Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. LBA4513-LBA4513 ◽  
Author(s):  
N. Boku ◽  
S. Yamamoto ◽  
K. Shirao ◽  
T. Doi ◽  
A. Sawaki ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Final Analysis ◽  
Phase Iii ◽  
Survival Times ◽  
Time To Treatment Failure ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Significant Superiority

LBA4513 Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m2/d, ci, d1–5, q4w), CP (irinotecan, 70mg/m2, div, d1&15 and cisplatin, 80mg/m2, div, d1, q4w) and S-1 (40mg/m2, b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases. [Table: see text] [Table: see text]

Randomized phase III study of 5-fluorouracil continuous infusion (5FUci) versus methotrexate and 5-FU sequential therapy (MF) in gastric cancer with peritoneal metastasis (JCOG0106)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4545-4545 ◽  
Author(s):  
K. Shirao ◽  
N. Boku ◽  
Y. Yamada ◽  
K. Yamaguchi ◽  
T. Doi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Peritoneal Metastasis ◽  
Final Analysis ◽  
Sequential Therapy ◽  
Nutrition Support ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Intestinal Stenosis ◽  
Secondary Endpoints ◽  
Phase Iii Study

4545 Background: Gastric cancer (GC) with peritoneal metastasis (PM) often complicates ascites or intestinal stenosis and the prognosis is still poor. Anti-cancer drugs generally can not be administered for such patients (pts) due to the risk of serious and prolonged adverse events. However, 5FU-based chemotherapy is reportedly relatively safe for PM. We conducted a phase III study to investigate the superiority of MF over 5FUci for GC with PM with a primary endpoint of overall survival (OS) and secondary endpoints of toxicities, ingestion-possible survival (IPS) in pts with initially possible ingestion and proportion of ingestive improvement (%II) in pts requiring nutrition support. Methods: Eligibility criteria included pts with histologically proven gastric adenocarcinoma; inoperable or recurrent GC; PM with radiologically confirmed intestinal stenosis or ascites; 20–75 years old; PS 0–2; no prior treatment except surgery or adjuvant chemotherapy. Treatment with 5FUci (800mg/m2/d, civ, d1–5, q4w) or MF (methotrexate, 100mg/m2, iv, followed 3 h later by 5FU, 600mg/m2, iv, with leucovorin rescue, q1w) were continued until disease progression or unacceptable toxicities. Projected sample size was 236 in total, which had 80% power to detect 40% increase of median OS in MF with 1-sided alpha 0.05. Results: A total of 237 pts were randomized between Oct 2002 and Apr 2007. Final analysis was performed in Dec 2008 when 224 pts (95%) were dead. Results of OS are shown in Table . Median IPS was 8.1M for 5FUci(n=102) and 9.0M for MF(n=103) (p=0.60). %II was 41%(7/17) for 5FUci and 57%(8/14) for MF (p=0.48). Frequencies (%) of grade 4 neutropenia, grade >3 febrile neutropenia, infection with neutropenia, anemia, anorexia, diarrhea, abdominal pain within 6M, and treatment related death (5-FUci/MF) were 0/9, 0/3, 0/5, 10/16, 27/34, 1/10, 5/10 and 2/1, respectively. Conclusions: MF could not become new standard therapy for GC with PM. [Table: see text] No significant financial relationships to disclose.

Potential predictive markers of chemotherapy for advanced gastric cancer: Biomarker study in GC0301/TOP-002, randomized phase III study of irinotecan plus S-1 versus S-1.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 55-55
Author(s):  
Naotoshi Sugimoto ◽  
Akira Tsuburaya ◽  
Ryohei Kawabata ◽  
Kazuhiro Nishikawa ◽  
Haruhiko Imamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Median Survival ◽  
Cox Regression ◽  
Phase Iii ◽  
Model Interaction ◽  
Phase Iii Study ◽  
Baseline Factors ◽  
Significant Superiority

55 Background: Irinotecan plus S-1(IRI-S) achieved longer median survival than S-1 monotherapy and was well tolerated for patients with advanced gastric cancer (AGC) in GC0301/TOP-002, but it did not show significant superiority (Gastric Cancer 2011). According to subset analyses, IRI-S may have extra survival benefit in some group of patients, prompting to explore prognostic or predictive markers.We correlated expression of 5 genes related to DNA and anticancer drug metabolism (TS, DPD, Topo-I, ERCC1, TP) with outcome of patients in each arm. Methods: Paraffin-embedded primary tumor specimens before chemotherapy were available from 126 of 326 patients. mRNA expression in microdissected tumors was measured by real-time RT-PCR, and categorized into low and high using the median as a cut-off. Multivariate analysis for overall survival (OS) adjusting baseline factors, gene expression and treatment (S-1/IRI-S) was performed with a Cox regression model. Interaction tests were also carried out between gene expression and treatment. Results: Although baseline factors of the subjects were similar to the entire GC0301/TOP-002 trial, median survival seemed opposite; 13.1M for S-1 and 11.4M for IRI-S arm, p=0.192. 92 samples, 47 of S-1 and 50 of IRI-S arm, were assessable for 5 genes. Multivariate analyses showed that liver metastasis correlated with poor prognosis (HR, 2.73; 95% CI, 1.50-5.01; P=0.011), but no gene was significantly correlated with OS. There were interactions between the treatment effect for DPD and TP. HRs between high and low DPD were 3.02 in S-1 and 0.96 in IRI-S arm, p=0.012 for interaction; while those for TP were 2.98 in S-1 and 0.38 for IRI-S arm, p=0.002. In patients with low TS and high Topo-I (n=18), OS was 11.2M for S-1 and 18.6M for IRI-S arm, p=0.531. Conclusions: The correlative analyses suggest DPD and TP are predictive factor for the first-line treatment of AGC including S-1 and irinotecan. Combined biomarker analyses with the previous randomized phase III study including S-1 or irinotecan is warranted to verify these findings.

scholarly journals Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

2015 ◽  
Vol 26 (1) ◽  
pp. 141-148 ◽  
Author(s):  
Y. Yamada ◽  
K. Higuchi ◽  
K. Nishikawa ◽  
M. Gotoh ◽  
N. Fuse ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Iii ◽  
Phase Iii Study

Irinotecan plus S-1 (IRIS) versus S-1 alone as first line treatment for advanced gastric cancer: Preliminary results of a randomized phase III study (GC0301/TOP-002)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4525-4525 ◽  
Author(s):  
K. Chin ◽  
H. Iishi ◽  
H. Imamura ◽  
O. Kobayashi ◽  
H. Imamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Cancer Survival ◽  
Single Agent ◽  
Rest Period ◽  
Phase Iii ◽  
Best Response ◽  
Independent Review ◽  
Grade 3 ◽  
Gastric Cancer Patients

4525 Background: Irinotecan has single agent activity and combination activity with S-1 reportedly in phase I/II studies with advanced gastric cancer patients (pts). S-1, oral fluoropyrimidine, also has activity on gastric cancer. A multicenter, randomized phase III trial comparing IRIS to S-1 alone in advanced gastric cancer was conducted. Methods: Pts with previously untreated gastric cancer were randomized to Arm A (oral S-1 80 mg/m2/day from day 1 to 28 followed by a 14-day rest period), or Arm B (oral S-1 80 mg/m2/day from day 1 to 21 and intravenous irinotecan 80 mg/m2 on days 1 and 15 followed by a 14-day rest). Treatment was continued unless disease progression was observed. Inclusion criteria: PS (ECOG) of 0 to 2; adequate major organ functions. Primary endpoint was overall survival. Results: From June 2004 to November 2005, 326 pts were randomized to arm A (162 pts) and arm B (164 pts). Pts characteristics (arm A vs. arm B) were as follows: median age: 63 vs. 63 years, PS 0–1: 97% vs. 97%, and distribution of subtype of intestinal/diffuse/others: 44%/55%/1% vs. 41%/58%/1%. Among 187 RECIST-evaluable pts (93 vs 94) reviewed by independent review panel, best response rates were 26.9% for arm A and 41.5% for arm B(p=0.035). Among 319 toxicity-evaluable patients (161 vs 158), grade 3 or 4 toxicities for arm A vs arm B (% of pts) were as follows: neutropenia 9.3% vs 26.6%, diarrhea 5.6% vs 15.8%, anorexia 9.9% vs 15.8%, nausea 3.7% vs 7.0%, vomiting 0.6% vs 2.5%. Conclusions: IRIS is effective, and well tolerated in pts with advanced gastric cancer. Survival analysis is underway. No significant financial relationships to disclose.

International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): Final results of the AGITG MAX trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4023-4023
Author(s):  
N. C. Tebbutt ◽  
V. Gebski ◽  
K. Wilson ◽  
M. Cummins ◽  
Y. Chua ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Phase Iii ◽  
First Line ◽  
Treatment Regimens ◽  
Intention To Treat ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Low Toxicity ◽  
Grade 3

4023 Background: The addition of Bev to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in mCRC. Cap± MMC are alternate chemotherapy regimens suitable for patients (pts) who are either unfit for or who do not require initial oxaliplatin/irinotecan. This phase III study compared Cap with Cap Bev and Cap Bev MMC. The aim was to develop a low toxicity regimen suitable for a broad population of pts with mCRC. Methods: Previously untreated pts with unresectable mCRC considered suitable for Cap monotherapy were randomised to arm A Cap (Cap 2000mg/m2/d or 2500mg/m2 d1–14 q21d), arm B Cap Bev (Bev 7.5mg/kg q3w) or arm C Cap Bev MMC (MMC 7mg/m2 q6w). Primary endpoint: PFS, secondary endpoints: RR, toxicity, OS, QoL . Randomisation was stratified by age, PS, centre and Cap dose. Response was assessed every 6w. The study was designed to detect an increase in the median PFS from 5.5m (arm A) to 8m (arm B or C) at p<0.025 with 80% power. Results: A total of 471 pts were randomised from July 2005-June 2007. Outcomes were evaluated on an intention to treat basis and included 15 ineligible pts. Baseline demographics were well balanced between arms with median age 67y (range 31–86y). Toxicity was reported: ASCO 2008 abstr 4029. The most common grade 3/4 toxicities were PPE (16%, 26%, 28%) and diarrhoea (11%, 17%, 16%) for arms (A,B,C). However, adjusted rates per cycle were similar as arms B & C received more cycles of Cap (A8.3, B10.8, C10.5). Other toxicity rates were generally <10%. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B & C. RR and OS are summarized ( Table ). Conclusions: All treatment regimens were well tolerated in a relatively elderly patient cohort. The addition of Bev±MMC to Cap significantly improved PFS without significant additional toxicity. OS was similar for all arms. Cap Bev±MMC is an active, low toxicity regimen that may be considered as a treatment option for pts with mCRC. [Table: see text] [Table: see text]

A single-arm, phase II feasibility study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 96-96
Author(s):  
M. Ryu ◽  
Y. Choi ◽  
B. Kim ◽  
Y. Park ◽  
H. Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Advanced Gastric Cancer ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Phase Iii ◽  
R0 Resection ◽  
Locally Advanced Gastric Cancer ◽  
Grade 3

96 Background: The aim of this study was to evaluate feasibility and safety of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in patients with potentially resectable adenocarcinoma of stomach or gastroesophageal junction. Methods: Forty-one patients with clinical stage T3-4N0M0 or T2-4N+M0 determined by CT, endoscopic ultrasonography, and laparoscopy were enrolled between DEC 2008 and MAR 2010. Gastrectomy with D2 lymph node dissection was conducted after 3 cycles of DOS chemotherapy. DOS chemotherapy consists of docetaxel 50 mg/m2 iv (day1), oxaliplatin 100 mg/m2 iv (day1), and S-1 40 mg/m2 po bid (days1-14) at 3 weeks interval. After curative gastrectomy, the patients were given 1 year of adjuvant chemotherapy with S-1 (40 mg/m2 D1-28, every 6 weeks). Results: All patients finished the planned neoadjuvant chemotherapy. Twenty-three (56%) patients achieved a partial response, and the remaining 18 patients had stable disease by CT scan after 3 cycles of DOS chemotherapy. No disease progression was observed during the neoadjuvant chemotherapy. A median 4.7 weeks (range, 4.0-7.6) after the start of the 3rd cycle of DOS chemotherapy, 39 (95%) patients underwent R0 resection with no pathologic residual disease in 4 (10%) patients. Hematologic toxicities were common including grade 4 neutropenia (32%), grade 3 thrombocytopenia (17%), and febrile neutropenia (10%). However, hematologic toxicities were generally transient and manageable. There were no grade 3 or 4 non-hematologic toxicities with frequency > 5% of patients. With all toxicities taken together, 21 (51%) patients experienced grade 3 or 4 toxicities (except grade 3 neutropenia). There was no treatment-related death, and surgical complications included only mild wound problem in 4 (10%) patients. Conclusions: In this study, neoadjuvant DOS chemotherapy could induce a sufficient down-staging and R0 resection of locally advanced gastric cancer with mild and manageable toxicities. A phase III randomized trial is planned for evaluating the benefit of neoadjuvant DOS chemotherapy in patients with locally advanced gastric cancer. [Table: see text]

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