Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201).

BACKGROUND: Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer. METHODS: This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma. DISCUSSION: GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Pembrolizumab or pembrolizumab plus chemotherapy versus standard of care chemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062.

OBJECTIVE: First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia. METHODS: Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary). RESULTS: A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively. CONCLUSIONS: This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.

A modified MethyLight assay predicts the clinical outcomes of anti-epidermal growth factor receptor treatment in metastatic colorectal cancer.

DNA methylation status correlates with clinical outcomes of anti-epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti-EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low-methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor-derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression-free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild-type mCRC who were refractory or intolerable to oxaliplatin- and irinotecan-based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti-EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.

Phase IIb study of pembrolizumab combined with S-1 + oxaliplatin or S-1 + cisplatin as first-line chemotherapy for gastric cancer.

The KEYNOTE-659 study evaluated the efficacy and safety of first-line pembrolizumab plus S-1 and oxaliplatin (SOX) (cohort 1) or S-1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open-label phase IIb study enrolled patients with advanced programmed death-ligand 1 (PD-L1)-positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)-negative G/GEJ adenocarcinoma. The primary end-point was the objective response rate (ORR). Other end-points were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow-up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment-related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD-L1-positive, HER2-negative G/GEJ adenocarcinoma.

Impact of chronological age on efficacy and safety of fluoropyrimidine plus bevacizumab in older non-frail patients with metastatic colorectal cancer: a combined analysis of individual data from two phase II studies of patients aged >75 years.

OBJECTIVE: Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. METHODS: Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. RESULTS: We enrolled 102 patients with a median age of 80 years (range, 75-88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, -0.06; P = 0.56) adverse events. CONCLUSIONS: The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer.

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.

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.

Cancer-related FGFR2 overexpression and gene amplification in Japanese patients with gastric cancer.

OBJECTIVE: Fibroblast growth factor receptor 2 (FGFR2) has been proposed as a novel druggable target in unresectable gastric cancer. FGFR2 alteration has been reported as associated with poor prognosis even in patients with gastric cancer who received systemic chemotherapy. This study aimed to evaluate the frequency of FGFR2 overexpression and gene amplification in clinical specimens from Japanese patients with recurrent or unresectable gastric cancer. METHODS: This observational study enrolled patients who were histologically or cytologically confirmed with unresectable HER2-negative or unknown gastric or gastroesophageal junctional adenocarcinoma treated with at least one previous chemotherapy. FGFR2 overexpression and gene amplification in the specimens were evaluated by immunohistochemical staining and fluorescence in situ hybridization methods, respectively. RESULTS: In a total of 173 eligible cases, FGFR2 immunohistochemistry score was evaluated as 0, 1, 2, 3 and 4 for 20, 80, 35, 28 and 10 cases, respectively. In 151 evaluable cases with FGFR2 immunohistochemistry scores of 1-4, FGFR2 copy number expressed as fluorescence in situ hybridization signals were detected as <4, ≥4 < 10 and ≥10 copies for 123, 16 and 12 cases, respectively. FGFR2 copy number showed an increasing tendency along with higher FGFR2 immunohistochemistry scores in the corresponding specimen. The response rate and time to treatment failure for first line chemotherapy did not have any obvious relationship to FGFR2 immunohistochemistry score and FGFR2 copy number. CONCLUSIONS: Although FGFR2 overexpression and gene amplification were shown in Japanese patients with unresectable gastric cancer, these alterations did not impact the effects of cytotoxic agents as first line chemotherapy.

Efficacy of Endoscopic Resection and Selective Chemoradiotherapy for Stage I Esophageal Squamous Cell Carcinoma.

BACKGROUND & AIMS: Esophagectomy is the standard treatment for stage I esophageal squamous cell carcinoma (ESCC). We conducted a single-arm prospective study to confirm the efficacy and safety of selective chemoradiotherapy (CRT) based on findings from endoscopic resection (ER). METHODS: We performed a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC from December 2006 through July 2012; 176 patients underwent ER. Based on the findings from ER, patients received the following: no additional treatment for patients with pT1a tumors with a negative resection margin and no lymphovascular invasion (group A); prophylactic CRT with 41.4 Gy delivered to locoregional lymph nodes for patients with pT1b tumors with a negative resection margin or pT1a tumors with lymphovascular invasion (group B); or definitive CRT (50.4 Gy) with a 9-Gy boost to the primary site for patients with a positive vertical resection margin (group C). Chemotherapy comprised 5-fluorouracil and cisplatin. The primary end point was 3-year overall survival in group B, and the key secondary end point was 3-year overall survival for all patients. If lower limits of 90% confidence intervals for the primary and key secondary end points exceeded the 80% threshold, the efficacy of combined ER and selective CRT was confirmed. RESULTS: Based on the results from pathology analysis, 74, 87, and 15 patients were categorized into groups A, B, and C, respectively. The 3-year overall survival rates were 90.7% for group B (90% confidence interval, 84.0%-94.7%) and 92.6% in all patients (90% confidence interval, 88.5%-95.2%). CONCLUSIONS: In a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC, we confirmed the efficacy of the combination of ER and selective CRT. Efficacy is comparable to that of surgery, and the combination of ER and selective CRT should be considered as a minimally invasive treatment option. UMIN-Clinical Trials Registry no.: UMIN000000553.

Sex differences in the safety of S-1 plus oxaliplatin and S-1 plus cisplatin for patients with metastatic gastric cancer.

Previous studies have shown sex-related differences in the incidence of adverse events following treatment with fluoropyrimidines, however the mechanism of this difference is unknown. We examined sex-related differences in the safety of S-1 plus oxaliplatin (SOX) and S-1 plus cisplatin (CS) in 663 metastatic gastric cancer patients taking part in a phase III study. The incidences of leukopenia (odds ratio [OR] 1.9; P = .015), neutropenia (OR 2.2; P = .002), nausea (OR 2.0; P = .009), and vomiting (OR 2.8; P < .001) were increased in women versus men treated with SOX, while vomiting (OR 2.9; P < .001) and stomatitis (OR 1.8; P = .043) were increased in women versus men treated with CS. In contrast, male patients treated with CS experienced thrombocytopenia more often (OR 0.51; P = .009). The mean relative dose intensity of S-1 in SOX was 75.4% in women and 81.4% in men (P = .032). No difference in efficacy was observed between women and men undergoing either regimen. Sex-related differences in adverse reactions during SOX and CS treatment were confirmed in this phase III study. Further translational research studies are warranted to pursue the cause of this difference.

Early tumor shrinkage and depth of response in patients with advanced gastric cancer: a retrospective analysis of a randomized phase III study of first-line S-1 plus oxaliplatin vs. S-1 plus cisplatin.

BACKGROUND: We investigated early tumor shrinkage (ETS) and depth of response (DpR) using data from the G-SOX study comparing S-1 plus oxaliplatin with S-1 plus cisplatin as the first-line treatment for advanced gastric cancer (AGC). METHODS: ETS was determined as % decrease in the sum of the longest diameters of the target lesions at the first evaluation of week 6 compared to baseline. DpR was the maximum % shrinkage during the study treatment. The impact of ETS (cutoff value 20%) and DpR (continuous value) on progression-free survival (PFS) and overall survival (OS) were assessed by the log-rank test and Cox regression analysis including prognostic factors obtained in the G-SOX study; ECOG performance status, baseline sum of tumor diameters, disease status (recurrent/unresectable), and histology (diffuse/intestinal). RESULTS: Among 685 patients enrolled in the G-SOX study, 632 patients who had the first tumor evaluation were analyzed. Patients with ETS ≥ 20% had longer PFS (median 4.5 vs. 2.8 months, p < 0.0001) and OS (median 14.8 vs. 10.5 months, p < 0.0001) than those with ETS < 20%. Adjusted hazard ratios of ETS < 20 vs. ≥ 20% were 0.606 (95% confidence interval (CI) 0.506-0.725) for PFS and 0.589 (95% CI 0.492-0.704) for OS. DpR was also significantly associated with PFS and OS (both p < 0.0001). These results were similar between the SOX and CS groups. CONCLUSIONS: In AGC patients receiving the first-line therapy, ETS and DpR might be predictors for PFS and OS.

Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naïve, HER2-positive advanced gastric cancer.

BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidines improves overall survival (OS) in patients with HER2-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan. However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC. METHODS: This was a multicenter, phase II study conducted at 10 institutions in Japan. Patients with HER2-positive AGC received S-1 twice a day on days 1-14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle. The primary endpoint was the confirmed overall response rate (ORR), and the secondary endpoints were OS, progression-free survival (PFS), and safety. The sample size was 75 to have 90% power with an alpha error of 0.1 (one-sided), expecting an ORR of 65% and threshold of 50%. RESULTS: From June 2015 to January 2018, 75 patients were enrolled. The ORR was 70.7% [95% confidence interval (CI) 59.0-80.6]. The median OS and PFS were estimated as 18.1 months (95% CI 15.6-26.5) and 8.8 months (95% CI 7.4-12.2), respectively. The major grade 3 or 4 adverse events were sensory neuropathy (16.0%) and neutropenia (10.7%). CONCLUSIONS: Trastuzumab with SOX had promising activity with well-tolerated toxicities for patients with HER2-positive AGC. CLINICAL TRIAL REGISTRATION: UMIN000017602.

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.

Phase II study of S-1 on alternate days plus bevacizumab in patients aged ≥ 75 years with metastatic colorectal cancer (J-SAVER).

BACKGROUND: Alternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had histologically proven colorectal adenocarcinoma, measurable metastatic lesions, age ≥ 75 years, Eastern Cooperative Oncology Group performance status ≤ 1, no previous chemotherapy, and refused oxaliplatin- or irinotecan-containing regimens. Patients received 40 mg, 50 mg, or 60 mg (body surface area ≤ 1.25 m2, > 1.25 to ≤ 1.50 m2, or > 1.50 m2, respectively) of S-1 twice orally on Sunday, Monday, Wednesday, and Friday every week. Bevacizumab (7.5 mg/kg) was administered every 3 weeks. The primary endpoint was progression-free survival. RESULTS: Of 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75-88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7-9.5 months). The median overall survival was 23.1 months (95% CI 17.4-28.8 months). The response rate was 44% (95% CI 30.2-57.8%), and the disease control rate was 88% (95% CI 79.0-97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events. CONCLUSION: S-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies.

Randomized controlled trial: PPI-based triple therapy containing metronidazole versus clarithromycin as first-line treatment for Helicobacter pylori in adolescents and young adults in Japan.

BACKGROUND/AIMS: Treating Helicobacter pylori infection in young people is effective for preventing gastric cancer. This study compares the efficacy of triple therapies in adolescents and young adults in Japan. METHODS: This multicenter, randomized trial was conducted between February 2012 and March 2015. Infected participants were stratified into adolescents (13-19 years) and young adults (20-39 years). They were randomly assigned to a clarithromycin based (PAC) or metronidazole based (PAM) triple therapy for 1 week. RESULTS: Overall, 137 and 169 participants received the PAC and PAM treatments, respectively. In adolescents, the H. pylori eradication rates were 60.5% and 63.4% for PAC, and 98.3% and 100% for PAM in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively. In young adults, the eradication rates were 67.0% and 66.7% for PAC, and 95.5% and 96.3% for PAM in ITT and PP analyses, respectively. The eradication rate of PAM was significantly higher than that of PAC in both strata. No severe adverse events were observed. CONCLUSION: In Japan, PAM may be selected as a first-line treatment for young people with H. pylori if antibiotic susceptibility tests cannot be performed.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study.

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

Usefulness of detection of clarithromycin-resistant Helicobacter pylori from fecal specimens for young adults treated with eradication therapy.

BACKGROUND: To prevent Helicobacter pylori infection in the younger generation, it is necessary to investigate the prevalence of antibiotic-resistant H. pylori. OBJECTIVE: The aim of this study was to evaluate the method of PCR-based sequencing to detect clarithromycin (CAM) resistance-associated mutations using fecal samples as a noninvasive method. METHODS: DNA extracted from fecal specimens and isolates from gastric biopsy specimens were collected from patients with H. pylori infection. Antibiotic resistance to CAM was analyzed by molecular and culture methods. The detection rates of CAM resistance-associated mutations (A2142C or A2143G) were compared before and after eradication therapy. RESULTS: With CAM resistance of H. pylori evaluated by antibiotic susceptibility test as a gold standard, the sensitivity and the specificity of gene mutation detection from fecal DNA were 80% and 84.8%, respectively. In contrast, using DNA of isolated strains, the sensitivity and the specificity were 80% and 100%. Of the seven cases in which eradication was unsuccessful by triple therapy including CAM, CAM-resistant H. pylori, and resistance-associated mutations were detected in three cases, CAM-resistant H. pylori without the mutation was detected in two patients, and resistance-associated mutation was only detected in one patient. CONCLUSION: PCR-based sequencing to detect CAM resistance-associated mutations using isolates or fecal samples was useful for finding antibiotic-resistant H. pylori infection. Although the specificity of the detection from fecal samples compared with antibiotic susceptibility testing was lower than that from isolates, this fecal detection method is suitable especially for asymptomatic subjects including children. Further improvement is needed before clinical application.

Impact of progression type on overall survival in patients with advanced gastric cancer based on randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin.

BACKGROUND: The association between progression type and survival has been reported in breast cancer, but remains unclear in advanced gastric cancer (AGC). Here, this association was assessed using data obtained from an earlier randomized phase III study demonstrating the non-inferiority of S-1 plus oxaliplatin (SOX) to S-1 plus cisplatin (CS) on progression-free survival and overall survival (OS) in the first-line treatment of AGC. METHODS: A Cox regression model including two time-dependent covariates, progression with new lesions and with no new lesions, was used to determine their effect on OS in each treatment group. When both types of progression were detected simultaneously, this was categorized as progression with new lesions. RESULTS: Progression with and with no new lesions was identified in 91 and 167 patients, respectively, in the SOX group (333 patients) and 95 and 147 patients, respectively, in the CS group (330 patients). The association between progression type and OS was similar in both treatment groups; both progression types were strong poor prognostic factors, particularly progression with new lesions [hazard ratio (HR), 7.26; 95% confidence interval (CI), 4.89-10.80 in SOX and HR, 5.78; 95% CI, 4.13-8.08 in CS] compared to no new lesions (HR, 4.66; 95% CI, 3.21-6.77 in SOX and HR, 2.71; 95% CI, 1.95-3.75 in CS). CONCLUSIONS: Progression accompanied by new lesions had a strong negative impact on OS in patients treated with S-1 and platinum for AGC.

Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

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.