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PurposePrior to publication of the Clavien-Dindo classification in 2004, there were no grading definitions for surgical complications in either clinical practice or surgical trials. This report establishes supplementary criteria for this classification to standardize the evaluation of postoperative complications in clinical trials.MethodsThe Japan Clinical Oncology Group (JCOG) commissioned a committee. Members from nine surgical study groups (gastric, esophageal, colorectal, lung, breast, gynecologic, urologic, bone and soft tissue, and brain) specified postoperative complications experienced commonly in their fields and defined more detailed grading criteria for each complication in accordance with the general grading rules of the Clavien-Dindo classification.ResultsWe listed 72 surgical complications experienced commonly in surgical trials, focusing on 17 gastroenterologic complications, 13 infectious complications, six thoracic complications, and several other complications. The grading criteria were defined simply and were optimized for surgical complications.ConclusionsThe JCOG postoperative complications criteria (JCOG PC criteria) aim to standardize the terms used to define adverse events (AEs) and provide detailed grading guidelines based on the Clavien-Dindo classification. We believe that the JCOG PC criteria will allow for more precise comparisons of the frequency of postoperative complications among trials across many different surgical fields.

BackgroundEndoscopic resection has been limited to intestinal-type gastric cancer (cT1a) with a low risk of lymph node metastasis (T1a ≤2 cm, without ulcers). This single-arm confirmatory trial evaluated the efficacy and safety of endoscopic submucosal dissection (ESD) for >2 cm ulcer-negative and ≤3 cm ulcer-positive intestinal-type gastric cancer (cT1a).MethodsThe eligibility criteria included endoscopically diagnosed cT1a, a single primary intestinal-type gastric adenocarcinoma, an ulcer-negative lesion of any size or a ≤3 cm ulcer-positive lesion, cN0M0, and no prior treatment. If ESD resulted in noncurative resection, surgical resection was added. The primary endpoint was the 5-year overall survival (OS) (planned sample size was 470, with a one-sided alpha level of 2.5%). The threshold 5-year OS was 86.1%.ResultsWe enrolled 470 early gastric cancer patients [median tumor size, 25 (5–130) mm] from 29 institutions between June 2007 and October 2010. These patients had 152 ulcer-negative lesions (>2 and ≤3 cm), 111 ulcer-negative lesions (>3 cm), and 207 ulcer-positive lesions (≤3 cm). The success rate for en block resection was 99.1% (466/470). Additional gastrectomy was conducted in 131 patients (28%) who did not fulfill the curative resection criteria. The 5-year OS of all patients was 97.0% (95% confidence interval, 95.0–98.2%), which was higher than the threshold 5-year OS (86.1%). The 317 patients who satisfied the curative resection criteria had no recurrence. There were no ESD-related grade 4 adverse events.ConclusionESD for early gastric cancers that met the expanded criteria for intestinal-type gastric cancer (cT1a) was acceptable and should be the standard treatment instead of gastrectomy.

BackgroundWhile endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC.MethodsThe key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC.ResultsThree hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1–99.8).ConclusionsESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.

The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20–75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m 2 per day, on days 1–5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m 2, on days 1 and 15) and cisplatin (80 mg/m 2, on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m 2, twice a day, on days 1–28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. All randomised patients were included in the primary analysis. Median overall survival was 10·8 months (IQR 5·7–17·8) for individuals assigned fluorouracil, 12·3 months (8·1–19·5) for those allocated irinotecan plus cisplatin (hazard ratio 0·85 [95% CI 0·70–1·04]; p=0·0552), and 11·4 months (6·4–21·3) for those assigned S-1 (0·83 [0·68–1·01]; p=0·0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting. Ministry of Health, Labour, and Welfare of Japan; Taiho Pharmaceutical; Yakult Honsha.

Low‐dose cisplatin and 5‐fluorouracil (LDPF) chemotherapy with daily radiotherapy (RT) is used as an alternative chemoradiotherapy regimen for locally advanced esophageal carcinoma. We evaluated whether RT plus LDPF chemotherapy had an advantage in terms of survival and/or toxicity over RT plus standard‐dose cisplatin and 5‐fluorouracil (SDPF) chemotherapy in this study. This multicenter trial included esophageal cancer patients with clinical T4 disease and/or unresectable regional lymph node metastasis. Patients were randomly assigned to receive RT (2 Gy/fraction, total dose of 60 Gy) with SDPF (arm A) or LDPF (arm B) chemotherapy. The primary endpoint was overall survival (OS). A total of 142 patients (arm A/B, 71/71) from 41 institutions were enrolled between April 2004 and September 2009. The OS hazard ratio in arm B versus arm A was 1.05 (80% confidence interval, 0.78–1.41). There were no differences in toxicities in either arm. Arm B was judged as not promising for further evaluation in the phase III setting. Thus, the Data and Safety Monitoring Committee recommended that the study be terminated. In the updated analyses, median OS and 3‐year OS were 13.1 months and 25.9%, respectively, for arm A and 14.4 months and 25.7%, respectively, for arm B. Daily RT plus LDPF chemotherapy did not qualify for further evaluation as a new treatment option for patients with locally advanced unresectable esophageal cancer. This study was registered at the UMIN Clinical Trials Registry as UMIN000000861. LDPF‐RT vs SDPF‐RT for thoracic EC

BackgroundPerioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with < 10% residual tumor is a globally accepted prognosticator in LAGC patients who received neoadjuvant chemotherapy (NAC) and curative surgery. However, despite a response of the primary tumor, a significant percentage of patients dies from recurrence and identification of those at risk for relapse remains challenging. We re-estimated the value of histopathological tumor regression as a prognosticator alongside other factors, especially posttherapy topographical nodal status, ypN-site.Patients and methodsIndividual patient data including clinicopathological variables were used from the four JCOG trials investigating NAC (JCOG0001, JCOG0002, JCOG0210, JCOG0405) for analyzing prognosticators in patients with curative surgery excluding those with type 4 AGC by univariable and multivariable Cox regression analyses.ResultsAmong 85 patients, 5-year overall survival (OS) was 46.0% [95% confidence interval (CI) 35.0–56.4] with a median follow-up of 3.2 years. On univariable analysis, histopathological tumor regression with ≥ 10% residual tumor and ypN-site 2–3 were negatively associated with OS [≥ 10% residual tumor: hazard ratio (HR) 2.60; 95% CI 1.22–5.54; P = 0.014; ypN2–3: HR 3.59; 95% CI 1.60–8.06; P = 0.002). On multivariable analysis, only ypN-site 2–3 was predictive of OS (HR 3.67; 95% CI 1.55–8.69; P = 0.003), whereas histopathological tumor regression with ≥ 10% residual tumor was not (HR 2.24; 95% CI 0.98–5.10; P = 0.055).ConclusionsypN-site may have greater impact on OS than histopathological tumor regression in patients who received NAC plus surgery for non-type 4 LAGC.

It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC. This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m2 per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665. 200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3–33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5–33·6) and 16·9 months (13·4–20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47–0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3–4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3–4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group. For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population. Ministry of Health, Labour, and Welfare of Japan.

Background Although the number of patients undergoing laparoscopy-assisted distal gastrectomy (LADG) has been increasing, a prospective study with a sample size sufficient to investigate the benefit of LADG has never been reported. We conducted a multi-institutional phase II trial to evaluate the safety of LADG with nodal dissection for clinical stage I gastric cancer patients. Methods The subjects comprised patients with clinical stage I gastric cancer who were able to undergo a distal gastrectomy. LADG with D1 plus suprapancreatic node dissection was performed. The primary endpoint was the proportion of patients who developed either anastomotic leakage or a pancreatic fistula. The secondary endpoints included surgical morbidity and short-term clinical outcome. Results Between November 2007 and September 2008, 176 eligible patients were enrolled. The proportion of patients who developed anastomotic leakage or a pancreatic fistula was 1.7%. The overall proportion of in-hospital grade 3 or 4 adverse events was 5.1%. The short-term clinical outcomes were as follows: 43.2% of the patients requested an analgesic on postoperative days 5-10; the median time from surgery until the first episode of flatus was 2 days; and 88 patients (50.0%) had a body temperature of 38 °C or higher during their hospital stay. Conclusions This trial confirmed the safety of LADG performed by credentialed surgeons in terms of the incidence of anastomotic leakage or pancreatic fistula formation. A phase III trial (JCOG 0912) to confirm the noninferiority of LADG to an open gastrectomy in terms of overall survival is ongoing.

Background The immunogenic cell death induced by radiotherapy (RT) has been demonstrated to enhance the systemic antitumor effect of immune checkpoint inhibitors (ICIs). The incorporation of RT into ICIs has the potential to mitigate the occurrence of early treatment failure, particularly with dual ICI combination, in patients with advanced or recurrent esophageal cancer. Methods This randomized phase II trial, initiated in November 2024, aims to explore the superiority of the combination of RT with nivolumab plus ipilimumab over nivolumab plus ipilimumab alone in patients with advanced or recurrent esophageal squamous cell carcinoma. The primary endpoint is progression-free survival, while the secondary endpoints include overall survival, response rate, duration of response, and adverse events. We assumed a 6-month PFS of 35% in the nivolumab plus ipilimumab alone arm and expected a 15% increase in the 6-month PFS for the RT with nivolumab plus ipilimumab arm (HR, 0.66). The total required sample size was calculated to be 70 (35 per arm) to achieve a desired power of 80% with an overall one-sided alpha of 20%, an accrual period of 2.5 years, and a follow-up period of 1 year. A total of 74 patients will be enrolled from 41 institutions in Japan. An ancillary study analyzes cytokine profiles and phenotypic characteristics in peripheral blood mononuclear cells during treatment with the protocol. Discussion The objective of this trial is to assess the safety and efficacy of RT in combination with dual ICIs in reducing early treatment failure and improving outcomes with translational research. Findings from this trial will inform a future phase III trial in this patient population. Trial registration This trial has been registered on November 5th, 2024, in the Japan Registry of Clinical Trials as jRCT1031240461 ( https://jrct.mhlw.go.jp/en-latest-detail/jRCT1031240461 ).

Background[18F] fluorodeoxyglucose-positron emission tomography is incorporated in response criteria currently used for lymphoma; however, the primary endpoint in earlier phase study is an overall response, which includes the partial response of 50% shrinkage in two dimensions. Therefore, the measurement of target lesions is still prerequisite to determine the destiny of new, promising agents. Since required is calculating the sum of the product of bidimensional diameters of maximal six target lesions, the International Workshop Criteria (IWC) used as response evaluation in lymphoma is more time-consuming than the Response Evaluation Criteria in Solid Tumors (RECIST). This study aimed to examine whether the RECIST could replace the IWC using data from a phase II/III study of R-CHOP-21 versus R-CHOP-14 for advanced-stage indolent B-cell lymphoma, JCOG0203.MethodsTo evaluate the degree of agreement between them, the Kappa coefficient (KC) was calculated. Excluding patients without target lesions for the RECIST following central pathological review, 269 patients were evaluable. We determined which criterion was more predictive for progression-free survival. The criterion showing the lower point estimate of the hazard ratio (HR) of a complete response (CR) vs. a non-CR was defined as more useful.ResultsThe KC between them was 0.34 (95% confidence interval [CI] 0.26–0.42); namely, indicating poor agreement. The HR of the IWC (0.47: 95% CI 0.33–0.68, log-rank test p < 0.001) was lower than that of the RECIST (0.64: 95% CI 0.45–0.89, p = 0.0075).ConclusionWe conclude that unidimensional measurements cannot be substituted for the bidimensional ones for indolent lymphoma.