Keiko Minashi

Early Detection of Superficial Squamous Cell Carcinoma in the Head and Neck Region and Esophagus by Narrow Band Imaging: A Multicenter Randomized Controlled Trial

PURPOSE Most of the esophageal squamous cell carcinomas (ESCCs) and cancers of the head and neck (H&N) region are diagnosed at later stages. To achieve better survival, early detection is necessary. We compared the real-time diagnostic yield of superficial cancer in these regions between conventional white light imaging (WLI) and narrow band imaging (NBI) in high-risk patients. PATIENTS AND METHODS In a multicenter, prospective, randomized controlled trial, 320 patients with ESCC were randomly assigned to primary WLI followed by NBI (n = 162) or primary NBI followed by WLI (n = 158) in a back-to-back fashion. The primary aim was to compare the real-time detection rates of superficial cancer in the H&N region and the esophagus between WLI and NBI. The secondary aim was to evaluate the diagnostic accuracy of these techniques. RESULTS NBI detected superficial cancer more frequently than did WLI in both the H&N region and the esophagus (100% v 8%, P < .001; 97% v 55%, P < .001, respectively). The sensitivity of NBI for diagnosis of superficial cancer was 100% and 97.2% in the H&N region and the esophagus, respectively. The accuracy of NBI for diagnosis of superficial cancer was 86.7% and 88.9% in these regions, respectively. The sensitivity and accuracy were significantly higher using NBI than WLI in both regions (P < .001 and P = .02 for the H&N region; P < .001 for both measures for the esophagus, respectively). CONCLUSION NBI could be the standard examination for the early detection of superficial cancer in the H&N region and the esophagus.

Development and evaluation of FSSG: frequency scale for the symptoms of GERD.

BackgroundThe aim of this study was to produce a simplified questionnaire for evaluation of the symptoms of gastroesophageal reflux disease (GERD).MethodsA total of 124 patients with an endoscopic diagnosis of GERD completed a 50-part questionnaire, requiring only “yes” or “no” answers, that covered various symptoms related to the upper gastrointestinal tract, as well as psychosomatic symptoms. The 12 questions to which patients most often answered “yes” were selected, and were assigned scores (never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4) to produce a frequency scale for symptoms of GERD (FSSG). Sensitivity, specificity, and accuracy of the FSSG questionnaire were evaluated in another group of patients with GERD and non-GERD. The usefulness of this questionnaire was evaluated in 26 other GERD patients who were treated with proton pump inhibitors for 8 weeks.ResultsWhen the cutoff score was set at 8 points, the FSSG showed a sensitivity of 62%, a specificity of 59%, and an accuracy of 60%, whereas a cutoff score of 10 points altered these values to 55%, 69%, and 63%. The score obtained using the questionnaire correlated well with the extent of endoscopic improvement in patients with mild or severe GERD.ConclusionsThis new questionnaire is useful for the objective evaluation of symptoms in GERD patients.

Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II–III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

PURPOSE In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m(2)/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m(2)) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m(2)/day) on Days 1-5 and CDDP (80 mg/m(2)) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. RESULTS The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. CONCLUSIONS CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. METHODS In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. FINDINGS Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57-12·37) in the nivolumab group and 8·59 months (5·65-11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60-6·37) in the nivolumab group and 4·14 months (3·42-4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51-0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7-32·0) with nivolumab and 10·9% (6·2-17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed. INTERPRETATION In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. FUNDING Ono Pharmaceutical and Bristol-Myers Squibb.

Magnifying narrow-band imaging versus magnifying white-light imaging for the differential diagnosis of gastric small depressive lesions: a prospective study

BACKGROUND The accurate diagnosis of gastric small depressive lesions (SDLs), including gastritis and cancerous lesions, is difficult with conventional endoscopy when using white-light imaging (WLI). Narrow-band imaging (NBI) is expected to make a more accurate diagnosis of gastric SDLs than WLI because it provides better visualization of the mucosal surface and microvascular architecture when combined with magnifying endoscopy. OBJECTIVE To compare the real-time diagnostic accuracy of magnifying WLI and magnifying NBI for gastric SDLs. DESIGN Prospective study. SETTING National Cancer Center Hospital East, Kashiwa, Japan. PATIENTS Fifty-seven lesions in 53 consecutive patients were analyzed: 30 cancers and 27 benign lesions. INTERVENTIONS If previously undiagnosed gastric SDLs smaller than 10 mm were identified during an endoscopic examination, magnifying observation with both WLI and NBI was performed for each SDL. Endoscopic diagnosis of SDLs was made by each method on site. MAIN OUTCOME MEASUREMENTS The diagnostic accuracy and the time required for diagnosis. RESULTS The diagnostic accuracy was significantly higher for NBI than for WLI (79% vs 44%; P = .0001), as was its sensitivity (70% vs 33%; P = .0005). The diagnostic specificity of NBI (89%) was higher than that of WLI (67%), but the difference was not statistically significant. The time required for the diagnosis was equivalent with both methods. LIMITATIONS Single-center study, small sample size. CONCLUSIONS Adding NBI to the WLI examination is essential for making an accurate diagnosis of gastric SDLs compared with magnifying WLI alone. (UMIN Clinical Trials Registry identification number C000000421).

Efficacy of preventive endoscopic balloon dilation for esophageal stricture after endoscopic resection

Background and Aim We earlier reported that mucosal defect involving over three-fourths of the circumference of the esophagus after endoscopic mucosal resection (EMR) is a risk factor for the development of the stricture. Although endoscopic balloon dilation (EBD) is a useful procedure to relieve the stricture, there is no standard strategy for preventing development of the stricture. The aim of this study was to evaluate the efficacy and the safety of preventive EBD. Methods From 1993 to 2008, 41 consecutive patients with extensive mucosal defect involving over three-fourths of the esophageal circumference after EMR or endoscopic submucosal dissection (ESD) were investigated. Preventive EBD was carried out for 29 cases within 1 week just after EMR/ESD and was repeated once a week until the mucosal defect was completely healed. The remaining 12 cases were not underwent preventive EBD and used as a historic control. If postEMR/ESD stricture developed regardless of preventive EBD, conventional EBD was given repeatedly until the stricture was completely relieved. Results Preventive EBD decreased the incidence of stricture (59% vs. 92%, P =0.04), reduced the severity of stricture [(⩽2 mm; >2 mm and ⩽5 mm; >5 mm)=(1; 2; 14) vs. (4; 4; 3), P = 0.01] and shortened the duration required for resolving the stricture (29 d vs. 78 d, P =0.04) even when stricture developed. There was no complication associated with preventive EBD procedure. Conclusions Preventive EBD is an effective procedure to prevent postEMR/ESD stricture. Preventive EBD should be considered when EMR/ESD results in a mucosal defect with a circumference greater than three-fourths of the esophageal lumen.

Elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for squamous cell carcinoma of the thoracic esophagus

BACKGROUND AND PURPOSE There are some reports indicating that prophylactic three-field lymph node dissection for esophageal cancer can lead to improved survival. But the benefit of ENI in CRT for thoracic esophageal cancer remains controversial. The purpose of the present study is to retrospectively evaluate the efficacy of elective nodal irradiation (ENI) in definitive chemoradiotherapy (CRT) for thoracic esophageal cancer. MATERIALS AND METHODS Patients with squamous cell carcinoma (SCC) of the thoracic esophagus newly diagnosed between February 1999 and April 2001 in our institution was recruited from our database. Definitive chemoradiotherapy consisted of two cycles of cisplatin/5FU repeated every 5 weeks, with concurrent radiation therapy of 60 Gy in 30 fractions. Up to 40 Gy radiation therapy was delivered to the cervical, periesophageal, mediastinal and perigastric lymph nodes as ENI. RESULTS One hundred two patients were included in this analysis, and their characteristics were as follows: median age, 65 years; male/female, 85/17; T1/T2/T3/T4, 16/11/61/14; N0/N1, 48/54; M0/M1, 84/18. The median follow-up period for the surviving patients was 41 months. Sixty patients achieved complete response (CR). After achieving CR, only one (1.0%; 95% CI, 0-5.3%) patient experienced elective nodal failure without any other site of recurrence. CONCLUSION In CRT for esophageal SCC, ENI is effective for preventing regional nodal failure. Further evaluation of whether ENI leads to an improved overall survival is needed.

Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma

BACKGROUND AND STUDY AIMS Local failure after definitive chemoradiotherapy (CRT) in patients with esophageal cancer remains one of the major problems in finding a cure. Endoscopic mucosal resection (EMR) is one treatment option when failure lesions are superficial. However, there are no relevant long-term survival data. The aim of this study was to clarify the long-term survival of salvage EMR. PATIENTS AND METHODS Between January 1998 and March 2004, 289 patients with esophageal squamous cell carcinoma were treated with definitive CRT at the National Cancer Center Hospital East, Japan. Of these 289 patients, 21 patients with local failure without lymph-node or distant metastases were treated with salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively analyzed the long-term survival data for the patients who underwent salvage EMR. RESULTS At a median follow-up period of 54 months (range, 16-108 months), eight of 21 patients (38%) were alive with no recurrence and two patients had died from another disease but with no recurrence of esophageal cancer. Local recurrence after EMR was detected in four patients, with local and lymph-node recurrence in two patients, and lymph-node and/or distant metastases in five patients. The 5-year survival rate from the initiation of salvage EMR was 49.1%. There were no severe complications associated with EMR. CONCLUSION EMR is one of the curative salvage treatment options for local failure after definitive CRT, if the failure lesion is superficial and there are no lymph-node or distant metastases.

Long-term outcome of transoral organ-preserving pharyngeal endoscopic resection for superficial pharyngeal cancer.

BACKGROUND Early detection of pharyngeal cancer has been difficult. We reported that narrow-band imaging (NBI) endoscopy can detect superficial pharyngeal cancer, and these lesions can be treated endoscopically. OBJECTIVE To assess the safety and long-term efficacy of transoral organ-preserving pharyngeal endoscopic resection (TOPER) for superficial pharyngeal cancer. DESIGN AND SETTING Retrospective 2-center cohort study. PATIENTS The study included 104 consecutive patients with superficial pharyngeal cancer. INTERVENTION TOPER with the patients under general anesthesia. MAIN OUTCOME MEASUREMENTS Safety of the procedure, long-term survival, clinical outcome. RESULTS A total of 148 consecutive lesions were resected in 104 patients. There was no severe adverse event. Temporary tracheostomy was required in 17 patients (16%) to prevent airway obstruction. The median fasting period and hospital stay after TOPER were 2 days (range 1-20 days) and 8 days (range 3-58 days), respectively. Ninety-six patients (92%) had no local recurrence or distant metastases. Local recurrence at the primary site developed in 6 patients, but all were resolved by repeat TOPER. With a median follow-up period of 43 months (range 3-96 months), the overall survival rate at 5 years was 71% (95% CI, 59-82). Cause-specific survival rate at 5 years was 97% (95% CI, 93-100). The cumulative development rate of multiple cancers in pharyngeal mucosal sites at 5 years was 22% (95% CI, 12-33). The pharynx was preserved in all patients, and they experienced no loss of function. LIMITATION Retrospective design. CONCLUSIONS Peroral endoscopic resection of superficial pharyngeal cancer is a feasible and effective treatment with curative intent.

Long-term results of salvage photodynamic therapy for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma

BACKGROUND AND STUDY AIMS Local failure after chemoradiotherapy (CRT) remains a major problem for patients with esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the long-term results of salvage photodynamic therapy (PDT) for local failure. PATIENTS AND METHODS Patients were treated with CRT, consisting of more than 50 Gy irradiation and concurrent chemotherapy. The indications for salvage PDT were as follows: 1) absence of lymph-node or distant metastasis after CRT; 2) failure lesion limited to T2; 3) refusal by patient to undergo salvage esophagectomy; 4) written informed consent. PDT was performed using an excimer dye laser at 48 and 72 hours after administration of Photofrin. RESULTS A total of 37 consecutive patients underwent salvage PDT. The baseline stage before CRT was as follows: T1/T2/T3/T4 in 3/4/24/6 and N0/1 in 13/24 patients, respectively. Prior to PDT, 20 patients had a uT1 lesion, and 17 had a uT2 lesion; 24 patients had histologically proven local failure. A complete response was achieved in 22 patients (59.5%) following PDT. Esophageal fistulae, stenosis, and phototoxicity occurred in 4 (10.8%), 20 (54.1%), and 2 (5.4%) patients, respectively. Over a median follow-up period of 55 months, the 5-year progression-free (PFS) and overall survival rates of 37 patients following PDT were 20.7% and 36.1%, respectively. The 5-year PFS and overall survival of 24 patients with proven local failure were 17.6% and 34.6%, respectively. CONCLUSION Salvage PDT is a curative treatment option for patients with local failure after CRT for ESCC.