Clinical Review

Evaluating Sorafenib in Veterans With Advanced Hepatocellular Carcinoma

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

References

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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.

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Based on medication refill history and VA acquisition cost, the total prescription drug cost of treating 42 patients with sorafenib was $388,370.40. The total number of days survived for these patients was 16,607 days, which equates to $8,535.87 per year lived.

Safety

Of the 42 patients, 35 patients experienced ≥ 1 AE for a total of 122 AEs reported. The median number of AEs per patient was 2.5. The median time to the first AE was 21 days and ranged from 3 to 244 days. In the first 30 days of treatment, 23 patients (54.7%) reported 47 AEs (39.5%). In the first 90 days of treatment, 33 patients (78.6%) reported 88 AEs (73.9%). Common AEs in both instances were diarrhea, fatigue, erythematous plantar-palmar rash, and nausea (Table 3).

The predominant classes of AEs were GI (39.3%), dermatologic (18.9%), and neurologic (15.6%). Erythematous palmar-plantar rash, also known as hand-foot syndrome, has been noted as a potential dose-limiting sorafenib AE if the rash is recurrent or severe. One patient experienced recurrent grade-2 rashes, and sorafenib was immediately discontinued after an attempt to lower the dose. There were 8 patients who reported serious AEs, and 5 were hospitalized. One patient continued therapy despite GI hemorrhage. The other 4 patients discontinued therapy on hospitalization and were seen for intracranial hemorrhage, GI perforation, acute renal failure, and acute liver failure. In the first 3 cases, sorafenib could not be ruled out as the primary cause of death. None of these patients presented with comorbidities, such as hypertension, which predisposed them to AEs.

Overall, 38 patients ended therapy at the recommended regimen of 400 mg twice daily, and the average total daily dose was 619 mg, just below 80% of the recommended daily dose. Reasons for not achieving 400 mg twice daily included slow titration, AEs, and dose adjustments for compromised renal and hepatic function such as dialysis. Patients who had an ECOG-PS score of  0 or 1 or Child-Pugh class A reported ≥ 3 AEs, but when normalized to duration of treatment, no difference was observed. No correlations were found for average dose, creatinine clearance, aspartate aminotransferase, platelets, total bilirubin, or weight and number or frequency of AEs.

In regard to potential dose adjustments, the doses (400 mg twice daily, 600 mg daily [400 mg + 200 mg in 2 doses], 200 mg twice daily, and 200 mg daily) did not correlate well with AEs. Patients who had < 3 AEs presented with the breakdown 23%, 16%, 22%, and 38%, similar to patients who had ≥ 3 AEs—30%, 19%, 14%, and 37%. Likewise, patients who had a frequency of AEs lower than the median presented with the breakdown 22%, 22%, 15%, and 40% compared with patients who had more AEs than the median—37%, 9%, 23%, and 31%.

Discussion

Sorafenib is the only oral oncology medication approved by the FDA for treatment of unresectable HCC.³ Prior to sorafenib, the AASLD recommendation was supportive care for patients presenting with BCLC-Stage C liver cancer. However, guidelines changed when SHARP showed that sorafenib provided a survival benefit with a tolerable AE profile. The survival benefit of sorafenib has been replicated in a few large, multicenter trials. In Asia, Cheng and colleagues saw improved median OS of 6.5 months for sorafenib compared with 4.2 months with placebo, and in Italy, Iavarone and colleagues showed a median OS of 10.5 months without a placebo comparator.^11,12

In the veteran population for this study, the OS rate of 40.5% was similar to the rate reported in the SHARP study, although the patients’ median OS fell short of the time described in SHARP and other trials. The medical complexities involved in treating veterans may explain this difference. The veteran population is heterogeneous with diverse ethnic backgrounds, several comorbidities, and varying degrees of organ dysfunction. The authors compared survival rates of different subgroups to test the hypothesis that the probability of survival while on therapy should not depend on demographics or medical history. However, in this study, patients with minimal impact from HCC, such as mild hepatic  impairment and high-functional status, demonstrated higher survival rates at 1-year follow-up than did those without significant compromise.Although the high prevalence of HCV and alcohol abuse in the veteran population has resulted in a high incidence of hepatic dysfunction, this study suggests that these factors are independent of survival if liver function or integrity has not been compromised.⁹

Some researchers have hypothesized that clinical toxicities from tyrosine kinase inhibitors may correlate with survival.¹³ The authors noticed that the presentation of dermatologic AEs may reflect improved survival. In this study, patients who experienced ≥ 1 AE and ≥ 3 AEs had survival rates at the 1-year follow-up of 45.7% and 61.9%, respectively. Moreover, patients affected by AEs in the first 90 days of treatment had a survival rate at the 1-year follow-up of 42.4%.