Keun Won Ryu

We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 plus docetaxel in locally advanced gastric cancer (LAGC) and to investigate the association between CYP2A6 genotype and outcome. Patients with LAGC [clinical stage III–IV (M0) by the Japanese staging system] received three cycles of pre- and postoperative chemotherapy (S-1 40 mg/m² twice daily on days 1–14; intravenous docetaxel 35 mg/m² on days 1 and 8, every 3 weeks) followed by gastrectomy with D2 dissection. We also performed a pharmacokinetic and CYP2A6 genotyping study (*1, *4, *7, *9, *10) for S-1. From October 2006 to June 2008, 44 patients entered the study. 43 eligible patients completed preoperative chemotherapy and 40 completed postoperative chemotherapy. The most common G3/4 toxicities during pre- and postoperative chemotherapy were neutropenia, stomatitis, and abdominal pain. The clinical response rate by RECIST was 74.4 % (95 % CI, 61.4–87.4 %), and the R0 resection rate was 97.7 %. Clinical downstaging in T or N occurred in 41.9 % of patients. The 3-year progression-free survival (PFS) rate was 62.8 % and 5-year overall survival (OS) rate was 69.6 %. PFS and OS differed significantly according to clinical response, clinical downstaging, and CYP2A6 genotype. Patients with CYP2A6 variant/variant genotypes had a higher tegafur C _max and worse survival than those with wild/wild or wild/variant genotypes. Perioperative S-1 plus docetaxel is active with a manageable toxicity in patients with LAGC receiving D2 surgery. Clinical tumor response, clinical downstaging, and CYP2A6 genotype may predict efficacy.

We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. Among MGC patients (n=108), who received S-1 (40 mg m⁻² b.i.d., days 1–14) and cisplatin (60 mg m⁻², day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Background: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. Patients and methods: Patients with previously untreated MGC received S-1 40 mg/m² b.i.d. on days 1–14 and irinotecan 150 mg/m² plus oxaliplatin 85 mg/m² on day 1 every 3 weeks. Results: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). Conclusions: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

We conducted the current study to investigate the clinical outcomes of metastatic gastric carcinoma (MGC) patients who experienced gastrointestinal (GI) perforation during palliative chemotherapy and to examine the prognostic factors associated with survival after perforation. We reviewed the medical records of patients at the Center for Gastric Cancer of the National Cancer Center, Korea who developed GI perforation during palliative chemotherapy between January 2001 and December 2008. Of the 1,856 patients who received palliative chemotherapy for MGC, 32 patients (1.7%) developed GI perforation during chemotherapy. Patients with perforation at the primary gastric site were more likely to have ulcerative gastric cancer lesion (90.5 vs. 40.0%, P = 0.034) or gastric tumor bleeding (28.6 vs. 0%, P = 0.298), and less likely to have Bormann type IV (14.3 vs. 60.0%, P = 0.062), than patients with perforation at nongastric sites. In 14 patients (43.8%) who resumed chemotherapy after perforation, the disease control rate was 57.1%, and median overall survival (OS) after perforation was 7.5 months [95% confidence interval (CI), 6.0–9.0 months]. In all patients, median OS following perforation was 4.0 months (95% CI, 1.5–6.6 months), and multivariate analysis revealed that differentiated tumor histology, response to chemotherapy before perforation, and absence of septic shock at time of perforation were significantly associated with favorable OS after perforation. As patients experiencing GI perforation during palliative chemotherapy have heterogeneous clinical presentation, we need to adopt different approaches in the management of the patients that are compatible with the favorable prognostic factors.

Background Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated. Patients and methods We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area. Results The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8 months vs. 11.4 months vs. 8.4 months; P < 0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7 months; P = 0.037) and OS (23.8 vs. 12.8 months; P = 0.010) than those with de novo metastatic disease and it was validated by multivariate analysis. Conclusion Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1–14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30–45 mg m⁻² b.i.d.) and docetaxel (25–40 mg m⁻²); MTD was 45 mg m⁻² b.i.d. S-1/35 mg m⁻² docetaxel and RD was 40 mg m⁻² b.i.d. S-1/35 mg m⁻² docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8–79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9–8.1) and 13.7 months (95% CI: 9.9–17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.