Prevention of delirium with agitation by yokukansan in older adults after cancer surgery.

OBJECTIVE: Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection. METHODS: We performed a secondary per-protocol analysis of 149 patients' data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4-8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression. RESULTS: Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01-0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation. CONCLUSIONS: This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection.

Yokukansan for Treatment of Preoperative Anxiety and Prevention of Postoperative Delirium in Cancer Patients Undergoing Highly Invasive Surgery. J-SUPPORT 1605 (ProD Study): A Randomized, Double-Blind, Placebo-Controlled Trial.

CONTEXT: No standard preventive or therapeutic methods have been established for preoperative anxiety and postoperative delirium in patients with cancer. OBJECTIVES: To clarify the therapeutic effect of yokukansan for perioperative psychiatric symptoms in patients with cancer as well as to confirm its safety profile. METHODS: This is a randomized, double-blind, and placebo-controlled trial conducted at a single center in Tokyo, Japan. About 195 patients with cancer scheduled to undergo tumor resection took one packet of the study drug, which was administered orally. Coprimary outcomes were change in preoperative anxiety assessed with the Hospital Anxiety and Depression Scale-Anxiety and incidence of postoperative delirium assessed with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Interim analysis was performed with one-third (n = 74) of the target number of registered patients. RESULTS: Because this trial was canceled based on the results of the interim analysis and the protocol treatment was discontinued in patients who were already registered, conclusions were based on the full analysis set of 160 participants. There were no significant differences between groups in the change of mean Hospital Anxiety and Depression Scale-Anxiety score (intervention group [SD] 0.4 [3.0] vs. placebo group 0.5 [3.0]; P = 0.796) or the incidence of postoperative delirium (32% vs. 30%; P = 0.798). There were no serious adverse events in either group. CONCLUSION: In patients with cancer undergoing highly invasive surgeries, yokukansan demonstrated no significant efficacy for the treatment of preoperative anxiety or the prevention of postoperative delirium. Yokukansan is already used in daily practice in Japan, but we should be careful with its future use.

Novel minimally invasive approach to lymph node dissection around the left renal vein in patients with esophagogastric junction cancer.

The left renal vein lymph node (LRVLN) may be the extended locoregional node in esophagogastric junction cancer; however, only open-surgical methods of dissection have been reported. We therefore developed a novel minimally invasive laparoscopic method for LRVLN dissection. Following esophagectomy, the stomach was mobilized and LRVLN dissection was started by taping the pancreatic body using two silicone drains. The transverse mesocolon was then retracted through the superior duodenal fossa to expose the horizontal duodenum and permit LRVLN dissection. We carried out the procedure successfully in 17 patients with advanced esophagogastric cancer. The median total and laparoscopic operative times were 415 and 161 min, respectively. Postoperative esophagectomy-related complications occurred in six patients. The median estimated blood loss was 120 ml and hospital stay was 15 days. This minimally invasive laparoscopic LRVLN dissection method was safe and effective, and may support faster recovery and earlier postoperative adjuvant therapy in patients with esophagogastric junction cancer.

Long-term Clinical Results of Concurrent Chemoradiotherapy for Patients with Cervical Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: We assessed the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma of the cervical esophagus. PATIENTS AND METHODS: We retrospectively analyzed 37 patients treated with definitive CCRT. The patients received radiotherapy at a fraction dose of 2 Gy (total; 60 or 70 Gy) and concurrent chemotherapy. Adjuvant chemotherapy consisted of 1 to 2 cycles of 5-fluorouracil plus cisplatin or nedaplatin. RESULTS: The median follow-up was 119.0 months, the 10-year overall survival, progression-free survival and laryngectomy-free survival rates were 35.6, 19.9 and 30.2% respectively. In the univariate analysis, T stage (T4 vs. T1-3) was the only prognostic factor for PFS. The most common acute toxicity was leukocytopenia (Grade 3; 27%). As for late toxicities, 4 patients (11%) developed Grade 2 or 3 esophageal strictures. CONCLUSION: The results of this study demonstrated that CCRT yielded satisfactory clinical outcomes with acceptable toxicities.

Multicenter Phase 2 Study of Cisplatin and 5-Fluorouracil With Concurrent Radiation Therapy as an Organ Preservation Approach in Patients With Squamous Cell Carcinoma of the Cervical Esophagus.

PURPOSE: To clarify, in a multicenter, single-arm, phase 2 study (UMIN Clinical Trials Registry no. UMIN000001439), the clinical profile of chemoradiotherapy (CRT) for cervical esophageal cancer. PATIENTS AND METHODS: Patients with operable cervical esophageal cancer, excluding candidates for endoscopic resection, were enrolled. Protocol treatment consisted of CRT and adjuvant chemotherapy (CT). First, patients received concurrent CRT with 5-fluorouracil (5-FU) plus cisplatin (CDDP). Chemotherapy consisted of 5-FU at 700 mg/m2 intravenous on days 1 to 4 and CDDP at 70 mg/m2 intravenous on day 1, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 60 Gy in 30 fractions. After completion of CRT, 2 additional cycles of CT with 5-FU (800 mg/m2, days 1-5) and CDDP (80 mg/m2, day 1) were repeated at a 4-week interval. The primary endpoint was 3-year overall survival. RESULTS: Thirty patients were enrolled across 8 institutions in Japan, consisting of 26 men and 4 women with a median age of 64.5 years (range, 50-75 years). No grade 4 hematologic toxicity was seen in the CRT phase, and 1 grade 4 thrombocytopenia was seen in the CT phase. Grade 3 nonhematologic acute toxicities in the CRT phase were nausea (10%), mucositis (13.3%), and dysphagia (13.3%). No treatment-related death in either phase occurred. Overall complete response rate was 73%, and 3-year overall and laryngectomy-free survival were 66.5% and 52.5%, respectively. Regarding T4 disease, 3-year overall and laryngectomy-free survival were 58.3% and 38.5%, respectively. CONCLUSIONS: This study, the first prospective study for cervical esophageal cancer, showed that CRT has sufficient efficacy and safety for use as an alternative to surgery for these patients.

Prognostic significance of tumor regression grade for patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy followed by surgery.

BACKGROUND AND OBJECTIVES: To clarify prognostic factors for the patients with esophageal squamous cell carcinoma (ESCC) through an assessment of surgically resected specimens modified by neoadjuvant chemotherapy (nCT). METHODS: We retrospectively reviewed the clinicopathological data of 143 consecutive patients with ESCC who underwent nCT followed by surgery between 2008 and 2012 at our institution and conducted survival analysis. The tumor regression grade (TRG) was classified based on the proportion of residual tumor cells in the area where the tumor was thought to have existed before nCT as follows: Grade 0 (no therapeutic effect), Grade 1a (residual tumor cells ≥2/3), Grade 1b (1/3≤ residual tumor cells <2/3), Grade 2 (residual tumor cells <1/3), and Grade 3 (no residual tumor). RESULTS: The 3-year OS and RFS of patients with tumor regression grade 0/1a/1b-3 were 53.6%/73.3%/88.6% and 37.7%/60.5%/83.8%, respectively. A multivariate analysis demonstrated that TRG was an independent predictor of OS (TRG 1a-3: HR, 0.46; 95%CI, 0.23-0.89), in addition to venous invasion, and of RFS (TRG 1a-3: HR, 0.49; 95%CI, 0.28-0.84), in addition to ypT factor, and venous invasion. CONCLUSIONS: TRG is a critical prognostic factor in patients with ESCC who had undergone nCT followed by surgery. J. Surg. Oncol. 2016;113:390-396. © 2016 Wiley Periodicals, Inc.

The prognostic significance of the positive circumferential resection margin in pathologic T3 squamous cell carcinoma of the esophagus with or without neoadjuvant chemotherapy.

BACKGROUND: To improve the therapeutic strategy for esophageal squamous cell carcinoma (ESCC), combined neoadjuvant chemotherapy (NAC) followed by operative surgical resection has been applied recently to patients at clinical stages II/III. Our study aimed to elucidate the impact of the circumferential resection margin (CRM) status of surgically resected specimens on the prognosis of patients undergoing neoadjuvant therapy. METHODS: We enrolled 160 consecutive ESCC patients who underwent esophagectomy. The CRM status of specimens obtained was examined pathologically according to both the College of American Pathologists (CAP) and the Royal College of Pathologists (RCP) criteria. We examined the relationship between CRM status and several clinicopathologic factors among ESCC patients with or without NAC. RESULTS: The local recurrence rate was significantly higher in patients with R1 compared with that of patients with R0 according to CAP criteria (12.5% vs 0.7%; P = .02; Chi-square test). Regarding the prognosis of all patients, Kaplan-Meier analyses showed that there were significant differences between R0 and R1 groups by CAP or RCP criteria (CAP, P < .001; RCP, P = .017). Additionally, Kaplan-Meier analyses showed that R1 was a significant prognostic factor for poor survival, judged by CAP criteria in both surgery alone (P < .001) and NAC plus surgery subgroups (P < .001). CONCLUSION: Positive CRM according to CAP criteria after multimodality treatment significantly affects the overall and relapse-free survival of ESCC patients.

Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma.

The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70-75 mg/m(2)) and cisplatin (70-75 mg/m(2)) on day 1, and continuous infusion of fluorouracil (750 mg/m(2)/day) on days 1-5. Antibiotic prophylaxis on days 5-15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty-two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty-one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment-related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2-year progression-free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).

The effectiveness of chemoradiation therapy and salvage surgery for hypopharyngeal squamous cell carcinoma.

OBJECTIVE: The objective of this study was to evaluate the results of salvage surgery after definitive chemoradiation for hypopharyngeal squamous cell carcinoma. METHODS: This was a retrospective cohort study. Of the 79 patients with previously untreated hypopharyngeal squamous cell carcinoma who received definitive chemoradiation from January 2004 to January 2009, 24 who had recurrence and underwent salvage surgery at the National Cancer Center Hospital East, Chiba, Japan, were enrolled in this study. RESULTS: Of the 24 patients who underwent salvage surgery with curative intent, 13 had an isolated local failure, eight had an isolated neck failure and three had combined local and regional failure. Postoperative surgical complications were observed in eight (33.3%) patients. Of the 24 patients undergoing salvage surgery, 12 (50%) had recurrence. In 11 of these patients, death ensued from salvage failure, defined as the presence of any recurrence after salvage treatment. The causes of cancer-specific death ensuing from salvage failure were regional recurrence of the tumor (n = 6) (one of whom had concurrent distant metastases) and distant metastases alone (n = 5). No local recurrence after salvage surgery was observed in our group of patients. The disease-free and overall 24-month survival rates were 49.0 and 50.0%, respectively. Those patients who initially presented with unresectable disease had lower overall survival compared with those who initially presented with resectable disease (P = 0.0003). CONCLUSIONS: The oncologic outcomes were acceptable in those patients in whom salvage surgery was carried out. Those who initially presented with unresectable disease had a poor prognosis.

Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study).

A three-arm Phase III trial was started in November 2012. Preoperative chemotherapy with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced esophageal cancer in Japan, while preoperative chemoradiotherapy with cisplatin plus 5-fluorouracil is the standard in Western countries. Preoperative chemotherapy with docetaxel, cisplatin plus 5-fluorouracil is another promising regimen. The purpose of this study is to confirm the superiority of docetaxel, cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil and the superiority of cisplatin plus 5-fluorouracil with chemoradiotherapy over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of esophagus. A total of 501 patients will be accrued from 41 Japanese institutions within 6.25 years. The primary endpoint is overall survival and the secondary endpoints include progression-free survival, %R0 resection, response rate, pathologic complete response rate and adverse events.