Safety of Sorafenib Therapy in Elderly Adults with Advanced Hepatocellular Carcinoma

To the Editor: The incidence of hepatocellular carcinoma (HCC) is increasing worldwide and even more significantly with advancing age, reaching a peak at approximately age 75. Therefore, the proportion of elderly adults with HCC is expected to rise steadily in the coming years. Sorafenib represents the standard of care for individuals with advanced HCC, but data on the safety of this drug in elderly adults is lacking in the literature. Because a cancer treatment in older adults should be evaluated first in terms of tolerability and quality of life and only secondarily in terms of efficacy, it was decided to assess the safety of sorafenib-based therapy in elderly adults with advanced HCC. Therefore, a consecutive cohort of 51 individuals with advanced HCC aged 70 to 83, Child-Pugh A or B, and Eastern Cooperative Oncology Group performance status 0 to 2 who were not suitable candidates for or had progressed after locoregional therapies were retrospectively analyzed. Treatment with single-agent sorafenib at a standard dose of 400 mg was administered twice daily orally after informed consent was obtained. Therapy was continued until disease progression or unacceptable toxicity. Effect of treatment on quality of life and self-sufficiency were evaluated according to the instrumental activity of daily living (IADL) scale at baseline and every clinic visit. Adverse events were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Because the study population was composed of elderly individuals, comorbidities were frequent, with cardiovascular diseases being the most common (72.6%), with hypertension the most represented. The median duration of sorafenib treatment was 217.5 days (~7 months; range 1–48 months). Nonhematological toxicity was reported in all participants, mostly during the first month and of Grade 1 or 2 according to NCI CTCAE version 3.0 grading scale. The most common were hypertransaminasemia (74.5%), fatigue (64.7%), hand–foot syndrome (49.0%), hyperbilirubinemia (49.0%), diarrhea (47.1%), abdominal pain (41.2%), anorexia (29.4%), high blood pressure (11.7%), and nausea (9.8%). The most frequent Grade 3 adverse reactions were fatigue (15.7%), hand–foot syndrome (15.7%), abdominal pain (11.7%), and hyperbilirubinemia (11.7%). Of the six individuals with high blood pressure, who were receiving proper antihypertensive treatment before starting sorafenib, only one interrupted sorafenib therapy because of progressive disease and hypertensive crises; the antihypertensive therapy was modified according to the increases in blood pressure during sorafenib treatment in the remaining five. Hematological toxicity, commonly of Grade 1, was observed as thrombocytopenia in 60.7% of cases, of which 11.7% were Grade 3. No Grade 4 was reported (Table 1). Dose reduction (from 800 to 400 mg/d) due to toxicity was required in 28 individuals (54.9%), mainly because of thrombocytopenia (15.7%). Twenty-four individuals (47.1%) interrupted treatment, mostly because of fatigue (13.7%), thrombocytopenia (11.7%), and diarrhea (11.7%). Data obtained in other studies of sorafenib in elderly adults with cancer confirm these data. As reported in studies of older adults with renal cell carcinoma, those adverse events could be attributable to greater sensitivity of elderly adults than of younger individuals to the drug, although lower efficacy was not described in older adults. In the current study, the disease control rate, which was higher in the first 12 weeks than during the rest of the follow-up, was 45.1%, and partial response was achieved in five individuals over the first 12 weeks and in one individual over the first 24 weeks; furthermore, over the first 48 weeks, partial response was seen in one individual and complete response was obtained and maintained in two individuals for 5 and 4 years, respectively. Finally, stable disease was achieved during treatment in most individuals, as frequently reported in the literature. All participants showed good self-sufficiency (IADL score >5 in 68.6%, median at baseline 5.8 1.7). During treatment, IADL score decreased in 13 patients (25.5%). Mean IADL score was 5.5 2.2 at Day 30, 5.8 2.0 at Day 60, 5.9 1.8 at Day 90, 6.1 1.4 at day 120, and 6.1 1.3 at Day 150, indicating that the observed toxicity only modestly affected the quality of life and selfsufficiency of most participants.