Phase II study of oral S‐1 for treatment of metastatic colorectal carcinoma

Abstract

BACKGROUNDThe goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S‐1 (a combination of tegafur, 5‐chloro‐2,4‐dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma.METHODSThirty‐eight patients were enrolled in the study. S‐1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14‐day rest period. Treatment was repeated every 6 weeks unless disease progression was observed.RESULTSA combined total of 173 courses of S‐1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1–18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0–56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305–490 days), and the 1‐year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment‐related death was observed during the study.CONCLUSIONSOrally administered S‐1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option. Cancer 2004. © 2004 American Cancer Society.

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

“…SOX regimen has demonstrated promising efficacy with a response rate of 50%, median PFS of 196 days, and a 1-year survival rate of 78.6%. Efficacy of this combination is superior to that reported for monotherapy by each drug (DiazRubio et al, 1998;Ohtsu et al, 2000;Shirao et al, 2004;Boku et al, 2007). No DLTs were observed during the first cycle at levels 1 and 2.…”

“…Grade 3 or 4 thrombocytopaenia was observed in 28% of patients, and this incidence seems to be higher than that reported by FOLFOX4 (de Gramont et al, 2000). Grade 3 or 4 thrombocytopaenia with oxaliplatin monotherapy was reported in 12% of patients (Boku et al, 2007), and that with S-1 monotherapy in 0 -8% of patients in previous phase II studies (Ohtsu et al, 2000;Shirao et al, 2004). The most commonly observed grade 3 or 4 toxicity after SOX therapy was cumulative prolonged thrombocytopaenia in this phase I/II trial, which is a well-known toxicity of oxaliplatin.…”

“…There was no grade 3 neurotoxicity observed. Although the incidence of grade 3 or 4 thrombocytopaenia seems to be higher with SOX compared with the reported result of FOLFOX4 (Diaz-Rubio et al, 1998;Shirao et al, 2004), it was well managed by adequate dose modification of oxaliplatin and S-1 in subsequent cycles (Goldberg et al, 2004). Since the severity of thrombocytopaenia is dependent on the dose of oxaliplatin, FOLFOX7 with oxaliplatin at a dose of 130 mg m À2 caused 9% of grade 3 thrombocytopaenia (Maindrault-Goebel et al, 2001;Tournigand et al, 2006).…”

“…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).…”

“…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%.…”