Starting at a low dose of sorafenib (Nexavar) and titrating up to the full dose of 800 mg, rather than starting the full dose, does not adversely affect outcomes, while improving tolerability and reducing costs in the treatment of patients with hepatocellular carcinoma (HCC). This was the conclusion from a review of 4900 veterans diagnosed with HCC who were prescribed sorafenib at Veterans Administration (VA) hospitals.
Patients starting sorafenib therapy at a dose of <800 mg daily had more prescription fills and longer exposure to therapy at a lower total cost, with no difference in the median overall survival (OS) compared with patients who initiated full-dose therapy with the drug, said David E. Kaplan, MD, MSc, FACP, Director of Hepatology, Philadelphia VA Medical Center, at the 2017 Gastrointestinal Cancers Symposium.
“We know that a large percentage of patients who start sorafenib don’t tolerate the full dose. Many providers, as a matter of course, started doing dose titration rather than starting at full dose,” said Dr Kaplan.
“The preponderance of dose escalation starts at a dose of 400 mg once daily, going up to 600 mg 2 weeks later, and then at week 4 going up to 800 mg if tolerated. Our data are supportive that this practice is not compromising outcomes,” he said.
Reduced Dosing Has a Lower Cost, Similar Survival
Dr Kaplan and his colleagues examined the records of 4900 patients who were prescribed sorafenib for HCC between 2007 and 2015. A total of 3094 patients started therapy with standard-dose sorafenib, and 1809 patients started with reduced-dose sorafenib; of the latter group, 43% of patients had dose uptitration and 57% did not.
“As time goes on, there’s a suggestion that more patients are being started on the reduced dose rather than the standard dose, when we look at these data nationally from 128 VA hospitals. Part of that is due to negative covariates, primarily liver disease severity,” Dr Kaplan said.
The patients who started with reduced-dose sorafenib received fewer total pills (median, 180 vs 276, respectively; P <.001), and the same 90-day median duration of therapy (P = .20) but at a lower total cost for sorafenib (median, $5636 vs $8661, respectively; P <.001) than those who started with standard-dose sorafenib.
The median OS was not significantly different between the standard-dose and reduced-dose groups (233 vs 200 days, respectively; P = .002). When comparing the patients in the reduced-dose group who had dose escalation (N = 722) with those who received standard-dose sorafenib, the OS was a median of 281 days and 233 days, respectively.
“On propensity matching that balances out the covariates, the adjusted hazard ratio for OS was 0.92, showing a trend toward a survival benefit to starting at the lower dose,” Dr Kaplan pointed out.
The patients in the reduced-dose group who had no dose escalation had significantly lower total costs but significantly worse OS than those who had dose escalation. Dr Kaplan explained that patients are selected for uptitration because they are tolerating the drug and are otherwise doing well; an improvement in OS is to be expected more in the group that starts with a reduced dose but has dose escalation than in patients who do not receive dose escalation.
Adverse events were significantly fewer (P = .001) in the reduced-dose group with dose escalation than in those without dose escalation, including considerably reduced fatigue (P = .012), progression of disease (P <.001), and functional decline (P = .02).
“There’s absolutely no impact on OS, so there’s no disadvantage to starting at a reduced dose and dose escalating for those who tolerate it. There ends up being a cost-savings, because a patient who started on a full dose and takes it for a week and can’t tolerate it, has 3 weeks of [drugs in] their pill bottle that is wasted expenditure,” Dr Kaplan concluded.