Thalidomide is 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It was withdrawn from the European and Canadian markets in early 1960s because of its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 . It was not until 1998 when FDA approved thalidomide in the US for the
treatment of erythema nodosum leprosum , ENL.
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, such as myeloma, hormone-refractory prostate cancer, high-grade glioma, renal
cell carcinoma, and melanoma.
UFUR® is a composite drug composed of 100mg tegafur and 224mg uracil (molar ratio:1:4). It
was marketed as UFT® in Japan and marketed as UFUR® in Taiwan.
Tegafur, a prodrug of 5-FU, is easily absorbed though the gastro-intestinal tract slowly
metabolized to 5-FU mainly in liver . Uracil is an inhibitor of dihydro-pyrimidine
dehydrogenase (DPD), the rate-limiting enzyme of 5-FU degradation.
Tegafur/urail 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, which are traditionally indicated for the therapy of
5-FU-based chemotherapy, in Japan and Taiwan.
We hypothesize that combination of tegafur/uracil (UFUR®) 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, UFUR appears to be a good candidate for metronomic
chemotherapy because UFUR and its metabolites have already been shown to inhibit
angiogenesis in several pre-clinical models.
The combination of tegafur/uracil (UFUR®) 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Kun Huei Yeh, Ph.D.
Far Eastern Memorial Hospital
Taiwan: Department of Health