S-1 Plus Cisplatin Research Articles

Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.

LBA4024 Background: 5-weekly S-1 plus cisplatin (SP5: S-1 80-120 mg/body/day on D1-21, cisplatin 60 mg/m2 on D8, every 5 weeks) has become a standard first-line chemotherapy for AGC in Japan based on the SPIRITS trial (Lancet Oncol. 2008;9:215). To strengthen the low-dose intensity of cisplatin in this SP5 for greater efficacy, a 3-weekly S-1 plus cisplatin (SP3: S-1 80 mg/m2/day on D1-14, cisplatin 60 mg/m2on D1, every 3 weeks) has been developed in Korea (Cancer Chemother Pharmacol. 2008;61:837). Methods: This SOS study was a multicenter, randomized, open-label, phase III study to evaluate whether SP3 was non-inferior/superior to SP5 in terms of progression-free survival (PFS) determined by a blinded central radiology review according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and with no prior chemotherapy were randomized 1:1 to receive either SP3 or SP5 until disease progression or unacceptable toxicities. Results: Between February 2009 and January 2012, a total of 625 pts were randomized from 42 sites in Korea and Japan. Median age was 59.6 years. 99% of pts had ECOG performance status 0-1. 16% of pts had prior gastrectomy. 62% of pts had measurable lesions. With a median follow-up of 34.7 months (range, 14.2-48.8) in surviving pts, SP3 was significantly noninferior and superior to SP5 in PFS (median 5.5 months vs. 4.9 months; HR 0.82, 95% CI 0.68-0.99, p=0.0418). Overall response rate (ORR) was also better with SP3 than with SP5 (60% vs. 50%, p=0.029). However, OS of both groups was equivalent (median 14.1 vs. 13.9 months; HR 0.99, 95% CI 0.81-1.21, p=0.9068). Treatment was well tolerated in both arms, while SP3 was associated with more frequent G3/4 anemia (19% vs. 9%) and neutropenia (39% vs. 9%). Dose intensity was higher in SP3 than in SP5 for both agents (median 331 vs. 317 mg/m2/week for S-1, p<0.001; median 18 vs. 12 mg/m2/week for cisplatin, p<0.001). Conclusions: SP3 was noninferior and superior to SP5 in terms of PFS and ORR. However, considering the small benefit in PFS and no difference in OS, both SP3 and SP5 can be recommended for the first-line treatment of AGC. Clinical trial information: NCT00915382.

A phase ll study of new combination regimen with trastuzumab, S-1, and CDDP in HER2-positive advanced gastric cancer (HERBIS-1).

4072 Background: S-1, a novel oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. ToGA study demonstrated that trastuzumab (T-mab) combination regimen improved the overall survival of patients with HER2-positive advanced gastric cancer. However, there was no study evaluating the efficacy and the safety of T-mab in combination with S-1 plus cisplatin (SP) regimen. Therefore, we planned this study to examine the efficacy and the safety of the SP plus T-mab. Methods: Patients confirmed to be HER2-positive by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive) received S-1 at 80 mg/m2 po, day 1-14, and cisplatin 60 mg/m2 iv, day 1 plus trastuzumab 8 mg/kg iv, day 1 (6 mg/kg iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR). Secondary endpoints were progression-free survival, overall survival and safety. The threshold response rate was defined as 35%, and the expected rate was set at 50% with a 80% power and a 1-sided alpha value of 0.1 and the calculated sample size was 50 patients. Results: A total of 56 patients (median age 66) were enrolled in this study. The efficacy and the safety analyses were conducted in the full analysis set of 53 patients. (Two patients were excluded for ineligibility and one was for no treatment). The confirmed RR assessed by the independent review committee was 67.9% (95% CI: 53.7 – 80.1), and the disease control rate was 94.3%. The median PFS was 7.1 months (95% CI: 6.0 – 10.1). The median OS was not reached. (The median follow-up time: 9.2 months) The main grade 3/4 adverse events were as follows: neutropenia 34%, leucopenia 8%, anorexia 23%, diarrhea 8%, hypoalbuminemia 4%, vomiting 6%, and increased creatinine 6%. Conclusions: This tri-week regimen with SP plus T-mab showed promising results in patients with HER2-positive advanced gastric cancer. Clinical trial information: UMIN000005739.

Survival analysis of linitis plastica advanced gastric cancer patients receiving S-1 plus cisplatin.

e15105 Background: Linitis plastica gastric cancer (LPGC) has been known to have worse prognosis than non-LPGC. Clinical trial using molecular targeting agent has been ongoing for LPGC. However it remains unknown whether to be better to change the chemotherapy for the patients. S-1 plus cisplatin (SP) is the standard chemotherapy for previously untreated Japanese advanced gastric cancer (AGC). Methods: To clarify the clinical feature and outcome of LPGC treated with chemotherapy, we retrospectively compared the patients with unresectable or metastatic LPGC and non-LPGC who received SP as the first-line chemotherapy in Cancer Institute Hospital of JFCR between 2007 and 2011. Results: In the period there were 687 patients with AGC who received systemic chemotherapy and 223 (LPGC 63 and non- LPGC 160) patients received SP as first-line chemotherapy. LPGC patients were more frequent in female (44.0% vs. 26.9%; P=0.016). LPGC was more likely to have non-measurable disease (39.7% vs. 14.4%; P<0.001), peritoneal metastasis (73% vs. 35.6% P<0.001), and diffuse type histology (diffuse type 85.7% vs. 56.3%, intestinal type 7.9% vs. 27.5%; P<0.001). LPGC was less likely to have liver metastasis (7.9% vs. 27.5%; P<0.001), and no evaluable distant metastasis in computed tomography (81.0% vs. 93.8%; P=0.010). Other clinicopathological characteristics were follows (LPGC patients vs. non-LPGC patients): median age (57 vs. 62 years), disease status (recurrent 11.1% vs. 18.8%), ECOG PS 0 (81.0% vs. 81.9%), number of metastatic sites (1: 52.4% vs. 46.9, 2: 39.7% vs. 46.9%, ³a3: 7.9% vs. 6.2%), lymph node metastasis (63.5% vs. 70.6%), prior gastrectomy (31.7% vs. 35.6%). They were not significantly different. Median overall survival time is 383 days (95% CI 332-564) in LPGC patients and 473 days (95% CI 412-555) in non-LPGC patients (P=0.363). Median time to treatment failure is 229 days (95% CI 155 - 280) in LPGC patients and 189 days (95% CI 156 -219) in non-LPGC patients (P=0.245). Conclusions: Although clinicopathological backgrounds were not identical, it was suggested that the prognosis of the patients treated with SP was not different between advanced or metastatic LPGC and non-LPGC.

Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.

LBA4024 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin for first-line treatment of advanced gastric cancer.

60 Background: S-1 plus cisplatin (SP) is the standard first-line treatment regimen for advanced gastric cancer (AGC) in Japan. S-1 plus oxaliplatin (SOX) for AGC showed promising efficacy and safety outcomes in the previous phase II study. We aimed to evaluate the non-inferiority of SOX to SP for AGC. Methods: Patients (Pts) with unresectable advanced or recurrent gastric cancer were randomly assigned to SOX (oral S-1 40 mg/m2 b.i.d. for 14 days plus oxaliplatin 100 mg/m2 iv on day 1, q3w) or SP (oral S-1 40 mg/m2 b.i.d. for 21 days plus cisplatin 60 mg/m2iv on day 8, q5w). Eligibility criteria included PS 0-2, age 20 years or older, adequate major organ functions. Primary endpoints were non-inferiority in progression-free survival (PFS) as compared with SP and relative efficacy in overall survival among the groups. Main secondary endpoints included response rate (RR), safety, and length of hospital stay (LOS) per cycle. The primary analysis for PFS was planned after 456 PFS events occurred. Results: Six hundred eighty five pts enrolled were randomly assigned to SOX (n=342) or SP (n=343) between Jan. 2010 and Oct. 2011. The evaluable pts for safety and efficacy were 673 (SOX/SP, 335/338) and 642 (SOX/SP, 318/324), respectively. The median PFS was 5.5 months for SOX vs. 5.4 months for SP (hazard ratio [HR] =1.004; 95% confidence interval [CI], 0.840-1.199). The upper limit of the 95% CI for HR was not above the margin of 1.30 and met the predefined criterion for non-inferiority. RR was 55.7% for SOX and 52.2% for SP (P=0.374). Grade 3 or 4 toxicities in SOX v. SP were neutropenia 19.5% v. 41.5%, thrombocytopenia 9.5% v. 10.4%, febrile neutropenia 0.9% v. 6.9%, hyponatremia 7.1% v. 15.2%, sensory neuropathy 4.4% v. 0%, respectively. Serious adverse events were occurred in 29.3 % for SOX and 37.9% for SP. Eight treatment-related deaths were reported in SP (2.4%) and four in SOX (1.2%). The median LOS per cycle was 0.85 day for SOX and 6.00 days for SP (P<0.0001). Conclusions: SOX showed non-inferiority to SP in PFS and the treatment was well tolerated, with benefit in terms of outpatient-based treatment in pts with AGC. SOX is considered as a new standard regimen for the first-line treatment of AGC on an outpatient basis. Clinical trial information: JapicCTI 101021.

IS7-20 - S-1 Plus Cisplatin Versus Docetaxel Plus Cisplatin in Chemotherapy-Naive Patients with Advanced Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase III Study (TCOG0701)

ABSTRACT Background Platinum-based chemotherapy has been a standard of care in patients with advanced non-small-cell lung cancer (NSCLC). S-1 plus cisplatin (SP) was shown good activity and tolerability in previous phase II trials. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival (OS) and quality of life (QOL), compared with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Method This randomized phase III study compared the OS between SP and DP in patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions. Patients received oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks in SP arm, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks in DP arm, both up to six cycles. The non-inferiority study design was employed as upper confidence interval (CI) limit for HR Results From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n = 303) or DP (n = 305). Patient demographics were well balanced between the two arms. Two interim analyses were preplanned. At the final analysis, a total of 480 death events were observed. OS for SP was non-inferior to DP (median survival, 16.1 versus 17.1 months, respectively; HR = 1.013; 96.4% CI, 0.837–1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), grade 1/2 alopecia (59.3% versus 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusion S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.

WS3-3 - Capecitabine Plus Cisplatin (XP) Combination Chemotherapy is Manageable and Effective for Advanced Gastric Cancer Patients in Clinical Practice

ABSTRACT Background Capecitabine plus cisplatin (XP) combination chemotherapy is one of the global standard regimens as first-line for HER2-negative AGC. But in Japan, S-1 plus cisplatin (SP) combination chemotherapy is regarded as a standard regimen by SPIRITS trial. So, few data are existed for the results of XP in Japan. Methods Thirteen AGC patients were treated XP (capecitabine 2000 mg/m2 on day 1–14, CDDP 80 mg/m2 on day 1, q3w) as first-line in clinical practice. We estimated response rate (RR), time to treatment failure (TTP), progression-free survival, overall survival (OS), and toxic effects. Results Between December 2010 and November 2011, 13 AGC patients were treated XP in our hospital. PS0/1/2: 8/4/1, median age: 70 years old (22–80), gender: m/f: 5/8, differentiated type/undifferentiated type: 5/8. Median courses were 3 (1–6). The most common grade 3/4 adverse events were neutropenia (23%), anemia (8%), and AST elevated (8%). Two patients died within 30 days after the last administration due to disease progression. In seven patients who had measurable lesions, five patients were partial response (71%). Median PFS were 188 days and median OS was not reached. Conclusions XP combination therapy was feasible and effective as first-line chemotherapy for AGC in clinical practice in Japan.

O1-006 - Early Clinical Experience of Trastuzumab Plus Capecitabine/Cisplatin (HXP) Therapy for Patients with Unresectable Advanced Gastric Cancer

ABSTRACT Background After the result of ToGA study, trastuzumab was introduced in Japan, which is the first molecular targeting therapy in the era of gastric cancer. Aims To investigate HER2 overexpression in advanced gastric cancer (stage 4) by immunohistchemistry using endoscopic biopsy samples. To discuss the feasibility and problems of trastuzumab plus capecitabine/cisplatin (HXP) therapy. Methods We investigated HER2 overexpression in 35 patients of advanced gastric cancer from March 2011 to December 2011. Among these, 12 patients revealed HER2 positive by endoscopic biopsy, and 9 patients were introduced HXP. As a rule, we investigated the overexpression of HER2 protein in all cases of unresectable gastric cancer by immunohistchemistry. Basically, we carried out endoscopic biopsy from different several sites (if possible six sites) of the main tumor, considering the heterogeneity of HER2 overexpression. Results We introduced HXP for five males and four females. Median age was 67. Tumor location: body/antrum/cardia = 6/2/1. Histology: well/moderately/poorly = 1/5/3. In four cases, HXP was carried out as the first-line chemotherapy, whereas the others had been received previous chemotherapy such as S-1 plus cisplatin (SP) therapy. Effect evaluation: CR/PR/SD/PD/NE = 0/2/3/2/2. Remarkable adverse events due to trastuzumab were seen in only one case; fever and chills considered as infusion reaction. On the other hand, six cases showed renal dysfunction. No one showed serious adverse events regarded as grade 3/4. Discussion Trastuzumab was well tolerated without significant adverse events in our clinical experience. Trastuzumab seems to be safe for elder patients. Due to renal dysfunction, whenever necessary we reduced or interrupted cisplatin administration and continued trastuzumab. There is no evidence for the efficacy of trastuzumab beyond second-line therapy and there remains a question whether it is effective to continue trastuzumab beyond PD. Therefore, future clinical trials can be expected in this regard.

1234PD - Randomized Phase III Trial of S-1 Plus Cisplatin Versus Docetaxel Plus Cisplatin for Advanced Non-Small-Cell Lung Cancer (TCOG0701)

ABSTRACT Background Quality of life (QOL) should be an explicit priority throughout the course of care for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel plus cisplatin (DP) is the only third-generation regimen that has demonstrated statistically significant improvements in overall survival and QOL by a head-to-head comparison with a second-generation regimen (vindesine plus cisplatin) in patients with advanced NSCLC. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Method Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). A non-inferiority study design was employed; the upper confidence interval (CI) limit of the hazard ratio (HR) was Results From April 2007 through December 2008, 608 patients were randomly assigned to SP (n = 303) or DP (n = 305) at 66 sites in Japan. Patient demographics were well balanced between the two groups. Two interim analyses were preplanned. At the final analysis, a total of 480 deaths had occurred. The primary endpoint was met. OS in the SP arm was non-inferior to that in the DP arm (median survival, 16.1 vs. 17.1 months, respectively; HR = 1.013; 96.4% confidence interval, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. The rates of febrile neutropenia (7.4% vs. 1.0%), grade 3/4 neutropenia (73.4% vs. 22.9%), grade 3/4 infection (14.5% vs. 5.3%), and grade 1/2 alopecia (59.3% vs. 12.3%) were significantly lower in the SP arm than in the DP arm. In terms of physical functioning and global functioning on the EORTC QLQ-C30 and lung cancer module (LC-13), QOL was worse in the DP arm (repeated measures ANOVA: p Conclusion S-1 plus cisplatin is a standard first-line chemotherapeutic regimen for advanced NSCLC. Disclosure M. Nishio: HONORARIA: Chugai Pharma. K. Kobayashi: HONORARIA: a reasonal payment for lectuture speech from Taiho Pharmaceutical Company. M. Takeuchi: CONSULTANT OR ADVISORY ROLE; Taiho. All other authors have declared no conflicts of interest.

A randomized phase II trial to elucidate the efficacy of capecitabine plus cisplatin (XP) and S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment vs. SP randomized PII trial (XParTS II)

BackgroundOn the basis of international clinical trials, capecitabine plus cisplatin (XP) as a first-line treatment of advanced gastric cancer is considered a global standard regimen. However, the usefulness of XP as compared with S-1 plus cisplatin (SP), which is considered standard therapy in Japan, has not yet been assessed.Methods/designThis is a multicenter randomized phase II trial to elucidate the efficacy of XP as compared with SP for first-line treatment of advanced gastric cancer. Patients with unresectable metastatic or recurrent gastric cancer, 20–74 years of age and human epidermal growth factor 2 (HER2)-negative status, will be assigned in a 1:1 ratio to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. Patients will be also asked to the analysis of tumor tissues for translational investigations. The Primary endpoint is progression-free survival and secondary endpoints are overall survival, time to treatment failure, tumor response rate and safety. These comparisons will also be evaluated in terms of biomarkers. Planned sample size is 100 (50 in each arm), which is appropriate for this trial.DiscussionFluoropyrimidine plus cisplatin combination is the standard regimen of the first line treatment for advanced gastric cancer. Both S-1 and capecitabine are the prodrug of 5-FU but differ from their process of metabolism. Result of this trial and translational research will provide the important clues to prepare the individualized therapy for advanced gastric cancer in the near future.Trial registrationClinicalTrials.gov Identifier NCT01406249

Randomized phase III trial of S-1 plus cisplatin versus docetaxel plus cisplatin for advanced non-small-cell lung cancer (TCOG0701).

7515 Background: Although molecularly targeted therapy improves outcome of selected patients with advanced non-small-cell lung cancer (NSCLC), most of the patients ultimately become candidates of cytotoxic chemotherapy, which is the cornerstone of patient management. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival and quality of life by head to head comparison with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Methods: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomized to receive either oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks or docetaxel 60mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is overall survival (OS). Non-inferiority study design was employed as upper confidence interval (CI) limit for HR<1.322. Secondary endpoints include progression-free survival (PFS), response, safety, and quality of life (QOL). Results: From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n=303) or DP (n=305). Patient demographics were well balanced between the two groups. Two interim analyses were preplanned. At the final analysis, total of 480 death events were observed. The primary endpoint was met. OS for SP was non inferior to DP (median survival, 16.1 v 17.1 months, respectively; HR=1.013; 96.4% CI, 0.837-1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% v 1.0%), grade 3/4 neutropenia (73.4% v 22.9%), grade 3/4 infection (14.5% v 5.3%), grade 1/2 alopecia (59.3% v 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusions: S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.

A retrospective comparison of S-1 plus cisplatin and capecitabine plus cisplatin for patients with advanced or recurrent gastric cancer

Based on the results of the SPIRITS trial, combination chemotherapy of S-1 plus cisplatin (SP) is now considered the standard treatment for patients with advanced gastric cancer (AGC) in Japan. On the other hand, several non-Japanese studies have shown the efficacy of capecitabine plus cisplatin (XP), which has been used as the reference arm in recent global studies of AGC. We retrospectively compared the efficacy and safety of SP and XP in first-line treatment for patients with AGC. From August 2006 to November 2008, 26 AGC patients received XP in the context of 2 global trials (AVAGAST and ToGA), and 50 patients received SP during the same period. The objective response rate was 43.2 % in the SP group and 50 % in the XP group, with no significant difference (p = 0.62). There were also no significant differences in progression-free survival (median 5.8 vs. 5.2 months; p = 0.91) and overall survival (median 13.8 vs. 13.5 months; p = 0.97) between the SP and XP groups. The frequencies of hematological toxicities of grade 3 or more and non-hematological toxicities were not significantly different between the 2 groups. Although grade 1 or 2 hand-foot syndrome was more common in the XP group, no patients experienced grade 3 or more. Although the retrospective nature of this study and the small number of patients is a major limitation, SP and XP were associated with similar efficacy and safety in patients with AGC.

What are the limiting factors related to discontinuance of chemotherapy after failure of first-line S-1 plus CDDP in Japanese patients with advanced gastric cancer?

149 Background: Recently, it is suggested that second-line chemotherapy improved survival in advanced gastric cancer (AGC) and it is commonly performed in Japanese daily practice in these several years. We investigated the limiting factor not to be able to receive second-line chemotherapy in Japanese patients with AGC. Methods: Between 2007 and 2009, 155 patients received S-1 plus cisplatin (SP) treatment as first-line chemotherapy in Cancer Institute Hospital of JFCR, Japan. Among them, 148 patients could not continue SP treatment because of disease progression or unacceptable toxicity. 109 patients could receive second-line chemotherapy (Group A), while 39 patients could not (Group B). We evaluated the clinicopathologic factors that affected not to receive second-line chemotherapy, retrospectively. Univariate and multivariate analyses were performed on the baseline factors before starting first-line chemotherapy. Results: Characteristics of patients were below (Group A vs B): median age, 60 vs 66 (years); gender (male), 71.6 % vs 66.7 %. Median progression-free survival were not different in both Group statistically (6.5 vs 7.2 months; log-rank, p=0.861). Median overall survival were 16.5 vs 10.3 months (log-rank, p<0.001), respectively. Univariate analyses found 4 limiting factors not to initiate second-line chemotherapy: age over 65 years old (p=0.025), performance status>1 (p=0.017), alkaline phosphatase (ALP) >400 IU/l (p<0.001), C-reactive protein (CRP) >1.0 mg/dl (p=0.004). Multivariate analyses showed ALP elevation was a limiting factor (HR 4.122, p=0.003). Conclusions: Alkaline phosphatase can be an uncomplicated and potent limiting factor of discontinuance of chemotherapy after failure of the first line S-1 plus CDDP in Japanese patients with AGC.

S-1 Plus Cisplatin with Concurrent Radiotherapy for Locally Advanced Non-small Cell Lung Cancer: A Multi-Institutional Phase II Trial (West Japan Thoracic Oncology Group 3706)

To evaluate the combination chemotherapy using oral antimetabolite S-1 plus cisplatin (SP) with concurrent thoracic radiotherapy (RT) followed by the consolidation SP for locally advanced non-small cell lung cancer. Patients with stage III non-small cell lung cancer, 20 to 74 years of age, and Eastern Cooperative Oncology Group performance status 0 to 1 were eligible. The concurrent phase consisted of full dose S-1 (orally at 40 mg/m/dose twice daily, on days 1-14) and cisplatin (60 mg/m on day 1) repeated every 4 weeks for two cycles with RT delivered beginning on day 1 (60 Gy/30 fractions over 6 weeks). After SP-RT, patients received an additional two cycles of SP as the consolidation phase. Fifty-five patients were registered between November 2006 and December 2007. Of the 50 patients for efficacy analysis, the median age was 64 years; male/female 40/10; Eastern Cooperative Oncology Group performance status 0/1, 21/29; clinical stage IIIA/IIIB 18/32; and adenocarcinoma/others 20/30. There were 42 clinical responses including one complete response with an objective response rate of 84% (95% confidence interval [CI], 71-93%). The 1- and 2-year overall survival rates were 88% (95% CI, 75-94%) and 70% (95% CI, 55-81%), respectively. The median progression-free survival was 20 months. Of the 54 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 neutropenia (26%), thrombocytopenia (9%), and grade 3 esophagitis (9%) and febrile neutropenia (9%). In one patient, grade 3 pneumonitis was observed in the consolidation phase. There were two treatment-related deaths caused by infection in the concurrent phase. SP-RT showed a promising efficacy against locally advanced NCSLC with acceptable toxicity.

Comparison of safety and efficacy of S-1 monotherapy and S-1 plus cisplatin therapy in elderly patients with advanced gastric cancer

Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently. We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m(2), bid) was administered for 3 weeks and cisplatin (60 mg/m(2)) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m(2), bid) was administered for 4 weeks, every 6 weeks. SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively. SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.

A pilot study of S-1 plus cisplatin versus 5-fluorouracil plus cisplatin for postoperative chemotherapy in histological stage IIIB-IV (M0) gastric cancer

Although its efficacy is unproven, 5-fluorouracil plus cisplatin (FP) is used to prevent postoperative relapse in gastric cancer. We investigated the safety and feasibility of S-1 plus cisplatin (SP) vs. FP for stage IIIB-IV (M0) gastric cancer. Following curative resection, 41 stage IIIB-IV (M0) gastric cancer patients were assigned to SP (eight 14-day cycles of S-1 [40 mg/m(2) twice daily] plus cisplatin [60 mg/m(2) day 1] administered every 3 weeks) or FP (six 3-day cycles of FU [1 g/m(2) per day] plus cisplatin [80 mg/m(2) day 1] every 4 weeks). Doses were reduced based on predefined criteria. Patient characteristics were balanced between the two arms. In total, 124 cycles of SP (N = 20, median = 7, range 1-8) and 113 cycles of FP (N = 21, median 6, range 1-6) were administered. The median relative dose intensity per patient was 75% (49.99-100%) for S-1, 100% (75-100%) for cisplatin in SP, and 100% (64-100%) for 5-FU, 100% (60-100%) for cisplatin in FP. The relative dose intensity of FP was stable, while that of SP decreased during treatment. After median follow-up of 7.9 months (3.8-14.55), the median RFS was not reached. Relapse occurred in two (10%) patients on SP and five (23.8%) in the FP arm (P = 0.24). The incidence of grade 3-4 granulocytopenia was 36.8% with SP and 14.3% with FP. Grade 3-4 non-hematologic toxicities included fatigue (5.2% with SP vs. 4.8% with FP), vomiting (10.5% with SP vs. 0% with FP), and infection (5.2% with SP vs. 0% FP). S-1 plus cisplatin was feasible and tolerable as adjuvant treatment for stage IIIB-IV (M0) gastric cancer. However, because of decreased relative dose intensity during treatment, further study is warranted to determine optimal dosage and combination.

Impacts of fluorouracil‐metabolizing enzymes on the outcomes of patients treated with S‐1 alone or S‐1 plus cisplatin for first‐line treatment of advanced gastric cancer

A phase III trial of S-1 plus cisplatin (SP) versus S-1 alone, for first-line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S-1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S-1 alone than SP. We studied 120 patients who received S-1 alone or SP for first-line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor-A, and epidermal growth factor receptor in paraffin-embedded specimens of primary tumors. Multivariate survival analysis in patients who received S-1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n = 23) than their cutoff values, the S-1 alone group (n = 15) had longer overall survival than the SP group (n = 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S-1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S-1 alone will yield survival benefit.