Kenji Ishido

Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system

This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176.

Preliminary results of multicenter questionnaire study on long-term outcomes of curative endoscopic submucosal dissection for early gastric cancer.

There are a number of published reports on long‐term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), but most reports are from single centers with median follow‐up periods shorter than 5 years. This questionnaire study investigated long‐term outcomes of curative ESD for EGC at six Japanese institutions with follow‐up rates of at least 90% over a minimum 5‐year period.

A phase II study of endoscopic submucosal dissection for superficial esophageal neoplasms (KDOG 0901)

BACKGROUND Most previous studies of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms were retrospective; prospective studies are scant. OBJECTIVE To prospectively assess the efficacy and safety of ESD for superficial esophageal neoplasms. DESIGN Phase II study. SETTING University hospital. PATIENTS Fifty-two patients (median age 68 years; 48 men) who had a histologic diagnosis of superficial esophageal cancer without metastasis on CT or high-grade intraepithelial neoplasia (HGIN) were enrolled from April 2009 through November 2011. INTERVENTION ESD was used to treat 56 lesions. All procedures were done by 4 endoscopists who each had previously performed ESD in more than 100 patients with gastric tumors. MAIN OUTCOME MEASUREMENTS The primary endpoint was the R0 resection rate, and secondary endpoints were the safety and the rate of accurately diagnosing tumor depth on endoscopic examination. RESULTS The median treatment time was 69 minutes (24-168 minutes). The histopathologic diagnosis was squamous cell carcinoma in 49 lesions, HGIN in 5, and tubular adenocarcinoma in 2. The en bloc resection rate and R0 resection rate were 100% and 94.6%, respectively. The rates of adverse events during ESD and after ESD were 22.2% and 53.8%, respectively, but most events were mild. One patient (1.9%) had mediastinal emphysema without perforation. The rate of accurately diagnosing tumor depth on endoscopic examination was 76.8%. LIMITATIONS Single-center, nonrandomized study. CONCLUSION Our study showed that ESD was an effective and relatively safe treatment for superficial esophageal neoplasms. ESD may be a useful treatment option for superficial esophageal neoplasms in hospitals with endoscopists who are experts in performing ESD for gastric tumors. ( CLINICAL TRIAL REGISTRATION NUMBER UMIN000002047.).

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

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

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.

Definitive Chemoradiation Therapy With Docetaxel, Cisplatin, and 5-Fluorouracil (DCF-R) in Advanced Esophageal Cancer: A Phase 2 Trial (KDOG 0501-P2)

PURPOSE A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer (AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC. METHODS AND MATERIALS Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m(2)) and cisplatin (40 mg/m(2)) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate. RESULTS Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval [CI]: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). CONCLUSIONS DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.

Risk of superficial squamous cell carcinoma developing in the head and neck region in patients with esophageal squamous cell carcinoma

Multicentric squamous dysplasia in the esophagus can be visualized by Lugol chromoendoscopy as multiple Lugol‐voiding lesions (LVLs). Narrow‐band imaging combined with magnifying endoscopy (NBI‐ME) facilitates the detection of superficial squamous cell carcinoma within the head and neck region (HNSCC). We investigated risk factors for superficial HNSCC in patients with esophageal squamous cell carcinoma (ESCC).

Management and clinical outcomes of type I gastric carcinoid patients: retrospective, multicenter study in Japan.

Type I gastric carcinoids (TIGC) are associated with chronic atrophic gastritis (CAG) with hypergastrinemia and hyperplasia of enterochromaffin‐like cells. Several treatment options are currently available for these tumors including total gastrectomy, partial resection, antrectomy, endoscopic resection and endoscopic surveillance. The present study evaluated different treatment approaches and clinical outcomes of patients with TIGC in Japan.

Clinical outcomes of endoscopic oblique aspiration mucosectomy for superficial esophageal cancer.

BACKGROUND EMR is now a widely accepted option for the treatment for superficial esophageal cancer (SEC). However, studies of medium-term to long-term outcomes are scarce. OBJECTIVE To evaluate outcomes in patients with SEC who are undergoing medium-term to long-term follow-up after endoscopic oblique aspiration mucosectomy (EOAM). DESIGN A single-center retrospective study. SETTING Kitasato University East Hospital, Sagamihara, Kanagawa, Japan. PATIENTS AND INTERVENTIONS From November 1999 to October 2005, 85 patients with SEC underwent EOAM. All tumors were macroscopically classified as the superficial type on the basis of preoperative endoscopic and EUS findings. Patients were followed-up, with an endoscopy every 6 months. MAIN OUTCOME MEASUREMENTS Therapeutic efficacy, complications, and follow-up results. RESULTS The rate of complete resection was 82.5% (70/85). In patients who underwent an incomplete resection, argon plasma coagulation and heat probe coagulation were, in addition, performed. The median longest diameter of the resected specimens was 25 mm. The median time required for a resection was 27 minutes. There was no perforation. Bleeding after an EOAM occurred in 1 patient (1.2%). Esophageal stenosis developed in 8 patients (9.4%). All strictures were managed by endoscopic balloon dilation, and symptoms improved. The median follow-up period after EMR was 36 months (range 6-72 months). Local recurrence occurred in 5 patients (5.9%); the nonrecurrence rate was 96.4% at 1 year, 95.0% at 2 years, and 93.4% at 3 years. As additional treatment, argon plasma coagulation was performed in 4 patients, and endoscopic mucosal dissection was conducted in 1 patient. CONCLUSIONS EOAM is a safe, easy, and effective procedure for the treatment of SEC that can be completed within a short time. The rate of local recurrence is low on medium-term to long-term follow-up.

Surveillance after endoscopic mucosal resection or endoscopic submucosal dissection for esophageal squamous cell carcinoma.

The objectives of surveillance after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma are: (i) early detection and treatment of recurrence; and (ii) early detection and treatment of metachronous esophageal squamous cell carcinoma and second primary cancers. Protocols for follow up after EMR or ESD for esophageal squamous cell carcinoma should be based on the risks of lymph node metastasis and distant metastasis as assessed on the basis of tumor staging at initial treatment. Early detection of recurrence or metachronous carcinomas often allows curative or less invasive treatment. Particular attention should be paid to the development of metachronous esophageal squamous cell carcinomas and second primary cancers (in particular, head and neck cancer and gastric cancer because of their high incidence).