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Background: Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers., Methods: A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety., Results: Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively., Conclusion: The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation., Clinicaltrials.gov Identifier: NCT03162510., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC)., Methods: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS)., Results: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group., Conclusion: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308)., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: We evaluated the efficacy and safety of first-line S-1 plus cisplatin in combination with cetuximab for Japanese patients with advanced gastric cancer, including gastroesophageal junction adenocarcinoma., Methods: This open-label, single arm, multicenter, phase 2 trial was conducted to assess first-line cetuximab plus S-1 plus cisplatin for advanced gastric cancer. A total of 40 patients from 10 centers were enrolled. Cetuximab was administered weekly, with the initial infusion at 400 mg/m2 and then 250 mg/m2 each subsequent week. S-1 plus cisplatin chemotherapy was concomitantly conducted in a 5-week cycle: S-1 (40-60 mg, adjusted for body surface area) was given twice daily for 3 consecutive weeks, followed by a 2-week rest period, and cisplatin (60 mg/m2) was given on day 8 of each cycle for a maximum of 8 cycles. Treatment continued until the occurrence of radiographically confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary endpoint was the best overall response. Secondary endpoints included progression-free survival and safety., Results: A total of 40 patients were evaluable. One patient (2.5%) had a complete response; 15 patients (37.5%) had a partial response. The observed overall response rate according to the independent review committee was 40.0% (95% confidence interval, 24.9-56.7; P = 0.7043 [one-sided null hypothesis: overall response rate ≤ 43%]); median PFS was 5.6 months (95% confidence intervals, 4.2-8.3). No adverse events leading to death were reported during the study, and no specific safety concerns were observed., Conclusions: Overall, the addition of cetuximab to S-1 plus cisplatin was well tolerated in patients with advanced gastric cancer but provided no additional clinical benefit in this study. ClinicalTrials.gov identifier: NCT01388790., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Preoperative chemoradiotherapy with capecitabine or 5-fluorouracil is a standard treatment for locally advanced rectal cancer (LARC). S-1, a prodrug of 5-fluorouracil, is a candidate for this chemoradiotherapy regimen in Japan; however, treatment outcomes after S-1 treatment alone are not clear. This study aimed to assess the efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for LARC. We retrospectively evaluated 54 LARC patients who underwent preoperative chemoradiotherapy with S-1 alone in our institution between 2005 and 2017. The clinical tumor stage was cT2-3 in 31 patients and cT4 in 23 patients, and lymph node metastases were clinically evident in 31 patients. S-1, at a dose of 80 mg/m2/day, was orally administered during radiotherapy. A total dose of 45-50.4 Gy was delivered in 25-28 fractions (median: 50.4 Gy). Surgical resections were scheduled 6-10 weeks after chemoradiotherapy completion. The 3- and 5-year overall survival rates were 92.4 and 72.8%, respectively, with a median follow-up time of 51 months. The 3- and 5-year local control rates were 96.2 and 85.9%, respectively. A pathological complete response was observed in 7 patients (13.0%) at the time of surgery. Ten patients (18.5%) had grade 3 acute toxicities and 5 patients (9.3%) had grade 3 late toxicities. No grade 4 or 5 toxicities were observed. Preoperative chemoradiotherapy with S-1 alone followed by total mesorectal excision resulted in a low incidence of toxicities and comparable clinical results. Therefore, S-1 alone can be a treatment option for preoperative chemoradiotherapy in LARC patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: A multi-institutional phase II study was conducted to evaluate the efficacy and safety of preoperative docetaxel, cisplatin and S-1 therapy in marginally resectable advanced gastric cancer., Methods: Patients with macroscopic type 4, large macroscopic type 3 and bulky lymph node metastasis received two cycles of preoperative docetaxel, cisplatin and S-1 therapy (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 80 mg/m2 for 14 days, every 4 weeks). The primary endpoint was the pathological response rate, with an expected value of 65%., Results: Thirty-one patients were enrolled in this study. The pathological response rate was 54.8%, and it was higher than the threshold value but lower than the expected rate. The R0 resection rate was 93.5%. The frequencies of grade 3-4 toxicities during docetaxel, cisplatin and S-1 therapy were 41.9% for neutropenia, 6.5% for febrile neutropenia and 32.3% for nausea/vomiting. Grade 2 and 3 surgical morbidities occurred in 23.3 and 6.7% of the patients, respectively., Conclusions: Preoperative docetaxel, cisplatin and S-1 therapy was feasible in terms of chemotherapy-related toxicities and surgical morbidity, but the effect did not achieve the expected value. The association between the pathological response rate and survival will be evaluated in the final analysis of this clinical trial., (© The Author(s) 2020. Published by Oxford University Press.)

This study aimed to determine the maximum tolerance dose (MTD) and to estimate the recommended dose (RD) of concomitant S-1 with carbon-ion radiotherapy (RT) for sinonasal squamous cell carcinoma (SCC). Nine patients with sinonasal SCC received carbon-ion RT with escalating doses of S-1 according to phase I methods. Doses of 40, 60 and 80 mg/m2/day were administered twice daily in dose levels 1, 2 and 3, respectively, from days 1 to 14 and 22 to 35. Carbon-ion RT was administered at a dose of 70.4 Gy (relative biological effectiveness) in 32 fractions, 5 days a week. Two patients developed grade 3 acute dermatitis. However, none developed dose-limiting toxicities. Therefore, the MTD of S-1 could not be determined; the RD was estimated to be 80 mg/m2/day with concurrent carbon-ion RT. Partial response and stable disease were noted in 5 and 4 patients, respectively. The 2-year overall survival and local control rates were 56 and 74%, respectively. Overall, 2 patients developed ≥grade 3 late toxicities; among them, 1 patient developed grade 3 cataract and the other developed grade 4 cataract, optic nerve disorder and hearing impairment. To the best of our knowledge, this phase I study is the first clinical trial to evaluate concomitant S-1 with carbon-ion RT for sinonasal SCC. The MTD of S-1 could not be determined, and the RD was estimated to be 80 mg/m2/day. This study demonstrated a manageable safety profile for this combination. The observed outcomes may facilitate further evaluation of this novel therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objectives: To explore the risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months in patients with unresectable locally advanced head and neck carcinomas who received chemoradiotherapy in a phase II trial of JCOG0706 (UMIN000001272)., Methods: Forty-five patients received radiation therapy for a total of 70 Gy/35fr concurrently with S-1 and cisplatin. Risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months were analyzed using Cox regression models and logistic regression models, respectively, with consideration to patient laboratory data just before chemoradiotherapy. Radiation fields were reviewed to analyze the relationship between the extent of the irradiated field and functional outcome., Results: With a median follow-up period of 3.5 years, 3-year laryngo-esophageal dysfunction-free survival was 48.9%. For laryngo-esophageal dysfunction-free survival, hazards ratio of 2.35 in patients with nutritional support at registration (vs. without nutritional support; 95% confidence interval 0.96-5.76). For nutritional support dependence over 12 months, odds ratio was 6.77 in patients with hemoglobin less than the median of 13.4 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.24-36.85) and was 6.00 in patients with albumin less than the median of 3.9 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.11-32.54). Primary sites in disease-free patients with nutritional support dependence over 12 months were the oropharynx (N = 2) or hypopharynx (N = 1), and all pharyngeal constrictor muscles were included in irradiated fields with a curative dose., Conclusions: This supplementary analysis showed that pretreatment severe dysphagia requiring nutritional support, anemia and hypoalbuminemia might have a negative prognostic impact on long-term functional outcomes after curative chemoradiotherapy in head and neck cancer., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine., Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL)., Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen., Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer., Background: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC., Methods: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m 2 , respectively. PTX was administered at 80 mg/m 2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety., Results: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed., Conclusion: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Objectives: We conducted a Phase I/II study of carboplatin, S-1 and concurrent thoracic radiotherapy (TRT) for elderly patients (71 years or older) with unresectable stage III non-small cell lung cancer (NSCLC)., Materials and Methods: Patients received carboplatin (AUC 3-5) on Day 1 and S-1 (30-40 mg/m2 two times daily) on Days 1-14, every 2 weeks, for up to four cycles, plus concurrent TRT at a total dose of 60 Gy. The primary endpoint for the Phase II study was the 1-year progression-free survival (PFS) rate., Results: Eighteen patients were enrolled in the Phase I study. Febrile neutropenia, a decreased platelet count and esophagitis were dose-limiting toxicities. The recommended doses for the Phase II study were determined to be an AUC of 3 for carboplatin, 40 mg/m2 twice daily for S-1. Twenty-eight patients were evaluated in the Phase II study. The 1-year PFS rate was 57.1% (90% CI 41.6-71.4%), and the median PFS was 16.8 months (95% CI 7.8-not assessable [NA]). The lower limit of the 90% CI for 1-year PFS exceeded the prespecified threshold value of 30%; therefore, the primary endpoint was met. Grades 3-4 toxicities included thrombocytopenia (21%) and hyponatremia (11%). Grade 3 radiation pneumonitis was observed in 18% of patients. No treatment-related deaths were observed., Conclusion: Combination chemotherapy consisting of carboplatin plus S-1 and concurrent TRT had a promising efficacy in elderly patients with locally advanced NSCLC; however, radiation pneumonitis was frequently observed., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare efficacy and safety of nabpaclitaxel plus S-1 (AS) with gemcitabine plus S-1 (GS) as first-line treatment for metastatic pancreatic cancer., Methods: We conducted a retrospective cohort, single-institution analysis by reviewing medical records of 38 patients who received either AS (nabpaclitaxel 125 mg/m2 on Days 1, 8 and S-1 80 mg/m2 on Days 1 to 14) or GS (gemcitabine 1000 mg/m2 on Days 1, 8 and S-1 80 mg/m2 on Days 1 to 14) chemotherapy., Results: AS was associated with a prolonged median time to progression (TTP; 7.1 months, 95% CI, 4.5-9.7 vs. 3.6 months, 95% CI, 1.8-5.4; P value = 0.022) and improved median overall survival (OS; 10.2 months, 95% CI, 9.1-11.3 vs. 6 months, 95% CI, 4.2-7.8; P value <0.001) compared with GS. In cox proportional hazards model, treatment regimen was the only variable to be significantly associated with improvements in both TTP and OS. Subgroup analyses based on HER2 expression showed that AS seemed to have better outcome of OS in HER2 positive patients (HR = 0.168; 95% CI, 0.022-1.27; P value = 0.084). Hematological adverse events were commonly seen in both group (12.5% and 22.7%, GS and AS group, Grade 3 or 4; P value = 0.675) while AS got increased risk of sensory neuropathy (6 of 22 patients in AS, 27.3% vs. 0 of 16 patients in GS, all grade; P value = 0.03)., Conclusions: AS could be an effective treatment regimen for metastatic pancreatic cancer under surveillance of toxicity.

Objective: This study aimed to determine the maximum tolerated dose and the recommended dose of combining S-1 with gemcitabine and cisplatin for advanced biliary tract adenocarcinoma first-line therapy., Methods: Chemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic biliary tract adenocarcinoma were enrolled. Patients with advanced biliary tract adenocarcinoma received gemcitabine and cisplatin intravenously on Days 1 and 8 and S-1 orally twice daily from Days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m(2)/week), cisplatin (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels: 800/25/40 (level 0), 1000/25/40 (level 1), 1000/25/60 (level 2) and 1000/25/80 (level 3). Level 1 was chosen as the starting dose. For cases where recommended dose could not be determined within the triweekly schedule, we prepared a biweekly schedule to find recommended dose., Results: Seventeen patients with advanced biliary tract adenocarcinoma were treated across three dose levels. Maximum tolerated dose and recommended dose were defined as level 0. Dose-limiting toxicities included a Grade 3 maculopapular rash, Grade 4 thrombocytopenia and consecutive administration skips of gemcitabine and cisplatin on Day 8. Five partial responses were observed., Conclusions: This triweekly triplet regimen was well tolerated and showed promising antitumor activity in patients with advanced biliary tract adenocarcinoma. We recommend level 0, gemcitabine at 800 mg/m(2)/week, cisplatin at 25 mg/m(2)/week and S-1 at 40 mg/m(2)/day during a 21-day cycle, in further studies with this schedule., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Gemcitabine-based chemotherapy is widely used for unresectable advanced pancreatic cancer which contains locally advanced and metastatic pancreatic cancer. We performed meta-analysis to examine whether gemcitabine plus S-1 could improve treatment efficacy as first-line chemotherapy for those patients when compared with gemcitabine alone., Methods: STATA was used to estimate the summary hazard ratios or odds ratios and their 95% confidence intervals. Heterogeneity among trials was examined by Cochran's χ(2) test. Publication bias was evaluated by Begg's and Egger's tests. Subgroup analysis based on the extent of disease was performed., Results: Four randomized controlled trials including 878 Asian patients were analyzed. In total meta-analysis, gemcitabine plus S-1 significantly improved overall survival (hazard ratio, 0.82; 95% confidence interval, 0.70-0.96; P = 0.015), progression-free survival (hazard ratio, 0.64; 95% confidence interval, 0.55-0.74; P < 0.001), overall response rate (odds ratio, 3.00; 95% confidence interval, 2.04-4.41; P < 0.001) and disease control rate (odds ratio, 1.78; 95% confidence interval, 1.32 to 2.39; P < 0.001), and was associated with more but manageable hematologic (leukocytopenia, neutropenia, thrombocytopenia) and non-hematologic (diarrhea, stomatitis, nausea, rash) adverse events. In subgroup analysis, gemcitabine plus S-1, comparing with gemcitabine, significantly improved overall survival in locally advanced patients (hazard ratio, 0.69; 95% confidence interval, 0.48 to 0.99; P = 0.022) but not in metastatic patients (hazard ratio, 0.75; 95% confidence interval, 0.46-1.23; P = 0.256)., Conclusion: This meta-analysis confirmed the survival benefits of gemcitabine plus S-1 as first-line treatment for unresectable advanced pancreatic cancer at least in Asia, while good Eastern Cooperative Oncology group performance status was warranted. Importantly, we highlighted the significant overall survival benefit of gemcitabine plus S-1 in locally advanced patients but not in metastatic patients., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This Phase II study was conducted to evaluate the efficacy and safety of S-1 and irinotecan combination therapy as a second-line treatment in patients with advanced non-small cell lung cancer., Methods: Irinotecan was administered at 60 mg/m(2) on Days 1 and 8. Oral S-1 was administered on Days 1-14 every 3 weeks at 80 mg/day for patients with a body surface area of <1.25 m(2), 100 mg/day for patients with a body surface area of 1.25-1.5 m(2) and 120 mg/day for patients with a body surface area of >1.5 m(2). The primary endpoint was response rate, while the secondary endpoints were progression-free survival, overall survival and safety., Results: Thirty-one patients were enrolled in this study. The response and disease control rates were 6.5 and 58.1%, respectively. Progression-free survival and median survival time were 2.8 and 12.6 months, respectively. Grade 3-4 adverse events were reported for 29.0% of the patients. Hematological toxicities of Grade 3 or 4 included leukopenia (9.7%), neutropenia (9.7%), febrile neutropenia (3.2%), thrombopenia (3.2%) and anemia (6.5%). Non-hematological toxicities of Grade 3 or 4 included pneumonitis (6.5%), diarrhea, colitis, dyspnea, rash, oral mucositis, anorexia and pulmonary thromboembolism/deep vein thrombosis (3.2% each)., Conclusions: S-1 and irinotecan combination therapy at the present dose and schedule exhibited only modest efficacy with mild toxicities in previously treated patients with non-small cell lung cancer. No further clinical investigation with current dose and schedules is warranted for patients with non-small cell lung cancer who failed first-line platinum-based doublet chemotherapy., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: In this study, we compared the efficacy and safety of the oral fluoropyrimidine S-1 as monotherapy or in combination with leucovorin as the second-line treatment for patients with metastatic pancreatic cancer whose disease had progressed on gemcitabine treatment., Methods: The study was a randomized, open-label, controlled study. Patients randomly received S-1 or S-1 in combination with leucovorin (SL arm) in 21-day cycles. The primary endpoint was the 6-month survival rate., Results: A total of 92 patients were randomized to S-1 (n = 47) and SL (n = 45). No statistically significant differences were observed between the two arms with regard to 6-month survival rates (40% vs. 49%), median overall survival (5.5 vs. 6.3 months), median progression-free survival (1.9 vs. 3.0 months), and overall response rate (4.7% vs. 8.3%). The rate of major grade 3-4 adverse events of digestive toxicity was significantly higher in the SL arm than in the S-1 arm., Conclusion: Compared with S-1, SL did not improve the survival of patients with metastatic pancreatic cancer who had failed to benefit from prior gemcitabine treatment, but SL had a higher adverse event rate., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Objective: This study is aimed to assess the efficacy and toxicity of weekly liposome-paclitaxel and S-1 combination therapy as first-line treatment for advanced gastric cancer., Methods: The chemotherapy regime was 80 mg/m(2) liposome-paclitaxel given on days 1, 8, 15 and 22, combined with S-1 60 mg (body surface area > 1.5) or 50 mg (1.25 < body surface area < 1.5) twice a day on days 1-28, 6 weeks as one cycle. The patients continued to be treated until they received four cycles or until they developed either progressive disease or untolerated toxicity. The response rate, progression-free survival, overall survival and toxicity were evaluated., Results: A total of 56 patients were enrolled, and the median age was 60 years (range = 38-70 years; 39 males and 17 females). The response rate and disease control rate were 25% (14/56) and 87.5% (49/56), respectively. The median progression-free survival was 6.1 months (95% confidence interval: 5.0-7.2), and the median overall survival was 10.6 months (95% confidence interval: 7.2-14.0). The most frequent hematological toxicities were neutropenia and anemia, which occurred in 22 (48.9%) and 11 (19.6%) patients, respectively., Conclusions: The weekly administration of a combined regimen of liposome-paclitaxel plus S-1 is effective and has a favorable toxicity profile for advanced gastric cancer.

Objective: A planned primary analysis of a Phase II study of S-1 demonstrated that the drug was active and tolerable in Japanese patients with cytokine-refractory metastatic renal cell carcinoma. Furthermore, pharmacogenomic analysis suggested that low expression of thymidylate synthase mRNA may have been associated with clinical outcome in terms of overall response rate and progression-free survival. Here, we report the results of the final analysis assessing the efficacy and safety of S-1 including overall survival., Methods: Patients with renal cell carcinoma were eligible if they had had at least one regimen of cytokine for metastatic disease. S-1 was orally administered on Days 1-28 of a 42-day cycle until disease progression. The primary endpoint was the overall response rate, and the secondary endpoint included progression-free survival, overall survival and safety., Results: A total of 45 patients were treated with S-1 and were fully assessable for efficacy and safety. At the final analysis, a response was seen in 11 patients (overall response rate, 24.4%; 95% confidence interval: 12.9-39.5%), including two patients who achieved a complete response. The final median progression-free and overall survival were 9.2 and 42.8 months, respectively. The safety profile of S-1 was favorable. It was suggested that there was no relation between overall survival and the expression level of thymidylate synthase., Conclusion: This final analysis confirms that S-1 treatment is effective and safe in patients with cytokine-refractory renal cell carcinoma.

This study investigated the maximum tolerated dose (MTD) of S-1 with concurrent radiotherapy in patients with head and neck cancer, based on the frequency of dose-limiting toxicities (DLT). S-1 was administered orally at escalating doses from 40 mg/m(2) b.i.d. on the days of delivering radiotherapy, which was given at a total dose of 64-70 Gy in 32-35 fractions over 6-7 weeks. A total of 12 patients (3 patients at 40 mg/m(2), 6 patients at 60 mg/m(2), and 3 patients at 80 mg/m(2)) were enrolled in this trial. At the dose of 80 mg/m(2), two of the three patients developed DLT (Grade 3 anorexia and rhabdomyolysis) due to S-1, so the MTD was determined to be 80 mg/m(2). Among the 12 enrolled patients, 9 (75%) showed a complete response and 3 (25%) showed a partial response. The overall response rate was 100%. The recommended dose of S-1 with concurrent radiotherapy is 60 mg/m(2).

We report the development of spinal infarction during adjuvant chemotherapy with tegafur, gimeracil and oteracil (TS-1) after surgery for lung adenocarcinoma. A 69-year-old female had a left upper lobectomy for pulmonary adenocarcinoma, T2aN0M0. Six weeks after the surgery, tegafur, gimeracil and oteracil were administered orally as adjuvant chemotherapy for 1 year. After 10 months of adjuvant chemotherapy, the patient suddenly showed signs of numbness and weakness in both lower limbs. The patient did not have a previous medical history, and was receiving only tegafur, gimeracil and oteracil with the stomach medication. Neurological findings showed muscle weakness, numbness and a loss of tendon reflex in both lower limbs, as well as bladder and rectal disturbance. Blood tests, brain magnetic resonance imaging and chest computed tomography showed no signs of abnormalities or metastasis. Magnetic resonance imaging of the spine showed a hyperintense lesion between the Th12 and L1 spinal levels by T2-weighted image. A spinal fluid test indicated no abnormalities, and cytological diagnosis was class II. Anti-aquaporin 4, anti-ganglioside and anti-neuronal autoantibodies were all negative. These results indicated that the patient had a spinal infarction, rather than myelitis or paraneoplastic neurological syndrome. The patient was treated with heparin and steroid pulse treatment followed by rehabilitation, and recovered sufficiently to be able to walk using a cane after 2 months. The development of spinal infarction during anti-cancer chemotherapy has not been previously reported. In this case, an association of spinal infarction with the use of adjuvant chemotherapy was strongly indicated due to the lack of abnormalities in coagulability, atherosclerotic lesions and aortic disease.

Objective: S-1 and cisplatin combination therapy is a standard regimen for patients with advanced gastric cancer in Japan. The primary objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of a triplet regimen adding paclitaxel to S-1 and cisplatin combination therapy., Methods: Patients with previously untreated metastatic or recurrent gastric cancer were enrolled. Patients received S-1 (40 mg/m(2) p.o., twice daily, on days 1-21 every 35 days), cisplatin (30 mg/m(2) divided, on days 1 and 15) and paclitaxel (divided on days 1 and 15). The starting dose of paclitaxel was 50 mg/m(2) (level 1); the dose was escalated to 60 (level 2), 70 (level 3) and 80 mg/m(2) (level 4) in a stepwise fashion. Dose-limiting toxicity was determined during the first treatment cycle., Results: Eighteen patients enrolled. During the first cycle, no dose-limiting toxicity was observed at dose levels 1 and 2. At dose level 3, one of the six patients had dose-limiting toxicity (one patient had grade 4 neutropenia) and at dose level 4, one of the six patients had dose-limiting toxicity (one patient had febrile neutropenia, hypoalbuminemia and fatigue of grade 3). The maximum tolerated dose was not reached at level 4; however, grade 3 hyponatremia and hypokalemia in two of the six patients occurred during the second treatment course at level 4. From the point of view of safety in the outpatient setting, the recommended dose of paclitaxel was determined at 70 mg/m(2). The overall response rate was 50%., Conclusions: The recommended dose of paclitaxel added to S-1 (80 mg/m(2) days 1-21) plus cisplatin (30 mg/m(2) days 1 and 15) was 70 mg/m(2) on days 1 and 15 of a 5-week cycle.

Objective: Platinum compounds play pivotal roles in treatment for squamous cell carcinoma of the head and neck. The objective was to evaluate the efficacy of S-1 monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy., Methods: We retrospectively analyzed 39 consecutive patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received S-1 monotherapy after failure of platinum-based chemotherapy or chemoradiotherapy at the Shizuoka Cancer Center between August 2003 and October 2010. S-1 was given orally twice daily (80 mg/m(2)/day) for 28 days followed by a 14-day rest., Results: The median follow-up period in survivors was 31.5 months. Among 38 patients with measurable lesions, 9 (24%) showed partial response and 15 (39%) showed stable disease. The median progression-free survival was 4.9 months and the median overall survival was 13.2 months. The median progression-free survival for oropharyngeal cancer (n= 7) was significantly longer than for other cancers (n = 32) (14.9 vs. 4.7 months, P= 0.035). The response rate in patients with a recurrence-free interval since the last platinum administration >6.0 months was significantly better than with a recurrence-free interval <6.0 months (40 vs. 13%, P= 0.0102). Recurrence-free interval >6.0 months also showed a significantly better progression-free survival (6.0 vs. 2.6 months, P= 0.045). The frequency of Grade 3/4 toxicities was less than 10%., Conclusions: S-1 monotherapy shows promising signs of efficacy and tolerability in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy in this retrospective cohort and warrants further investigation in this population.

Objective: The purpose of this study was to assess the safety of S-1 in Japanese in inoperable or recurrent breast cancer patients., Methods: A prospective post-marketing surveillance was performed at 313 sites in Japan in patients with inoperable or recurrent breast cancer treated with S-1. We examined 1361 patients between January 2006 and December 2007 with regard to the incidence of adverse drug reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0., Results: At least one adverse drug reaction was encountered by 858 patients, with an overall incidence of 63.0% (858/1361). The incidence of Grade 3 or higher adverse drug reactions in a descending order was 14.7% (200/1361). In this study, the most common combination drug was trastuzumab. The overall incidence of adverse drug reactions was 63.5% (431/679 patients) in patients treated with S-1 alone, and 55.9% (66/118 patients) in patients treated with S-1 + trastuzumab., Conclusions: Monotherapy with S-1 or combination therapy with S-1 + trastuzumab was well tolerated for inoperable or recurrent breast cancer patients.

The safety of chemotherapy for patients with systemic sclerosis is unclear, and there are few published reports documenting the side effects of chemotherapy in patients with this condition. Here, we report the case of a patient with systemic sclerosis who developed severe digital ischemia during combination gemcitabine/S-1 chemotherapy for pancreatic cancer. In spite of aggressive treatment, the digital ischemia progressively worsened and gangrenous changes developed in multiple fingers and toes. In this patient, the systemic sclerosis had been well controlled, with no digital ischemic symptoms for the previous 6 years, so this progressive clinical course in spite of aggressive treatment strongly suggests that the chemotherapy triggered or aggravated the digital necrosis. To the best of our knowledge, this is only the third reported case of a patient with systemic sclerosis developing digital necrosis after gemcitabine-based chemotherapy. The incidence of digital necrosis during chemotherapy in patients with systemic sclerosis is unknown, and the mechanism by which it occurs is unclear, but the three reports published to date, including the present case, suggest that physicians should be very cautious about administering gemcitabine-based chemotherapy to patients with systemic sclerosis. Any resulting digital ischemia might be refractory to treatment and worsen progressively, even if chemotherapy is withdrawn in the early stages of digital ischemia.

A Phase I/II trial of chemoradiotherapy concurrent with S-1 plus mitomycin C in patients with clinical Stage II/III squamous cell carcinoma of the anal canal was started in Japan. The aim of this trial is to determine the recommended dose of S-1 combined with a fixed dose of mitomycin C plus radiotherapy in Phase I and to evaluate the efficacy and safety in Phase II. The primary endpoint for the Phase II part of this study is the proportion of 3-year event-free survival, in which the following are defined as events: disease progression, residual tumor at the end of chemoradiotherapy, colostomy or death, whichever comes first. Secondary endpoints are progression-free survival, proportion of complete response and adverse events. In the Phase II part of this study, a total of 65 patients will be enrolled from 42 institutions over 6 years.

A 64-year-old female who has undergone D2 total gastrectomy was started on adjuvant treatment with TS-1. Four weeks after initiation of TS-1, the patient developed a rare complication of life-threatening toxic epidermal necrolysis. TS-1 was discontinued and the patient received treatment with intravenous immunoglobulin and supportive care with resolution of toxic epidermal necrolysis. TS-1 has been used for the treatment of gastric cancer, both in the adjuvant and metastatic setting, and is increasingly being used in other malignancies such as colon, pancreatic and non-small cell lung cancer. TS-1 is generally well tolerated. To our knowledge, this is the first reported case of toxic epidermal necrolysis associated with the usage of TS-1.

The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m²) was noninferior to 5-FU plus cisplatin (100 mg/m²) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m² (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m² cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks. The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu).

A randomized Phase II selection design trial comparing gemcitabine plus S-1 combination therapy with S-1 monotherapy for chemo-naïve unresectable or recurrent biliary tract cancer patients was started in Japan. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen to be compared with the current standard regimen, gemcitabine plus cisplatin, in a subsequent Phase III trial. Patients with unresectable or recurrent biliary tract cancer are randomized to either gemcitabine plus S-1 combination therapy arm or S-1 monotherapy arm. A total of 100 patients will be accrued for this study from 18 institutions over 1 year. The primary endpoint is the proportion of 1-year overall survival, and the secondary endpoints are progression-free survival, response rate and adverse events.

Objective: A Phase I/II study of S-1 combined radiation therapy was conducted in patients with Stage II (T2N0) glottic cancer. The purpose of the Phase I study was to identify the maximum tolerated dose, the recommended dose and the dose limiting toxicity. The objectives in the phase II study were to estimate the local control and the overall survival, and the incidence of adverse events., Methods: In Phase I, S-1 was administered orally in a split-course fashion as two doses of 40 mg/m(2), for a total daily dose of 80 mg/m(2). The course involved a 2-week rest after a 2-week administration (Level 1) and a 1-week rest after a 3-week administration (Level 2). Radiation therapy was administered in 2-Gy daily (total 60-Gy) standard fractionation., Results: Seven patients were enrolled in the Phase I, and 19 in the Phase II study. Mucositis was the most common toxicity encountered. All 26 patients completed radiation therapy without delay. The overall response rate was 100% (26/26) with all patients showing a complete response. One patient developed a local recurrence 28 months after the treatment. The 3-year local control and overall survival rates were 94.7 and 85.4%, respectively (limited to 22 patients from Level 2)., Conclusions: The use of S-1 at 80 mg/m(2) per day in a split-course with 1-week rest during the course of radiation therapy was safe and effective for Stage II glottic cancer. The treatment strategy employing orally available S-1 proved to be beneficial over the conventional injection of antitumor agents for maintaining the patients' quality of life.

Objective: No standard salvage chemotherapy regimen has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a Phase II study of S-1 monotherapy was conducted in patients with gemcitabine-refractory advanced pancreatic cancer, the number of patients enrolled was small., Methods: We retrospectively reviewed 84 consecutive patients who received S-1 monotherapy as a second-line treatment after gemcitabine failure at the Shizuoka Cancer Center between May 2004 and April 2008. The selection criteria in this study were age 20-75 years, ECOG performance status

Objective: Although combination chemotherapy with 3 weeks of S-1 and cisplatin is effective for advanced gastric cancer, the toxicities of S-1 which mostly occur during the third week of administration are a major problem. To achieve fewer adverse effects with S-1 and higher dose intensity of cisplatin, we performed combination chemotherapy with 2 weeks of S-1 and cisplatin as first line. The aim of this retrospective study was to analyse the efficacy and feasibility of this regimen., Methods: S-1 (40-60 mg depending on patient's body surface area) was given orally twice daily for 2 consecutive weeks, and 70 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period., Results: Forty-eight patients received a total of 184 courses of chemotherapy. Overall response rate was 40.6% and median survival time was 411 days. Dose intensities were 257.6 mg/m(2)/week for S-1 and 16.4 mg/m(2)/week for cisplatin. The incidences of grade 3/4 haematological toxicities were leucopenia (19%), neutropenia (29%) and anaemia (17%), and those of grade 3 non-haematological toxicities were anorexia (31%) and nausea (21%). The rate of treatment discontinuation owing to toxicity was 10%., Conclusions: This regimen may be effective as an alternative therapy to 3 weeks of S-1 and cisplatin to reduce the toxicity of chemotherapy for advanced gastric cancer.

This randomized Phase II trial compares neoadjuvant chemotherapy of two or four courses of S-1 (1 M tegafur-0.4 M gimestat-1 M ostat potassium) plus cisplatin or paclitaxel plus cisplatin by a two-by-two factorial design for patients with macroscopically resectable locally advanced gastric cancer. The primary endpoint is the 3-year overall survival. The sample size is 60-80 in a total for two hypotheses of the superiority of four courses to two courses and the superiority of paclitaxel plus cisplatin to S-1 plus cisplatin. In both arms, S-1 is strongly recommended post-operatively for at least 6 months but no adjuvant chemotherapy is permitted other than S-1 until recurrence. This trial could appraise more suitable cycles and regimen as neoadjuvant chemotherapy for gastric cancer.

Background: S-1, an oral fluoropyrimidine carbamate, is an active and well-tolerated agent against solid cancer. However, the clinical efficacy of S-1 in patients with metastatic breast cancer has not been determined., Methods: We retrospectively evaluated the efficacy of S-1 and identified its adverse effects in patients with metastatic breast cancer who had failed to respond to prior chemotherapy regimens. All the patients were treated at the National Cancer Center Hospital and received S-1 twice daily at a dose of 80 mg/m(2) for 4 weeks, followed by a 2-week rest interval., Results: Between 2003 and 2007, 37 women with metastatic breast cancer received S-1 as a third line or greater chemotherapy regimen. All the patients had been previously treated with both anthracyclines and taxanes prior to S-1 chemotherapy. The median order of S-1 administration was as a fifth-line treatment, and 23 patients (62%) received S-1 as their final anticancer drug. One (3%) partial response and two (5%) stable diseases were observed. The median time to progression (TTP) was 84 days. Grade 2 adverse events, such as diarrhea, stomatitis and neutropenia occurred in 5 (16%), 1 (3%) and 1 (3%) patients, respectively., Conclusions: S-1 was safety administered to heavily treated metastatic breast cancer patients with limited efficacy. Further evaluation of S-1 is necessary to elucidate its clinical role in breast cancer treatment.

Objective: We conducted a Phase I study to evaluate the safety and efficacy of a combination of S-1 with semi-weekly low-dose cisplatin in patients with unresectable/recurrent gastric cancer to determine the recommended dose (RD) for a subsequent Phase II study., Methods: S-1 was administered orally at 80-120 mg/body/day based on body surface area. One cycle consisted of the consecutive administration of S-1 for 28 days followed by 14 days rest. Three dose levels, 7.5, 10, and 15 mg/m(2)/day, were set for cisplatin, which was administered twice-a-week for 4 weeks followed by 2 weeks of rest in each cycle. Dose-limiting toxicity (DLT) data were continually monitored to enable decisions regarding cisplatin dose escalation and deescalation based on a new dose-finding algorithm using a continual reassessment method (CRM). The CRM target toxicity level to estimate the RD was set at 20%., Results: Eight and five patients were treated at cisplatin dose levels of 10 and 15 mg/m(2)/day, respectively. Two DLTs occurred at both dose levels. On the basis of this data, the CRM estimated the RD to be 10 mg/m(2)/day of cisplatin. Three patients of eight patients treated with 10 mg/m(2)/day of cisplatin exhibited a confirmed partial response during the treatment period., Conclusion: For future trials examining the safety and efficacy of daily S-1 with semi-weekly cisplatin in patients with unresectable/recurrent gastric cancer, we found a cisplatin RD of 10 mg/m(2)/day.

This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarray-based comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m(2) twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m(2) bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m(2) bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment.

Objective: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer., Methods: S-1 was administered orally at 80 mg/m(2)/day for 21 consecutive days followed by a 2 week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 40 mg/m(2)/day, stepping up to 60, 80, 100 or 120 mg/m(2)/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study., Results: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m(2), because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m(2). The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15., Conclusions: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.

A phase I/II clinical trial has been planned to evaluate the safety and efficacy of combination therapy of S-1 with low-dose cisplatin in patients with unresectable or recurrent gastric cancer. A new statistically as well as clinically deliberated study design is applied to determine the maximal benefits of combination chemotherapy. This trial uses a 'continual reassessment method' for evaluating toxicity and a "two-stage method" for assessing the response rate to determine the combination that achieves adequate tumor response without toxicity in a high proportion of patients. Three specialized institutions will recruit 10-16 patients for the phase I part of the trial, and 14 institutions, in conjunction with the three specialized ones, will enroll 42 patients for the phase II part. The goal of this trial is to establish a useful chemotherapeutic treatment in an outpatient setting.

A newly approved oral fluoropyrimidine, TS-1, is a dihydropyrimide dehydrogenase (DPD)-inhibiting fluoropyrimidine (DIF) drug. We describe a case of interstitial pneumonia probably caused by TS-1. A peripheral blood lymphocytes stimulating test (DLST) with TS-1 demonstrated a substantial positive reaction. So far only three cases of TS-1-induced interstitial pneumonia have been reported but the relationship between interstitial pneumonia and TS-1 was demonstrated only in this case. Considering that interstitial pneumonia has also been reported with 5-FU, it is necessary in the future to clarify which component of this drug is directly related to interstitial pneumonia.

Hand-foot syndrome (HFS) is a relatively common side effect of fluorouracil (5-FU) chemotherapy that has also been associated with the oral fluoropyrimidine capecitabine. Interestingly, HFS is virtually unknown to result from treatment with UFT, a combination of tegafur and uracil. Tegafur is a prodrug of 5-FU and is a component of S-1, another oral fluoropyrimidine active in a variety of solid tumors. We know of only one previously described case of S-1-induced HFS and the case reported here is the first to provide full documentation of this occurrence. The pathophysiology of chemotherapy-induced HFS remains unknown and very little pathological information is available. Treatment consists of topical emollient therapy, although pyridoxine has occasionally been beneficial. The study of HFS may provide an important insight into the pharmacology of fluoropyrimidines and allow for effective preventive strategies for this side effect of chemotherapy.