A Randomized Phase II Study of Docetaxel vs. Docetaxel Plus Cisplatin vs. Docetaxel Plus S-1 as Second-line Chemotherapy After Cisplatin Plus S-1 or Capecitabine in Metastatic Gastric Cancer
To date, the most commonly used first-line chemotherapies have been based on fluorouracil
and/or cisplatin in patients with metastatic gastric cancer. Unfortunately, considerable
proportions of patients with metastatic gastric cancer do not respond to first-line
chemotherapy and most of the patients who do respond eventually experience disease
progression. In the second-line treatment, however, standard therapies are less clearly
Meanwhile, regarding re-challenge of previous failed drugs as a combination with an other
newly introduced chemotherapeutic agent, there are few data. Increased expression and
activity of thymidylate synthase, which is inhibited by fluoropyrimidine, is regarded to be
the main reason for the development of clinical resistance to fluoropyrimidine. Since the
cotreatment of docetaxel and 5-fluorouracil decreases the activity and expression of
thymidylate synthase and dihydropyrimidine dehydrogenase (5-fluorouracil degradation
enzyme), and increases the expression of orotate phosphoribosyl transferase, the addition of
docetaxel into S-1 may recover the sensitivity to S-1 in patients previously resistant to
Several reports found that MDR-1 and MRP-1 are related to cisplatin-resistance; cisplatin
induces the overexpression of MRP-1, which reduces intracellular cisplatin accumulation.
Since docetaxel suppresses the cisplatin-induced MRP-1 upregulation, the addition of
docetaxel into cisplatin may recover the sensitivity to cisplatin in patients previously
resistant to cisplatin.
Based on these synergism mechanisms, we speculate that the cotreatment of docetaxel and
cisplatin or S-1 has better anti-tumor activity than docetaxel alone in patients resistant
to cisplatin or S-1.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
every 2 cycles
Sook Ryun Park, Dr.
Research Institute and Hospital, National Cancer Center Korea
Korea: Food and Drug Administration