A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan.

This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018-March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.

Predictive Significance of Promoter DNA Methylation of Cysteine Dioxygenase Type 1 (CDO1) in Metachronous Gastric Cancer.

PURPOSE: Promoter DNA methylation of various genes has been associated with metachronous gastric cancer (MGC). The cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), has been implicated in the occurrence of residual gastric cancer. We evaluated whether DNA methylation of CDO1 could be a predictive biomarker of MGC using specimens of MGC developing on scars after endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: CDO1 methylation values (TaqMeth values) were compared between 33 patients with early gastric cancer (EGC) with no confirmed metachronous lesions at >3 years after ESD (non-MGC: nMGC group) and 11 patients with MGC developing on scars after ESD (MGCSE groups: EGC at the first ESD [MGCSE-1 group], EGC at the second ESD for treating MGC developing on scars after ESD [MGCSE-2 group]). Each EGC specimen was measured at five locations (at tumor [T] and the 4-point tumor-adjacent noncancerous mucosa [TAM]). RESULTS: In the nMGC group, the TaqMeth values for T were significantly higher than that for TAM (P=0.0006). In the MGCSE groups, TAM (MGCSE-1) exhibited significantly higher TaqMeth values than TAM (nMGC) (P<0.0001) and TAM (MGCSE-2) (P=0.0041), suggesting that TAM (MGCSE-1) exhibited CDO1 hypermethylation similar to T (P=0.3638). The area under the curve for discriminating the highest TaqMeth value of TAM (MGCSE-1) from that of TAM (nMGC) was 0.81, and using the cut-off value of 43.4, CDO1 hypermethylation effectively enriched the MGCSE groups (P<0.0001). CONCLUSIONS: CDO1 hypermethylation has been implicated in the occurrence of MGC, suggesting its potential as a promising MGC predictor.

Usefulness of argon plasma coagulation for superficial esophageal squamous cell neoplasia in patients at high risk or with limited endoscopic resectability.

BACKGROUND/AIMS: Endoscopic resection is the standard treatment for superficial esophageal squamous-cell neoplasia (SESCN). However, we encounter patients in whom endoscopic resection is difficult to perform. We retrospectively studied the usefulness of argon plasma coagulation (APC) in patients with SESCN. MATERIALS AND METHODS: The study comprised 45 patients with SESCN (81 lesions) who underwent APC in our hospital from March 1999 through August 2016. Clinicopathological characteristics, treatment time, the presence or absence of metastasis and recurrence, adverse events, and outcomes were studied. RESULTS: The median follow-up was 40 months. The median age was 70 years. The tumor diameter was 10 mm or longer in 48 lesions and less than 10 mm in 33 lesions. The median treatment time was 22 minutes. The reasons for selecting APC were as follows: technical difficulty caused by the presence of metachronous multiple lesions in the radiation field after chemoradiotherapy or close proximity to the ulcer scar remaining after endoscopic treatment in 49 lesions (60.4%), and the presence of underlying diseases in 26 lesions (32.0%). Adverse events occurred in 2 patients (4.4%) who had hypoxemia due to over-sedation. Two lesions (2.5%) recurred locally but could be locally controlled by additional APC. No patient had metastasis or recurrence or died of esophageal neoplasia. The 3-year overall survival rate was 87.0%, and the 3-year recurrence-free survival rate was 97.2%. CONCLUSION: APC can be a useful treatment option for SESCN in patients with a limited life expectancy, poor performance status, or technical difficulty in resection of superficial neoplasms.

A phase I study of docetaxel/oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction.

BACKGROUND: The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG). METHODS: Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m2, day 1), oxaliplatin (mg/m2, day 1), and S-1 (mg/day, days 1-14) were: 50/100/80-120 at level 1, and 60/100/80-120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210). RESULTS: We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. CONCLUSION: Recommended doses of docetaxel (mg/m2), oxaliplatin (mg/m2), and S-1 (mg/day) were 60/100/80-120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.

Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study.

AIM: The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab). METHODS: This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status. RESULTS: Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). CONCLUSIONS: SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer. TRIAL REGISTRATION: NCT03382600/JapicCTI-183829.

A retrospective study of definitive chemoradiotherapy in patients with resectable small cell neuroendocrine carcinoma of the esophagus.

BACKGROUND: Standard treatment for resectable small cell neuroendocrine carcinoma of the esophagus (SCNEC-E) remains to be established. METHODS: We retrospectively studied 7 consecutive patients with resectable SCNEC-E who received definitive chemoradiotherapy (dCRT) to evaluate the safety and efficacy. Treatment consisted of two courses of chemotherapy with cisplatin (80 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1-3) or carboplatin (AUC 5 on day 1) and etoposide (80 mg/m2 on days 1-3) given every 4 weeks during dCRT. The total radiation dose was 50.4 Gy (28 fractions). RESULTS: The clinical stage was IA in 1 patient, IB in 2 patients, IIA in 3 patients, and IIB in 1 patient. Definitive CRT was completed in all patients. The median overall treatment time of radiotherapy was 44 days. The chemotherapy regimen included in dCRT was cisplatin and etoposide in 3 patients and carboplatin and etoposide in 4 patients. Acute adverse events of grade 3 or 4 were neutropenia 100%, thrombocytopenia 43%, febrile neutropenia 43%, and nausea 14%. There were no late grade 3 or 4 adverse events. The median survival time was 32 months. The complete response rate was 100%. The recurrence rate was 43%. The median survival of the 4 patients without recurrence was 56 months. CONCLUSIONS: Definitive CRT with cisplatin and etoposide or carboplatin and etoposide is a feasible treatment for the resectable SCNEC-E, and long-term survival can be achieved in some patients.

[Questionnaire Survey of Secondary Chemotherapy for Gastric Cancer in the Yamaguchi Prefecture].

A questionnaire survey was conducted on the administration of secondary chemotherapy for unresectable or recurrent gastric cancer by 43 doctors involved in gastric cancer treatment in the Yamaguchi prefecture. Seventy-one percent of doctors replied that the secondary chemotherapy transfer rate was more than 60%, and 29% of doctors replied that the secondary chemotherapy transfer rate was less than 60%. The reasons why patients could not be transferred to secondary chemotherapy included inferior performance status, poor general condition, and elderly age, among others. Weekly paclitaxel plus ramucirumab therapy was used as the major regimen of secondary chemotherapy by 95% of doctors. In addition, 93% of doctors indicated that weekly nab-paclitaxel would be an option for gastric cancer secondary chemotherapy. Secondary chemotherapy for gastric cancer in the Yamaguchi prefecture has a standard regimen selection according to guidelines.

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.

Retrospective Assessment of the Diagnostic Accuracy of the Depth of Invasion by Narrow Band Imaging Magnifying Endoscopy in Patients with Superficial Esophageal Squamous Cell Carcinoma.

PURPOSE: Treatment strategies for superficial esophageal squamous cell carcinoma (S-ESCC) are determined mainly on the basis of the depth of invasion. We retrospectively studied the accuracy of the depth of tumor invasion, comprehensively assessed using the Japan Esophageal Society (JES) classification. METHODS: The study group comprised 256 patients who underwent narrow band imaging (NBI) magnifying endoscopy, and endoscopic submucosal dissection for S-ESCC. The depth of invasion of S-ESCC was classified into three groups: EP/LPM, MM/SM1, and SM2. The following variables were studied retrospectively: (1) the diagnostic accuracy of non-magnifying white-light endoscopy, (2) the diagnostic accuracy of type B vessels, (3) the diagnostic accuracy of avascular area (AVA), (4) the diagnostic accuracy of the JES classification, and (5) the diagnostic accuracy of comprehensive diagnosis. The depth of invasion was assessed by white-light non-magnifying endoscopy, followed by NBI magnifying endoscopy. RESULTS: The positive predictive value (PPV) of white-light non-magnifying endoscopy was 86% for EP/LPM, 53% MM/SM1, and 74% for SM2. The PPV of the diagnosis of type B vessels was 93% for EP/LPM, 62% for MM/SM1, and 74% for SM2. The PPV of the AVA diagnosis was 73% for EP/LPM, 89% for MM/SM1, and 100% for SM2. The PPV of diagnosis according to the JES classification was 93% for EP/LPM, 65% for MM/SM1, and 77% for SM2. The PPV of the comprehensive diagnosis was 94% for EP/LPM, 63%, for MM/SM1, and 75% for SM2. CONCLUSIONS: The additional use of NBI magnifying endoscopy can enhance the diagnostic accuracy of the depth of invasion in patients with S-ESCC.

A phase II study of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1, followed by gastrectomy with D2 lymph node dissection for high-risk advanced gastric cancer: results of the KDOG1001 trial.

BACKGROUND: The prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis. METHODS: Patients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%. RESULTS: Between 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%. CONCLUSIONS: Neoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.

Effectiveness and safety of endoscopic aspiration mucosectomy and endoscopic submucosal dissection in patients with superficial esophageal squamous-cell carcinoma.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been performed in a high proportion of patients with superficial esophageal squamous-cell carcinoma. Endoscopic aspiration mucosectomy (EAM) is a more straightforward technique that is easier to perform. We retrospectively evaluated the safety and efficacy of EAM and ESD to clarify the advantages and disadvantages of each procedure. METHODS: A total of 374 patients (423 lesions) who underwent endoscopic resection were retrospectively studied. The following variables were evaluated (1) procedure time and adverse events as safety, and (2) en bloc complete resection rate, local recurrence rate, lymph node recurrence rate, overall survival rate, and cause-specific survival rate as efficacy. RESULTS: EAM was performed in 134 patients (149 lesions), and ESD was performed in 240 patients (274 lesions). The procedure times of EAM and ESD were 31.0 ± 22.4 and 85.7 ± 46.5 min (p < 0.001), respectively. The perforation rates were 0 and 6.2% (p = 0.002), respectively. The en bloc complete resection rates were 48.3 and 91.6% (p < 0.001), respectively. The local recurrence rates were 5.5 and 0% (p < 0.001), respectively. For lesions measuring less than 15 mm in diameter, EAM had a relatively good en bloc complete resection rate (EAM, 76.1% vs. ESD, 100%) and a significantly short procedure time (EAM, 25.2 ± 15.2 min vs. ESD, 62.7 ± 35.2 min; p < 0.001). CONCLUSIONS: ESD has a higher en bloc complete resection rate and a better local control rate than EAM. For lesions measuring less than 15 mm in diameter, EAM may be a treatment option.

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.

A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2).

BACKGROUND: Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. METHODS: Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6-7.4 versus 3.6 months, 95% CI 2.8-5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42-0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. CONCLUSIONS: In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials.

A giant trichobezoar extracted by laparoscopic and endoscopic cooperative surgery (LECS).

A gastric bezoar is a mass that forms in the stomach. A giant gastric bezoar is particularly difficult to treat medically, and surgical therapy is selected. We describe our experience with a patient who had a giant gastric trichobezoar that was extracted by laparoscopic and endoscopic cooperative surgery (LECS) in accordance with the principles of LECS. The patient was a 32-year-old woman who presented at our hospital because of abdominal pain. Upper gastrointestinal endoscopy confirmed the presence of a giant gastric trichobezoar extending from the gastric cardia to the gastric angle. Because endoscopic removal was considered difficult, we extracted the giant gastric trichobezoar by LECS. The concurrent use of endoscopy was considered to allow a gastric bezoar to be extracted more safely and reliably than was previously possible.

Feasibility of definitive chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma: A retrospective study.

PURPOSE: This study was designed to retrospectively analyze the safety and efficacy of chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma. METHODS AND MATERIALS: Eligible patients were aged 76 years or older, had a histopathologic diagnosis of esophageal squamous cell carcinoma, and were treated at the Kitasato University Hospital between January 2010 and March 2016. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m2 on days 1 to 5, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 50.4 Gy in 28 fractions for thoracic tumors and 61.2 Gy for cervical tumors. RESULTS: Twenty-five patients were studied. Patient characteristics were as follows: median age 79 years (range, 76-85 years), clinical stage I/II/III/IV (7/8/8/2, respectively), and surgically resectable/unresectable (17/8, respectively). The completion rates of radiation therapy and chemoradiation therapy were 100% and 84%, respectively. Grade ≥3 acute toxicities included neutropenia (76%), leukopenia (72%), thrombocytopenia (32%), anemia (28%), anorexia (32%), oral mucositis (20%), febrile neutropenia (12%), and esophagitis (8%). Grade ≥3 late toxicities included esophageal stenosis (12%) and pleural effusion (4%). The complete response rate was 64%. In the median follow-up period of 18.9 months, the 1-year overall survival rate was 68%. CONCLUSIONS: Definitive chemoradiation therapy with nedaplatin and 5-fluorouracil may be a feasible treatment option for elderly patients with esophageal squamous cell carcinoma.

A retrospective study of treatment for curative synchronous double primary cancers of the head and neck and the esophagus.

OBJECTIVE: Curative synchronous double primary cancers of the head and neck and the esophagus (CSC-HE) are frequently detected, but a standard treatment remains to be established. We studied the clinical course to explore appropriate treatment strategies. METHODS: We retrospectively studied consecutive 33 patients who had CSC-HE. The disease stage was classified into 4 groups: group A, early head and neck cancer (HNC) and early esophageal cancer (EC); group B, early HNC and advanced EC; group C, advanced HNC and early EC; and group D, advanced HNC and advanced EC. As induction chemotherapy, the patients received 3 courses of TPF therapy (docetaxel 75mg/m2 on day 1, cisplatin 75mg/m2 on day 1, and 5-fluorouracil 750mg/m2 on days 1-5) at 3-week intervals. The clinical courses and treatment outcomes were studied according to the disease stage of CSC-HE. RESULTS: The disease stage of CSC-HE was group A in 1 patient (3%), group B in 9 patients (27.3%), group C in 3 patients (9.1%), and group D in 20 patients (60.6%). The median follow-up was 26months, and the 2-year overall survival rate was 67.4%. In groups A, B, and C, the 2-year overall survival rate was 83.3%. In group D, the 2-year overall survival rate was 62.6%. Ten of 20 patients in group D received induction chemotherapy with TPF, and 6 patients were alive and disease free at the time of this writing. CONCLUSION: The treatment outcomes of patients with CSC-HE were relatively good. TPF induction chemotherapy might be an effective treatment for patients with advanced HNC and advanced EC.

A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer.

BACKGROUND: Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility and does not need premedication to avoid infusion-related reactions associated with solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated advanced gastric cancer. PATIENTS AND METHODS: Patients with unresectable advanced gastric cancer refractory to first-line chemotherapy were administered nab-paclitaxel 100 mg/m2 intravenously on days 1, 8 and 15, plus ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary end-point was Independent Review Committee (IRC)-assessed overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and quality of life (QOL). RESULTS: Forty-five patients were enrolled; 43 received the study treatment. The ORR assessed by the IRC was 54.8% (90% confidence interval [CI] 41.0-68.0) and the primary end-point was met. The DCR was 92.9% (95% CI 80.5-98.5). The IRC-assessed median PFS was 7.6 months (95% CI 5.4-8.1). The median OS was not reached at the data cutoff. The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (76.7%), decreased white blood cell count (27.9%), anaemia (11.6%), decreased appetite (7.0%), febrile neutropenia (4.7%), hypertension (4.7%) and proteinuria (4.7%). No treatment-related deaths occurred. No QOL deterioration was observed during study treatment. CONCLUSION: Nab-paclitaxel plus ramucirumab combination therapy shows promising activity and manageable toxicities and could be a useful second-line treatment option for patients with previously treated advanced gastric cancer.

Long-term outcomes of patients with early gastric cancer found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after endoscopic submucosal dissection.

BACKGROUND: Gastric cancer treatment guidelines recommend additional surgery as the standard treatment for lesions for which endoscopic submucosal dissection (ESD) is not indicated. However, the incidence of lymph-node metastasis is low in most patients. METHODS AND MATERIALS: The study comprised 231 patients (231 lesions) who underwent ESD for early gastric cancer (EGC) in our hospital from September 2002 through March 2015 and were found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD. The patients were divided into the additional operation group and the follow-up group, and long-term outcomes were studied retrospectively. Risk factors for metastasis and recurrence were also studied (capture rate, 98.7%). RESULTS: The median follow-up was 48 months. There were 174 men and 57 women with a median age of 72 years. The additional operation group comprised 118 patients, and the follow-up group comprised 113 patients. The rates of 5-year cause-specific survival and 5-year overall survival were significantly higher in the additional operation group (100 and 96.0%, respectively) than in the follow-up group (92.6 and 73.3%, respectively; p = 0.010, p < 0.001). In the follow-up group, 5 patients (4.4%) died of gastric cancer (p = 0.021). Among elderly patients 75 years or older, long-term outcomes did not differ significantly between the groups. Sixteen patients had metastasis or recurrence, and the presence of lymphatic involvement was an independent risk factor for metastasis, recurrence, or both (p = 0.003; odds ratio 10.594; 95% confidence interval 2.294-48.927). CONCLUSIONS: In patients with EGC who are confirmed to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD, additional surgery should be aggressively performed if the patient can tolerate such treatment. In elderly patients aged 75 years or older and patients with serious underlying diseases, follow-up observation was suggested to be one option in patients who give informed consent after receiving an explanation of the risk of recurrence.

Comparison of oral and intravenous lansoprazole for the prevention of bleeding from artificial ulcers after endoscopic submucosal dissection for gastric tumors: a prospective randomized phase II study (KDOG 0802).

BACKGROUND: Very few studies have evaluated the effectiveness of oral proton-pump inhibitors for the prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric tumors. The aim of our study was to establish the non-inferiority of lansoprazole orally disintegrating (OD) tablets to intravenous lansoprazole for the prevention of bleeding from artificial ulcers after ESD. PATIENTS AND METHODS: Consecutive patients who underwent ESD for gastric tumors were randomly assigned to receive lansoprazole OD tablets (OD group) or intravenous lansoprazole (IV group). In the OD group, lansoprazole OD tablets (30 mg) were given orally once daily for 8 weeks (56 days), starting on the day before ESD. In the IV group, lansoprazole (30 mg) was given as a continuous intravenous infusion twice daily for 3 days, starting on the day before ESD, and lansoprazole OD tablets (30 mg) were given orally once daily on days 4-56. The primary endpoint was the incidence of bleeding events within 8 weeks after ESD. RESULTS: Among 310 enrolled patients, 304 patients (152 in the OD group and 152 in the IV group) were included in the analysis. Endoscopic hemostasis was performed in 38 patients (19 in the OD group and 19 in the IV group). The incidence of bleeding events within 8 weeks after ESD did not differ significantly between the groups (p = 0.487). Endoscopic hemostasis was performed at second-look endoscopy in 17 patients (11.2%) in the OD group and 19 patients (12.5%) in the IV group (difference, 1.3 percentage points; 90% confidence interval, - 4.8-7.4%; non-inferiority, p < 0.001). CONCLUSIONS: The effectiveness of lansoprazole OD tablets for the prevention of bleeding from artificial ulcers after ESD was similar to that of intravenous lansoprazole. Lansoprazole OD tablets are thus considered a treatment option in patients who undergo ESD.