Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

Nakamura, Kazuhiko; Yamaguchi, Taketo; Ishihara, Takeshi; Sudo, Kentaro; Kato, Hiroyuki; Saisho, Hiromitsu

doi:10.1038/sj.bjc.6603168

Cited by 117 publications

(84 citation statements)

References 17 publications

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“…S-1 is composed of the 5-FU prodrug tegafur, gimeracil (5-chloro-2,4-dihydroxypyridine), which reversibly inhibits dihydropyrimidine dehydrogenase (DPD)-mediated inactivation of 5-FU in the liver and tumors, and potassium oteracil (potassium oxonate), an inhibitor of orotate phosphoribosyltransferase (OPRT) that protects against 5-FU-induced GI damage (16,17). S-1 was found to be clinically effective against NSCLC and pancreatic, gastric, CRC, head and neck, and breast cancers (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Fukushima

Sakamoto²,

Sakata³

et al. 2010

Oncol Rep

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Abstract. Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dosedependent manner. Furthermore, we observed decreased expression of Á-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.

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Section: Introductionmentioning

confidence: 99%

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Fukushima

Sakamoto²,

Sakata³

et al. 2010

Oncol Rep

View full text Add to dashboard Cite

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“…S-1 has already undergone phase I and phase II testing in several solid tumours in Japan and Western countries (Koizumi et al, 2000;Ohtsu et al, 2000;van Groeningen et al, 2000;Kawahara et al, 2001;Hoff et al, 2003;Ueno et al, 2005;Nakamura et al, 2006). The main adverse reaction was myelosuppression in a Japanese phase-I study, and diarrhoea in a European and a North-American phase-I study (van Groeningen et al, 2000;Hoff et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer

et al. 2007

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In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy Â 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m -2 day -1 on days 1 -7 and 15 -21 (level 1), 1 -14 (level 2), and 1 -21 (level 3a) and 80 mg m -2 day -1 on days 1 -21 (level 3b) and 1 -28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19 -9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m -2 day -1 given on days 1 -21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

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“…In Japan combination therapy using T-S1 and Gemcitabine is noteworthy to have a high response rate at the present time. 6,7 Antecedent T-S1 given everyday for seven days and gemcitabine infused at the eighth day prolonged the patient's survival rate to 47.7% at one year and 20.7% at two years. Although a surgeon may be relieved to know that among the various choices of treatment, such as palliative surgery, radical surgery, chemotherapy or radiotherapy, results following resection with adjuvant chemoradiation therapy were the best, 8 adjuvant chemoradiation was not widely adopted in Japan.…”

Section: Discussionmentioning

confidence: 99%

Pancreatectomy for Pancreatic Cancer with Reference to Combined Resection of the Vessels, Twenty Nine Year Experience by a Single Surgeon

et al. 2009

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Between 1978 and 2007 one hundred and seven patients consecutively underwent resection for primary pancreatic adenocarcinoma. There were 28 pN0 patients, 41 pN1 and 37 pN2 or more (one unknown). Combined resection of the portal vein was performed in 62 out of 107 patients (58%). The hepatic artery in 10 patients, superior mesenteric artery in 8 patients and celiac trunk in 7 patients were also resected additionally to the portal vein. The 5-year survival rate and 10-year survival rate of all 107 cases were 12.1% and 2.8% respectively. The 5-year survival rate of the pN0 group was 37%, significantly better than the 14% 5-year survival rate in the pN1 group (p=0.043). Of 69 patients with pN0 or pN1, 38 patients underwent combined resection of the portal vein. There was not significant difference between the 24% 5-year survival rate in the group without the portal vein resection and the 19% 5-year survival rate in the group with portal vein resection. The 20% 5-year survival rate of the portal vein only group and the 5-year survival rate of both the portal vein and hepatic artery group were the same. The groups of the further resection of the superior mesenteric artery and of the celiac trunk showed no long-term survival. It is concluded that aggressive combined resection of the portal vein or additional resection of the hepatic artery be feasible for a survival benefit in pN0 and pN1 diseases. (Keio J Med 58 (2) : 103

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Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

Cited by 117 publications

References 17 publications

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer

Pancreatectomy for Pancreatic Cancer with Reference to Combined Resection of the Vessels, Twenty Nine Year Experience by a Single Surgeon

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