Therapy of hepatocellular carcinoma in cirrhotic patients is
challenging. Liver dysfunction, portal hypertension, third spacing,
thrombocytopenia, and neutropenia limit the choice of
chemotherapeutic agents. However, the abundant vascularity of
hepatocellular carcinoma presents an attractive target for
antiangiogenic therapy, potentially tolerable even in cirrhotics.
Thalidomide (Thalomid), a sedative with putative antiangiogenic
properties, was tested in a phase II trial in hepatocellular
carcinoma patients using 400 mg at bedtime daily for the first week,
and escalating to 1,000 mg by the fifth week. One-third of the dose
was given in the afternoon and two-thirds at bedtime. The trial was
prompted by the observation of a radiologic partial response and a
decrease in alpha-fetoprotein from 109,000 to 99 ng/mL in a patient
who failed all prior therapies but responded to thalidomide.
Twenty-seven patients were accrued between March 18, 1999, and
October 14, 1999, and 10 more are anticipated. The pretreatment
median platelet count was 122.5 ´ 109/L
(range: 43390 ´ 109/L),
and the median alpha-fetoprotein level was 1,435.2 ng/mL. Twenty-one
patients. were evaluable for response; four were too early and two
were not restaged following treatment. One partial response and one
minor response were observed, and 10 patients had stable disease for
at least 2 months. Responses were associated with a slight decrease
in serum alpha-fetoprotein ( £ 25%).
Toxicities included somnolence in all patients, with grade 3/4 (³
3 hours of sleep during the normal waking hours) in nine patients
(35%) and grade 2 in 30%.
Grade 3/4 skin reactions were observed in 20%, and an exfoliative
dermatitis prompted treatment discontinuation in one responding
patient. Thus, thalidomide may be administered to patients with
significant liver cirrhosis even if they are not candidates for other therapies.
CONCLUSION: With a 5% partial response, 5% minor response, and
48% stable disease rate, it would seem that thalidomide may offer
hepatocellular carcinoma patients disease stabilization, but not
significant antitumor activity. However, thalidomide should be
considered for combination with other agents that could be safely
administered to patients with severe cirrhosis, such as capecitabine