A Phase II Study of Tegafur/Uracil(UFUR) Plus Thalidomide for the Treatment of Advanced or Metastatic Hepatocellular Carcinoma (HCC)
Thalidomide, a glutamic acid derivative first developed in 1950s, was marketed as a
sedative, tranquilizer, and antiemetic for morning sickness. It was withdrawn from the
European and Canadian markets in early 1960s because of its teratogenic effects. In recent
years, thalidomide is emerging as a novel treatment for cancer because of its
anti-angiogenic properties. The clinical efficacy has been demonstrated in various types of
human cancers, including HCC.
Tegafur and uracil is a composite drug, which has been marketed as UFT® in Japan and
marketed as UFUR® in Taiwan. Tegafur, a prodrug of 5-FU, is easily absorbed though the
gastrointestinal tract slowly metabolized to 5-FU mainly in liver. Uracil is an inhibitor of
dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU degradation.
Therefore, tegafur/uracil is expected to maintain a stably high concentration in liver and
in circulation. Tegafur/uracil has been approved for the indications of advanced gastric
cancer and colorectal cancer. In several phase II studies conducted in Japan, tegafur/uracil
induced a response rate of 0 to 17% in advanced HCC patients.
We hypothesize that combination of tegafur/uracil and thalidomide, both of which have been
shown to be active in some HCC patients, may be a highly useful regimen for the treatment of
advanced HCC. There are several rationales underlying this combination. First,
anti-angiogenesis therapy may improve the efficacy of chemotherapy by normalizing the
abnormal vasculature in tumors, and thus improving the delivery of chemotherapeutic agents
to the tumor cells. Second, chemotherapeutic drugs given in a low-dose, un-interrupted, and
protracted way can induce anti-neoplasm effect through the anti-angiogenesis activity. What
so-called "metronomic chemotherapy" is based on direct targeting of the activation, growth,
and proliferation of vascular endothelial cells by cytotoxic chemotherapeutic agents. The
anti-angiogenesis effect of metronomic chemotherapy is suppressed by VEGF/VEGFR signaling
pathways and thus can be further potentiated by agents blocking those survival signals of
endothelial cells. In this regard, tegafur/uracil appears to be a good candidate for
metronomic chemotherapy because tegafur/uracil and its metabolites have already been shown
to inhibit angiogenesis in several pre-clinical models.
The combination of tegafur/uracil and thalidomide has clinical advantages for patients with
HCC. Both drugs are orally active, thus are convenient to be given on an out-patient basis.
More importantly, the low and non-overlapping toxicity profiles of the two drugs make the
combination relatively safe in patients of HCC.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the overall response rate of UFUR and thalidomide in the treatment of advanced HCC by RECIST criteria
Confirmed response within 4 weeks
Chih-Hung Hsu, M.D. Ph.D.
Department of Oncology, National Taiwan University hospital
Taiwan: Department of Health