Clinical Review

Evaluating Sorafenib in Veterans With Advanced Hepatocellular Carcinoma

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

References

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Caution is advised when drawing conclusions from the number of AEs or when they appear, because this may falsely favor correlation. Patients who survive longer have additional time to report an AE. Therefore, the authors also looked at the ratio of AEs over time per patient to consider the number of AEs per duration of treatment and saw that there was little difference in survival rate in this regard. When considering patients affected by AEs only in the first 30 days of treatment, the survival rate at the 1-year follow-up fell to 30.2%.

A more likely factor for the survival of the 17 patients who were alive at the 1-year follow-up was their overall health relative to the rest of the study group. Overall health may indicate survival independent of sorafenib. The group of 17 who survived at the 1-year follow-up reflected a population that was different from the rest of the study population. The subset was generally healthier with better ECOG-PS scores and Child-Pugh classes, was not followed by Palliative Care Services, and had a mean AFP level under the threshold for diagnosis of HCC in patients who present with hepatic lesions and elevated AFP.¹⁴ This subset’s MPR, a surrogate marker for adherence, was less than the accepted threshold in clinical practice for oral medications.¹⁵Evaluating the patient’s dose regimen was expected to reveal a relationship between dosing and clinical outcomes, such as low survival rates with low doses or more AEs with high doses. However, the authors were not able to establish this link. In fact, the median time to discontinuation of 3.⁴ months for the study group, or duration of treatment, was much shorter than the median OS of 5.9 months.

These findings were consistent with Cabibbo and colleagues, who conducted a meta-analysis of survival rates for untreated patients and found that impaired performance status and Child-Pugh class B or C were independently associated with shorter survival.¹⁶ The SHARP study and Cheng and colleagues also attempted to exclude patients who were not Child-Pugh class A in their studies, which suggests a negligible correlation between sorafenib and survival time and a close relationship between baseline clinical status and survival.

The authors determined that prior treatment, including locoregional therapy, was not a factor in predicting survival. This observation is confirmed by the results of a phase 3 study that looked at sorafenib as adjuvant treatment for patients who had no detectable disease after surgical resection or local ablation.¹⁷ The trial did not meet its primary endpoint of improved recurrence-free survival. However, the authors observed in this study that 4 patients who underwent resection of the liver before sorafenib had a mean OS of 2.9 years. One patient, who was alive at the time of the study conclusion, received only  22 days of sorafenib treatment and survived for 4.9 years after sorafenib discontinuation. Patients who received concurrent or postsorafenib treatment had higher survival rates.

The cost of treatment in this study was found to be $8,535.87 per year lived. Although formal quality of life assessments were not captured, medication was discontinued at the first sign of disease progression or AE as determined by the provider or patient. When the cost of treatment was adjusted to account for median OS time and VA drug acquisition costs, estimated at average wholesale price minus 40%, the cost of treatment was within the threshold of $50,000-$100,000 per quality-adjusted life-year.^7,18Of the 42 patients in this study, 28.6% discontinued therapy due to AEs, compared with 32% observed in the SHARP study. Common GI, dermatologic, and CNS AEs were comparable between the 2 studies. Serious AEs included intracranial hemorrhage, GI hemorrhage, GI perforation, acute liver failure, and acute renal failure; 3 of these events led to death. About 12% of patients experienced bleeding, regardless of severity, compared with the 18% seen in SHARP, despite no prior history of hemorrhage or GI perforation.⁵ The authors did not find any clinical factors at baseline that predisposed patients to AEs. It was also difficult to distinguish between drug-related AEs and general disease progression.

Although the authors did not find a relationship between dose or dose adjustments and the number or frequency of AEs, there were serious adverse outcomes in this study that were also rare complications observed in SHARP. The decision to start sorafenib should not be taken lightly.

Limitations

This retrospective review had several limitations. In SHARP and other large, multicenter trials, patients were continued on therapy until they experienced both symptomatic and radiographic progression. In this study, patients were discontinued at the first sign of progression, either symptomatic or radiographic or both. Had all patients remained on therapy until symptomatic and radiographic signs of progression were observed, there could have been a better correlation between duration of treatment and OS, symptomatic progression, or radiographic progression. The authors acknowledge, however, that there is diminishing benefit of administering chemotherapy when there are known and potentially serious AEs.