Estrogen receptor-beta genetic variations and overall survival in patients with locally advanced gastric cancer.

Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor ß gene, ESR2, correlate with colorectal cancer survival. To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C>A) and rs3020443 (T>G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T>C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC.

Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.

Association of variants in genes encoding for macrophage-related functions with clinical outcome in patients with locoregional gastric cancer.

BACKGROUND: Nuclear factor-kappaB (NF-κB) and CCL2/CCR2 chemokine axis play a central role in tumor progression such as stimulation of angiogenesis, acceleration of tumor invasion and migration, and suppression of innate immunosurveillance in the macrophage-related functions. There have been few reports regarding association of the macrophage function-related genes with the clinical outcome in gastric cancer. We hypothesized that variants in genes encoding for NF-κB and CCL2/CCR2 axis may predict prognosis in gastric cancer and tested whether the functional single-nucleotide polymorphisms (SNPs) will be associated with clinical outcome in patients with gastric cancer across two independent groups. PATIENTS AND METHODS: This study enrolled two cohorts which consisted of 160 Japanese patients and 104 US patients with locoregional gastric cancer. Genomic DNA was analyzed for association of 11 SNPs in NFKB1, RELA, CCL2, and CCR2 with clinical outcome using PCR-based direct DNA sequencing. RESULTS: The univariable analysis showed four SNPs had significant association with clinical outcome in the Japanese cohort, NFKB1 rs230510 remained significant upon multivariable analysis. The patients with the A allele of the NFKB1 rs230510 had significantly longer overall survival (OS) compared with those with the T/T genotype in both the Japanese and US cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared with the C/C genotype in the US cohort [hazard ratio (HR) 2.43; P = 0.015] but longer OS in the Japanese cohort (HR 0.58; P = 0.021), resulting in the statistically significant opposite impact on OS (P = 0.001). CONCLUSIONS: Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with the clinical outcome in patients with locoregional gastric cancer. These results also suggest that the genetic predisposition of the host may dictate the immune-related component of the tumor for progression in gastric cancer.

Factors associated with the presence of multiple Lugol-voiding lesions in patients with esophageal squamous-cell carcinoma.

Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol-voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence-specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84-122.45: P = 0.011), presence of the ALDH2-2 allele (OR 4.5, 95% CI 1.55-13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02-6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13-88.44: P = 0.038) and presence of the ALDH2-2 allele (OR 4.56, 95% CI 1.4-14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2-2 allele (OR 17.5, 95% CI 1.97-155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2-2 allele (OR 8.85, 95% CI 1.68-46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2-2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2-2 allele (OR 4.0, 95% CI 0.54-29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2-2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal squamous cell carcinoma. Among drinkers with the ALDH2-2 allele, the risk of multiple LVLs increased in parallel to the daily alcohol intake.

Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer.

BACKGROUND: This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment. METHODS: Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP. CONCLUSION: Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.

Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours.

BACKGROUND: TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours. METHODS: TAS-102 was administered twice daily on days 1-5 and days 8-12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1. RESULTS: Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m(-2) per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m(-2). α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m(-2) per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m(-2) per day was the recommended dose for phase II studies. CONCLUSIONS: TAS-102 at 70 mg m(-2) per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.

Propofol sedation with bispectral index monitoring is useful for endoscopic submucosal dissection: a randomized prospective phase II clinical trial.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) has become a standard treatment. However, the treatment time tends to be relatively long and insufflation and manipulation of the endoscope can increase pain and discomfort. We aimed to find an optimal method for sedation during ESD. PATIENTS AND METHODS: Patients scheduled to undergo ESD for early gastric cancer or adenoma were randomly assigned to sedation with midazolam or propofol, and consciousness level was evaluated by bispectral index (BIS) monitoring. Primary end points of effectiveness (three parameters) and secondary end points of safety during ESD and after return to the ward were compared between the groups. Study registration was in the UMIN Clinical Trial Registry (UMIN 000001497), and the institutional trial number was KDOG 0801. RESULTS: From June 2008 through June 2009, we enrolled 178 patients (90 midazolam, 88 propofol). Regarding safety after ESD, recovery was significantly better in the propofol group immediately after and at 1 hour and 2 hours after return to the ward (P < 0.001). The number of patients who required a continuous supply of oxygen 2 hours after returning to the ward was significantly lower in the propofol group (midazolam 18; propofol 6; P = 0.010). Though propofol seemed to be better for effectiveness and safety, there were no statistically significant differences for all three primary end points and the safety parameters (hypotension, hypoxia, bradycardia). CONCLUSIONS: Propofol with BIS monitoring improved recovery of patients after ESD, though this study was underpowered to prove the effectiveness and safety of propofol.

Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention.

BACKGROUND AND STUDY AIMS: Recent progress in chemotherapy has prolonged the survival of patients with malignant biliary strictures, leading to increased rates of stent occlusion. Occlusion of covered metallic stents now occurs in about half of all patients with malignant biliary strictures. The removal of metallic stents followed by placement of a second stent has been attempted, but outcomes remain controversial. The aim of the current study was to evaluate the effectiveness and safety of the primary placement and secondary placement (re-intervention) of covered metallic stents and to assess the feasibility and safety of stent removal. PATIENTS AND METHODS: The study included 186 patients with unresectable malignant biliary strictures who underwent primary stent placement between October 2001 and March 2010.  Covered biliary self-expandable metal stents (SEMSs) were removed in 39 of these patients, and 36 underwent re-intervention. The patency times, occlusion rates of the first stent and re-intervention, success rates of stent removal, and complications were investigated. RESULTS: Covered SEMSs were placed in 186 patients. The median patency time of the first stent was 352 days. Stent occlusion occurred in 48.9 % of the patients and was mainly caused by debris or food residue (37 %), dislocation (19 %), and migration with hyperplasia (19 %). Stent removal was attempted in 50 patients and was successful without complication in 39 (78 %). Most of the patients in whom stent removal was unsuccessful had migration with hyperplasia. The median patency time of the second stent was 263 days. The stent patency time did not significantly differ between the first and the second stent. CONCLUSIONS: Covered SEMSs could be safely removed at the time of stent occlusion. Patency rates were similar for initial stent placement and re-intervention.

Fine needle aspiration using forward-viewing endoscopic ultrasonography.

BACKGROUND AND STUDY AIM: A prototype forward-viewing instrument has been developed for therapeutic endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA). We had the opportunity to use this forward-viewing echo endoscope and to study its clinical usefulness, mainly for diagnostic EUS-FNA. PATIENTS AND METHODS: The prototype forward-viewing echo endoscope was used for 15 months between November 2006 and March 2010, in a study group comprising 47 consecutive patients. Diagnostic EUS-FNA was done in 38 patients and the diagnostic accuracy of the forward-viewing device was compared with that from an oblique-viewing echo endoscope in reference patients who were matched by disease and puncture route. Therapeutic EUS was done in nine patients (pseudocyst drainage in six; celiac ganglia neurolysis, biliary drainage, and pancreatic duct drainage in one each). RESULTS: Diagnostic EUS-FNA provided a correct diagnosis in 97.4 % (37/38 patients), which was not significantly different from the 94.7 % (36/38) in the reference patients. Lesions considered difficult to access with an oblique-viewing scope, such as those located at the fornix, or the head of the pancreas, or associated with strictures, were easily punctured, as were those located at the body or tail of the pancreas or at the porta hepatis. Treatment was successful in all nine patients who underwent therapeutic EUS procedures. None of the 47 patients had any complications. CONCLUSIONS: A forward-viewing echo endoscope that allows target sites to be punctured more perpendicularly with minimal effort, can be used for diagnostic EUS-FNA and this may be advantageous, depending on the site of target lesions.

Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels.

The association between viral level and the long-term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow-up in 104 HBeAg-negative Japanese carriers with PNALT. During a mean follow-up period of 6.4 ± 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of ≥5 log10 copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of ≥5 log10 copies/mL and an alanine aminotransferase (ALT) level of >20 to ≤40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of ≥5 log10 copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg-negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk.

Quadruple therapy with ecabet sodium, omeprazole, amoxicillin and metronidazole is effective for eradication of Helicobacter pylori after failure of first-line therapy (KDOG0201 Study).

BACKGROUND AND OBJECT: An antiulcer agent, ecabet sodium, is active against Helicobacter pylori. The aim of the present study was to clinically examine whether eradication therapy, which includes ecabet sodium, is effective in eradication of H. pylori after failure of first-line therapy. METHODS: Patients with peptic ulcer who failed with first-line triple eradication therapy containing clarithromycin received quadruple therapy with omeprazole (20 mg, twice daily), amoxicillin (750 mg, twice daily), metronidazole (500 mg, twice daily) and ecabet sodium (1000 mg, twice daily) for 14 days. Eradication of H. pylori was judged by 13C-urea breath test 8 weeks later. RESULTS: Fifty-two patients (36 men and 16 women) were included. Their mean age was 51.4 years (range 28-73). One patient dropped out because of diarrhoea. The eradication rate was 98.0% (50/51) according to the per-protocol analysis and 96.2% (50/52) according to the intention-to-treat analysis. Side effects occurred in seven patients, but none were serious. CONCLUSIONS: Quadruple therapy including ecabet sodium is useful as second-line eradication treatment for H. pylori.

Narrow band imaging for detecting superficial squamous cell carcinoma of the head and neck in patients with esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Narrow band imaging combined with magnifying endoscopy (NBI-ME) is useful for the detection of superficial squamous cell carcinoma (SCC) within the oropharynx, hypopharynx, and oral cavity. The risk of a second primary SCC of the head and neck is very high in patients with esophageal SCC. This prospective study evaluated the detection rate of superficial SCC within the head and neck region (superficial SCCHN) with NBI-ME in patients with esophageal SCC. PATIENTS AND METHODS: Between March 2006 and February 2008, 112 patients with a current or previous diagnosis of esophageal SCC were enrolled. All patients underwent endoscopic screening of the head and neck by NBI-ME. The primary end point was the detection rate for superficial SCCHN. Secondary end points were to compare demographic characteristics between patients with and without superficial SCCHN and to assess the clinical course of patients with superficial SCCHN. RESULTS: The detection rate for superficial SCCHN was 13 % (15/112). The prevalence of multiple Lugol-voiding lesions, observed endoscopically throughout the esophageal mucosa after application of Lugol dye solution, was significantly higher in patients with superficial SCCHN than in those without (100 % vs. 24 %, P < 0.0001). Minimally invasive curative treatment with organ preservation was feasible without severe complications in patients with superficial SCCHN after curative treatment of esophageal SCC. CONCLUSIONS: In patients with esophageal SCC, NBI-ME is useful for detecting superficial SCCHN, thereby facilitating minimally invasive treatment.

Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer.

BACKGROUND: S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC. PATIENTS AND METHODS: S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1. RESULTS: Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%). CONCLUSION: S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study).

BACKGROUND: The efficacy and safety of oxaliplatin combined with S-1 (SOX regimen) for unresectable advanced or recurrent gastric cancer were investigated. PATIENTS AND METHODS: Oxaliplatin was administered i.v. (100 mg/m(2)) on day 1, while S-1 was administered orally (80 mg/m(2)/day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks. RESULTS: Among 55 patients enrolled, one patient received oxaliplatin for the other study, and three patients were considered unsuitable against the inclusion criteria. Accordingly, 51 patients were assessable for efficacy. The response rate was 59%, and the disease control rate was 84%. The median progression-free survival time was 6.5 months, the 1-year survival rate was 71%, and the median survival time was 16.5 months. In 54 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (22%), thrombocytopenia (13%), anemia (9%), anorexia (6%), fatigue (6%), and sensory neuropathy (4%). CONCLUSION: These findings indicate that SOX regimen with oxaliplatin at a dose of 100 mg/m(2) is feasible and shows promising efficacy against advanced gastric cancer.

Successful treatment of S-1 + CDDP followed by salvage EMR for a case with metastatic Barrett's esophageal cancer.

A 62-year-old woman with Barrett's esophageal cancer was hospitalized. Abdominal CT confirmed metastases to the liver and lymph nodes, for which surgical excision and radiotherapy were not indicated. We started chemotherapy with a course of daily oral S-1 at a dose of 80 mg/m(2) for 21 days, with a 2-hour drip of cisplatin at 60 mg/m(2) on day 8. Breaks of 14 drug-free days were given between courses. After two courses, a repeat CT confirmed that the liver and lymph node metastases had disappeared; after three courses, another CT confirmed that the metastatic foci were still absent, so we judged the disease to be in complete remission. Endoscopy and upper GI series confirmed that the primary tumor was reduced, and endoscopic mucosal resection performed using the strip biopsy method. The excision specimen was well differentiated adenocarcinoma, and mucosal invasion, and the excision stump was negative. After two more courses of S-1 + cisplatin, chemotherapy has been suspended with the patient's consent, and in the 21 months after endoscopic mucosal resection, no recurrence has been observed. This is a rare case of metastatic Barrett's esophageal cancer in which the metastases were eradicated by S-1 + cisplatin, and the primary tumor successfully excised by endoscopic mucosal resection after downstaging.

Treatment for developmental dysplasia of the hip using the Pavlik harness: long-term results.

We reviewed the medical records of 115 patients with 130 hips with developmental dysplasia with complete dislocation in the absence of a neuromuscular disorder, spontaneous reduction with a Pavlik harness, and a minimum of 14 years' follow-up. The mean age at the time of harness application was 4.8 months (1 to 12) and the mean time spent in the harness was 6.1 months (3 to 12). A total of 108 hips (83.1%) were treated with the harness alone and supplementary surgery for residual acetabular dysplasia, as defined by an acetabular index > 30 degrees , was performed in 22 hips (16.9%). An overall satisfactory outcome (Severin grade I or II) was achieved in 119 hips (91.5%) at a mean follow-up of 16 years (14 to 32) with a follow-up rate of 75%. Avascular necrosis of the femoral head was noted in 16 hips (12.3%), seven of which (44%) underwent supplementary surgery and nine (56%) of which were classified as satisfactory. The acetabular index was the most reliable predictor of residual acetabular dysplasia.

Expansion of the indications for endoscopic mucosal resection in patients with superficial esophageal carcinoma.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is a minimally invasive local treatment for superficial esophageal carcinoma (SEC). The use of EMR in patients with m3 or sm1 SEC remains controversial, however. The aim of this retrospective study was to evaluate the histopathological risk factors for lymph-node metastasis and recurrence in patients with m3 or sm1 SEC. PATIENTS AND METHODS: The study subjects were 43 patients with m3 or sm1 esophageal squamous-cell carcinomas: 23 patients were treated surgically (the surgery group), and 20 were treated by EMR (the EMR group). We assessed the following variables of the specimens resected by surgery or EMR: tumor depth, maximal surface diameter of the tumor (superficial size), maximum diameter of tumor invasion at the lamina muscularis mucosae (LMM invasion width), and lymphatic invasion. The relationships of these variables to lymph-node metastasis and recurrence were examined. RESULTS: In the surgery group, lymph-node metastasis was found in four patients, all of whom had tumors with lymphatic invasion, a superficial size of at least 25 mm, and an LMM invasion width of at least 2500 microm. In the EMR group, no patient met all three of these criteria, and there was no evidence of lymph-node metastasis or distant metastasis on follow-up after EMR (median follow-up 39 months). CONCLUSIONS: In patients with m3 or sm1 SEC, tumors that have lymphatic invasion, larger superficial size, and wider LMM invasion are associated with a high risk for lymph-node metastasis. EMR might be indicated for the treatment of patients with m3 or sm1 SECs without these characteristics.

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer.

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

Phase 1/11 study of bi-weekly irinotecan plus cisplatin in the treatment of advanced gastric cancer.

OBJECTIVES: To conduct a phase I/II study of irinotecan with cisplatin to establish a recommended dose, and assess the safety, efficacy and feasibility of this regimen in unresectable advanced or recurrent gastric cancer. PATIENTS AND METHODS: In the phase I portion of the study, patients received a fixed dose of cisplatin (30 mg/m2) with escalating doses of irinotecan, ranging from 30 mg/m2 to 70 mg/m2, on days 1 and 15. In the phase II portion of the study, 40 patients were evaluated for response and safety at the recommended dose. RESULTS: Eighteen patients were enrolled in the phase I study. Dose-limiting toxicity (diarrhea and neutropenia) appeared at the irinotecan dose of 70 mg/m2. Therefore, the recommended irinotecan dose was 60 mg/m2. In the phase II study, 40 patients received cisplatin (30 mg/m2) plus irinotecan (60 mg/m2). Twenty-five out of 40 patients had received prior chemotherapy. The median number of cycles was 3.5. The response rate was 32.5% (13/40) overall, and 53.3% (8/15) in patients without prior chemotherapy. The median time to tumor progression (TTP) was 162 days. The median survival time was 288 days. Four patients (10%) developed grade 4 neutropenia and 3 patients (7.5%) developed grade 4 anemia. The only observed non-hematological toxicity at grade 3 or higher was diarrhea, seen in 2.5% (1/40) of the patients. CONCLUSION: Bi-weekly administration of irinotecan and cisplatin is safe and active for the management of unresectable advanced or recurrent gastric cancer.

Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer.

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.