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow for unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies can detect rare adverse events or monitor the occurrence of long-term adverse events. How best to harness real world data, which refers to data generated from the routine care of patients, and real-world ‘evidence’, which is the evidence generated from real-world data, represents an open challenge. In this review article, we aim to provide an overview of the benefits and limitations of different study designs, particularly focusing on randomised-controlled trials and observational studies, to address important and not fully resolved questions in HCC research.
