Clinical Review

Evaluating Sorafenib in Veterans With Advanced Hepatocellular Carcinoma

Sorafenib remains a viable therapeutic option for patients with advanced hepatocellular  carcinoma but may present some risks for a veteran population.

Fed Pract. 2015 November;32(11):28-34

Author(s):

Daniel Luu, PharmD, MS

Kirby A. Lim, PharmD

Diep N. Seversen, PharmD

Wayman T. Lee

PDF Download

References

1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015.

2. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-1273.

3. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist. 2010;15(suppl 4):14-22.

4. Nexavar [package insert]. Emeryville, CA: Bayer HealthCare Pharmaceuticals, Inc; 2009.

5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. Version 2. 2015. National Comprehensive Cancer Network Website. http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed October 13, 2015.

6. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.

7. Carr BI, Carroll S, Muszbek N, Gondek K. Economic evaluation of sorafenib in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol. 2010;25(11):1739-1746.

8. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257.

9. U.S. Department of Veterans Affairs, Veterans Health Administration. National Viral Hepatitis Program. VHA Directive 1300.01. U.S. Department of Veterans Affairs Website. http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=1586. Updated February 22, 2013. Accessed October 13, 2015.

10. Patterson CJ. Best practices in specialty pharmacy management. J Manag Care Pharm. 2013;19(1):42-48.

11. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34.

12. Iavarone M, Cabibbo G, Piscaglia F, et al; SOFIA (SOraFenib Italian Assessment) study group. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology. 2011;54(6):2055-2063.

13. Di Fiore F, Rigal O, Ménager C, Michel P, Pfister C. Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib. Br J Cancer. 2011;105(12):1811-1813.

14. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022.

15. Blandford L, Dans PE, Ober JD, Wheelock C. Analyzing variations in medication compliance related to individual drug, drug class, and prescribing physician. J Managed Care Pharm. 1999;5(1):47-51.

16. Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology. 2010;51(4):1274-1283.

17. Bayer HealthCare. Sorafenib as Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma (STORM). ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT00692770. Updated May 28, 2015. Accessed October 21, 2015.

18. Academy of Managed Care Pharmacy. AMCP Guide to Pharmaceutical Payment Methods, 2009 Update (Version 2.0). J Manag Care Pharm. 2009;15(suppl 6-a):S3-S57.

19. Valgus JM, Faso A, Gregory KM, et al. Integration of a clinical pharmacist into the hematology-oncology clinics at an academic medical center. Am J Health Syst Pharm. 2011;68(7):613-619.

20. Tschida SJ, Aslam S, Lal LS, et al. Outcomes of a specialty pharmacy program for oral oncology medications. Am J Pharm Benefits. 2012;4(4):165-174.

In 2015, more than 35,660 new cases of liver cancer and 24,550 liver cancer-related deaths are expected to occur in the U.S. About 80% of these cases will consist of hepatocellular carcinoma, (HCC).¹ The incidence of HCC varies throughout the world: Incidence is as low as 5 in 100,000 individuals in North America and ranges up to > 20 in 100,000 individuals in sub-Saharan Africa and Eastern Asia.² Nearly half of all cases of HCC are associated with hepatitis B virus (HBV), and another 25% are associated with hepatitis C virus (HCV). Other risk factors for developing HCC include alcoholic liver disease, nonalcoholic steatohepatitis, flatoxin-contaminated food, diabetes, and obesity.³

Therapeutic options for advanced HCC are limited. The FDA approved sorafenib in 2008 for the treatment of unresectable HCC.⁴ According to the American Association for the Study of Liver Diseases (AASLD) and the Barcelona Clinic Liver Cancer (BCLC) staging system, patients with Stage C liver cancer may undergo a trial of sorafenib.⁴ National Comprehensive Cancer Network (NCCN) clinical guidelines for hepatobiliary cancers reserve sorafenib for patients with inoperable tumors, metastatic disease, or extensive liver tumor burden.⁵ Sorafenib is shown to inhibit multiple intracellular and cell surface kinases. Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis.⁴ In the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, median overall survival (OS) was 10.7 months in the sorafenib group and 7.9 months in the placebo group.⁶ The predicted survival rates at 1 year were 44% in the sorafenib group and 33% in the placebo group.⁶The economic impact of oral chemotherapy on health care cannot be discounted. At about $50,000 to $100,000 per quality-  adjusted life-year, the incremental cost-effectiveness ratio (ICER) of sorafenib over placebo was $62,473 per quality-adjusted life-year in 2007.⁷The purpose of this retrospective chart review was to evaluate sorafenib for efficacy and safety in a veteran population. Veterans have poorer health and more medical conditions compared with nonveterans.⁸ Furthermore, in the VHA, about 170,000 veterans have HCV.⁹ The rate of progression from HCV to HCC is about 3% to 5% annually. More than half of those diagnosed with HCC are late stage, and unfortunately, the 5-year OS rate for patients with liver cancer is 9% and 4% for those patients who are diagnosed at regional and distant stages of the disease.¹ As the practice of oncology grows, it is necessary for pharmacists to be involved in the selection of chemotherapeutic agents in order to provide optimal pharmaceutical care.¹⁰

Methods

A retrospective chart review was conducted to identify patients who were prescribed sorafenib from November 1, 2007, to September 30, 2011, at the VA Greater Los Angeles Healthcare System (VAGLAHS). Inclusion criteria included patients who had a diagnosis of advanced HCC, who were initiated and managed by a VAGLAHS provider and who were eligible for a 1-year safety evaluation period. The study was approved by the VAGLAHS institutional review board.

Baseline demographic, clinical, laboratory, and medication data were collected. Demographic, clinical, laboratory, and medication data were obtained from CPRS (Computerized Patient Record System) and VistA (Veterans Health Information Systems and Technology Architecture). Data were collected on secured servers and saved on encrypted files. The master list was destroyed once the records control schedule was finalized. No identifiers were collected on the data collection sheet.

Standard practice at VAGLAHS is to monitor European Cooperative Oncology Group Performance Status (ECOG-PS), Child-Pugh class, and alpha-fetoprotein (AFP) at initiation and every 3 months and to obtain laboratory data at initiation and every month before each medication refill. Patients were seen in the Oncology Clinic periodically at the provider’s discretion. The time of drug discontinuation and the reason for drug discontinuation were recorded. Time of death at any point was collected to measure OS.

It was determined that a total sample size of 42 patients would be insufficient to achieve 80% power to demonstrate any hypothesized effects. However, the Fisher exact test was used to calculate P values for simple comparison. Patient demographics and clinical characteristics were reported as total numbers and frequencies when applicable. Survival rate was measured from the time of sorafenib initiation to 1 year after therapy initiation. Overall survival was measured from the time of sorafenib initiation to time of death. Duration of therapy was measured from the time of sorafenib initiation to time of discontinuation, either by  provider or by patient.

Results

There were 83 patients who were prescribed sorafenib between November 1, 2007, and September 30, 2011. Of the 83 patients, 27 patients were ineligible for a 1-year follow-up period, 9 patients were diagnosed with non-HCC, 3 were initiated or managed by providers outside the institution, and 2 were not started on therapy. In all, 42 patients met inclusion criteria and had received at least 1 dose of sorafenib. The primary etiologies for HCC were history of alcohol abuse, HCV, and HBV. The primary risk factors were obesity, smoking, and diabetes. Many patients presented with multiple etiologies and risk factors. Ten patients (23.8%) had moderate-to-severe hepatic impairment (Child-Pugh class B or C). Baseline characteristics of these patients are listed in Table 1.