Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35 -40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m À2 (level 1) or 130 mg m À2 (level 2) on day 1, and S-1 (80 -120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2 -14), RR of 50% (1 CR and 13 PR: 95% CI 31 -69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea. F-b-alanine (FBAL) is the main metabolite of 5-FU. F-b-alanine and fluorocitrate are thought to cause the neurotoxic and cardiotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Okeda et al, 1990;Robben et al, 1993;Diasio 1998). The CDHP component of S-1 inhibits DPD, the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after continuous infusion of 5-FU (Yamada et al, 2003). Therefore, S-1 may decrease the incidence of neurotoxicity and cardiotoxicity. The response rate of S-1 monotherapy has been found to be 35-40% for patients with metastatic colorectal cancer (Ohtsu et al, 2000;Shirao et al, 2004), with grade 3 or 4 neutropaenia observed in 5-13%, thrombocytopaenia in 0-8%, diarrhoea in 2-3%, and grade 1 hand-foot syndrome (HFS) in 5%.Oxaliplatin is a third-generation platinum compound with less toxicity and improved convenience. The regimen of infusional 5-FU and leucovorin (LV) with oxaliplatin is the standard for firstand second-line chemotherapy in patients with metastatic colorectal cancer (de Gramont et al, 2000;Rothenberg et al, 2003;Goldberg et al, 2004). However, infusional 5-FU with LV has the disadvantages of increased inconvenience, cost, and morbidity related to the use of a portable infusion pump and a central venous catheter. Therefore, oral fluoropyrimidine monotherapy has been commonly used in Japan.The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of S-1 plus oxal...
