Effect of early tumor response on the health-related quality of life among patients on second-line chemotherapy for advanced gastric cancer in the ABSOLUTE trial.

BACKGROUND: This study evaluated the association between early tumor response at 8 weeks, previously reported as a positive outcome prognosticator, and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients enrolled in the ABSOLUTE trial. METHODS: HRQOL was assessed using the EuroQol-5 Dimension (EQ-5D) utility index score in patients with complete response (CR) + partial response (PR) and progressive disease (PD) at 8 weeks, and time-to-deterioration (TtD) of the EQ-5D score, with the preset minimally important difference (MID) of 0.05, was compared between these populations. Among the enrolled patients, 143 and 160 patients were assessable in weekly solvent-based paclitaxel (Sb-PTX) arm and weekly nanoparticle albumin-bound paclitaxel (nab-PTX) arm, respectively. RESULTS: Changes of the EQ-5D score from baseline to 8 weeks in the nab-PTX arm were 0.0009 and - 0.1229 in CR + PR and PD patients, respectively; the corresponding values for the Sb-PTX arm were - 0.0019 and - 0.1549. For both treatments, changes of the EQ-5D score from baseline at 8 weeks were significantly larger in patients with PD than in those with CR + PR. The median TtD was 3.9 and 2.2 months in patients with CR + PR and PD, respectively, for nab-PTX [hazard ratio (HR) = 0.595, 95% confidence interval (CI) 0.358-0.989]. For Sb-PTX, the corresponding values were 4.7 and 2.0 months (HR = 0.494, 95% CI 0.291-0.841). CONCLUSIONS: Early tumor shrinkage was associated with maintained HRQOL in AGC patients on the second-line chemotherapy with taxanes.

S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial.

BACKGROUND: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING: Taiho Pharmaceutical and Yakult Honsha.

Meta-analysis of two randomized phase III trials (TCOG GI-0801 and ECRIN TRICS) of biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer.

BACKGROUND: Biweekly irinotecan (CPT-11) plus cisplatin (CDDP) combination (BIRIP) and CPT-11 alone are both expectable options for treating advanced gastric cancer (AGC) in a second-line setting. We conducted a meta-analysis to compare the efficacy and safety of these two regimens in patients enrolled two randomized phase III trials. PATIENTS AND METHODS: Individual patient-level data from two randomized phase III trials were collected for this study. In both trials, patients with AGC refractory to S-1-based chemotherapy were randomly allocated to BIRIP (CPT-11, 60 mg/m2; CDDP, 30 mg/m2, q2w) or to CPT-11 (150 mg/m2, q2w). RESULTS: Cumulative data from 290 eligible patients were evaluated. The OS was 12.3 months [95% confidence interval (CI) 10.5-14.1] in the BIRIP group and 11.3 months (95% CI 10.0-13.2) in the CPT-11 group (hazard ratio 0.87; 95% CI 0.68-1.12, P = 0.272), while PFS was significantly longer in the BIRIP group (4.3 months [95% CI 3.5-5.1]) than in the CPT-11 group (3.3 months [2.9-4.1]; HR 0.77; 95% CI 0.61-0.98, P = 0.035). The response rate was 20.5% in the BIRIP group and 16.0% in the CPT-11 group (P = 0.361). However, the disease control rate was significantly better in the BIRIP group (72.1%) than in the CPT-11 group (59.2%) (P = 0.032). The two groups did not differ significantly in the incidences of grade 3 or worse adverse events. CONCLUSIONS: Both BIRIP and CPT-11 may be good therapeutic options for patients with AGC as second-line treatment. CLINICAL TRIAL REGISTRATION: UMIN 000025367.

Association between the findings of metachronous secondary primary malignancies and the number of Lugol-voiding lesions.

This study was designed to evaluate the relation between dysplastic squamous epithelium in the esophageal mucosa and the development of metachronous secondary primary malignancies (mSPM) other than esophagus after endoscopic resection (ER) in patients with early esophageal squamous cell carcinoma (SCC). We studied 330 patients with early esophageal SCC who underwent ER as a post hoc analysis of a prospective multicenter cohort study (UMIN Clinical Trials Registry ID UMIN000001676). Lugol-voiding lesions (LVL) were graded into 3 categories (A = no lesion; B = 1 to 9 lesions; C ≥ 10 lesions). The following variables were studied: (i) the incidences of mSPM other than esophagus; (ii) the standardized incidence ratios (SIRs) of mSPM; (iii) the cumulative incidence and total number of mSPM other than esophagus; and (iv) predictors of mSPM other than esophagus on analysis with a multivariate Cox proportional-hazards model. After a median follow-up of 46.6 months, mSPM other than esophagus was diagnosed in a total of 73 patients (90 lesions). Among the 106 patients in group C, 37 patients had mSPM (51 lesions), including head and neck cancer in 14 patients (24 lesions) and gastric cancer in 12 patients (16 lesions). The SIR of mSPM was 3.61 in this study subjects. An increase in the LVL grade (A to B to C) was associated with a progressive increase in the cumulative incidence rate of mSPM other than esophagus (P = 0.017 for A vs. C, P = 0.023 for B vs. C). An increase in the LVL grade (A to B to C) was also associated with a progressive increase in the total number of mSPM other than esophagus per 100 person-years (primary events, relative risk [RR] = 1.66 and 3.24 for grades B and C, respectively, vs. A, P = 0.002 for trend; all events, RR = 1.81 and 4.66 for grades B and C, respectively, vs. A, P < 0.0001 for trend). LVL grade C was a strong predictor of mSPM other than esophagus (RR = 3.41 for A vs. C). LVL grade may be a useful predictor of the risk of mSPM other than esophagus after ER in patients with early esophageal SCC.

Association between macrocytosis and metachronous squamous cell carcinoma of the esophagus after endoscopic resection in men with early esophageal squamous cell carcinoma.

BACKGROUND: Macrocytosis is associated with an increased risk of squamous cell carcinoma (SCC) arising in the esophagus in men. The aim of this study was to evaluate the association between macrocytosis and metachronous SCC of the esophagus after endoscopic resection (ER) of early esophageal SCC in men. METHODS: The study group comprised 278 men with early esophageal SCC after ER. The main study variables were as follows: (1) cumulative incidence and total number of metachronous SCC of the esophagus according to the presence or absence of macrocytosis (mean corpuscular volume ≥ 106 fl) and (2) predictors of metachronous SCC of the esophagus as assessed with a multivariate Cox proportional-hazards model. RESULTS: The median follow-up was 50.3 months. Macrocytosis was associated with a higher 2-year cumulative incidence of metachronous SCC of the esophagus (without macrocytosis vs. with macrocytosis: 11.4% vs. 38.1%, p = 0.002). Macrocytosis was also associated with a higher total number of metachronous SCC of the esophagus per 100 person-years (without macrocytosis vs. with macrocytosis: 7.7 vs. 31.5 per 100 person-years, p < 0.0001). In addition, macrocytosis was a significant predictor of metachronous SCC of the esophagus on multivariate Cox proportional-hazards analysis (relative risk 2.23). CONCLUSION: Macrocytosis is a useful predictor of the risk of metachronous SCC of the esophagus after ER of early esophageal SCC in men.

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial.

BACKGROUND: In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second-line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. METHODS: Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. RESULTS: This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45-0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06-1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42-0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01-1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). CONCLUSIONS: The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pretreated AGC patients. TRIAL REGISTRATION NUMBER: JapicCTI-132059.

A phase I study of S-1 in combination with nab-paclitaxel in patients with unresectable or recurrent gastric cancer.

BACKGROUND: In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study. METHODS: The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m2 twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m2 on day 1 or 8. RESULTS: Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 220 mg/m2 on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). The most common grade 3-4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone. CONCLUSIONS: Based on the present results, the RD was determined as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma.

BACKGROUND: Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. PATIENTS AND METHODS: This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20-80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. RESULTS: Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31-79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7-40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0-10.2) and 17.3 months (95% CI 11.7-19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. CONCLUSIONS: Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

Randomized phase II study of second-line chemotherapy with the best available 5-fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5-fluorouracil-containing regimens (JCOG0407).

BACKGROUND: This randomized phase II study compared weekly administration of paclitaxel (wPTX) with the best available 5-fluorouracil (5-FU) regimen as second-line treatment for advanced gastric cancer patients with severe peritoneal metastasis refractory to fluoropyrimidine. METHODS: In the best available 5-FU arm, continuous infusion of 5-FU (800 mg/m(2)/day, days 1-5, every 4 weeks) was given to patients with prior chemotherapy including bolus 5-FU, and methotrexate and 5-FU sequential bolus injection (methotrexate at 100 mg/m(2) followed by bolus 5-FU at 600 mg/m(2) with leucovorin, weekly) was given to those who had previously received continuous infusion of 5-FU or oral administration of fluoropyrimidine. In the wPTX arm, paclitaxel (80 mg/m(2)) was administered on days 1, 8, and 15, every 4 weeks. This study adopted a screening design (one-sided α = 30 %) with the primary end point of overall survival. RESULTS: One hundred patients were randomized to the 5-FU arm (n = 49) or the wPTX arm (n = 51). Although the median survival time was 7.7 months in both arms, the 2-year survival rates were 2.9 % in the 5-FU arm and 9.1 % in the wPTX arm [hazard ratio 0.89 (95 % confidence interval 0.57-1.38), one-sided p = 0.298}. The median progression-free survival was longer with wPTX than with 5-FU [3.7 months vs 2.4 months; hazard ratio 0.58 (95 % confidence interval 0.38-0.88), one-sided p = 0.005]. The incidences of grade 4 neutropenia, grade 3/4 febrile neutropenia, diarrhea, and treatment-related death were 6 %, 4 %, 10 %, and 2 %, respectively, in the 5-FU arm and 2 %, 0 %, 0 %, and 0 %, respectively, in the wPTX arm. CONCLUSIONS: As second-line chemotherapy, wPTX appears feasible and promising. This regimen can be included in a test arm in future phase III trials for treatment of advanced gastric cancer with severe peritoneal metastasis.

A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.

BACKGROUND: Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS: Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS: The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS: Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.

A phase I/II study of XELIRI plus bevacizumab as second-line chemotherapy for Japanese patients with metastatic colorectal cancer (BIX study).

BACKGROUND: Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study. METHODS: Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m(2) twice daily on days 1-15), irinotecan (200 mg/m(2) on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II. RESULTS: A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22-74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179-311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%). CONCLUSION: Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens.

Multicenter feasibility study of combination therapy with fluorouracil, leucovorin and paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake.

OBJECTIVE: Oral fluoropyrimidine plus cisplatin is a standard treatment for advanced gastric cancer, but patients with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy in such patients. METHODS: In the first phase of the study, we investigated the maximum tolerated dose and recommended dose in Cycle 1 of fluorouracil, l-leucovorin and paclitaxel, at two dose levels [Level 1 (n = 6): 5-fluorouracil/l-leucovorin/paclitaxel = 500/250/60 mg/m(2); Level 2 (n = 6): 600/250/80 mg/m(2) on Days 1, 8 and 15, every 28 days]. Nineteen additional patients at the recommended dose level were enrolled in the second phase to investigate the feasibility of fluorouracil, l-leucovorin and paclitaxel therapy. The primary endpoint in the second phase was the completion rate of two cycles. RESULTS: Dose-limiting toxicities were observed in a patient at Level 1 with Grade 4 gastrointestinal perforation (the site of primary tumor), and in two patients at Level 2 with Grade 3 febrile neutropenia and Grade 3 infection, respectively. In Cycle 2, treatment-related death occurred at Level 2 in one patient who had Grade 4 febrile neutropenia with pneumonia. The maximum tolerated dose was set at Level 2, and the recommended dose was determined as Level 1. In the second phase, the completion rate of two cycles was 92% and the ascites response was 44%. Median progression-free survival was 4.2 months and overall survival was 8.0 months. Grade 3/4 neutropenia was observed in 12% of patients. CONCLUSIONS: Fluorouracil, l-leucovorin and paclitaxel at Level 1 is feasible as first-line treatment for peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake.

Phase II study of bolus 5-fluorouracil and leucovorin combined with weekly paclitaxel as first-line therapy for advanced gastric cancer.

OBJECTIVE: We evaluated the efficacy and safety of bolus 5-fluorouracil (5-FU) and leucovorin combined with weekly paclitaxel (FLTAX) in advanced gastric cancer (GC) patients. METHODS: Patients with untreated stage IV GC received paclitaxel 80 mg/m(2) as a 1-hour infusion, followed by 5-FU 600 mg/m(2) as a bolus infusion and L-leucovorin 250 mg/m(2) as a 2-hour infusion on days 1, 8 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was response rate. RESULTS: Thirty-five patients were enrolled. The median age was 62 years (range 34-75). Twenty-one patients (60%) had diffuse-type cancer and 11 had peritoneal metastasis. The confirmed response rate was 43% (95% CI 26-61) with 15 partial responses. Stable disease was observed in 16 (46%) patients. Median progression-free survival and overall survival were 6.8 months (95% CI 5.8-7.4) and 16.2 months (95% CI 10.0-22.8), respectively. Grade 3-4 adverse events were: neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and sensory neuropathy (11%). CONCLUSION: FLTAX showed a desirable safety profile, and the efficacy against advanced GC was encouraging. FLTAX may be a good option for GC patients with deteriorated general condition, and a randomized clinical trial in such patients is currently underway.

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.

Clinical significance of evaluating primary lesions in patients with gastric cancer who receive chemotherapy.

BACKGROUND: In Western countries, the response of gastric cancer to chemotherapy is evaluated by assessing measurable metastatic lesions (MMLs) according to the response evaluation criteria in solid tumors (RECIST). In Japan, the response of primary lesions is assessed according to local Japanese criteria. We compared the response to chemotherapy as evaluated by these two sets of criteria. METHODS: Patients with unresectable, advanced gastric cancer who had primary lesions and had received first-line chemotherapy were studied. Responses of MMLs were evaluated with RECIST. Responses of primary lesions were evaluated with the Japanese criteria. Median survival times (MSTs) were compared according to treatment response by each set of criteria. RESULTS: Data from 341 patients were analyzed. Of the 242 patients with MMLs, 108 were MML responders and 134 were MML nonresponders. MST was significantly longer in MML responders (293 days; 95% confidence interval [CI], 244-342) than in MML nonresponders (159 days; 95% CI, 127-191; P < 0.0001). According to the Japanese criteria, there were 128 primary-lesion responders and 213 primary-lesion nonresponders. MST was significantly longer in responders (304 days; 95% CI, 266-342) than in nonresponders (168 days; 95% CI, 143-193, P < 0.0001). Of the 99 patients without MMLs, 26 were primary-lesion responders and 73, primary-lesion nonresponders; MST was significantly longer in the former (300 days; 95% CI, 266-334) than in the latter group (173 days; 95% CI, 111-235; P = 0.019). CONCLUSION: The responses of primary lesions according to the Japanese criteria and the responses of MMLs according to the RECIST were both significantly related to the MST. Use of the RECIST alone might bias the evaluation of treatment response because response cannot be evaluated in patients without an MML.

[Three cases of radiotherapy combined with S-1 and mitomycin C for anal canal squamous cell carcinomas].

We report three cases of anal canal squamous cell carcinoma treated with radiotherapy combined with S-1 and mitomycin C(MMC). During radiotherapy, MMC was administered as intravenous bolus injection at a dose of 10mg/m2 on day 1 and 29. S-1 was administered orally at a dose of 80mg/m2 on days 1-14 and 29-43. Total radiation doses ranged 55. 8-60 Gy to pelvic lesions. The rates of grade 3 toxicity were: neutropenia, 100%; leucopenia, 100%; anemia, 33. 3%; anorexia, 66. 7%. These adverse events were tolerated. All of the three cases showed complete response without recurrences. These results suggested that this treatment schedule was safe and effective for anal canal carcinomas.

Second-line chemotherapy with biweekly paclitaxel after failure of fluoropyrimidine-based treatment in patients with advanced or recurrent gastric cancer: a report from the gastrointestinal oncology group of the Tokyo cooperative oncology group, TCOG GC-0501 trial.

OBJECTIVE: A multicenter trial was conducted to evaluate the efficacy and safety of paclitaxel every 2 weeks in patients with advanced or recurrent gastric cancer who had previously received fluoropyrimidine-based chemotherapy. METHODS: The subjects were patients with gastric cancer who had disease progression or recurrence while receiving fluoropyrimidine-based chemotherapy. All patients had adequate major organ functions with an Eastern Cooperative Oncology Group performance status (PS) of 0-2. Paclitaxel 140 mg/m(2) was administered intravenously on days 1 and 15 of a 4-week cycle. The primary endpoint was the response rate. Secondary endpoints were progression-free survival (PFS), overall survival and safety. RESULTS: Response was assessable in 40 of 41 enrolled patients. Their median age was 63 (range: 48-77) years, and PS was 0 in 22 patients, 1 in 13 and 2 in 5. Previous treatment included S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) monotherapy in 32 patients and S-1-based combination therapy in 5. The median number of administered courses of paclitaxel was 3.5 (1-14). The response rate was 17.5% (95% confidence interval: 7.3-32.8%, partial response: 7, stable disease: 21, progressive disease: 10 and not evaluable: 2). The disease control rate was 70.0%, the median PFS was 111 days and the median overall survival was 254 days. Major adverse events of Grade 3 or 4 were neutropenia (27.5%), anemia (12.5%), diarrhea (2.5%) and sensory neuropathy (2.5%). CONCLUSIONS: Biweekly paclitaxel seemed to be one of the useful chemotherapies after failure of fluoropyrimidine-based treatment in patients with advanced or recurrent gastric cancer.

Endoscopic submucosal dissection (two-point fixed ESD) for early esophageal cancer.

BACKGROUND: We have been attempting to improve the safety, reliability and simplicity of endoscopic submucosal dissection for the treatment of early esophageal cancer and to shorten the time needed for this operation. METHODS: The present study involved nine patients with well-differentiated intramucosal early esophageal cancer over 20 mm in diameter. Two-point fixed endoscopic submucosal dissection was carried out. RESULTS: In all nine cases, the mucosal area to be dissected was successfully identified and kept under direct vision, allowing two-point fixation of the mucosa with forceps and the hood during adequate counter-traction. In this way, the respiration-caused movement of submucosal tissue between the two fixing points was suppressed almost completely. Hemostasis and manipulation on blood vessels were easy with this procedure and dissection could be completed safely, without causing perforation. CONCLUSION: Endoscopic submucosal dissection with a transparent hood fitted with a mucosa-holding forceps channel is highly useful, safe and simple when applied to the esophagus.

Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial.

BACKGROUND: We investigated the superiority of docetaxel plus cisplatin and S-1 compared with cisplatin and S-1 in chemotherapy-naive patients with advanced gastric cancer. METHODS: In this open-label, phase 3, randomised controlled trial, patients were recruited from 56 hospitals in Japan. We enrolled individuals aged 20-75 years who had unresectable or recurrent gastric cancer, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had received no previous chemotherapy (except adjuvant chemotherapy completed 24 weeks before reccurence), radiotherapy, or hormonal therapy, could take drugs orally, and had adequate organ function. Patients were randomly assigned (1:1) to receive docetaxel plus cisplatin and S-1 (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1 intravenously, and S-1 40-60 mg twice a day orally for 2 weeks, every 4 weeks) or cisplatin and S-1 (cisplatin 60 mg/m2 intravenously on day 8, and S-1 40-60 mg orally twice a day for 3 weeks, every 5 weeks). Randomisation was done centrally with the minimisation method, with a random component balancing for institution, ECOG performance status (0 vs 1), disease status at enrolment (unresectable vs recurrent), measurable lesion (yes vs no), number of metastatic sites (0-1 vs ≥2), and histological type (differentiated vs undifferentiated). Neither investigators or patients were masked to the study treatment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000007652. FINDINGS: Between April 3, 2012, and March 18, 2016, 741 patients were randomly assigned to receive docetaxel plus cisplatin and S-1 (n=370) or cisplatin and S-1 (n=371). Median overall survival was 14·2 months (95% CI 12·9-15·9) in the docetaxel plus cisplatin and S-1 group and 15·3 months (14·2-16·2) in the cisplatin and S-1 group (hazard ratio [HR] 0·99 [95% CI 0·85-1·16]; one-sided stratified log-rank p=0·47). The most common grade 3 or worse adverse events were neutropenia (209 [59%] of 357 patients in the docetaxel plus cisplatin and S-1 group vs 117 [32%] of 365 patients in the cisplatin and S-1 group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). The deaths of one patient in the cisplatin and S-1 group and in three patients in the docetaxel plus cisplatin and S-1 group were deemed treatment-related. INTERPRETATION: The addition of docetaxel to cisplatin and S-1 did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, cisplatin and S-1 remains the standard first-line chemotherapy. FUNDING: Ministry of Health, Labour and Welfare and Japan Agency for Medical Research and Development.