More Than Okay to Reduce Sorafenib Dose for Liver Cancer

Nick Mulcahy

September 15, 2017

In the treatment of hepatocellular carcinoma (HCC), it's "safe and reasonable" to start sorafenib (Nexavar, Bayer) at reduced dosages, conclude authors of a new retrospective analysis of nearly 5000 patients.

Reduced dosing was not associated with inferior overall survival compared with standard dosing, report the study authors, led by Kim Reiss Binder, MD, a medical oncologist at the University of Pennsylvania in Philadelphia.

Notably, the less intense dosing also had some benefits — a reduced pill burden and about $3000 in reduced costs, as well as a trend toward decreased discontinuation of sorafenib due to adverse events.

"It's important to remember that the reduced dose patients will ramp up as they show they can handle it," said Dr Reiss Binder in a press statement.

Patients' ability to handle sorafenib, which is the only approved first-line therapy for HCC, is a challenge because of toxicity. Previous research has shown about one third of patients permanently discontinue the drug (Int J Clin Pract. 2014;68:609-617). The standard dose is 400 mg twice daily.

The study's good news about overall survival is highly relevant as clinicians are increasingly starting patients at a lower initial dose. The authors report that full-dose initial prescriptions accounted for 78% of all new sorafenib prescriptions in 2007 but decreased to 51% in 2014.

The new study was published online September 5 in the Journal of Clinical Oncology.

"This paper confirms what we have experienced," said Sunyoung Lee, MD, PhD, a medical oncologist at the Roswell Park Cancer Institute in Buffalo, New York, who was not involved with the study.

At Roswell Park, "we go with an initially reduced dose only when a patient has a medical reason," he also said.

Dr Lee explained that many patients with HCC have abnormal liver function or kidney function and need to have the starting dose adjusted downward. For example, if bilirubin is greater than 1.5 to less than or equal to 3 times the upper limit of normal, the starting dose of sorafenib is 200 mg by mouth twice a day. 

However, Dr Lee also said that the clinical effect of lower doses is not similar to that of higher doses. Instead, he offered an example of what is happening here. Patients who do not have normal liver or kidney function will receive a decreased dose. But sorafenib is not well metabolized by such patients, so the drug remains in the body at higher concentrations than in patients without these comorbidities — and the reduced-dose patients may receive therapeutic benefit in a way that is similar to that seen in the standard-dose patients, who metabolize the drug more quickly.

Dr Reiss Binder said that other studies have suggested that it was safe to start with a reduced dose of sorafenib, but their sample sizes were small.

Therefore, the current investigators extracted data on patients with HCC treated with sorafenib between 2006 and 2015 at 128 Veterans Affairs hospitals. They ultimately identified 3094 patients classified as receiving the standard starting dose (800 mg/day) and 1809 classified as receiving the reduced starting dose (<800 mg/day).

Predictably, the reduced-dose patients were sicker at baseline. They more commonly had Barcelona Chronic Liver Cancer D stage (P < .001), higher Model for End-Stage Liver Disease Sodium scores (P < .001), higher electronic Child-Turcotte-Pugh scores (P < .001), higher cirrhosis comorbidity index scores (P = .01), more frequent active alcohol abuse (P = .003), increased severity of ascites (P < .001), and more frequent hepatic encephalopathy (P < .001). Additionally, there was a trend toward an older age (P = .07) and poorer Eastern Cooperative Oncology Group performance status (P = .07) in these patients.

Consequently, patients who started sorafenib on a reduced dose had lower overall survival (median, 200 days vs 233 days; hazard ratio [HR], 1.10).

But after the investigators adjusted for potential confounders and performed propensity score matching, there was no significant overall survival difference (adjusted HR, 0.92), falling well within the prespecified noninferiority boundary.

The reduced-dose patients were prescribed fewer pills (median, 180) than standard-dose patients (median, 276; P < .001). Thus, total pill-related costs were also significantly lower for reduced-dose patients (median, $5636) than for standard-dose patients (median, $8661; P < .001).

After matching, there was a trend toward fewer patients discontinuing sorafenib because of any adverse event among reduced-dose patients (19.6%) compared with standard-dose patients (22.4%; P = .056).

Furthermore, the reduced-dose patients were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% vs 10.8%; P = .047).

The new study also revealed that, in comparing the two dosage groups over time, there was a convergence of the average dosages.

The average sorafenib starting dosage for the reduced-dose patients was 367 mg/day. By the end of the first month, the average sorafenib dosage was 791 ± 62 mg/day for the standard group and 412 ± 152 mg/day for the reduced group (P < .001).

However, at 6 months, average dosages moved down in one group and up in the other: 678 ± 200 mg/day for standard-dose patients and 573 ± 227 mg/day for reduced-dose patients (P < .001).

This study was supported by research funds from Bayer Healthcare Pharmaceuticals and the Veterans Affairs HIV, Hepatitis, and Related Conditions Programs in the Office of Specialty Care Services. Multiple study authors have financial ties to Bayer.

J Clin Oncol. Published online September 5, 2017. Abstract

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