A STORM in a teacup?—the challenges of adjuvant therapy in hepatocellular carcinoma (HCC)

Transl Gastroenterol Hepatol 2016;1:2 tgh.amegroups. com Globally, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, with rising worldwide incidence (1). Surveillance programs for early detection of HCC in high-risk populations and improvement of therapeutic modalities have increased the likelihood of potentially curative treatments. Hepatic resection (HR) and radiofrequency ablation (RFA) result in 5-year survival rates of 40–70%. However, high tumor recurrence rates of 50% at 3 years and 70% at 5 years lead to sub-optimal curative outcomes (2). The prevention of recurrent HCC remains a significant challenge in this population and has led to interest in the development of adjuvant therapies. The oral multikinase inhibitor sorafenib is approved in patients with unresectable HCC based on two pivotal phase 3 randomized trials (3,4). Sorafenib acts on multiple targets such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, Raf, RET, and FLT3 (5) and has the dual antitumor effect of antiproliferation and antiangiogenesis. Since tumor recurrence is often predicated on the presence of vascular micro-invasion and micrometastases, these antitumor mechanisms provide rationale for the use of sorafenib as an adjuvant therapy. Bruix et al. recently reported on the results of the STORM study, which assesses the utility of sorafenib as an adjuvant therapy following HCC treatment (6). This multinational trial enrolled HCC patients who had undergone curative therapy with HR or RFA within 4 months and had no radiological evidence of residual tumor. Subjects were required to have baseline alpha-fetoprotein (AFP) level under 400 ng/mL, preserved performance status (Eastern Cooperative Oncology Group score of 0/hepatic synthetic function (Child Pugh score 5–7, Child-Pugh score 7 allowed only in the absence of ascites) and intermediate to high risk of recurrence [stratification based on pathological tumor characteristics (following HR) or imaging criteria (following RFA)]. The primary outcome measure was recurrence-free survival (RFS); secondary endpoints were time to recurrence and overall survival (OS). After a median follow up of 8.45 months (range, 2.9–29.8 months) there was no significant difference in RFS, time to recurrence or OS in the sorafenib treated group compared to placebo. How can we best explain the lack of benefit seen with sorafenib adjuvant therapy in this study? One possible explanation is the unexpectedly high rate of treatment discontinuation, and consequently fewer recurrence events than expected. The number of subjects discontinuing sorafenib (50% at 1 year) was higher than noted in other studies and may represent a lower threshold of tolerance for a drug considered to be an adjunctive rather than primary form of therapy, although the reported grade 3 or 4 toxicities were not too different compared to the toxicities observed in other studies. The statistical analysis was adjusted to reflect the fewer recurrence events reported as a result of higher than expected treatment discontinuation by reducing the power from 90% to 80%. Additionally, sorafenib dose reduction was required in 79% of subjects resulting in a mean daily dose of sorafenib (578 mg) much lower than the intended 800 mg dose. This dose reduction is in contrast to the SHARP study in which 76% of subjects received more than 80% of the planned dose. Interestingly, the median treatment duration in the sorafenib groups was shortest in the Americas. This is the region in which the majority of HCC was related Editorial