Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

Abstract

Background: Phase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC.

Materials and methods: Patients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis.

Results: Of 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30-107 days), and median survival from first prescription was 3 months (IQR, 1-8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78-1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72-1.07]), but no reduction thereafter.

Conclusion: Survival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use-high drug-related symptom burden and high drug cost-must be considered in light of this minimal benefit.

Implications for practice: The findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

Keywords: Aged; Carcinoma, hepatocellular; Drug costs; Liver diseases; Liver neoplasms; Medicare; Sorafenib.

Figure 1.

Consolidated Standards of Reporting Trials diagram of cohort assembly. Abbreviations: HCC, hepatocellular carcinoma; HMO, health maintenance organization; ICD-O-3, International Classification of Diseases for Oncology, 3rd edition.

Figure 2.

Effectiveness of initial sorafenib compared with no treatment. (A): Kaplan-Meier survival estimates from 60-day landmark of propensity score-matched patients. (B): Risk ratio for mortality shown with 95% confidence intervals at 3, 6, and 12 months from the 60-day landmark.

Figure 3.

Effectiveness of sorafenib in clinically relevant subgroups. The risk ratios for mortality shown with 95% confidence intervals at 3 months from the 60-day landmark (the time of maximal sorafenib benefit) are shown for the strata of age, Charlson Comorbidity Index, number of liver comorbidities, receipt of prior AFP screening, and tumor extent in the propensity score-matched cohort. Abbreviation: AFP, α-fetoprotein.

Figure 4.

Clinical benefit, toxicity, NHB, and DAC of sorafenib using the American Society of Clinical Oncology Value Framework [24]. The data for each parameter are shown above the bar. Clinical outcomes are taken from the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial [5]. Drug costs are the average cost for Medicare part D plans in 2014. Abbreviations: DAC, drug acquisition cost; NHB, net health benefit.