Kim Reiss, MD
Results from a retrospective, multi-institutional study showed that lowering the dose of sorafenib (Nexavar) for patients with hepatocellular carcinoma (HCC) reduced pill burden and treatment costs, while showing a trend toward improved treatment completion.
Investigators evaluated 4903 patients with HCC treated with sorafenib at 128 Veterans Health Administration hospitals from January 2006 to April 2015. Patients were assigned to a standard starting dose of 800 mg daily (n = 3094) or a reduced dose of <800 mg of daily sorafenib (n = 1809).
After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HR) were calculated using Cox regression and tested against a noninferiority margin of HR equal to 1.1. Investigators performed a matched multivariate logistic regression to adjust for potential confounders.
The primary endpoint was overall survival (OS).
Patients in the reduced-dose group had more Barcelona Clinic Liver Cancer (BCLC) stage D (P
<.001), higher Model for End-Stage Liver Disease Sodium scores (P
<.001), higher Child-Turcotte-Pugh (CTP) scores (P
<.001), and higher Cirrhosis Comorbidity Index scores (P
= .01). Furthermore, these patients tended to be older and have poorer ECOG performance status. As expected, those patients had lower OS, at 200 days versus 233 days (HR, 1.10).
However, after propensity score-matching and adjusting for potential confounders, the difference in OS was no longer significant (HR, 0.92; 95% CI, 0.83-1.01). Investigators said the difference was well within the noninferiority margin (P
“Ultimately, we did not find evidence that starting patients with HCC on a [reduced starting dose of sorafenib] led to a significant difference in OS, and the 95% CI included an HR of 1.0 across all examined subgroups,” first author Kim A. Reiss, MD, Perelman Center for Advanced Medicine, and co-investigators wrote. “Our data suggest that the initiation of sorafenib at a reduced dosage may be a safe and reasonable strategy for some patients with HCC.”
The median patient age was 62 years, and the cohort was overwhelmingly male (98.9%) and white (61.2%). The majority of patients (58%) had CTP class A disease, 37% had class B, and 4% had class C. Six in 10 patients had been diagnosed with either active hepatitis B or C, 43% had BCLC stage A or B HCC, 46% had BCLC stage C, and 8% had BCLC stage D.
Among standard-dose patients, 68 (2.2%) required dosage reduction within the first month, and 360 (11.6%) within the first 2 months. In contrast, 211 patients (11.7%) in the reduced-dose group needed escalation within the first month, and 539 (29.8%) within the first 2 months. After 2 months, 31.7% of reduced-dose and 33.7% of standard-dose patients had stopped sorafenib for any reason.
Reduce-dose and standard-dose patients had similar rates of discontinuation due to an adverse event (AE; 20% v 21%; P
= .18), and were equally likely to remain on treatment until disease progression (27% v 28%; P
= .26). Gastrointestinal toxicity was the most common reason for treatment discontinuation (456 patients), followed by fatigue (265 patients) and hand-foot skin reaction (205 patients). Patients in the reduced-dose group were significantly less likely to discontinue sorafenib for a hand-foot skin reaction (5% vs 3%; P
= .05), and less likely to discontinue because of gastrointestinal AEs (8.7% vs 10.8%; P
Patients in both groups received a median of 90 days of sorafenib treatment (P
<.20). However, because reduced-dose patients received less sorafenib per day, they were prescribed far fewer pills (180 vs 276; P
<.001). As a result, total pill-related costs were also significantly lower for reduced-dose patients ($5636 vs 8661; P
“After propensity score matching, [reduced-dose sorafenib] patients were less likely to discontinue sorafenib because of gastrointestinal toxicity, and there were trends toward a decreased risk of discontinuing the drug for any AE,” wrote Reiss et al. [Reduced-dose sorafenib] patients experienced decreased treatment cost and a trend toward a decreased incidence of discontinuing sorafenib because of AEs.”
Reiss KA, Yu S, Mamtani R, et al. Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multi-institutional study. J Clin Oncol. 2017;35(31):3575-3581. doi: 10.1200/JCO.2017.73.8245.