Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial that compared 5-FU alone with 5-FU+cisplatin (JCOG 9205). The primary endpoint of this study was overall survival, and both regimens showed equivalence not only in median survival time (approximately 7 months) but also in one- and two-year survival rate (28% vs 29%, and 7% vs 7%, respectively). The toxicities were significantly lower with 5-FU alone than with 5-FU+cisplatin. Then the JCOG steering committee determined that 5-FU alone should be the reference arm and overall survival should still be the primary endpoint in the next study (JCOG 9912). According to the monitoring report of this study at the interim analysis, median survival time of all patients registered for the study exceeded 11 months. Surprisingly, there was an improvement in median survival time from 7 months in JCOG 9205 to 11 months in JCOG 9912. Many newer agents were used, such as TS-1, CPT-11, docetaxel, and paclitaxel, which were absent during the previous study (JCOG 9205). Using these agents as a second-line treatment may cause the improvement of survival. Two phase II studies of CPT-11- and paclitaxel-based regimens indicate that patients derive benefit from second-line treatment, and this warrants further investigation in a randomized trial.